https://hemonc.org/w/api.php?action=feedcontributions&user=Karine&feedformat=atomHemOnc.org - A Hematology Oncology Wiki - User contributions [en]2024-03-28T19:28:13ZUser contributionsMediaWiki 1.35.14https://hemonc.org/w/index.php?title=Antiemesis&diff=77307Antiemesis2023-09-05T15:56:03Z<p>Karine: /* Emetic risk of chemotherapy, immunotherapy, TKIs and other agents */</p>
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Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://ascopubs.org/doi/abs/10.1200/JCO.20.01296<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
=Guidelines=<br />
==ASCO==<br />
*'''2020:''' Hesketh et al. [https://doi.org/10.1200/jco.20.01296 Antiemetics: ASCO Guideline Update]<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: less than 10% frequency of emesis<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2021)<br />
!ASCO emetogenic potential<br />
(2020)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|Moderate/High<br />
|Moderate/High<br />
|<br />
|NCCN and ASCO did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg/m2<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Low<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Atezolizumab (Tecentriq)]]<br />
|Minimal<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Minimal/Low<br />
|Minimal/Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Belinostat (Beleodaq)]]<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Blinatumomab (Blincyto)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: at least 4 mg/day <br> Low/Minimal: less than 4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: at least 4 mg/day<br>Low/Minimal: less than 4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC 4 or more<br />
Moderate: AUC less than 4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC 4 or more)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Ceritinib (Zykadia)]]<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose 70 mg/m<sup>2</sup> or more<br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: greater than 1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: up to and including 1500 mg/m<sup>2</sup><br />
|High: 1500 mg/m<sup>2</sup> or more, or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: less than 1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m<sup>2</sup> or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: 100 mg/m<sup>2</sup>/day or more<br>Low/Minimal: less than 100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: less than 100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2<br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Daratumumab (Darzalex)]]<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: 60 mg/m<sup>2</sup> or more, or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: less than 60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: 2000 mg/m<sup>2</sup> or more per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: 10 million international units/m<sup>2</sup> or more<br>Low: between 5 and 10 million international units/m<sup>2</sup><br>Minimal: 5 million international units/m<sup>2</sup> or less<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: 10 million international units/m<sup>2</sup> or more<br>Low: between 5 and 10 million international units/m<sup>2</sup><br>Minimal: 5 million international units/m<sup>2</sup> or less<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|align="left" |[[Lenvatinib (Lenvima)]] (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lurbinectedin (Zepzelca)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
|[[Margetuximab-cmkb]] (Margenza)<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: 250 mg/m<sup>2</sup> or more<br>Low: between 50 and 250 mg/m<sup>2</sup><br>Minimal: 50 mg/m<sup>2</sup> or less<br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Niraparib (Zejula)]] (oral)<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Olaparib (Lynparza)]] (oral)<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (Sylatron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Pembrolizumab (Keytruda)]] <br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pixantrone (Pixuvri)]]<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Rucaparib (Rubraca)]]<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Selinexor (Xpovio)]] (oral)<br />
|Moderate/High<br />
|Moderate/High<br />
|<br />
|NCCN and ASCO did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Trabectedin (Yondelis)]]<br />
|<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab deruxtecan (Enhertu)]]<br />
|High<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|[[Umbralisib (Ukoniq)|Umbralisib (Ukoniq]]) (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinflunine (Javlor)]]<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine]] (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2022<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
''(if po APR on day 1, then + APR days 2-3)''<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
''(if po APR on day 1, then + APR days 2-3)''<br />
|-<br />
| - OLN + Palonosetron + DEX<br />
|OLN<br />
|}<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*Aprepitant injectable emulsion (Cinvanti) 130 mg IV once on day 1<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.31.7859 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21383291/ PubMed]</ref>''<br />
===Serotonin (5-HT3) antagonist===<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
*If [[Aprepitant (Emend)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref><br />
==Netupitant-containing regimen==<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
==Olanzapine (OLN) containing regimen==<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
Reference: <br />
#''[https://doi.org/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://doi.org/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922/ PubMed]</ref>''<br /><br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2022<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|Aprepitant PO daily days 2 and 3 if aprepitant POused on day 1<br />
<nowiki>+/- DEX</nowiki><br />
|-<br />
| - OLN + Palonosetron + DEX<br />
|OLN<br />
|}<br />
===Serotonin (5-HT3) antagonist===<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
*If [[Aprepitant (Emend)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
==Netupitant-containing regimen==<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://doi.org/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://doi.org/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922/ PubMed]</ref>''<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
AUC 4 or more<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
AUC 4 or more (HEC)<br />
<br />
AUC less than 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016<br />
https://pubmed.ncbi.nlm.nih.gov/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://pubmed.ncbi.nlm.nih.gov/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant''<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
==Optional==<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2022<br />
|DEX or Metoclopramide or Prochlorperazine or<br />
5-HT3 other than Palonosetron<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.'''<br />
*[[Dexamethasone (Decadron)]]<br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
=Minimal emetic risk chemotherapy=<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
=Low to minimal emetic risk PO chemotherapy=<br />
*use antiemetics prn first<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
==Optional==<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
==Metoclopromide==<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
==Benzodiazepine==<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
==Cannabinoid==<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
==Other agents==<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
=Anticipatory nausea/vomiting=<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 1 mg PO beginning the night before treatment and then repeat the next 1-2 hours before anticancer therapy begins<br />
=Reference=<br />
<references /><br />
[[Category:Supportive oncology]]<br />
[[Category:General reference pages]]<br />
[[Category:Emesis prevention]]</div>Karinehttps://hemonc.org/w/index.php?title=Neuroendocrine_tumor&diff=77061Neuroendocrine tumor2023-09-02T20:40:04Z<p>Karine: /* All lines of therapy */</p>
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{{#lst:Editorial board transclusions|endo}}<br />
''Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit [[Neuroendocrine tumor - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''<br><br />
<big>Note: This page is now exclusively focused on those tumors commonly called carcinoids, which may or may not be associated with the carcinoid syndrome; there are now separate pages for '''[[pancreatic NET]]''' and other endocrine cancers. Neuroendocrine tumors of unknown primary and poorly differentiated (high-grade) neuroendocrine carcinomas are usually treated with a '''[[small cell lung cancer]]''' regimen; see [[Neuroendocrine carcinoma|this page]] for histology-specific options.</big><br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==CommNETS/NANETS==<br />
*'''2020:''' Singh et al. [https://doi.org/10.1016/j.jtho.2020.06.021 Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society Guidelines for the Diagnosis and Management of Patients With Lung Neuroendocrine Tumors: An International Collaborative Endorsement and Update of the 2015 European Neuroendocrine Tumor Society Expert Consensus Guidelines]<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2021:''' Baudin et al. [https://doi.org/10.1016/j.annonc.2021.01.003 Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
===Older===<br />
*'''2012:''' Öberg et al. [https://www.esmo.org/Guidelines/Endocrine-and-Neuroendocrine-Cancers/Neuroendocrine-Bronchial-and-Thymic-Tumours Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.]<br />
*'''2012:''' Öberg et al. [http://annonc.oxfordjournals.org/content/23/suppl_7/vii124.full.pdf+html Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.] [https://pubmed.ncbi.nlm.nih.gov/22997445/ PubMed]<br />
==NANETS==<br />
*'''2017:''' Strosberg et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5642985/ The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Midgut Neuroendocrine Tumors]<br />
===Older===<br />
*'''2013:''' Kunz et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4304762/ Consensus Guidelines for the Management and Treatment of Neuroendocrine Tumors]<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf NCCN Guidelines - Neuroendocrine Tumors]<br />
===Older===<br />
*'''2015:''' Kulke et al. [https://doi.org/10.6004/jnccn.2015.0011 Neuroendocrine Tumors, Version 1.2015] [https://pubmed.ncbi.nlm.nih.gov/25583772/ PubMed]<br />
<br />
=All lines of therapy=<br />
==Capecitabine & Temozolamide {{#subobject:d69a17|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #1 {{#subobject:9dd15|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Dates of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099746/ Jeong et al. 2021]<br />
|2017-2021<br />
| style="background-color:#91cf61" |Phase 2<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 750mg/m2 twice daily on days 1-14<br />
====Chemotherapy====<br />
*[[Temozolomide (Temodar)]] 200 mg/m2 once daily on days 10-14<br />
'''28-day cycles'''<br />
</div></div><br />
===References===<br />
# Jeong H, Shin J, Jeong JH, Kim KP, Hong SM, Kim YI, Ryu JS, Ryoo BY, Yoo C. Capecitabine plus temozolomide in patients with grade 3 unresectable or metastatic gastroenteropancreatic neuroendocrine neoplasms with Ki-67 index <55%: single-arm phase II study. ESMO Open. 2021 Jun;6(3):100119. [https://www.sciencedirect.com/science/article/pii/S2059702921000776?via%3Dihub link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099746/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33901869/ PubMed]<br />
<br />
==Everolimus monotherapy {{#subobject:99989f|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:4ef82e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Dates of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063317/ Yao et al. 2015 (RADIANT-4)]<br />
{| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"<br />
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-93-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''<br />
|-<br />
|}<br />
|2012-2013<br />
|style="background-color:#1a9851"|Phase 3 (E-RT-esc)<br />
|[[Neuroendocrine_tumor_-_null_regimens#Placebo|Placebo]]<br />
| style="background-color:#d9ef8b" |Superior PFS (primary endpoint)<br>Median PFS: 11 vs 3.9 mo<br>(HR 0.48, 95% CI 0.35-0.67)<br><br>Might have superior OS (secondary endpoint)<br>Median OS: NYR vs NYR<br>(HR 0.64, 95% CI 0.40-1.05)<br />
|style="background-color:#eeee01"|Equivalent HRQoL<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Targeted therapy====<br />
*[[Everolimus (Afinitor)]] 10 mg PO once per day<br />
'''Continued indefinitely'''<br />
</div></div><br />
===References===<br />
# '''RADIANT-4:''' Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H, Voi M, Pacaud LB, Rouyrre N, Sachs C, Valle JW, Fave GD, Van Cutsem E, Tesselaar M, Shimada Y, Oh DY, Strosberg J, Kulke MH, Pavel ME; RAD001 in Advanced Neuroendocrine Tumours Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016 Mar 5;387(10022):968-977. Epub 2015 Dec 17. [https://doi.org/10.1016/S0140-6736(15)00817-X link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063317/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26703889/ PubMed] [https://clinicaltrials.gov/study/NCT01524783 NCT01524783]<br />
## '''HRQoL analysis:''' Pavel ME, Singh S, Strosberg JR, Bubuteishvili-Pacaud L, Degtyarev E, Neary MP, Carnaghi C, Tomasek J, Wolin E, Raderer M, Lahner H, Valle JW, Pommier R, Van Cutsem E, Tesselaar MET, Fave GD, Buzzoni R, Hunger M, Eriksson J, Cella D, Ricci JF, Fazio N, Kulke MH, Yao JC. Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1411-1422. Epub 2017 Aug 30. [https://doi.org/10.1016/S1470-2045(17)30471-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28838862/ PubMed]<br />
<br />
==Everolimus & Octreotide {{#subobject:d69a17|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #1 {{#subobject:9dd15|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Dates of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008]<br />
|2005-2006<br />
| style="background-color:#91cf61" |Phase 2<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Targeted therapy====<br />
*[[Everolimus (Afinitor)]] 5 mg PO once per day<br />
====Endocrine therapy====<br />
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1<br />
'''28-day cycles'''<br />
</div></div><br><br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #2 {{#subobject:867317|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008]<br />
|2005-2006<br />
| style="background-color:#91cf61" |Phase 2<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1016/S0140-6736(11)61742-X Pavel et al. 2011 (RADIANT-2)]<br />
|2007-2010<br />
|style="background-color:#1a9851"|Phase 3 (E-esc)<br />
|[[#Octreotide_LAR_monotherapy|Octreotide LAR]]<br />
|style="background-color:#91cf60"|Seems to have superior PFS (primary endpoint)<br>Median PFS: 16.4 vs 11.3 mo<br>(HR 0.77, 95% CI 0.59-1.00)<br />
|-<br />
|}<br />
''Note: RADIANT-2 did not meet its primary endpoint, based on a pre-specified p-value cutoff of 0.0246.''<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Targeted therapy====<br />
*[[Everolimus (Afinitor)]] 10 mg PO once per day<br />
====Endocrine therapy====<br />
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1<br />
'''28-day cycles'''<br />
</div></div><br />
===References===<br />
# Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008 Sep 10;26(26):4311-8. [https://doi.org/10.1200/jco.2008.16.7858 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18779618/ PubMed]<br />
# '''RADIANT-2:''' Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011 Dec 10;378(9808):2005-12. Epub 2011 Nov 25. [https://doi.org/10.1016/S0140-6736(11)61742-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22119496/ PubMed] [https://clinicaltrials.gov/study/NCT00412061 NCT00412061]<br />
## '''Update:''' Pavel ME, Baudin E, Öberg KE, Hainsworth JD, Voi M, Rouyrre N, Peeters M, Gross DJ, Yao JC. Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. 2017 Jul 1;28(7):1569-1575. [https://doi.org/10.1093/annonc/mdx193 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7360141/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28444114/ PubMed]<br />
==Fluorouracil & Streptozocin {{#subobject:bd8397|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:d34072|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1984.2.11.1255 Engstrom et al. 1984 (ECOG E5275)]<br />
|1976-1981<br />
|style="background-color:#1a9851"|Phase 3 (E-esc)<br />
|[[#Doxorubicin_monotherapy_888|Doxorubicin]]<br />
| style="background-color:#ffffbf" |Did not meet co-primary endpoints of ORR/OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.03.616 Sun et al. 2005]<br />
|1981-1990<br />
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)<br />
|[[#Doxorubicin_.26_Fluorouracil_888|Doxorubicin & Fluorouracil]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]]<br />
*[[Streptozocin (Zanosar)]]<br />
</div></div><br />
===References===<br />
# '''ECOG E5275:''' Engstrom PF, Lavin PT, Moertel CG, Folsch E, Douglass HO Jr. Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol. 1984 Nov;2(11):1255-9. [https://doi.org/10.1200/JCO.1984.2.11.1255 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6238136/ PubMed]<br />
# '''ECOG E1281:''' Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG; [[Study_Groups#ECOG|ECOG]]. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005 Aug 1;23(22):4897-904. [https://doi.org/10.1200/JCO.2005.03.616 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16051944/ PubMed]<br />
==Interferon alfa-2b monotherapy {{#subobject:557a2f|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:a0cb2f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1056/NEJM198307213090301 Oberg et al. 1983]<br />
|NR<br />
| style="background-color:#ffffbe" |Non-randomized, fewer than 20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|rowspan=2|[https://doi.org/10.1200/jco.2003.12.142 Faiss et al. 2003]<br />
|rowspan=2|1995-1998<br />
|rowspan=2 style="background-color:#1a9851"|Phase 3 (E-de-esc)<br />
|1. [[#Lanreotide_monotherapy|Lanreotide]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo<br />
|-<br />
|2. [[#Lanreotide_.26_Interferon_alfa-2b|Lanreotide & Interferon alfa-2b]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo<br />
|-<br />
|}<br />
''Note: Treatment details are from Faiss et al. 2003.''<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Immunotherapy====<br />
*[[Interferon alfa-2b (Intron-A)]] 5,000,000 units SC once per day, 3 times per week<br />
'''Continued indefinitely'''<br />
</div><br />
<div class="toccolours" style="background-color:#cbd5e7"><br />
====Subsequent treatment====<br />
*Patients who progressed on monotherapy then received [[#Lanreotide_.26_Interferon_alfa-2b|lanreotide & interferon alfa]]<br />
</div></div><br />
===References===<br />
# Oberg K, Funa K, Alm G. Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med. 1983 Jul 21;309(3):129-33. [https://doi.org/10.1056/NEJM198307213090301 linkt to original article] [https://pubmed.ncbi.nlm.nih.gov/6191217/ PubMed]<br />
# Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. [https://doi.org/10.1200/jco.2003.12.142 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12860945/ PubMed]<br />
==Lanreotide monotherapy {{#subobject:c44a4e|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:171ae2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://doi.org/10.1200/jco.2003.12.142 Faiss et al. 2003]<br />
|rowspan=2|1995-1998<br />
|rowspan=2 style="background-color:#1a9851"|Phase 3 (E-de-esc)<br />
|1. [[#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo<br />
|-<br />
|2. [[#Lanreotide_.26_Interferon_alfa-2b|Lanreotide & Interferon alfa-2b]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Lanreotide (Somatuline)]] 1 mg SC three times per day<br />
'''Continued indefinitely''' <br />
</div><br />
<div class="toccolours" style="background-color:#cbd5e7"><br />
====Subsequent treatment====<br />
*Faiss et al. 2003, patients who progressed on monotherapy: [[#Lanreotide_.26_Interferon_alfa-2b|Lanreotide & interferon alfa]]<br />
</div></div><br />
===References===<br />
# Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. [https://doi.org/10.1200/jco.2003.12.142 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12860945/ PubMed]<br />
==Lanreotide LAR monotherapy {{#subobject:c4ugjc|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:741ae2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.4158/ep151172.or Vinik et al. 2016 (ELECT)]<br />
|NR in abstract<br />
| style="background-color:#1a9851"|Phase 3 (E-esc)<br />
|[[#Placebo_888|Placebo]]<br />
| style="background-color:#1a9850" |Decreased need for short-acting octreotide rescue (primary endpoint)<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Lanreotide LAR (Somatuline Depot)]] 120 mg IM once on day 1<br />
'''28-day cycle for 4 cycles''' <br />
</div></div><br />
===References===<br />
# '''ELECT:''' Vinik AI, Wolin EM, Liyanage N, Gomez-Panzani E, Fisher GA; ELECT Study Group. Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment (ELECT): A Randomized, Double-Blind, Placebo-Controlled Trial. Endocr Pract. 2016 Sep;22(9):1068-80. Epub 2016 May 23. [https://doi.org/10.4158/ep151172.or link to original article] [https://pubmed.ncbi.nlm.nih.gov/27214300/ PubMed] [https://clinicaltrials.gov/study/NCT00774930 NCT00774930]<br />
==Lanreotide & Interferon alfa-2b {{#subobject:ce8ef2|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:87b3d6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://doi.org/10.1200/jco.2003.12.142 Faiss et al. 2003]<br />
|rowspan=2|1995-1998<br />
|rowspan=2 style="background-color:#1a9851"|Phase 3 (E-esc)<br />
|1. [[#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo<br />
|-<br />
|2. [[#Lanreotide_monotherapy|Lanreotide]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Lanreotide (Somatuline)]] 1 mg SC three times per day<br />
====Immunotherapy====<br />
*[[Interferon alfa-2b (Intron-A)]] 5,000,000 units SC once per day, 3 times per week<br />
</div></div><br />
===References===<br />
# Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. [https://doi.org/10.1200/jco.2003.12.142 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12860945/ PubMed]<br />
==Lutetium Lu 177 dotatate & Octreotide LAR {{#subobject:eca71b|Regimen=1}}==<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:9df044|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;"<br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1158/1078-0432.ccr-16-2743 Brabander et al. 2017 (ERASMUS)]<br />
|2000-2015<br />
| style="background-color:#ffffbe" |Case series (RT)<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ Strosberg et al. 2017 (NETTER-1)]<br />
|2012-2016<br />
|style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc)<br />
|[[#Octreotide_LAR_monotherapy|Octreotide LAR]]<br />
|style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: NYR vs 8.4 mo<br>(HR 0.21, 95% CI 0.13-0.33)<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Radioconjugate therapy====<br />
*[[Lutetium Lu 177 dotatate (Lutathera)]] 7.4 GBq (200 mCi) IV over 30 minutes once on day 1<br />
'''8-week cycle for 4 cycles'''<br />
====Endocrine therapy====<br />
*[[Octreotide LAR (Sandostatin LAR)]] as follows:<br />
**Cycles 1 to 4: 30 mg IM once on day 2, '''given approximately 24 hours after lutetium Lu 177 dotatate'''<br />
**Cycle 5 onwards: 30 mg IM once on day 1<br />
'''8-week cycle for 4 cycles, then monthly cycles'''<br />
</div></div><br />
===References===<br />
# '''NETTER-1:''' Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. [https://doi.org/10.1056/NEJMoa1607427 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28076709/ PubMed] [https://clinicaltrials.gov/study/NCT01578239 NCT01578239]<br />
## '''Update:''' Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. [https://doi.org/10.1016/s1470-2045(21)00572-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34793718/ PubMed]<br />
# '''ERASMUS:''' Brabander T, van der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA, de Herder WW, van Eijck CHJ, Franssen GJH, Krenning EP, Kwekkeboom DJ. Long-Term Efficacy, Survival, and Safety of [177Lu-DOTA0,Tyr3]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors. Clin Cancer Res. 2017 Aug 15;23(16):4617-4624. Epub 2017 Apr 20. [https://doi.org/10.1158/1078-0432.ccr-16-2743 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28428192/ PubMed]<br />
==Octreotide monotherapy {{#subobject:1b6b74|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #1 {{#subobject:eb529b|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://annonc.oxfordjournals.org/content/15/6/966.long Oberg et al. 2004]<br />
|style="background-color:#ffffbe"|Consensus guideline<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Octreotide (Sandostatin)]] 0.1 to 0.5 mg SC given 2 to four times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms<br />
**"A reasonable starting dose is" 0.15 mg SC three times per day<br />
'''Continued indefinitely'''<br />
</div></div><br><br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #2 {{#subobject:29f57|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1056/NEJM198609113151102 Kvols et al. 1986]<br />
|style="background-color:#91cf61"|Phase 2<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Octreotide (Sandostatin)]] 0.15 mg SC twice per day on days 1 & 2, then 0.15 mg SC three times per day from day 3 onward<br />
'''Continued indefinitely'''<br />
</div></div><br><br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #3 {{#subobject:a531c2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1002/bjs.4149 Kölby et al. 2003]<br />
|1991-1998<br />
|style="background-color:#1a9851"|Randomized Phase 2 (C)<br />
|[[#Octreotide_.26_Interferon_alfa|Octreotide & Interferon alfa]]<br />
|style="background-color:#d73027"|Inferior TTP<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Octreotide (Sandostatin)]] 0.1 mg SC twice per day<br />
**Patients with persistent carcinoid symptoms could receive increased doses up to 0.2 mg SC three times per day<br />
'''Continued indefinitely'''<br />
</div></div><br><br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #4, low-dose {{#subobject:512195|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.3109/02841869309083916 Janson & Oberg 1993]<br />
|style="background-color:#91cf61"|Non-randomized<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Octreotide (Sandostatin)]] 0.05 mg SC twice per day<br />
'''Continued indefinitely'''<br />
</div></div><br />
===References===<br />
# Kvols LK, Moertel CG, O'Connell MJ, Schutt AJ, Rubin J, Hahn RG. Treatment of the malignant carcinoid syndrome: evaluation of a long-acting somatostatin analogue. N Engl J Med. 1986 Sep 11;315(11):663-6. [https://doi.org/10.1056/NEJM198609113151102 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2427948/ PubMed]<br />
# Janson ET, Oberg K. Long-term management of the carcinoid syndrome: treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. [https://doi.org/10.3109/02841869309083916 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7686765/ PubMed]<br />
# Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003 Jun;90(6):687-93. [https://doi.org/10.1002/bjs.4149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12808615/ PubMed]<br />
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [https://doi.org/10.1093/annonc/mdh216 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15151956/ PubMed]<br />
==Octreotide LAR monotherapy {{#subobject:3fde03|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #1, 30 mg {{#subobject:38d708|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2009.22.8510 Rinke et al. 2009 (PROMID)]<br />
{| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"<br />
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-150-1 <span style="color:white;">ESMO-MCBS (2)</span>]'''<br />
|-<br />
|}<br />
|2001-2008<br />
|style="background-color:#1a9851"|Phase 3 (E-esc)<br />
|[[Neuroendocrine_tumor_-_null_regimens#Placebo|Placebo]]<br />
|style="background-color:#1a9850"|Superior TTP (primary endpoint)<br>Median TTP: 14.3 vs 6 mo<br>(HR 0.34, 95% CI 0.20-0.59)<br><br>Did not meet secondary endpoint of OS<sup>1</sup><br>Median OS: 84.7 vs 83.7 mo<br>(HR 0.83, 95% CI 0.47-1.46)<br />
|-<br />
|[https://doi.org/10.1016/S0140-6736(11)61742-X Pavel et al. 2011 (RADIANT-2)]<br />
|2007-2010<br />
|style="background-color:#1a9851"|Phase 3 (C)<br />
|[[#Everolimus_.26_Octreotide|Octreotide LAR & Everolimus]]<br />
|style="background-color:#fc8d59"|Seems to have inferior PFS<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for OS in PROMID is based on the 2016 update.''<br><br />
''Note: RADIANT-2 did not meet its primary endpoint, based on a pre-specified p-value cutoff of 0.0246.''<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1, with potentially higher doses if needed for symptom control<br />
'''28-day cycles'''<br />
</div></div><br><br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #2, 40 mg {{#subobject:7c7215a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;"<br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562767/ Wolin et al. 2015 (CSOM230C2303)]<br />
|2008-2012<br />
|style="background-color:#1a9851"|Phase 3 (C)<br />
|[[#Pasireotide_LAR_777|Pasireotide LAR]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of symptom control<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Octreotide LAR (Sandostatin LAR)]] 40 mg IM once on day 1<br />
'''28-day cycles'''<br />
</div></div><br><br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #3, 60 mg {{#subobject:7c826a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;"<br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ Strosberg et al. 2017 (NETTER-1)]<br />
|2012-2016<br />
|style="background-color:#1a9851"|Phase 3 (C)<br />
|[[#Lutetium_Lu_177_dotatate_.26_Octreotide_LAR|Lutetium Lu 177 dotatate & Octreotide LAR]]<br />
|style="background-color:#d73027"|Inferior PFS<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Octreotide LAR (Sandostatin LAR)]] 60 mg IM once on day 1<br />
'''28-day cycles'''<br />
</div></div><br />
===References===<br />
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [https://doi.org/10.1093/annonc/mdh216 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15151956/ PubMed]<br />
# '''PROMID:''' Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. [https://doi.org/10.1200/jco.2009.22.8510 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19704057/ PubMed] [https://clinicaltrials.gov/study/NCT00171873 NCT00171873]<br />
##'''Update:''' Rinke A, Wittenberg M, Schade-Brittinger C, Aminossadati B, Ronicke E, Gress TM, Müller HH, Arnold R; PROMID Study Group. Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors (PROMID): Results of Long-Term Survival. Neuroendocrinology. 2017;104(1):26-32. Epub 2016 Jan 6. [https://doi.org/10.1159/000443612 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26731483/ PubMed]<br />
# '''RADIANT-2:''' Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011 Dec 10;378(9808):2005-12. Epub 2011 Nov 25. [https://doi.org/10.1016/S0140-6736(11)61742-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22119496/ PubMed] [https://clinicaltrials.gov/study/NCT00412061 NCT00412061]<br />
## '''Update:''' Pavel ME, Baudin E, Öberg KE, Hainsworth JD, Voi M, Rouyrre N, Peeters M, Gross DJ, Yao JC. Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. 2017 Jul 1;28(7):1569-1575. [https://doi.org/10.1093/annonc/mdx193 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7360141/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28444114/ PubMed]<br />
# '''CSOM230C2303:''' Wolin EM, Jarzab B, Eriksson B, Walter T, Toumpanakis C, Morse MA, Tomassetti P, Weber MM, Fogelman DR, Ramage J, Poon D, Gadbaw B, Li J, Pasieka JL, Mahamat A, Swahn F, Newell-Price J, Mansoor W, Öberg K. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther. 2015 Sep 3;9:5075-86. [https://doi.org/10.2147/DDDT.S84177 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562767/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26366058/ PubMed] [https://clinicaltrials.gov/study/NCT00690430 NCT00690430]<br />
# '''NETTER-1:''' Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. [https://doi.org/10.1056/NEJMoa1607427 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28076709/ PubMed] [https://clinicaltrials.gov/study/NCT01578239 NCT01578239]<br />
## '''Update:''' Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. [https://doi.org/10.1016/s1470-2045(21)00572-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34793718/ PubMed]<br />
<br />
==Octreotide & Interferon alfa {{#subobject:dea906|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:b5051e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1002/bjs.4149 Kölby et al. 2003]<br />
|1991-1998<br />
|style="background-color:#1a9851"|Randomized Phase 2 (E-esc)<br />
|[[#Octreotide_monotherapy|Octreotide LAR]]<br />
|style="background-color:#1a9850"|Superior TTP<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455764/ Yao et al. 2017 (SWOG S0518)]<br />
|2007-2012<br />
| style="background-color:#1a9851" |Phase 3 (C)<br />
|[[#Octreotide_.26_Bevacizumab_999|Octreotide & Bevacizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''Note: Kölby et al. 2003 did not specifically say whether [[Interferon alfa-2b (Intron-A)]] or [[Interferon alfa-2a (Roferon-A)]] was used.''<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Octreotide (Sandostatin)]] 0.1 mg SC twice per day<br />
**Patients with persistent carcinoid symptoms could receive increased doses up to 0.2 mg SC three times per day<br />
====Immunotherapy====<br />
*[[Interferon alfa-2b (Intron-A)]] 3,000,000 units (route not specified) once per day, 3 days per week<br />
**Increased as needed based on symptoms up to 5,000,000 units (route not specified) once per day, 5 days per week<br />
</div></div><br />
===References===<br />
# Janson ET, Oberg K. Long-term management of the carcinoid syndrome: treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. [https://doi.org/10.3109/02841869309083916 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7686765/ PubMed]<br />
# Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003 Jun;90(6):687-93. [https://doi.org/10.1002/bjs.4149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12808615/ PubMed]<br />
# '''SWOG S0518:''' Yao JC, Guthrie KA, Moran C, Strosberg JR, Kulke MH, Chan JA, LoConte N, McWilliams RR, Wolin EM, Mattar B, McDonough S, Chen H, Blanke CD, Hochster HS. Phase III Prospective Randomized Comparison Trial of Depot Octreotide Plus Interferon Alfa-2b Versus Depot Octreotide Plus Bevacizumab in Patients With Advanced Carcinoid Tumors: SWOG S0518. J Clin Oncol. 2017 May 20;35(15):1695-1703. Epub 2017 Apr 6. [https://doi.org/10.1200/JCO.2016.70.4072 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455764/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28384065/ PubMed] [https://clinicaltrials.gov/study/NCT00569127 NCT00569127]<br />
==Temozolomide monotherapy {{#subobject:5db4de|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:7e3904|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://clincancerres.aacrjournals.org/content/13/10/2986.long Ekeblad et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Chemotherapy====<br />
*[[Temozolomide (Temodar)]] as follows:<br />
**Cycle 1: 100 to 150 mg/m<sup>2</sup> PO once per day on days 1 to 5<br />
**Cycle 2 onwards: increased as tolerated up to 200 mg/m<sup>2</sup> PO once per day on days 1 to 5<br />
====Supportive therapy====<br />
*[[Tropisetron (Navoban)]] (dose/route/schedule not specified) routinely used as an antiemetic<br />
'''28-day cycles'''<br />
</div></div><br />
===References===<br />
# '''Retrospective:''' Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007 May 15;13(10):2986-91. [http://clincancerres.aacrjournals.org/content/13/10/2986.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17505000/ PubMed]<br />
[[Category:Neuroendocrine tumor regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Endocrine cancers]]</div>Karinehttps://hemonc.org/w/index.php?title=Neuroendocrine_tumor&diff=77060Neuroendocrine tumor2023-09-02T20:30:08Z<p>Karine: capecitabine & temozolomide for NET</p>
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{{#lst:Editorial board transclusions|endo}}<br />
''Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit [[Neuroendocrine tumor - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''<br><br />
<big>Note: This page is now exclusively focused on those tumors commonly called carcinoids, which may or may not be associated with the carcinoid syndrome; there are now separate pages for '''[[pancreatic NET]]''' and other endocrine cancers. Neuroendocrine tumors of unknown primary and poorly differentiated (high-grade) neuroendocrine carcinomas are usually treated with a '''[[small cell lung cancer]]''' regimen; see [[Neuroendocrine carcinoma|this page]] for histology-specific options.</big><br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==CommNETS/NANETS==<br />
*'''2020:''' Singh et al. [https://doi.org/10.1016/j.jtho.2020.06.021 Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society Guidelines for the Diagnosis and Management of Patients With Lung Neuroendocrine Tumors: An International Collaborative Endorsement and Update of the 2015 European Neuroendocrine Tumor Society Expert Consensus Guidelines]<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2021:''' Baudin et al. [https://doi.org/10.1016/j.annonc.2021.01.003 Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
===Older===<br />
*'''2012:''' Öberg et al. [https://www.esmo.org/Guidelines/Endocrine-and-Neuroendocrine-Cancers/Neuroendocrine-Bronchial-and-Thymic-Tumours Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.]<br />
*'''2012:''' Öberg et al. [http://annonc.oxfordjournals.org/content/23/suppl_7/vii124.full.pdf+html Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.] [https://pubmed.ncbi.nlm.nih.gov/22997445/ PubMed]<br />
==NANETS==<br />
*'''2017:''' Strosberg et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5642985/ The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Midgut Neuroendocrine Tumors]<br />
===Older===<br />
*'''2013:''' Kunz et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4304762/ Consensus Guidelines for the Management and Treatment of Neuroendocrine Tumors]<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf NCCN Guidelines - Neuroendocrine Tumors]<br />
===Older===<br />
*'''2015:''' Kulke et al. [https://doi.org/10.6004/jnccn.2015.0011 Neuroendocrine Tumors, Version 1.2015] [https://pubmed.ncbi.nlm.nih.gov/25583772/ PubMed]<br />
<br />
=All lines of therapy=<br />
==Capecitabine & Temozolamide {{#subobject:d69a17|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #1 {{#subobject:9dd15|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Dates of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099746/ Yeong et al. 2021]<br />
|2017-2021<br />
| style="background-color:#91cf61" |Phase 2<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 750mg/m2 twice daily on days 1-14<br />
====Chemotherapy====<br />
*[[Temozolomide (Temodar)]] 200 mg/m2 once daily on days 10-14<br />
'''28-day cycles'''<br />
</div></div><br><br />
<div class="toccolours" style="background-color:#eeeeee"><br />
<br />
==Everolimus monotherapy {{#subobject:99989f|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:4ef82e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Dates of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063317/ Yao et al. 2015 (RADIANT-4)]<br />
{| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"<br />
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-93-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''<br />
|-<br />
|}<br />
|2012-2013<br />
|style="background-color:#1a9851"|Phase 3 (E-RT-esc)<br />
|[[Neuroendocrine_tumor_-_null_regimens#Placebo|Placebo]]<br />
| style="background-color:#d9ef8b" |Superior PFS (primary endpoint)<br>Median PFS: 11 vs 3.9 mo<br>(HR 0.48, 95% CI 0.35-0.67)<br><br>Might have superior OS (secondary endpoint)<br>Median OS: NYR vs NYR<br>(HR 0.64, 95% CI 0.40-1.05)<br />
|style="background-color:#eeee01"|Equivalent HRQoL<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Targeted therapy====<br />
*[[Everolimus (Afinitor)]] 10 mg PO once per day<br />
'''Continued indefinitely'''<br />
</div></div><br />
===References===<br />
# '''RADIANT-4:''' Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H, Voi M, Pacaud LB, Rouyrre N, Sachs C, Valle JW, Fave GD, Van Cutsem E, Tesselaar M, Shimada Y, Oh DY, Strosberg J, Kulke MH, Pavel ME; RAD001 in Advanced Neuroendocrine Tumours Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016 Mar 5;387(10022):968-977. Epub 2015 Dec 17. [https://doi.org/10.1016/S0140-6736(15)00817-X link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063317/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26703889/ PubMed] [https://clinicaltrials.gov/study/NCT01524783 NCT01524783]<br />
## '''HRQoL analysis:''' Pavel ME, Singh S, Strosberg JR, Bubuteishvili-Pacaud L, Degtyarev E, Neary MP, Carnaghi C, Tomasek J, Wolin E, Raderer M, Lahner H, Valle JW, Pommier R, Van Cutsem E, Tesselaar MET, Fave GD, Buzzoni R, Hunger M, Eriksson J, Cella D, Ricci JF, Fazio N, Kulke MH, Yao JC. Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1411-1422. Epub 2017 Aug 30. [https://doi.org/10.1016/S1470-2045(17)30471-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28838862/ PubMed]<br />
<br />
==Everolimus & Octreotide {{#subobject:d69a17|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #1 {{#subobject:9dd15|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Dates of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008]<br />
|2005-2006<br />
| style="background-color:#91cf61" |Phase 2<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Targeted therapy====<br />
*[[Everolimus (Afinitor)]] 5 mg PO once per day<br />
====Endocrine therapy====<br />
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1<br />
'''28-day cycles'''<br />
</div></div><br><br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #2 {{#subobject:867317|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008]<br />
|2005-2006<br />
| style="background-color:#91cf61" |Phase 2<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1016/S0140-6736(11)61742-X Pavel et al. 2011 (RADIANT-2)]<br />
|2007-2010<br />
|style="background-color:#1a9851"|Phase 3 (E-esc)<br />
|[[#Octreotide_LAR_monotherapy|Octreotide LAR]]<br />
|style="background-color:#91cf60"|Seems to have superior PFS (primary endpoint)<br>Median PFS: 16.4 vs 11.3 mo<br>(HR 0.77, 95% CI 0.59-1.00)<br />
|-<br />
|}<br />
''Note: RADIANT-2 did not meet its primary endpoint, based on a pre-specified p-value cutoff of 0.0246.''<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Targeted therapy====<br />
*[[Everolimus (Afinitor)]] 10 mg PO once per day<br />
====Endocrine therapy====<br />
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1<br />
'''28-day cycles'''<br />
</div></div><br />
===References===<br />
# Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008 Sep 10;26(26):4311-8. [https://doi.org/10.1200/jco.2008.16.7858 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18779618/ PubMed]<br />
# '''RADIANT-2:''' Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011 Dec 10;378(9808):2005-12. Epub 2011 Nov 25. [https://doi.org/10.1016/S0140-6736(11)61742-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22119496/ PubMed] [https://clinicaltrials.gov/study/NCT00412061 NCT00412061]<br />
## '''Update:''' Pavel ME, Baudin E, Öberg KE, Hainsworth JD, Voi M, Rouyrre N, Peeters M, Gross DJ, Yao JC. Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. 2017 Jul 1;28(7):1569-1575. [https://doi.org/10.1093/annonc/mdx193 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7360141/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28444114/ PubMed]<br />
==Fluorouracil & Streptozocin {{#subobject:bd8397|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:d34072|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1984.2.11.1255 Engstrom et al. 1984 (ECOG E5275)]<br />
|1976-1981<br />
|style="background-color:#1a9851"|Phase 3 (E-esc)<br />
|[[#Doxorubicin_monotherapy_888|Doxorubicin]]<br />
| style="background-color:#ffffbf" |Did not meet co-primary endpoints of ORR/OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.03.616 Sun et al. 2005]<br />
|1981-1990<br />
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)<br />
|[[#Doxorubicin_.26_Fluorouracil_888|Doxorubicin & Fluorouracil]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]]<br />
*[[Streptozocin (Zanosar)]]<br />
</div></div><br />
===References===<br />
# '''ECOG E5275:''' Engstrom PF, Lavin PT, Moertel CG, Folsch E, Douglass HO Jr. Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol. 1984 Nov;2(11):1255-9. [https://doi.org/10.1200/JCO.1984.2.11.1255 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6238136/ PubMed]<br />
# '''ECOG E1281:''' Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG; [[Study_Groups#ECOG|ECOG]]. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005 Aug 1;23(22):4897-904. [https://doi.org/10.1200/JCO.2005.03.616 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16051944/ PubMed]<br />
==Interferon alfa-2b monotherapy {{#subobject:557a2f|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:a0cb2f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1056/NEJM198307213090301 Oberg et al. 1983]<br />
|NR<br />
| style="background-color:#ffffbe" |Non-randomized, fewer than 20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|rowspan=2|[https://doi.org/10.1200/jco.2003.12.142 Faiss et al. 2003]<br />
|rowspan=2|1995-1998<br />
|rowspan=2 style="background-color:#1a9851"|Phase 3 (E-de-esc)<br />
|1. [[#Lanreotide_monotherapy|Lanreotide]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo<br />
|-<br />
|2. [[#Lanreotide_.26_Interferon_alfa-2b|Lanreotide & Interferon alfa-2b]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo<br />
|-<br />
|}<br />
''Note: Treatment details are from Faiss et al. 2003.''<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Immunotherapy====<br />
*[[Interferon alfa-2b (Intron-A)]] 5,000,000 units SC once per day, 3 times per week<br />
'''Continued indefinitely'''<br />
</div><br />
<div class="toccolours" style="background-color:#cbd5e7"><br />
====Subsequent treatment====<br />
*Patients who progressed on monotherapy then received [[#Lanreotide_.26_Interferon_alfa-2b|lanreotide & interferon alfa]]<br />
</div></div><br />
===References===<br />
# Oberg K, Funa K, Alm G. Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med. 1983 Jul 21;309(3):129-33. [https://doi.org/10.1056/NEJM198307213090301 linkt to original article] [https://pubmed.ncbi.nlm.nih.gov/6191217/ PubMed]<br />
# Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. [https://doi.org/10.1200/jco.2003.12.142 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12860945/ PubMed]<br />
==Lanreotide monotherapy {{#subobject:c44a4e|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:171ae2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://doi.org/10.1200/jco.2003.12.142 Faiss et al. 2003]<br />
|rowspan=2|1995-1998<br />
|rowspan=2 style="background-color:#1a9851"|Phase 3 (E-de-esc)<br />
|1. [[#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo<br />
|-<br />
|2. [[#Lanreotide_.26_Interferon_alfa-2b|Lanreotide & Interferon alfa-2b]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Lanreotide (Somatuline)]] 1 mg SC three times per day<br />
'''Continued indefinitely''' <br />
</div><br />
<div class="toccolours" style="background-color:#cbd5e7"><br />
====Subsequent treatment====<br />
*Faiss et al. 2003, patients who progressed on monotherapy: [[#Lanreotide_.26_Interferon_alfa-2b|Lanreotide & interferon alfa]]<br />
</div></div><br />
===References===<br />
# Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. [https://doi.org/10.1200/jco.2003.12.142 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12860945/ PubMed]<br />
==Lanreotide LAR monotherapy {{#subobject:c4ugjc|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:741ae2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.4158/ep151172.or Vinik et al. 2016 (ELECT)]<br />
|NR in abstract<br />
| style="background-color:#1a9851"|Phase 3 (E-esc)<br />
|[[#Placebo_888|Placebo]]<br />
| style="background-color:#1a9850" |Decreased need for short-acting octreotide rescue (primary endpoint)<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Lanreotide LAR (Somatuline Depot)]] 120 mg IM once on day 1<br />
'''28-day cycle for 4 cycles''' <br />
</div></div><br />
===References===<br />
# '''ELECT:''' Vinik AI, Wolin EM, Liyanage N, Gomez-Panzani E, Fisher GA; ELECT Study Group. Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment (ELECT): A Randomized, Double-Blind, Placebo-Controlled Trial. Endocr Pract. 2016 Sep;22(9):1068-80. Epub 2016 May 23. [https://doi.org/10.4158/ep151172.or link to original article] [https://pubmed.ncbi.nlm.nih.gov/27214300/ PubMed] [https://clinicaltrials.gov/study/NCT00774930 NCT00774930]<br />
==Lanreotide & Interferon alfa-2b {{#subobject:ce8ef2|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:87b3d6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://doi.org/10.1200/jco.2003.12.142 Faiss et al. 2003]<br />
|rowspan=2|1995-1998<br />
|rowspan=2 style="background-color:#1a9851"|Phase 3 (E-esc)<br />
|1. [[#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo<br />
|-<br />
|2. [[#Lanreotide_monotherapy|Lanreotide]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Lanreotide (Somatuline)]] 1 mg SC three times per day<br />
====Immunotherapy====<br />
*[[Interferon alfa-2b (Intron-A)]] 5,000,000 units SC once per day, 3 times per week<br />
</div></div><br />
===References===<br />
# Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. [https://doi.org/10.1200/jco.2003.12.142 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12860945/ PubMed]<br />
==Lutetium Lu 177 dotatate & Octreotide LAR {{#subobject:eca71b|Regimen=1}}==<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:9df044|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;"<br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1158/1078-0432.ccr-16-2743 Brabander et al. 2017 (ERASMUS)]<br />
|2000-2015<br />
| style="background-color:#ffffbe" |Case series (RT)<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ Strosberg et al. 2017 (NETTER-1)]<br />
|2012-2016<br />
|style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc)<br />
|[[#Octreotide_LAR_monotherapy|Octreotide LAR]]<br />
|style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: NYR vs 8.4 mo<br>(HR 0.21, 95% CI 0.13-0.33)<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Radioconjugate therapy====<br />
*[[Lutetium Lu 177 dotatate (Lutathera)]] 7.4 GBq (200 mCi) IV over 30 minutes once on day 1<br />
'''8-week cycle for 4 cycles'''<br />
====Endocrine therapy====<br />
*[[Octreotide LAR (Sandostatin LAR)]] as follows:<br />
**Cycles 1 to 4: 30 mg IM once on day 2, '''given approximately 24 hours after lutetium Lu 177 dotatate'''<br />
**Cycle 5 onwards: 30 mg IM once on day 1<br />
'''8-week cycle for 4 cycles, then monthly cycles'''<br />
</div></div><br />
===References===<br />
# '''NETTER-1:''' Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. [https://doi.org/10.1056/NEJMoa1607427 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28076709/ PubMed] [https://clinicaltrials.gov/study/NCT01578239 NCT01578239]<br />
## '''Update:''' Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. [https://doi.org/10.1016/s1470-2045(21)00572-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34793718/ PubMed]<br />
# '''ERASMUS:''' Brabander T, van der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA, de Herder WW, van Eijck CHJ, Franssen GJH, Krenning EP, Kwekkeboom DJ. Long-Term Efficacy, Survival, and Safety of [177Lu-DOTA0,Tyr3]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors. Clin Cancer Res. 2017 Aug 15;23(16):4617-4624. Epub 2017 Apr 20. [https://doi.org/10.1158/1078-0432.ccr-16-2743 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28428192/ PubMed]<br />
==Octreotide monotherapy {{#subobject:1b6b74|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #1 {{#subobject:eb529b|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://annonc.oxfordjournals.org/content/15/6/966.long Oberg et al. 2004]<br />
|style="background-color:#ffffbe"|Consensus guideline<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Octreotide (Sandostatin)]] 0.1 to 0.5 mg SC given 2 to four times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms<br />
**"A reasonable starting dose is" 0.15 mg SC three times per day<br />
'''Continued indefinitely'''<br />
</div></div><br><br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #2 {{#subobject:29f57|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1056/NEJM198609113151102 Kvols et al. 1986]<br />
|style="background-color:#91cf61"|Phase 2<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Octreotide (Sandostatin)]] 0.15 mg SC twice per day on days 1 & 2, then 0.15 mg SC three times per day from day 3 onward<br />
'''Continued indefinitely'''<br />
</div></div><br><br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #3 {{#subobject:a531c2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1002/bjs.4149 Kölby et al. 2003]<br />
|1991-1998<br />
|style="background-color:#1a9851"|Randomized Phase 2 (C)<br />
|[[#Octreotide_.26_Interferon_alfa|Octreotide & Interferon alfa]]<br />
|style="background-color:#d73027"|Inferior TTP<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Octreotide (Sandostatin)]] 0.1 mg SC twice per day<br />
**Patients with persistent carcinoid symptoms could receive increased doses up to 0.2 mg SC three times per day<br />
'''Continued indefinitely'''<br />
</div></div><br><br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #4, low-dose {{#subobject:512195|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.3109/02841869309083916 Janson & Oberg 1993]<br />
|style="background-color:#91cf61"|Non-randomized<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Octreotide (Sandostatin)]] 0.05 mg SC twice per day<br />
'''Continued indefinitely'''<br />
</div></div><br />
===References===<br />
# Kvols LK, Moertel CG, O'Connell MJ, Schutt AJ, Rubin J, Hahn RG. Treatment of the malignant carcinoid syndrome: evaluation of a long-acting somatostatin analogue. N Engl J Med. 1986 Sep 11;315(11):663-6. [https://doi.org/10.1056/NEJM198609113151102 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2427948/ PubMed]<br />
# Janson ET, Oberg K. Long-term management of the carcinoid syndrome: treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. [https://doi.org/10.3109/02841869309083916 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7686765/ PubMed]<br />
# Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003 Jun;90(6):687-93. [https://doi.org/10.1002/bjs.4149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12808615/ PubMed]<br />
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [https://doi.org/10.1093/annonc/mdh216 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15151956/ PubMed]<br />
==Octreotide LAR monotherapy {{#subobject:3fde03|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #1, 30 mg {{#subobject:38d708|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2009.22.8510 Rinke et al. 2009 (PROMID)]<br />
{| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"<br />
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-150-1 <span style="color:white;">ESMO-MCBS (2)</span>]'''<br />
|-<br />
|}<br />
|2001-2008<br />
|style="background-color:#1a9851"|Phase 3 (E-esc)<br />
|[[Neuroendocrine_tumor_-_null_regimens#Placebo|Placebo]]<br />
|style="background-color:#1a9850"|Superior TTP (primary endpoint)<br>Median TTP: 14.3 vs 6 mo<br>(HR 0.34, 95% CI 0.20-0.59)<br><br>Did not meet secondary endpoint of OS<sup>1</sup><br>Median OS: 84.7 vs 83.7 mo<br>(HR 0.83, 95% CI 0.47-1.46)<br />
|-<br />
|[https://doi.org/10.1016/S0140-6736(11)61742-X Pavel et al. 2011 (RADIANT-2)]<br />
|2007-2010<br />
|style="background-color:#1a9851"|Phase 3 (C)<br />
|[[#Everolimus_.26_Octreotide|Octreotide LAR & Everolimus]]<br />
|style="background-color:#fc8d59"|Seems to have inferior PFS<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for OS in PROMID is based on the 2016 update.''<br><br />
''Note: RADIANT-2 did not meet its primary endpoint, based on a pre-specified p-value cutoff of 0.0246.''<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1, with potentially higher doses if needed for symptom control<br />
'''28-day cycles'''<br />
</div></div><br><br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #2, 40 mg {{#subobject:7c7215a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;"<br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562767/ Wolin et al. 2015 (CSOM230C2303)]<br />
|2008-2012<br />
|style="background-color:#1a9851"|Phase 3 (C)<br />
|[[#Pasireotide_LAR_777|Pasireotide LAR]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of symptom control<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Octreotide LAR (Sandostatin LAR)]] 40 mg IM once on day 1<br />
'''28-day cycles'''<br />
</div></div><br><br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen variant #3, 60 mg {{#subobject:7c826a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;"<br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ Strosberg et al. 2017 (NETTER-1)]<br />
|2012-2016<br />
|style="background-color:#1a9851"|Phase 3 (C)<br />
|[[#Lutetium_Lu_177_dotatate_.26_Octreotide_LAR|Lutetium Lu 177 dotatate & Octreotide LAR]]<br />
|style="background-color:#d73027"|Inferior PFS<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Octreotide LAR (Sandostatin LAR)]] 60 mg IM once on day 1<br />
'''28-day cycles'''<br />
</div></div><br />
===References===<br />
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [https://doi.org/10.1093/annonc/mdh216 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15151956/ PubMed]<br />
# '''PROMID:''' Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. [https://doi.org/10.1200/jco.2009.22.8510 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19704057/ PubMed] [https://clinicaltrials.gov/study/NCT00171873 NCT00171873]<br />
##'''Update:''' Rinke A, Wittenberg M, Schade-Brittinger C, Aminossadati B, Ronicke E, Gress TM, Müller HH, Arnold R; PROMID Study Group. Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors (PROMID): Results of Long-Term Survival. Neuroendocrinology. 2017;104(1):26-32. Epub 2016 Jan 6. [https://doi.org/10.1159/000443612 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26731483/ PubMed]<br />
# '''RADIANT-2:''' Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011 Dec 10;378(9808):2005-12. Epub 2011 Nov 25. [https://doi.org/10.1016/S0140-6736(11)61742-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22119496/ PubMed] [https://clinicaltrials.gov/study/NCT00412061 NCT00412061]<br />
## '''Update:''' Pavel ME, Baudin E, Öberg KE, Hainsworth JD, Voi M, Rouyrre N, Peeters M, Gross DJ, Yao JC. Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. 2017 Jul 1;28(7):1569-1575. [https://doi.org/10.1093/annonc/mdx193 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7360141/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28444114/ PubMed]<br />
# '''CSOM230C2303:''' Wolin EM, Jarzab B, Eriksson B, Walter T, Toumpanakis C, Morse MA, Tomassetti P, Weber MM, Fogelman DR, Ramage J, Poon D, Gadbaw B, Li J, Pasieka JL, Mahamat A, Swahn F, Newell-Price J, Mansoor W, Öberg K. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther. 2015 Sep 3;9:5075-86. [https://doi.org/10.2147/DDDT.S84177 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562767/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26366058/ PubMed] [https://clinicaltrials.gov/study/NCT00690430 NCT00690430]<br />
# '''NETTER-1:''' Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. [https://doi.org/10.1056/NEJMoa1607427 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28076709/ PubMed] [https://clinicaltrials.gov/study/NCT01578239 NCT01578239]<br />
## '''Update:''' Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. [https://doi.org/10.1016/s1470-2045(21)00572-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34793718/ PubMed]<br />
<br />
==Octreotide & Interferon alfa {{#subobject:dea906|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:b5051e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Dates of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1002/bjs.4149 Kölby et al. 2003]<br />
|1991-1998<br />
|style="background-color:#1a9851"|Randomized Phase 2 (E-esc)<br />
|[[#Octreotide_monotherapy|Octreotide LAR]]<br />
|style="background-color:#1a9850"|Superior TTP<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455764/ Yao et al. 2017 (SWOG S0518)]<br />
|2007-2012<br />
| style="background-color:#1a9851" |Phase 3 (C)<br />
|[[#Octreotide_.26_Bevacizumab_999|Octreotide & Bevacizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''Note: Kölby et al. 2003 did not specifically say whether [[Interferon alfa-2b (Intron-A)]] or [[Interferon alfa-2a (Roferon-A)]] was used.''<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Endocrine therapy====<br />
*[[Octreotide (Sandostatin)]] 0.1 mg SC twice per day<br />
**Patients with persistent carcinoid symptoms could receive increased doses up to 0.2 mg SC three times per day<br />
====Immunotherapy====<br />
*[[Interferon alfa-2b (Intron-A)]] 3,000,000 units (route not specified) once per day, 3 days per week<br />
**Increased as needed based on symptoms up to 5,000,000 units (route not specified) once per day, 5 days per week<br />
</div></div><br />
===References===<br />
# Janson ET, Oberg K. Long-term management of the carcinoid syndrome: treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. [https://doi.org/10.3109/02841869309083916 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7686765/ PubMed]<br />
# Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003 Jun;90(6):687-93. [https://doi.org/10.1002/bjs.4149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12808615/ PubMed]<br />
# '''SWOG S0518:''' Yao JC, Guthrie KA, Moran C, Strosberg JR, Kulke MH, Chan JA, LoConte N, McWilliams RR, Wolin EM, Mattar B, McDonough S, Chen H, Blanke CD, Hochster HS. Phase III Prospective Randomized Comparison Trial of Depot Octreotide Plus Interferon Alfa-2b Versus Depot Octreotide Plus Bevacizumab in Patients With Advanced Carcinoid Tumors: SWOG S0518. J Clin Oncol. 2017 May 20;35(15):1695-1703. Epub 2017 Apr 6. [https://doi.org/10.1200/JCO.2016.70.4072 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455764/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28384065/ PubMed] [https://clinicaltrials.gov/study/NCT00569127 NCT00569127]<br />
==Temozolomide monotherapy {{#subobject:5db4de|Regimen=1}}==<br />
<div class="toccolours" style="background-color:#eeeeee"><br />
===Regimen {{#subobject:7e3904|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://clincancerres.aacrjournals.org/content/13/10/2986.long Ekeblad et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<div class="toccolours" style="background-color:#b3e2cd"><br />
====Chemotherapy====<br />
*[[Temozolomide (Temodar)]] as follows:<br />
**Cycle 1: 100 to 150 mg/m<sup>2</sup> PO once per day on days 1 to 5<br />
**Cycle 2 onwards: increased as tolerated up to 200 mg/m<sup>2</sup> PO once per day on days 1 to 5<br />
====Supportive therapy====<br />
*[[Tropisetron (Navoban)]] (dose/route/schedule not specified) routinely used as an antiemetic<br />
'''28-day cycles'''<br />
</div></div><br />
===References===<br />
# '''Retrospective:''' Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007 May 15;13(10):2986-91. [http://clincancerres.aacrjournals.org/content/13/10/2986.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17505000/ PubMed]<br />
[[Category:Neuroendocrine tumor regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Endocrine cancers]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=50674Antiemesis2021-06-17T23:45:42Z<p>Karine: Selinexor added to antiemetic table</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://ascopubs.org/doi/abs/10.1200/JCO.20.01296<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Guidelines=<br />
==ASCO==<br />
<br />
*'''2020:''' Hesketh et al. [https://doi.org/10.1200/jco.20.01296 Antiemetics: ASCO Guideline Update]<br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2021)<br />
!ASCO emetogenic potential<br />
(2020)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|Moderate/High<br />
|Moderate/High<br />
|<br />
|NCCN and ASCO did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg/m2<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Low<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Atezolizumab (Tecentriq)]]<br />
|Minimal<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Minimal/Low<br />
|Minimal/Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Belinostat (Beleodaq)]]<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Blinatumomab (Blincyto)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Ceritinib (Zykadia)]]<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Daratumumab (Darzalex)]]<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|align="left" |[[Lenvatinib (Lenvima)]] (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lurbinectedin (Zepzelca)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Niraparib (Zejula)]] (oral)<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Olaparib (Lynparza)]] (oral)<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Pembrolizumab (Keytruda)]] <br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pixantrone (Pixuvri)]]<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Rucaparib (Rubraca)]]<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Selinexor (Xpovio)]] (oral)<br />
|Moderate/High<br />
|Moderate/High<br />
|<br />
|NCCN and ASCO did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Trabectedin (Yondelis)]]<br />
|<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinflunine (Javlor)]]<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine]] (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.31.7859 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://pubmed.ncbi.nlm.nih.gov/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://pubmed.ncbi.nlm.nih.gov/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]<br />
[[Category:Clinical pharmacology]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=50508Antiemesis2021-06-08T21:01:49Z<p>Karine: lurbinectedine emetic risk added</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://ascopubs.org/doi/abs/10.1200/JCO.20.01296<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Guidelines=<br />
==ASCO==<br />
<br />
*'''2020:''' Hesketh et al. [https://doi.org/10.1200/jco.20.01296 Antiemetics: ASCO Guideline Update]<br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2021)<br />
!ASCO emetogenic potential<br />
(2020)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|Moderate/High<br />
|Moderate/High<br />
|<br />
|NCCN and ASCO did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg/m2<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Low<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Atezolizumab (Tecentriq)]]<br />
|Minimal<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Minimal/Low<br />
|Minimal/Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Belinostat (Beleodaq)]]<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Blinatumomab (Blincyto)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Ceritinib (Zykadia)]]<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Daratumumab (Darzalex)]]<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|align="left" |[[Lenvatinib (Lenvima)]] (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lurbinectedin (Zepzelca)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Niraparib (Zejula)]] (oral)<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Olaparib (Lynparza)]] (oral)<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Pembrolizumab (Keytruda)]] <br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pixantrone (Pixuvri)]]<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Rucaparib (Rubraca)]]<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Trabectedin (Yondelis)]]<br />
|<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinflunine (Javlor)]]<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine]] (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.31.7859 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://pubmed.ncbi.nlm.nih.gov/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://pubmed.ncbi.nlm.nih.gov/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]<br />
[[Category:Clinical pharmacology]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=50507Antiemesis2021-06-08T15:58:46Z<p>Karine: formating</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://ascopubs.org/doi/abs/10.1200/JCO.20.01296<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Guidelines=<br />
==ASCO==<br />
<br />
*'''2020:''' Hesketh et al. [https://doi.org/10.1200/jco.20.01296 Antiemetics: ASCO Guideline Update]<br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2021)<br />
!ASCO emetogenic potential<br />
(2020)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|Moderate/High<br />
|Moderate/High<br />
|<br />
|NCCN and ASCO did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg/m2<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Low<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Atezolizumab (Tecentriq)]]<br />
|Minimal<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Minimal/Low<br />
|Minimal/Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Belinostat (Beleodaq)]]<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Blinatumomab (Blincyto)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Ceritinib (Zykadia)]]<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Daratumumab (Darzalex)]]<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|align="left" |[[Lenvatinib (Lenvima)]] (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Niraparib (Zejula)]] (oral)<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Olaparib (Lynparza)]] (oral)<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Pembrolizumab (Keytruda)]] <br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pixantrone (Pixuvri)]]<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Rucaparib (Rubraca)]]<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Trabectedin (Yondelis)]]<br />
|<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinflunine (Javlor)]]<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine]] (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.31.7859 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://pubmed.ncbi.nlm.nih.gov/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://pubmed.ncbi.nlm.nih.gov/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]<br />
[[Category:Clinical pharmacology]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=50506Antiemesis2021-06-08T15:58:13Z<p>Karine: formating, addting drug indexes</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://ascopubs.org/doi/abs/10.1200/JCO.20.01296<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Guidelines=<br />
==ASCO==<br />
<br />
*'''2020:''' Hesketh et al. [https://doi.org/10.1200/jco.20.01296 Antiemetics: ASCO Guideline Update]<br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2021)<br />
!ASCO emetogenic potential<br />
(2020)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|Moderate/High<br />
|Moderate/High<br />
|<br />
|NCCN and ASCO did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg/m2<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Low<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Atezolizumab (Tecentriq)]]<br />
|Minimal<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Minimal/Low<br />
|Minimal/Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Belinostat (Beleodaq)]]<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Blinatumomab (Blincyto)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Ceritinib (Zykadia)]]<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Daratumumab (Darzalex)]]<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|align="left" |[[Lenvatinib (Lenvima)]] (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Niraparib (Zejula)]] (oral)<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Olaparib(Lynparza)]] (oral)<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Pembrolizumab (Keytruda)]] <br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pixantrone (Pixuvri)]]<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Rucaparib (Rubraca)]]<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Trabectedin (Yondelis)]]<br />
|<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinflunine (Javlor)]]<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine]] (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.31.7859 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://pubmed.ncbi.nlm.nih.gov/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://pubmed.ncbi.nlm.nih.gov/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]<br />
[[Category:Clinical pharmacology]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=50505Antiemesis2021-06-08T15:47:50Z<p>Karine: formating antiemetic page</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://ascopubs.org/doi/abs/10.1200/JCO.20.01296<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Guidelines=<br />
==ASCO==<br />
<br />
*'''2020:''' Hesketh et al. [https://doi.org/10.1200/jco.20.01296 Antiemetics: ASCO Guideline Update]<br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2021)<br />
!ASCO emetogenic potential<br />
(2020)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|Moderate/High<br />
|Moderate/High<br />
|<br />
|NCCN and ASCO did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg/m2<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Low<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Atezolizumab (Tecentriq)]]<br />
|Minimal<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Minimal/Low<br />
|Minimal/Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Belinostat (Beleodaq)]]<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Blinatumomab (Blincyto)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Ceritinib (Zykadia)]]<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Daratumumab]]<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Niraparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
|Olaparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
|Pembrolizumab<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
|Pixantrone<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
|Rucaparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Trabectedin<br />
|<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Vinflunine<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.31.7859 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://pubmed.ncbi.nlm.nih.gov/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://pubmed.ncbi.nlm.nih.gov/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]<br />
[[Category:Clinical pharmacology]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=50504Antiemesis2021-06-08T15:44:42Z<p>Karine: formating antiemetic page</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://ascopubs.org/doi/abs/10.1200/JCO.20.01296<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Guidelines=<br />
==ASCO==<br />
<br />
*'''2020:''' Hesketh et al. [https://doi.org/10.1200/jco.20.01296 Antiemetics: ASCO Guideline Update]<br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2021)<br />
!ASCO emetogenic potential<br />
(2020)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|Moderate/High<br />
|Moderate/High<br />
|<br />
|NCCN and ASCO did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg/m2<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Low<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Atezolizumab (Tecentriq)]]<br />
|Minimal<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Minimal/Low<br />
|Minimal/Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Belinostat]]<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Blinatumomab]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Ceritinib]]<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Daratumumab]]<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Niraparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
|Olaparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
|Pembrolizumab<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
|Pixantrone<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
|Rucaparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Trabectedin<br />
|<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Vinflunine<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.31.7859 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://pubmed.ncbi.nlm.nih.gov/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://pubmed.ncbi.nlm.nih.gov/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]<br />
[[Category:Clinical pharmacology]]</div>Karinehttps://hemonc.org/w/index.php?title=Carcinoma_of_unknown_primary&diff=50369Carcinoma of unknown primary2021-06-04T22:19:32Z<p>Karine: Carboplatin & Paclitaxel 2019 regimen for CUP</p>
<hr />
<div>Carcinoma of unknown primary may also be referred to as carcinoma of unknown primary site, cancer/carcinoma of unknown primary (CUP), occult primary, or unknown primary carcinoma.<br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2015:''' Fizazi et al. [https://doi.org/10.1093/annonc/mdv305 Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
===Older===<br />
*'''2011:''' Fizazi et al. [https://doi.org/10.1093/annonc/mdr389 Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
*'''2010:''' Pavlidis et al. [https://doi.org/10.1093/annonc/mdq193 Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
*'''2009:''' Briasoulis et al. [https://doi.org/10.1093/annonc/mdp159 Cancers of unknown primary site: ESMO clinical recommendations for diagnosis, treatment and follow-up]<br />
*'''2008:''' Briasoulis et al. [https://doi.org/10.1093/annonc/mdn104 Cancers of unknown primary site: ESMO clinical recommendation for diagnosis, treatment and follow-up]<br />
*'''2007:''' [https://doi.org/10.1093/annonc/mdm049 Cancers of unknown primary site: ESMO clinical recommendations for diagnosis, treatment and follow-up]<br />
*'''2005:''' Briasoulis et al. [https://doi.org/10.1093/annonc/mdi804 ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cancers of unknown primary site (CUP)]<br />
*'''2001:''' [https://doi.org/10.1023/a:1017409423484 ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cancers of unknown primary site (CUP)]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/occult.pdf NCCN Guidelines - Occult Primary (Cancer of Unknown Primary (CUP)]<br />
<br />
=All lines of therapy=<br />
<br />
==BEP {{#subobject:cc3566|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
BEP: '''<u>B</u>'''leomycin, '''<u>E</u>'''toposide, '''<u>P</u>'''latinol (Cisplatin)<br />
<br>PEB: '''<u>P</u>'''latinol (Cisplatin), '''<u>E</u>'''toposide, '''<u>B</u>'''leomycin<br />
===Regimen {{#subobject:953c7d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.1992.10.6.912 Hainsworth et al 1992]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bleomycin (Blenoxane)]] 30 units IV once per day on days 1, 8, 15<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Hainsworth JD, Johnson DH, Greco FA. Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: results of a 12-year experience. J Clin Oncol. 1992 Jun;10(6):912-22. [https://doi.org/10.1200/jco.1992.10.6.912 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/1375284 PubMed]<br />
<br />
==Carboplatin & Docetaxel {{#subobject:44b3f6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1 {{#subobject:88482c|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.tandfonline.com/doi/full/10.1080/02841860701843043 Pentheroudakis et al. 2008]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 30 minutes once on day 1, '''given second'''<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given first'''<br />
<br />
====Supportive medications====<br />
*[[Dexamethasone (Decadron)]] 8 mg PO twice per day on day -1, then 16 mg IV once on day 1, '''prior to chemotherapy'''<br />
*[[Ondansetron (Zofran)]] 8 mg IV once on day 1, '''prior to chemotherapy'''<br />
*[[Ranitidine (Zantac)]] 100 mg IV once on day 1, '''prior to chemotherapy'''<br />
*[[Dimethindene maleate (Fenestil)]] 0.1 mg/kg (route unclear) prior to chemotherapy<br />
<br />
'''21-day cycle for up to 8 cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:a56594|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1023/a:1008369812295 Greco et al. 2000]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 20 minutes once on day 1, '''given second'''<br />
*[[Docetaxel (Taxotere)]] 65 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''<br />
<br />
====Supportive medications====<br />
*[[Dexamethasone (Decadron)]] 8 mg PO twice per day on days -1 to 2<br />
*One of the following serotonin 5-HT3 antagonists:<br />
**[[Ondansetron (Zofran)]] 32 mg IV once on day 1; 15 minutes prior to chemotherapy<br />
**[[Granisetron]] 10 mcg/kg IV once on day 1; 15 minutes prior to chemotherapy<br />
<br />
'''21-day cycle for 4 to 8 cycles'''<br />
<br />
===References===<br />
# Greco FA, Erland JB, Morrissey LH, Burris HA 3rd, Hermann RC, Steis R, Thompson D, Gray J, Hainsworth JD. Carcinoma of unknown primary site: phase II trials with docetaxel plus cisplatin or carboplatin. Ann Oncol. 2000 Feb;11(2):211-5. [https://doi.org/10.1023/a:1008369812295 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10761758 PubMed]<br />
# Pentheroudakis G, Briasoulis E, Kalofonos HP, Fountzilas G, Economopoulos T, Samelis G, Koutras A, Karina M, Xiros N, Samantas E, Bamias A, Pavlidis N; Hellenic Cooperative Oncology Group. Docetaxel and carboplatin combination chemotherapy as outpatient palliative therapy in carcinoma of unknown primary: a multicentre Hellenic Cooperative Oncology Group phase II study. Acta Oncol. 2008;47(6):1148-55. [https://www.tandfonline.com/doi/full/10.1080/02841860701843043 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18607872 PubMed]<br />
<br />
==Carboplatin & Paclitaxel (CP) {{#subobject:910bdc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a386ae|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2000.18.17.3101 Briasoulis et al. 2000]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.18.00771 Hayashi et al. 2019]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 30 minutes once on day 1, '''given first'''<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given second'''<br />
<br />
====Supportive medications==== <br />
per Briasoulis 2000 study<br />
*[[Methylprednisolone (Solumedrol)]] 32 mg PO for three doses, 24 and 12 hours before paclitaxel, and 10 minutes before carboplatin<br />
*[[Dexamethasone (Decadron)]] 16 mg IV once on day 1, at least 10 minutes prior to chemotherapy<br />
*One of the following antihistamines:<br />
**[[Diphenhydramine (Benadryl)]] 50 mg IV once on day 1, at least 10 minutes prior to chemotherapy<br />
**[[Dimethindene maleate (Fenestil)]] 0.1 mg/kg IV once on day 1, at least 10 minutes prior to chemotherapy<br />
*[[Ranitidine (Zantac)]] 100 mg IV once on day 1, at least 10 minutes prior to chemotherapy<br />
*[[Ondansetron (Zofran)]] 8 mg IV once on day 1, after the above premedications<br />
*Suggested: [[Filgrastim (Neupogen)]] 300 mcg SC once per day on days 5 to 12<br />
<br />
'''21-day cycle for 6 to 8 cycles'''<br />
<br />
===References===<br />
# Briasoulis E, Kalofonos H, Bafaloukos D, Samantas E, Fountzilas G, Xiros N, Skarlos D, Christodoulou C, Kosmidis P, Pavlidis N; Hellenic Cooperative Oncology Group. Carboplatin plus paclitaxel in unknown primary carcinoma: a phase II Hellenic Cooperative Oncology Group Study. J Clin Oncol. 2000 Sep;18(17):3101-7. [https://doi.org/10.1200/jco.2000.18.17.3101 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10963638 PubMed]<br />
# Hayashi H, Kurata T, Takiguchi Y, Arai M, Takeda K, Akiyoshi K, Matsumoto K, Onoe T, Mukai H, Matsubara N, Minami H, Toyoda M, Onozawa Y, Ono A, Fujita Y, Sakai K, Koh Y, Takeuchi A, Ohashi Y, Nishio K, Nakagawa K. Randomized Phase II Trial Comparing Site-Specific Treatment Based on Gene Expression Profiling With Carboplatin and Paclitaxel for Patients With Cancer of Unknown Primary Site. J Clin Oncol. 2019 Mar 1;37(7):570-579. [https://ascopubs.org/doi/full/10.1200/JCO.18.00771 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30653423/ PubMed]<br />
<br />
==Cisplatin monotherapy {{#subobject:21015c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a5832e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(12)00018-4/abstract Gross-Goupil et al. 2012 (GEFCAPI 02)]<br />
|2003-2007<br />
|style="background-color:#1a9851"|Randomized Phase II (C)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29|Cisplatin & Gemcitabine]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''GEFCAPI 02:''' Gross-Goupil M, Fourcade A, Blot E, Penel N, Négrier S, Culine S, Chaigneau L, Lesimple T, Priou F, Lortholary A, Kaminsky MC, Provencal J, Voog E, Bouzy J, Laplanche A, Fizazi K. Cisplatin alone or combined with gemcitabine in carcinomas of unknown primary: results of the randomised GEFCAPI 02 trial. Eur J Cancer. 2012 Mar;48(5):721-7. Epub 2012 Feb 6. [https://www.ejcancer.com/article/S0959-8049(12)00018-4/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22317952 PubMed] NCT00126269<br />
<br />
==Cisplatin & Docetaxel (DC) {{#subobject:27937b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:61bedc|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1023/a:1008369812295 Greco et al. 2000]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Supportive medications====<br />
*[[Dexamethasone (Decadron)]] 8 mg PO twice per day on days -1 to 2<br />
**Suggested: 20 mg IV once on day 1; 15 minutes prior to [[Cisplatin (Platinol)]]<br />
*2 liters of normal saline with chemotherapy<br />
*One of the following serotonin 5-HT3 antagonists:<br />
**[[Ondansetron (Zofran)]] 32 mg IV once on day 1; 15 minutes prior to [[Cisplatin (Platinol)]]<br />
**[[Granisetron]] 10 mcg/kg IV once on day 1; 15 minutes prior to [[Cisplatin (Platinol)]]<br />
*[[Ondansetron (Zofran)]] 8 mg PO three times per day on days 2 to 6<br />
<br />
'''21-day cycle for up to 8 cycles'''<br />
<br />
===References===<br />
# Greco FA, Erland JB, Morrissey LH, Burris HA 3rd, Hermann RC, Steis R, Thompson D, Gray J, Hainsworth JD. Carcinoma of unknown primary site: phase II trials with docetaxel plus cisplatin or carboplatin. Ann Oncol. 2000 Feb;11(2):211-5. [https://doi.org/10.1023/a:1008369812295 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10761758 PubMed]<br />
<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:a36533|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GC: '''<u>G</u>'''emcitabine & '''<u>C</u>'''isplatin<br />
===Regimen {{#subobject:2506f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2003.12.104 Culine et al. 2003 (GEFCAPI 01)]<br />
|1999-2000<br />
|style="background-color:#1a9851"|Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin_.26_Irinotecan_.28IC.29|Cisplatin & Irinotecan]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(12)00018-4/abstract Gross-Goupil et al. 2012 (GEFCAPI 02)]<br />
|2003-2007<br />
|style="background-color:#1a9851"|Randomized Phase II (E-esc)<br />
|[[#Cisplatin_monotherapy|Cisplatin]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''GEFCAPI 01:''' Culine S, Lortholary A, Voigt JJ, Bugat R, Théodore C, Priou F, Kaminsky MC, Lesimple T, Pivot X, Coudert B, Douillard JY, Merrouche Y, Allouache J, Goupil A, Négrier S, Viala J, Petrow P, Bouzy J, Laplanche A, Fizazi K; Trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01). Cisplatin in combination with either gemcitabine or irinotecan in carcinomas of unknown primary site: results of a randomized phase II study--trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01). J Clin Oncol. 2003 Sep 15;21(18):3479-82. [https://doi.org/10.1200/jco.2003.12.104 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12972523 PubMed] content property of [http://hemonc.org HemOnc.org] <br />
# '''GEFCAPI 02:''' Gross-Goupil M, Fourcade A, Blot E, Penel N, Négrier S, Culine S, Chaigneau L, Lesimple T, Priou F, Lortholary A, Kaminsky MC, Provencal J, Voog E, Bouzy J, Laplanche A, Fizazi K. Cisplatin alone or combined with gemcitabine in carcinomas of unknown primary: results of the randomised GEFCAPI 02 trial. Eur J Cancer. 2012 Mar;48(5):721-7. Epub 2012 Feb 6. [https://www.ejcancer.com/article/S0959-8049(12)00018-4/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22317952 PubMed] NCT00126269<br />
<br />
==Cisplatin & Irinotecan (IC) {{#subobject:a7a736|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
IC: '''<u>I</u>'''rinotecan & '''<u>C</u>'''isplatin<br />
===Regimen {{#subobject:3940e6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2003.12.104 Culine et al. 2003 (GEFCAPI 01)]<br />
|1999-2000<br />
|style="background-color:#1a9851"|Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29|Cisplatin & Gemcitabine]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''GEFCAPI 01:''' Culine S, Lortholary A, Voigt JJ, Bugat R, Théodore C, Priou F, Kaminsky MC, Lesimple T, Pivot X, Coudert B, Douillard JY, Merrouche Y, Allouache J, Goupil A, Négrier S, Viala J, Petrow P, Bouzy J, Laplanche A, Fizazi K; Trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01). Cisplatin in combination with either gemcitabine or irinotecan in carcinomas of unknown primary site: results of a randomized phase II study--trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01). J Clin Oncol. 2003 Sep 15;21(18):3479-82. [https://doi.org/10.1200/jco.2003.12.104 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12972523 PubMed]<br />
<br />
==DCF {{#subobject:3f05e4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
DCF: '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:2ae092|Variant=1}}===<br />
''Note: Various guidelines list this as a suitable regimen in this setting, but we are not aware of any specific protocols for this setting.''<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 750 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
*1 liter normal saline before and after [[Cisplatin (Platinol)]] +/- mannitol, potassium chloride, magnesium sulfate<br />
*[[Dexamethasone (Decadron)]] 8 mg PO once per day the day before, the day of, and day after chemotherapy<br />
*[[Ciprofloxacin (Cipro)]] 1000 mg PO (reference did not specify, but assume 500 mg twice per day) on days 5 to 15<br />
<br />
'''21-day cycle for 3 cycles'''<br />
===References===<br />
# None that we are aware of<br />
<br />
==Docetaxel & Gemcitabine {{#subobject:d61b91|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a67a4e|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.20100/full Pouessel et al. 2004]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 8<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
*[[:Category:Steroids|Corticosteroids]] PO the day before, the day of, and day after [[Docetaxel (Taxotere)]]<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# Pouessel D, Culine S, Becht C, Ychou M, Romieu G, Fabbro M, Cupissol D, Pinguet F. Gemcitabine and docetaxel as front-line chemotherapy in patients with carcinoma of an unknown primary site. Cancer. 2004 Mar 15;100(6):1257-61. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.20100/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15022294 PubMed]<br />
<br />
==Erlotinib & Bevacizumab {{#subobject:742957|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e0f611|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2006.09.3047 Hainsworth et al. 2007a]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO on days 1 to 28, 1 hour before or 2 hours after meals <br />
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15<br />
**Infusion time is 90 minutes for the first dose, then if tolerated, 60 minutes for the second dose, and 30 minutes for the third dose and later <br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Hainsworth JD, Spigel DR, Farley C, Thompson DS, Shipley DL, Greco FA; Minnie Pearl Cancer Research Network. Phase II trial of bevacizumab and erlotinib in carcinomas of unknown primary site: the Minnie Pearl Cancer Research Network. J Clin Oncol. 2007 May 1;25(13):1747-52. [https://doi.org/10.1200/jco.2006.09.3047 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17470864 PubMed]<br />
<br />
==GCP {{#subobject:4d259f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GCP: '''<u>G</u>'''emcitabine, '''<u>C</u>'''arboplatin, '''<u>P</u>'''aclitaxel<br />
===Regimen {{#subobject:96f90f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2002.20.6.1651 Greco et al. 2002]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 20 to 30 minutes once on day 1<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Supportive medications====<br />
*[[:Category:Steroids|Corticosteroids]] IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]<br />
*[[Diphenhydramine (Benadryl)]] 50 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]<br />
*[[Cimetidine (Tagamet)]] 300 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Greco FA, Burris HA 3rd, Litchy S, Barton JH, Bradof JE, Richards P, Scullin DC Jr, Erland JB, Morrissey LH, Hainsworth JD. Gemcitabine, carboplatin, and paclitaxel for patients with carcinoma of unknown primary site: a Minnie Pearl Cancer Research Network study. J Clin Oncol. 2002 Mar 15;20(6):1651-6. [https://doi.org/10.1200/jco.2002.20.6.1651 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11896116 PubMed]<br />
<br />
==Gemcitabine & Irinotecan {{#subobject:3f6501|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:6a2c02|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://journals.lww.com/journalppo/pages/articleviewer.aspx?year=2010&issue=02000&article=00013&type=abstract Hainsworth et al. 2010]<br />
|2003-2008<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[#PCE|PCE]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of OS24<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Irinotecan (Camptosar)]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# Hainsworth JD, Spigel DR, Clark BL, Shipley D, Thompson DS, Farley C, West-Osterfield K, Lane CM, Cescon T, Bury MJ, Greco FA. Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan in the first-line treatment of patients with carcinoma of unknown primary site: a randomized, phase III Sarah Cannon Oncology Research Consortium Trial. Cancer J. 2010 Jan-Feb;16(1):70-5. [http://journals.lww.com/journalppo/pages/articleviewer.aspx?year=2010&issue=02000&article=00013&type=abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/20164695 PubMed]<br />
<br />
==PCE {{#subobject:87de5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PCE: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''arboplatin, '''<u>E</u>'''toposide<br />
===Regimen {{#subobject:886058|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/1097-0142%2820001215%2989:12%3C2655::AID-CNCR19%3E3.0.CO;2-9/full Greco et al. 2000a]<br />
|1995-1996<br />
|style="background-color:#91cf61"|Phase II<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[http://journals.lww.com/journalppo/pages/articleviewer.aspx?year=2010&issue=02000&article=00013&type=abstract Hainsworth et al. 2010]<br />
|2003-2008<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[#Gemcitabine_.26_Irinotecan|Gemcitabine & Irinotecan]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of OS24<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 20 to 30 minutes once on day 1<br />
*[[Etoposide (Vepesid)]] as follows:<br />
**Days 1, 3, 5, 7, 9: 50 mg PO once per day<br />
**Days 2, 4, 6, 8, 10: 100 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO for two doses, 12 hours and 4 hours prior to [[Paclitaxel (Taxol)]]<br />
*[[Dexamethasone (Decadron)]] 20 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]<br />
*[[Diphenhydramine (Benadryl)]] 50 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]<br />
*[[Cimetidine (Tagamet)]] 300 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]<br />
<br />
'''21-day cycle for 4 to 8 cycles'''<br />
<br />
===References===<br />
# Greco FA, Burris HA 3rd, Erland JB, Gray JR, Kalman LA, Schreeder MT, Hainsworth JD. Carcinoma of unknown primary site. Cancer. 2000 Dec 15;89(12):2655-60. [https://onlinelibrary.wiley.com/doi/10.1002/1097-0142%2820001215%2989:12%3C2655::AID-CNCR19%3E3.0.CO;2-9/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11135228 PubMed]<br />
# Hainsworth JD, Spigel DR, Clark BL, Shipley D, Thompson DS, Farley C, West-Osterfield K, Lane CM, Cescon T, Bury MJ, Greco FA. Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan in the first-line treatment of patients with carcinoma of unknown primary site: a randomized, phase III Sarah Cannon Oncology Research Consortium Trial. Cancer J. 2010 Jan-Feb;16(1):70-5. [http://journals.lww.com/journalppo/pages/articleviewer.aspx?year=2010&issue=02000&article=00013&type=abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/20164695 PubMed]<br />
<br />
==PCF {{#subobject:71face|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PCF: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:c82ab5|Variant=1}}===<br />
''Note: Various guidelines list this as a suitable regimen in this setting, but we are not aware of any specific protocols for this setting.''<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 2<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 2 (total dose per cycle: 2500 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle for 3 cycles'''<br />
===References===<br />
# None that we are aware of<br />
<br />
[[Category:Carcinoma of unknown primary regimens]]<br />
[[Category:Site-agnostic regimens]]<br />
[[Category:Malignant solid neoplasm]]</div>Karinehttps://hemonc.org/w/index.php?title=User:Karine&diff=49819User:Karine2021-05-19T21:07:22Z<p>Karine: Karine bio update</p>
<hr />
<div>[[File:KarineDarbinyan.jpg|thumb|Karine Darbinyan, MD]]<br />
Karine works at Altru Health System in Grand Forks, North Dakota as attending physician in hematology and medical oncology. She is board certified in internal medicine and medical oncology and board eligible for hematology. She completed her fellowship at Montefiore Medical Center / AECOM. Her main interests are head and neck cancer, lung cancer and supportive care including antiemesis.</div>Karinehttps://hemonc.org/w/index.php?title=Urothelial_carcinoma&diff=49818Urothelial carcinoma2021-05-19T20:47:12Z<p>Karine: TROPHY-U-01 study evidence and reference</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" style="color:white; font-size:125%; background-color:#08519c" align="center" |'''Page editor'''<br />
! colspan="2" style="color:white; font-size:125%; background-color:#08519c" align="center" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:RisaWong.jpg|frameless|upright=0.3|center]]<br />
|<big>Risa L. Wong, MD<br>University of Washington<br>Fred Hutchinson Cancer Research Center<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/RisaWongMD RisaWongMD]<br />
| style="background-color:#F0F0F0" |[[File:Alikhaki.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Alikhaki|Ali Raza Khaki, MD]]<br>Stanford University<br>Palo Alto, CA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/arkhaki arkhaki]<br />
|-<br />
|}<br />
''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Bladder_cancer_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Bladder cancer - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''.<br />
<br><big>Note: the page has adjuvant and perioperative regimens specific to bladder cancer as well as systemic regimens for the more general category of urothelial cancer. <br />
<br />
*See the [[Upper tract urothelial carcinoma|'''upper tract urothelial carcinoma page''']] for regimens specific to UTUC.</big><br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==AUA, ASCO, ASTRO, SUO==<br />
<br />
*'''2017:''' Chang et al. [http://www.auanet.org/guidelines/muscle-invasive-bladder-cancer-new-(2017) Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO Guideline] [https://pubmed.ncbi.nlm.nih.gov/28456635 PubMed]<br />
<br />
==EAU-ESMO==<br />
<br />
*'''2019:''' Horwich et al. [https://academic.oup.com/annonc/article/30/11/1697/5629133 EAU–ESMO consensus statements on the management of advanced and variant bladder cancer—an international collaborative multi-stakeholder effort: under the auspices of the EAU and ESMO Guidelines Committees]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2019:''' [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer/eUpdate-Bladder-Cancer-Treatment-Recommendations1 eUpdate – Bladder Cancer Treatment Recommendations]<br />
*'''2019:''' [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer/eUpdate-Bladder-Cancer-Treatment-Recommendations2 eUpdate – Bladder Cancer Treatment Recommendations - Subsequent treatments post-chemotherapy or immunotherapy]<br />
*'''2014:''' Bellmunt et al. [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer Bladder cancer: ESMO Clinical Practice Guidelines] [https://pubmed.ncbi.nlm.nih.gov/25096609 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf NCCN Guidelines - Bladder Cancer]<br />
<br />
=Nonmuscle invasive bladder cancer/Intravesical chemotherapy=<br />
==Bacillus Calmette-Guérin (BCG) monotherapy {{#subobject:eojb2c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, low-dose (27 mg) {{#subobject:52ca75|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/j.eururo.2007.04.062 Ojea et al. 2007 (CUETO study 95011)]<br />
| rowspan="2" |1995-1998<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[Bladder_cancer#Mitomycin_monotherapy|Mitomycin]]<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|2. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]; very-low-dose<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#TURBT|TURBT]], within 14 to 21 days<br />
<br />
====Immunotherapy, induction====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 27 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
'''6-week course, then proceed to additional therapy'''<br />
<br />
====Immunotherapy, continuation====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 27 mg intravesicularly once on day 1<br />
<br />
'''14-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, intravesical (81 mg) & percutaneous, with maintenance therapy {{#subobject:221dfe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.auajournals.org/article/S0022-5347(05)67707-5/fulltext Lamm et al. 2000 (SWOG 8507)]<br />
|1985-1988<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|Intravesical & percutaneous BCG, without maintenance therapy<br />
| style="background-color:#1a9850" |Superior RFS<br />
|-<br />
|}<br />
====Immunotherapy, induction====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 81 mg in 50.5 mL saline suspension is created and administered as follows:<br />
**50 mL (~80.2 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15, 22, 29, 36. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.<br />
**0.5 mL (~0.8 mg) applied once per day on days 1, 8, 15, 22, 29, 36 to the inner thigh, which is first cleaned with alcohol. For percutaneous administration, the skin is punctured 3 times with a sterile 28 gauge needle. Each subsequent administration alternates between thighs (i.e. left thigh on one week, right thigh the next week, left thigh the week after, etc.).<br />
<br />
'''6-week course, then proceed to maintenance therapy'''<br />
<br />
====Immunotherapy, maintenance====<br />
''The authors were a bit unclear about the schedule of maintenance therapy. This is our best interpretation of how the schedule was described.''<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 81 mg in 50.5 mL saline suspension is created and administered as follows:<br />
**50 mL (~80.2 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.<br />
**0.5 mL (~0.8 mg) applied once per day on days 1, 8, 15 to the inner thigh, which is first cleaned with alcohol. For percutaneous administration, the skin is punctured 3 times with a sterile 28 gauge needle. Each subsequent administration alternates between thighs (i.e. left thigh on one week, right thigh the next week, left thigh the week after, etc.).<br />
<br />
'''3-week courses; each course is given at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, and 36 months after the start of induction therapy'''<br />
<br />
===Regimen variant #3, intravesical (81 mg) & percutaneous, without maintenance therapy {{#subobject:f5c250|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.auajournals.org/article/S0022-5347(05)67707-5/fulltext Lamm et al. 2000 (SWOG 8507)]<br />
|1985-1988<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Intravesical & percutaneous BCG, with maintenance therapy<br />
| style="background-color:#d73027" |Inferior RFS<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 81 mg in 50.5 mL saline suspension is created and administered as follows:<br />
**50 mL (~80.2 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15, 22, 29, 36. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.<br />
**0.5 mL (~0.8 mg) applied once per day on days 1, 8, 15, 22, 29, 36 to the inner thigh, which is first cleaned with alcohol. For percutaneous administration, the skin is punctured 3 times with a sterile 28 gauge needle. Each subsequent administration alternates between thighs (i.e. left thigh on one week, right thigh the next week, left thigh the week after, etc.).<br />
<br />
'''6-week course'''<br />
<br />
===Regimen variant #4, intravesical (120 mg) & percutaneous, with maintenance therapy {{#subobject:8e5276|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJM199110243251703 Lamm et al. 1991 (SWOG 8216)]<br />
|1983-1985<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|[[#Doxorubicin_monotherapy|Doxorubicin]]<br />
| style="background-color:#91cf60" |Seems to have superior DFS<br />
|-<br />
|}<br />
====Immunotherapy, induction====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 120 mg (3 vials) in 50.5 mL saline suspension is created and administered as follows:<br />
**50 mL (~120 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15, 22, 29, 36. Patients retain the BCG suspension for up to 2 hours if possible.<br />
**0.5 mL (~1.2 mg) applied once per day on days 1, 8, 15, 22, 29, 36 to the upper part of the inner thigh<br />
<br />
'''6-week course, then proceed to maintenance therapy'''<br />
<br />
====Immunotherapy, maintenance====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 120 mg (3 vials) in 50.5 mL saline suspension is created and administered as follows:<br />
**50 mL (~120 mg) intravesicularly once on day 1. Patients retain the BCG suspension for up to 2 hours if possible.<br />
**0.5 mL (~1.2 mg) applied once on day 1 to the upper part of the inner thigh<br />
<br />
'''Given at 3 months, 6 months, 12 months, 18 months, and 24 months'''<br />
<br />
===Regimen variant #5, 150 mg {{#subobject:d04712|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/s0022-5347(17)40002-4 Martínez-Piñeiro et al. 1990]<br />
| rowspan="2" |1980-1988<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|1. [[#Doxorubicin_monotherapy|Doxorubicin]]<br> 2. [[#Thiotepa_monotherapy|Thiotepa]]<br />
| style="background-color:#1a9850" |Superior RFS<br />
|-<br />
|}<br />
''Note: details are very sparse in the abstract and this is probably only of historic interest.''<br />
====Immunotherapy====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)]] 150 mg intravesicularly x 15 treatments<br />
<br />
===References===<br />
<br />
#Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. [https://doi.org/10.1016/s0022-5347(17)40002-4 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/2106041 PubMed]<br />
#'''SWOG 8216:''' Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA Jr, Sullivan J, Sarosdy MF, Crissman JD, Coltman CA. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med. 1991 Oct 24;325(17):1205-9. [https://www.nejm.org/doi/10.1056/NEJM199110243251703 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1922207 PubMed]<br />
#'''SWOG 8507:''' Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, Sarosdy MF, Bohl RD, Grossman HB, Beck TM, Leimert JT, Crawford ED. Maintenance bacillus Calmette-Guérin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000 Apr;163(4):1124-9. [http://www.auajournals.org/article/S0022-5347(05)67707-5/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10737480 PubMed]<br />
#'''Meta-analysis:''' Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guérin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol. 2002 Nov;168(5):1964-70. [http://www.auajournals.org/article/S0022-5347(05)64273-5/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/12394686 PubMed]<br />
#'''CUETO study 95011:''' Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, Chantada V, Camacho JE, Piñeiro LM, Rodríguez RH, Isorna S, Blas M, Martínez-Piñeiro JA, Madero R; CUETO. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guérin (27 mg) versus very low-dose bacillus Calmette-Guérin (13.5 mg) versus mitomycin C. Eur Urol. 2007 Nov;52(5):1398-406. Epub 2007 Apr 27. [https://doi.org/10.1016/j.eururo.2007.04.062 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17485161 PubMed]<br />
<br />
==Doxorubicin monotherapy {{#subobject:8034b6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:49ccdb|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0022-5347(17)40002-4 Martínez-Piñeiro et al. 1990]<br />
| rowspan="2" |1980-1988<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]<br />
| style="background-color:#d73027" |Inferior RFS<br />
|-<br />
|2. [[#Thiotepa_monotherapy|Thiotepa]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJM199110243251703 Lamm et al. 1991 (SWOG 8216)]<br />
|1983-1985<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]<br />
| style="background-color:#fc8d59" |Seems to have inferior DFS<br />
|-<br />
|}<br />
''Inferior to BCG, included for reference purposes only.''<br />
====Chemotherapy====<br />
<br />
*[[Doxorubicin (Adriamycin)]] 50 mg intravesicularly once on day 1<br />
<br />
'''7-day cycle for 5 cycles, then 30-day cycle for 11 cycles (approximately 1 year)'''<br />
<br />
===References===<br />
<br />
#Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. [https://doi.org/10.1016/s0022-5347(17)40002-4 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/2106041 PubMed]<br />
#'''SWOG 8216:''' Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA Jr, Sullivan J, Sarosdy MF, Crissman JD, Coltman CA. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med. 1991 Oct 24;325(17):1205-9. [https://www.nejm.org/doi/10.1056/NEJM199110243251703 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/1922207 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:343fc9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 1 treatment {{#subobject:170d3b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/2680547 Messing et al. 2018 (SWOG S0337)]<br />
|2008-2012<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Placebo (saline)<br />
| style="background-color:#1a9850" |Superior TTR<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#TURBT|TURBT]], up to 3 hours prior<br />
<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 2000 mg in 100 mL of saline instilled intravesicularly for up to 60 minutes<br />
<br />
'''One treatment'''<br />
<br />
===Regimen variant #2, 6 treatments {{#subobject:fa5bb2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2008.20.8199 Addeo et al. 2009]<br />
|2003-2005<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Mitomycin_monotherapy|Mitomycin]]<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 2000 mg in 50 mL of saline instilled intravesicularly for up to 60 minutes once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
<br />
#Addeo R, Caraglia M, Bellini S, Abbruzzese A, Vincenzi B, Montella L, Miragliuolo A, Guarrasi R, Lanna M, Cennamo G, Faiola V, Del Prete S. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. J Clin Oncol. 2010 Feb 1;28(4):543-8. Epub 2009 Oct 19. [https://doi.org/10.1200/JCO.2008.20.8199 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19841330 PubMed]<br />
#'''SWOG S0337:''' Messing EM, Tangen CM, Lerner SP, Sahasrabudhe DM, Koppie TM, Wood DP Jr, Mack PC, Svatek RS, Evans CP, Hafez KS, Culkin DJ, Brand TC, Karsh LI, Holzbeierlein JM, Wilson SS, Wu G, Plets M, Vogelzang NJ, Thompson IM Jr. Effect of intravesical instillation of gemcitabine vs saline immediately following resection of suspected low-grade non-muscle-invasive bladder cancer on tumor recurrence: SWOG S0337 randomized clinical trial. JAMA. 2018 May 8;319(18):1880-1888. [https://jamanetwork.com/journals/jama/fullarticle/2680547 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29801011 PubMed] NCT00445601<br />
<br />
==Mitomycin monotherapy {{#subobject:2e5944|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 30 mg x 12 {{#subobject:347e3e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/j.eururo.2007.04.062 Ojea et al. 2007 (CUETO study 95011)]<br />
| rowspan="2" |1995-1998<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]; low-dose<br />
| style="background-color:#d73027" |Inferior DFS<br />
|-<br />
|2. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]; very-low-dose<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#TURBT|TURBT]], 14 to 21 days prior<br />
<br />
====Chemotherapy====<br />
<br />
*[[Mitomycin (Mutamycin)]] as follows:<br />
**Cycles 1 to 3: 30 mg intravesicularly once per day on days 1 & 8<br />
**Cycles 4 to 9: 30 mg intravesicularly once on day 1<br />
<br />
'''14-day cycle for 9 cycles'''<br />
<br />
===Regimen variant #2, 40 mg x 11 {{#subobject:531377|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2011.39.2936 Lammers et al. 2012]<br />
|2003-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Keyhole limpet hemocyanin<br />
| style="background-color:#1a9850" |Superior RFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#TURBT|TURBT]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Mitomycin (Mutamycin)]] 40 mg intravesicularly once on day 1<br />
<br />
'''7-day cycle for 4 cycles, then monthly cycle for 4 cycles, then 3-month cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''CUETO study 95011:''' Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, Chantada V, Camacho JE, Piñeiro LM, Rodríguez RH, Isorna S, Blas M, Martínez-Piñeiro JA, Madero R; CUETO. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guérin (27 mg) versus very low-dose bacillus Calmette-Guérin (13.5 mg) versus mitomycin C. Eur Urol. 2007 Nov;52(5):1398-406. Epub 2007 Apr 27. [https://doi.org/10.1016/j.eururo.2007.04.062 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17485161 PubMed]<br />
#Lammers RJ, Witjes WP, Janzing-Pastors MH, Caris CT, Witjes JA. Intracutaneous and intravesical immunotherapy with keyhole limpet hemocyanin compared with intravesical mitomycin in patients with non-muscle-invasive bladder cancer: results from a prospective randomized phase III trial. J Clin Oncol. 2012 Jun 20;30(18):2273-9. Epub 2012 May 14. [https://doi.org/10.1200/JCO.2011.39.2936 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22585689 PubMed]<br />
#'''BOXIT:''' Kelly JD, Tan WS, Porta N, Mostafid H, Huddart R, Protheroe A, Bogle R, Blazeby J, Palmer A, Cresswell J, Johnson M, Brough R, Madaan S, Andrews S, Cruickshank C, Burnett S, Maynard L, Hall E; BOXIT Investigators. BOXIT-A Randomised Phase III Placebo-controlled Trial Evaluating the Addition of Celecoxib to Standard Treatment of Transitional Cell Carcinoma of the Bladder (CRUK/07/004). Eur Urol. 2019 Apr;75(4):593-601. Epub 2018 Sep 29. [https://doi.org/10.1016/j.eururo.2018.09.020 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30279015/ PubMed]<br />
<br />
==Pembrolizumab monotherapy {{#subobject:3cb963|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7ae9e3|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2019.37.7_suppl.350 Balar et al. (KEYNOTE-057)]<br />
|NR in abstract<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycle for 35 cycles (2 years)'''<br />
====References====<br />
<br />
#'''Abstract:''' Keynote-057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guerin (BCG). Arjun Vasant Balar, Girish S. Kulkarni, Edward M. Uchio, Joost Boormans, Loic Mourey, Laurence Eliot Miles Krieger, Eric A. Singer, Dean F. Bajorin, Ashish M. Kamat, Petros Grivas, Ho Kyung Seo, Hiroyuki Nishiyama, Badrinath R. Konety, Kijoeng Nam, Ekta Kapadia, Tara L. Frenkl, Ronald De Wit. Journal of Clinical Oncology 2019 37:7_suppl, 350-350. [https://doi.org/10.1200/JCO.2019.37.7_suppl.350 link to abstract] NCT02625961<br />
<br />
==Thiotepa monotherapy {{#subobject:5b9d6c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:97d2e7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0022-5347(17)40002-4 Martínez-Piñeiro et al. 1990]<br />
| rowspan="2" |1980-1988<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]<br />
| style="background-color:#d73027" |Inferior RFS<br />
|-<br />
|2. [[#Doxorubicin_monotherapy|Doxorubicin]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Inferior to BCG, included for reference purposes only.''<br />
====Chemotherapy====<br />
<br />
*[[Thiotepa (Thioplex)]] 50 mg intravesicularly x 15 treatments<br />
<br />
===References===<br />
<br />
#Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. [https://doi.org/10.1016/s0022-5347(17)40002-4 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/2106041 PubMed]<br />
<br />
==Valrubicin monotherapy {{#subobject:58jgac|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:74j2e7|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2967799-3 Steinberg et al. 2000]<br />
|1993-1996<br />
| style="background-color:#91cf61" |Non-randomized (RT)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Valrubicin (Valstar)]] 800 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
<br />
#Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M; Valrubicin Study Group. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guérin refractory carcinoma in situ of the bladder. J Urol. 2000 Mar;163(3):761-7. Erratum in: J Urol. 2008 Jan;179(1):386. [https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2967799-3 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10687972 PubMed]<br />
<br />
=Neoadjuvant chemotherapy=<br />
==Atezolizumab monotherapy {{#subobject:3cb963|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7ae9e3|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/s41591-019-0628-7 Powles et al. 2019 (ABACUS)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)|Atezolizumab]] 1200 mg IV over 60 minutes once on day 1<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Cystectomy|Radical cystectomy]] to be performed 4 to 8 weeks after completion of chemotherapy<br />
<br />
===References===<br />
<br />
#'''ABACUS:''' Powles T, Kockx M, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, Szabados B, Pous AF, Gravis G, Herranz UA, Protheroe A, Ravaud A, Maillet D, Mendez MJ, Suarez C, Linch M, Prendergast A, van Dam PJ, Stanoeva D, Daelemans S, Mariathasan S, Tea JS, Mousa K, Banchereau R, Castellano D. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med. 2019 Nov 4. [https://www.nature.com/articles/s41591-019-0628-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31686036 PubMed] NCT02662309<br />
<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:d08e11|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GC: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin<br />
===Regimen variant #1, single-dose cisplatin {{#subobject:dc99d5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585515/ Dash et al. 2008]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Bladder_cancer_surgery|Surgery]]<br />
<br />
===Regimen variant #2, split-dose cisplatin {{#subobject:be43aa|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585515/ Dash et al. 2008]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Bladder_cancer_surgery|Surgery]]<br />
<br />
===References===<br />
<br />
#'''Retrospective:''' Dash A, Pettus JA 4th, Herr HW, Bochner BH, Dalbagni G, Donat SM, Russo P, Boyle MG, Milowsky MI, Bajorin DF. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer. 2008 Nov 1;113(9):2471-7. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585515/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18823036 PubMed]<br />
<br />
==MCV {{#subobject:553fe2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MCV: '''<u>M</u>'''ethotrexate, '''<u>C</u>'''isplatin, '''<u>V</u>'''inblastine<br />
<br>CMV: '''<u>C</u>'''isplatin, '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine<br />
===Regimen variant #1, 2 cycles {{#subobject:450c9f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJM199311043291903 Kaufman et al. 1993]<br />
|NR<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.1996.14.1.119 Tester et al. 1996 (RTOG 88-02)]<br />
|1988-1990<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.1998.16.11.3576 Shipley et al. 1998 (RTOG 89-03)]<br />
|1990-1993<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant chemotherapy]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*Kaufman et al. 1993, CR: [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]<br />
*RTOG 88-02 & 89-03: [[#Cisplatin_.26_RT|Cisplatin & RT induction]]<br />
<br />
===Regimen variant #2, 3 cycles {{#subobject:3d008f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02292-8/abstract Griffiths et al. 1999 (BA06 30894)]<br />
|1989-1995<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 Zapatero et al. 2000]<br />
|1989-1997<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for BA06 30894 is based on the 2011 update.''<br><br />
''Patients in Zapatero et al. 2000 had T2 to T4 Nx M0 disease.''<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 2, before hydration<br />
*[[Vinblastine (Velban)]] 4 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*'''BA06 30894:''' [[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> IV or PO every 6 hours on days 2 & 9, given after hydration, with the first dose 24 hours after the previous day's dose of [[Methotrexate (MTX)]] (total dose per cycle: 120 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
====Subsequent treatment====<br />
<br />
*Zapatero et al. 2000: after 3 cycles of chemotherapy, patients underwent cystoscopy, biopsy, and abdominal CT<br />
**Patients with CR or who were not surgical candidates: [[#Radiation_therapy|RT consolidation]] which begins 4 to 6 weeks after completion of chemotherapy<br />
**Otherwise, patients proceeded to [[Surgery#Cystectomy|cystectomy]]<br />
<br />
===References===<br />
<br />
#Kaufman DS, Shipley WU, Griffin PP, Heney NM, Althausen AF, Efird JT. Selective bladder preservation by combination treatment of invasive bladder cancer. N Engl J Med. 1993 Nov 4;329(19):1377-82. [https://www.nejm.org/doi/10.1056/NEJM199311043291903 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8413433 PubMed]<br />
#'''RTOG 88-02:''' Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. [https://doi.org/10.1200/jco.1996.14.1.119 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8558186 PubMed]<br />
#'''RTOG 89-03:''' Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. [https://doi.org/10.1200/jco.1998.16.11.3576 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9817278 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''BA06 30894:''' Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; CUETO; International Collaboration of Trialists. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. Lancet. 1999 Aug 14;354(9178):533-40. Erratum in: Lancet 1999 Nov 6;354(9190):1650. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02292-8/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/10470696 PubMed]<br />
##'''Update:''' Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group); [[Study_Groups#EORTC|EORTC]] Genito-Urinary Tract Cancer Group; Australian Bladder Cancer Study Group; National Cancer Institute of Canada Clinical Trials Group; Finnbladder; Norwegian Bladder Cancer Study Group; Club Urologico Espanol de Tratamiento Oncologico Group. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011 Jun 1;29(16):2171-7. Epub 2011 Apr 18. [https://doi.org/10.1200/jco.2010.32.3139 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107740/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21502557 PubMed]<br />
#Zapatero A, Martín de Vidales C, Marín A, Cerezo L, Arellano R, Rabadán M, Pérez-Torrubia A. Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Int J Cancer. 2000 Oct 20;90(5):287-94. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11091353 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439%2809%2900029-5/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19362865 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
<br />
==MVAC {{#subobject:701fbe|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''isplatin<br />
===Regimen variant #1, 2 cycles {{#subobject:0f1661|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdu126 Kitamura et al. 2014 (JCOG0209)]<br />
|2003-2009<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Radical_cystectomy|Radical cystectomy]]<br />
<br />
===Regimen variant #2, 3 cycles {{#subobject:dc2c80|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa022148 Grossman et al. 2003 (SWOG S8710)]<br />
|1987-1998<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
<br />
'''28-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Radical_cystectomy|Radical cystectomy]]<br />
<br />
===References===<br />
<br />
#'''SWOG S8710:''' Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003 Aug 28;349(9):859-66. [https://www.nejm.org/doi/full/10.1056/NEJMoa022148 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12944571 PubMed]<br />
#'''JCOG0209:''' Kitamura H, Tsukamoto T, Shibata T, Masumori N, Fujimoto H, Hirao Y, Fujimoto K, Kitamura Y, Tomita Y, Tobisu K, Niwakawa M, Naito S, Eto M, Kakehi Y; Urologic Oncology Study Group of the Japan Clinical Oncology Group. Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209. Ann Oncol. 2014 Jun;25(6):1192-8. [https://doi.org/10.1093/annonc/mdu126 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24669010 PubMed] UMIN C000000093<br />
##'''HRQoL analysis:''' Kitamura H, Hinotsu S, Tsukamoto T, Shibata T, Mizusawa J, Kobayashi T, Miyake M, Nishiyama N, Kojima T, Nishiyama H; Urologic Oncology Study Group of the Japan Clinical Oncology Group. Effect of neoadjuvant chemotherapy on health-related quality of life in patients with muscle-invasive bladder cancer: results from JCOG0209, a randomized phase III study. Jpn J Clin Oncol. 2020 Dec 16;50(12):1464-1469. [https://doi.org/10.1093/jjco/hyaa123 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32699909 PubMed]<br />
<br />
==MVAC, dose-dense {{#subobject:3cb963|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ddMVAC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''isplatin<br />
<br>AMVAC: '''<u>A</u>'''ccelerated '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''isplatin<br />
===Regimen variant #1, 3 cycles {{#subobject:c4bf38|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050203/ Plimack et al. 2014 (FER-GU-026)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV over 30 minutes once on day 1<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV push once on day 2<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV push once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV in 1 liter normal saline once on day 2<br />
**Split dose could be used at physician discretion for patients with CrCl less than 60 mL/min/1.73m<sup>2</sup>: 35 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
<br />
====Supportive medications====<br />
<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once, 24 to 48 hours after completion of chemotherapy<br />
*Antiemetics used often included [[Aprepitant (Emend)]], [[Ondansetron (Zofran)]], and [[Dexamethasone (Decadron)]] but were not specified by the trial.<br />
<br />
'''14-day cycle for 3 cycles'''<br />
<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Radical_cystectomy|Radical cystectomy]] with bilateral [[Surgery#Lymphadenectomy|lymphadenectomy]], within 4 to 8 weeks after the last cycle of chemotherapy<br />
<br />
===Regimen variant #2, 4 cycles {{#subobject:7ae9e3|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7057274/ Choueiri et al. 2014 (DFCI 08-208)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV over 30 minutes once on day 1<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV push once on day 2<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV push once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV in 1 liter normal saline once on day 2<br />
<br />
====Supportive medications====<br />
<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 3 (approximately 24 hours after day 2 chemotherapy)<br />
<br />
'''14-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Cystectomy|Cystectomy]] to be performed 4 to 10 weeks after completion of chemotherapy<br />
<br />
===References===<br />
<!-- # Angela Q. Qu, Susanna J. Jacobus, Sabina Signoretti, Edward C. Stack, Katherine Maragaret Krajewski, Jonathan E. Rosenberg, Toni K. Choueiri. Phase II study of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) chemotherapy in patients with muscle-invasive urothelial cancer (MI-UC): Pathologic and radiologic response, serum tumor markers, and DNA excision repair pathway biomarkers in relation to disease-free survival (DFS). 2013 ASCO Annual Meeting abstract 4530. [http://meetinglibrary.asco.org/content/117233-132 link to abstract] --><br />
<br />
#'''DFCI 08-208:''' Choueiri TK, Jacobus S, Bellmunt J, Qu A, Appleman LJ, Tretter C, Bubley GJ, Stack EC, Signoretti S, Walsh M, Steele G, Hirsch M, Sweeney CJ, Taplin ME, Kibel AS, Krajewski KM, Kantoff PW, Ross RW, Rosenberg JE. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol. 2014 Jun 20;32(18):1889-94. Epub 2014 May 12. [https://doi.org/10.1200/jco.2013.52.4785 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7057274/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24821883 PubMed] NCT00808639<br />
#'''FER-GU-026:''' Plimack ER, Hoffman-Censits JH, Viterbo R, Trabulsi EJ, Ross EA, Greenberg RE, Chen DY, Lallas CD, Wong YN, Lin J, Kutikov A, Dotan E, Brennan TA, Palma N, Dulaimi E, Mehrazin R, Boorjian SA, Kelly WK, Uzzo RG, Hudes GR. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol. 2014 Jun 20;32(18):1895-901. Epub 2014 May 12. [https://doi.org/10.1200/jco.2013.53.2465 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050203/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24821881 PubMed] NCT01031420<br />
<br />
==Pembrolizumab monotherapy {{#subobject:3cfac3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c4bf38|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://pubmed.ncbi.nlm.nih.gov/30343614 Necchi et al. 2018 (PURE-01)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)|Pembrolizumab]] 200 mg IV over 30 minutes once on day 1<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Radical_cystectomy|Radical cystectomy]], within 1 to 3 weeks after the last cycle of chemotherapy<br />
<br />
===References===<br />
<br />
#'''PURE-01:''' Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Lucianò R, Colecchia M, Giannatempo P, Mortarini R, Bianchi M, Farè E, Monopoli F, Colombo R, Gallina A, Salonia A, Messina A, Ali SM, Madison R, Ross JS, Chung JH, Salvioni R, Mariani L, Montorsi F. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol. 2018 Oct 20. [https://doi.org/10.1200/jco.18.01148 Link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30343614 PubMed] NCT02736266<br />
##'''Update:''' Necchi A, Raggi D, Gallina A, Madison R, Colecchia M, Lucianò R, Montironi R, Giannatempo P, Farè E, Pederzoli F, Bandini M, Bianchi M, Colombo R, Gandaglia G, Fossati N, Marandino L, Capitanio U, Dehò F, Ali SM, Chung JH, Ross JS, Salonia A, Briganti A, Montorsi F. Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies. Eur Urol. 2019 Nov 7. [https://doi.org/10.1016/j.eururo.2019.10.026 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31708296 PubMed]<br />
<br />
=Induction chemoradiotherapy=<br />
<br />
==Cisplatin & RT {{#subobject:ebb6e9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Cisplatin & RT: Cisplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
<br />
===Regimen variant #1, cisplatin 40 mg/m<sup>2</sup> qwk x 3 {{#subobject:f782c3|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract Hagan et al. 2003 (RTOG 97-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|[http://www.urologiconcology.org/article/S1078-1439(09)00029-5/fulltext Zapatero et al. 2009]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
''Patients in '''Zapatero et al. 2000''' had T2 to T4 N0 M0 disease. Patients in RTOG 97-06 had T2 to T4a N0 M0 disease without hydronephrosis.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2 (per Figure 1 of Zapatero, et al. 2010), '''given first'''<br />
<br />
'''7-day cycle for 3 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:<br />
**'''Both trials:''' Accelerated hyperfractionated RT (AHFRT) with twice per day radiation, consisting of 1.8 Gy fractions x 12 fractions to the bladder and regional lymph nodes; 6 hours later, a 1.6 Gy fraction x 12 fractions is given to the "bladder tumor plus wide margin." Radiation therapy given 5 days per week. Total induction dose to bladder tumor: 40.8 Gy; total induction dose to regional lymph nodes: 21.6 Gy.<br />
**'''Zapatero et al. 2000 only:''' Normo-fractionated concurrent radiation therapy, 1.8 to 2 Gy fractions, given 5 times per week. Total induction and consolidation bladder dose of 64 to 66 Gy; total induction and consolidation pelvic lymph node dose of 44 to 46 Gy. Zapatero, et al. 2010 & Zapatero, et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy, nor what adjustments, if any, were made to chemotherapy for this radiation schedule.<br />
<br />
====Subsequent treatment====<br />
<br />
*3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT<br />
**Patients with complete regression (R0): [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]<br />
**Nonresponders: [[Surgery#Cystectomy|Cystectomy]]<br />
<br />
===Regimen variant #2, cisplatin 70 mg/m<sup>2</sup> q3wk x 2 {{#subobject:2443a6|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.1996.14.1.119 Tester et al. 1996 (RTOG 88-02)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#MCV|MCV]] x 2<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 22 fractions (total dose: 39.6 Gy)<br />
<br />
'''4.5-week course'''<br />
====Subsequent treatment====<br />
''Patient is restaged 2 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, urinary cytology, and computed tomographic scan of pelvis."''<br />
<br />
*Patients with CR: [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]<br />
*Patients without CR proceeded immediately to: [[Surgery#Cystectomy|cystectomy]]<br />
<br />
===Regimen variant #3, cisplatin 100 mg/m<sup>2</sup> q3wk x 2 {{#subobject:9a3fd0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/article-abstract/367764 Shipley et al. 1988]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|[https://doi.org/10.1200/jco.1998.16.11.3576 Shipley et al. 1998 (RTOG 89-03)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*RTOG 89-03: [[#MCV|MCV]] versus [[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|no neoadjuvant therapy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 2 cycles''' <br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 22 fractions (total dose: 39.6 Gy)<br />
<br />
'''4.5-week course'''<br />
====Subsequent treatment====<br />
''RTOG 89-03: Patient is restaged 4 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, and urinary cytology." ''<br />
<br />
*RTOG 89-03; Patients not in CR usually proceeded to: [[Surgery#Cystectomy|cystectomy]]<br />
*RTOG 89-03; Patients in complete remission usually proceeded to: [[#Cisplatin_.26_RT_2|cisplatin & RT consolidation]]<br />
<br />
===References===<br />
<br />
#Shipley WU, Prout GR Jr, Einstein AB, Coombs LJ, Wajsman Z, Soloway MS, Englander L, Barton BA, Hafermann MD. Treatment of invasive bladder cancer by cisplatin and radiation in patients unsuited for surgery. JAMA. 1987 Aug 21;258(7):931-5. [https://jamanetwork.com/journals/jama/article-abstract/367764 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3613023 PubMed]<br />
#'''RTOG 88-02:''' Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. [https://doi.org/10.1200/jco.1996.14.1.119 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8558186 PubMed]<br />
#'''RTOG 89-03:''' Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. [https://doi.org/10.1200/jco.1998.16.11.3576 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9817278 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 97-06:''' Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. [http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14529770 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439(09)00029-5/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19362865 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
<br />
==Cisplatin & Fluorouracil (CF) & RT {{#subobject:b5e26|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 90/2400/24 {{#subobject:598234|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://theoncologist.alphamedpress.org/content/5/6/471.long Kaufman et al. 2000 (RTOG 95-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Patients in RTOG 95-06 had clinical T2 to T4a Nx M0 disease without hydronephrosis and CrCl of at least 60 mL/min/1.73m<sup>2</sup>.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3, '''given second, before radiation'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*IV hydration at 500 mL/H (no total volume specified) prior to [[Fluorouracil (5-FU)]]<br />
<br />
'''14-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 3 Gy fractions twice per day, with the first fraction of each day given 1 to 2 hours after completion of chemotherapy and at least 4 hours between fractions, x 8 fractions, given on days 1, 3, 15, 17 (total induction dose: 24 Gy), administered to the whole bladder, bladder tumor volume, and pelvic lymph nodes<br />
<br />
'''17-day course'''<br />
====Dose modifications====<br />
<br />
*Patients with grade III hematologic toxicity, defined as platelets less than 50 x 10<sup>9</sup>/L or ANC less than 1800/uL, had chemotherapy and radiation therapy held for at least one week, with therapy resuming when platelets were at least 100 x 10<sup>9</sup>/L and ANC at least 1800/uL.<br />
<br />
====Subsequent treatment====<br />
<br />
*Treatment followed by repeat cystoscopy, biopsy, and urine cytology in week 7 or 8<br />
**Patients with complete response: [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT consolidation]] in week 9<br />
**Incomplete responders were recommended to undergo [[Surgery#Radical_cystectomy|radical cystectomy]]<br />
<br />
===Regimen variant #2, 135/2400/40.3 {{#subobject:6be392|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ Coen et al. 2018 (RTOG 0712)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Gemcitabine_.26_RT|Gemcitabine & RT]]<br />
|-<br />
|}<br />
''Note: this trial was not statistically powered to compare regimens.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3, 8 to 10, 15 to 17<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, 15 to 17<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:<br />
**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17<br />
**1.5 Gy fractions to the bladder every evening on days 1 to 5<br />
**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17<br />
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.<br />
<br />
'''17-day course'''<br />
====Subsequent treatment====<br />
<br />
*Treatment followed by repeat cystoscopy & biopsy<br />
**Patients with complete response: [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT consolidation]]<br />
**Incomplete responders: [[Surgery#Radical_cystectomy|Radical cystectomy]]<br />
<br />
===Regimen variant #3, 135/3600/40.3 {{#subobject:6be39|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day cycle for 3 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:<br />
**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17<br />
**1.5 Gy fractions to the bladder every evening on days 1 to 5<br />
**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17<br />
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.<br />
<br />
'''3-week course'''<br />
====Subsequent treatment====<br />
<br />
*On week 7, patients under reevaluation for response. <br />
**Patients with less than stage T1 disease: [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT consolidation]]<br />
**Patients with at least stage T1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]] on week 9, then [[#PGC|adjuvant PGC]]<br />
<br />
===References===<br />
<br />
#'''RTOG 95-06:''' Kaufman DS, Winter KA, Shipley WU, Heney NM, Chetner MP, Souhami L, Zlotecki RA, Sause WT, True LD. The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response. Oncologist. 2000;5(6):471-6. [http://theoncologist.alphamedpress.org/content/5/6/471.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11110598 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 0712:''' Coen JJ, Zhang P, Saylor PJ, Lee CT, Wu CL, Parker W, Lautenschlaeger T, Zietman AL, Efstathiou JA, Jani AB, Kucuk O, Souhami L, Rodgers JP, Sandler HM, Shipley WU. Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712-a randomized phase II trial. J Clin Oncol. 2019 Jan 1;37(1):44-51. Epub 2018 Nov 15. [https://doi.org/10.1200/JCO.18.00537 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30433852 PubMed] NCT00777491<br />
<br />
==Cisplatin, Paclitaxel, RT {{#subobject:803f28|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 40/50 x 3 + 40.3 Gy {{#subobject:b7ec20|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract Kaufman et al. 2009 (RTOG 99-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Note: the abstract of Kaufman et al. 2009 said that patients with "greater than Stage T1 disease" were recommended for cystectomy, but Figure 1 clarified that it was greater than or equal to ypT1 disease.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#TURBT|TURBT]], within 4 to 6 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycle for 3 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT on days 1 to 5, 8 to 12, 15 to 17; 4 to 6 hours between radiation sessions. Kaufman et al. 2009 (RTOG 99-06) was unclear about exact radiation treatment plan, but it appears to have been the same as described in Mitin et al. 2013 (RTOG 02-33), which used radiation as follows:<br />
**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17<br />
**1.5 Gy fractions to the bladder every evening on days 1 to 5<br />
**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17<br />
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.<br />
<br />
'''3-week course'''<br />
====Subsequent treatment====<br />
<br />
*On week 7, over 3 weeks after induction therapy, patients under reevaluation with exam under anesthesia, cystoscopy with tumor site biopsy, and urine cytology<br />
**Patients with less than stage ypT1 disease: [[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, paclitaxel, RT consolidation]]<br />
**Patients with at least stage ypT1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]], then [[#Cisplatin_.26_Gemcitabine_.28GC.29_2|adjuvant cisplatin & gemcitabine]]<br />
<br />
===Regimen variant #2, 45/50 x 3 + 40.3 Gy {{#subobject:6ecd8b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|Cisplatin, Fluorouracil, RT]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycle for 3 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:<br />
**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17<br />
**1.5 Gy fractions to the bladder every evening on days 1 to 5<br />
**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17<br />
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.<br />
<br />
'''3-week course''' <br />
====Subsequent treatment====<br />
<br />
*On week 7, patients under reevaluation for response<br />
**Patients with less than stage ypT1 disease: [[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, paclitaxel, RT consolidation]]<br />
**Patients with at least stage ypT1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]] on week 9, then [[#PGC|adjuvant PGC]]<br />
<br />
===References===<br />
<br />
#Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. [http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19100600 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==Fluorouracil, Mitomycin, RT {{#subobject:5e89d1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Fluorouracil, Mitomycin, RT: Fluorouracil, Mitomycin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:6a18dc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 James et al. 2012 (BC2001)]<br />
|2001-2008<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Radiation_therapy_2|Radiation therapy]]<br />
| style="background-color:#91cf60" |Seems to have superior locoregional DFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup>/day IV continuous infusion for 10 total days (total dose: 5000 mg/m<sup>2</sup>) during radiation fractions 1 to 5, 16 to 20<br />
*[[Mitomycin (Mutamycin)]] 12 mg/m<sup>2</sup> IV bolus once on day 1<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] given according to one of the following plans:<br />
**Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.75 Gy fractions x 20 fractions (total dose: 55 Gy)<br />
**Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 32 fractions (total dose: 64 Gy)<br />
<br />
'''4- to 6.5-week course'''<br />
===References===<br />
<br />
#'''BC2001:''' James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-88. [https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1106106/suppl_file/nejmoa1106106_appendix.pdf link to supplementary index] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22512481 PubMed] ISRCTN68324339<br />
<br />
==Gemcitabine & RT {{#subobject:91c0ea|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:6333a7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ Coen et al. 2018 (RTOG 0712)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-de-esc)<br />
|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|CF & RT]]<br />
|-<br />
|}<br />
''Note: this trial was not statistically powered to compare regimens.''<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 27 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
<br />
'''14-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 2 Gy per day to the pelvis on days 1 to 10, then 2 Gy per day to the bladder on days 11 to 14, then 2 Gy per day to the bladder tumor on days 15 to 20<br />
**Total doses: pelvis: 20 Gy; whole bladder: 28 Gy; bladder tumor volume 40 Gy<br />
<br />
'''3-week course'''<br />
====Subsequent treatment====<br />
<br />
*Treatment followed by repeat cystoscopy & biopsy<br />
**Patients with complete response: Gemcitabine & RT consolidation<br />
**Incomplete responders: [[Surgery#Radical_cystectomy|Radical cystectomy]]<br />
<br />
===References===<br />
<br />
#'''RTOG 0712:''' Coen JJ, Zhang P, Saylor PJ, Lee CT, Wu CL, Parker W, Lautenschlaeger T, Zietman AL, Efstathiou JA, Jani AB, Kucuk O, Souhami L, Rodgers JP, Sandler HM, Shipley WU. Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712-a randomized phase II trial. J Clin Oncol. 2019 Jan 1;37(1):44-51. Epub 2018 Nov 15. [https://doi.org/10.1200/JCO.18.00537 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30433852 PubMed] NCT00777491<br />
<br />
==Paclitaxel & RT {{#subobject:89c0ea|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:6222a7|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract Zapatero et al. 2012]<br />
| style="background-color:#ffffbe" |Non-randomized, <20 pts<br />
|-<br />
|}<br />
''Patients who had "mild renal insufficiency" received paclitaxel instead of cisplatin and had T2 to T4 N0 M0 disease.''<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per week, '''given 6 hours before radiation therapy'''<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:<br />
**Accelerated hyperfractionated RT (AHFRT) with twice per day radiation, consisting of 1.8 Gy fractions x 12 fractions to the bladder and regional lymph nodes; 6 hours later, a 1.6 Gy fraction x 12 fractions is given to the "bladder tumor plus wide margin." Total induction dose to bladder tumor: 40.8 Gy; total induction dose to regional lymph nodes: 21.6 Gy. Zapatero et al. 2012 did not specify the precise schedule of radiation therapy.<br />
**Normo-fractionated concurrent radiation therapy, total induction and consolidation dose of 64 to 66 Gy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*3 weeks after finishing radiation and chemotherapy, patients underwent restaging [[Surgery#TURBT|TURBT]]<br />
**Patients with complete regression (R0): [[#Paclitaxel_.26_RT_2|Paclitaxel & RT consolidation]]<br />
**Nonresponders: [[Surgery#Cystectomy|Cystectomy]]<br />
<br />
===Regimen variant #2 {{#subobject:6222a7|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5536836/ Michaelson et al. 2016 (RTOG 0524)]<br />
| style="background-color:#91cf61" |Phase 1/2, 47 pts<br />
|-<br />
|}<br />
<br />
==== Chemotherapy ====<br />
<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per week for 7 weeks <br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent daily [[External_beam_radiotherapy|radiation therapy]] 64.8 Gy total in 36 fractions<br />
<br />
'''One course'''<br />
===References===<br />
#Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
#'''RTOG 0524:''' Michaelson MD, Hu C, Pham HT, Dahl DM, Lee-Wu C, Swanson GP, Vuky J, Lee RJ, Souhami L, Chang B, George A, Sandler H, Shipley W. A Phase 1/2 Trial of a Combination of Paclitaxel and Trastuzumab With Daily Irradiation or Paclitaxel Alone With Daily Irradiation After Transurethral Surgery for Noncystectomy Candidates With Muscle-Invasive Bladder Cancer (Trial NRG Oncology RTOG 0524). Int J Radiat Oncol Biol Phys. 2017 Apr 1;97(5):995-1001. Epub 2016 Dec 19. [https://doi.org/10.1016/j.ijrobp.2016.12.018 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5536836/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28333021/ PubMed]<br />
<br />
==Radiation therapy {{#subobject:1103c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:e0ed54|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 Zapatero et al. 2000]<br />
|1989-1997<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 James et al. 2012 (BC2001)]<br />
|2001-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil.2C_Mitomycin.2C_RT|Fluorouracil, Mitomycin, RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior locoregional DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response, treatment in Zapatero et al. 2000 preceded by [[#MCV|MCV]] x 3 or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] as follows:<br />
**CR: 2 Gy fractions given 5 days per week, with total bladder dose of 60 Gy. Total dose to regional lymph nodes: 50 Gy.<br />
**Less than CR: total dose to the bladder of 64 to 66 Gy. No further details given about fractionation, schedule, or dose to lymph nodes.<br />
<br />
===References===<br />
<br />
#Zapatero A, Martín de Vidales C, Marín A, Cerezo L, Arellano R, Rabadán M, Pérez-Torrubia A. Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Int J Cancer. 2000 Oct 20;90(5):287-94. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11091353 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439%2809%2900029-5/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19362865 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
#'''BC2001:''' James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-88. [https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22512481 PubMed] ISRCTN68324339<br />
<br />
=Consolidation chemoradiotherapy=<br />
==Cisplatin & RT {{#subobject:308d11|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Cisplatin & RT: Cisplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen variant #1, cisplatin 40 mg/m<sup>2</sup>/wk x 2 {{#subobject:dc2b84|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 Zapatero et al. 2000]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|[http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract Hagan et al. 2003 (RTOG 97-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response: [[#Cisplatin_.26_RT|Cisplatin & RT induction]] or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2 (per Figure 1 of Zapatero et al. 2010), '''given first'''<br />
<br />
'''7-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:<br />
**'''Both trials:''' Accelerated hyperfractionated RT (AHFRT), 1.5 Gy fractions twice per day x 16 fractions (total consolidation dose: 24 Gy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 64.8 Gy; total dose to lymph nodes is 45.6 Gy.<br />
**'''Zapatero et al. 2000 only:''' Normo-fractionated concurrent radiation therapy, 1.8 to 2 Gy fractions, given 5 times per week. Total induction and consolidation bladder dose of 64 to 66 Gy; total induction and consolidation pelvic lymph node dose of 44 to 46 Gy. Zapatero, et al. 2010 & Zapatero, et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy, nor what adjustments, if any, were made to chemotherapy for this radiation schedule.<br />
<br />
====Subsequent treatment====<br />
<br />
*RTOG 97-06: [[#MCV_2|Adjuvant MCV]]<br />
<br />
===Regimen variant #2, cisplatin 70 mg/m<sup>2</sup> x 1 {{#subobject:314189|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.1996.14.1.119 Tester et al. 1996 (RTOG 88-02)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response, treatment preceded by [[#Cisplatin_.26_RT|cisplatin & RT induction]] or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy==== <br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 14 fractions (total dose in consolidation phase: 25.2 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)<br />
<br />
'''3-week course'''<br />
<br />
===Regimen variant #3, cisplatin 100 mg/m<sup>2</sup> x 1 {{#subobject:7afeca|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.1998.16.11.3576 Shipley et al. 1998 (RTOG 89-03)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response, treatment preceded by [[#Cisplatin_.26_RT|cisplatin & RT induction]] or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy==== <br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 14 fractions (total dose in consolidation phase: 39.6 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)<br />
<br />
'''3-week course'''<br />
<br />
===References===<br />
<br />
#'''RTOG 88-02:''' Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. [https://doi.org/10.1200/jco.1996.14.1.119 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8558186 PubMed]<br />
#'''RTOG 89-03:''' Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. [https://doi.org/10.1200/jco.1998.16.11.3576 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9817278 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#Zapatero A, Martín de Vidales C, Marín A, Cerezo L, Arellano R, Rabadán M, Pérez-Torrubia A. Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Int J Cancer. 2000 Oct 20;90(5):287-94. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11091353 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439%2809%2900029-5/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19362865 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
#'''RTOG 97-06:''' Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. [http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14529770 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==Cisplatin & Fluorouracil (CF) & RT {{#subobject:fe2538|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 30/1200 x 2 + 64.3 Gy {{#subobject:a18497|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, Paclitaxel, RT]]<br />
|-<br />
|}<br />
''Consolidation starts starts on week 8.''<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|Cisplatin, 5-FU, RT induction]]<br />
<br />
====Chemotherapy==== <br />
''Starts on week 8.''<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions x 16 fractions, given twice per day x 8 days. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.<br />
<br />
'''2-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[#PGC|Adjuvant PGC]]<br />
<br />
===Regimen variant #2, 45/1200 x 2 + 44 Gy {{#subobject:904a96|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://theoncologist.alphamedpress.org/content/5/6/471.long Kaufman et al. 2000 (RTOG 95-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Treatment starts on week 9.''<br />
====Preceding treatment====<br />
<br />
*Depending on response, treatment preceded by [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|cisplatin, fluorouracil, RT induction]] or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy==== <br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, '''given first'''<br />
<br />
'''14-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.5 Gy fractions twice per day, with at least 4 hours between fractions, x 8 fractions, given on days 1, 3, 15, 17 (total consolidation dose: 20 Gy), administered to the whole bladder and bladder tumor volume. The total dose to the whole bladder and bladder tumor volume was 44 Gy in 16 fractions; the total dose to the pelvic lymph nodes was 24 Gy in 8 fractions.<br />
<br />
====Dose modifications====<br />
<br />
*Patients with grade III hematologic toxicity, defined as platelets less than 50 x 10<sup>9</sup>/L or ANC less than 1800/uL, had chemotherapy and radiation therapy held for at least one week, with therapy resuming when platelets were at least 100 x 10<sup>9</sup>/L and ANC at least 1800/uL.<br />
<br />
====Supportive medications====<br />
<br />
*IV hydration at 500 mL/H (no total volume specified) prior to [[Fluorouracil (5-FU)]]<br />
<br />
'''17-day course'''<br />
<br />
===References===<br />
<br />
#'''RTOG 95-06:''' Kaufman DS, Winter KA, Shipley WU, Heney NM, Chetner MP, Souhami L, Zlotecki RA, Sause WT, True LD. The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response. Oncologist. 2000;5(6):471-6. [http://theoncologist.alphamedpress.org/content/5/6/471.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11110598 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==Cisplatin, Paclitaxel, RT {{#subobject:4bc0dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 30/50 x 2 + 64.3 Gy {{#subobject:9fefbd|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|Cisplatin, 5-FU, RT]]<br />
|-<br />
|}<br />
''Consolidation starts starts on week 8.''<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT induction]]<br />
<br />
====Chemotherapy==== <br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions x 16 fractions, given twice per day x 8 days. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.<br />
<br />
'''2-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[#PGC|Adjuvant PGC]]<br />
<br />
===Regimen variant #2, 40/50 x 2 + 64.3 Gy {{#subobject:6bec62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract Kaufman et al. 2009 (RTOG 99-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Consolidation starts starts on week 8.''<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT induction]]<br />
<br />
====Chemotherapy==== <br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions x 16 fractions, given twice per day (4 to 6 hour interval between treatments) on days 1 to 5, 8 to 10. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.<br />
<br />
'''2-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[#Cisplatin_.26_Gemcitabine_.28GC.29_2|Adjuvant cisplatin & gemcitabine]]<br />
<br />
===References===<br />
<br />
#'''RTOG 99-06:''' Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. [http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19100600 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==Paclitaxel & RT {{#subobject:039b5c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:de252a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract Zapatero et al. 2012]<br />
| style="background-color:#ffffbe" |Non-randomized, <20 pts<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response, treatment preceded by [[#Paclitaxel_.26_RT|paclitaxel & RT induction]] or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per week, given 6 hours before radiation therapy<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:<br />
**Accelerated hyperfractionated RT (AHFRT), 1.5 Gy fractions twice per day x 16 fractions (total consolidation dose: 24 Gy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 64.8 Gy; total dose to lymph nodes is 45.6 Gy.<br />
**Normo-fractionated concurrent radiation therapy, total induction and consolidation dose of 64 to 66 Gy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.<br />
<br />
'''One course'''<br />
===References===<br />
<br />
#Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
<br />
=Adjuvant chemotherapy=<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:684e48|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:72a413|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract Kaufman et al. 2009 (RTOG 99-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response to induction, treatment starts 12 weeks after [[#Cisplatin.2C_Paclitaxel.2C_RT_2|cisplatin, paclitaxel, RT consolidation]], or 8 weeks after [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. [http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19100600 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==Cisplatin & Methotrexate {{#subobject:684e48|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:72a413|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.11.094 Lehmann et al. 2005 (AUO-AB 05/95)]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|M-VEC x 3<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS<br />
| style="background-color:#1a9850" |Less toxic<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Cystectomy|Radical cystectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]]<br />
*[[Methotrexate (MTX)]]<br />
<br />
===References===<br />
<br />
#'''AUO-AB 05/95:''' Lehmann J, Retz M, Wiemers C, Beck J, Thüroff J, Weining C, Albers P, Frohneberg D, Becker T, Funke PJ, Walz P, Langbein S, Reiher F, Schiller M, Miller K, Roth S, Kälble T, Sternberg D, Wellek S, Stöckle M; AUO. Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter, phase III trial (AUO-AB 05/95). J Clin Oncol. 2005 Aug 1;23(22):4963-74. Epub 2005 Jun 6. [https://doi.org/10.1200/JCO.2005.11.094 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15939920 PubMed]<br />
<br />
==MCV {{#subobject:8e6bb8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MCV: '''<u>M</u>'''ethotrexate, '''<u>C</u>'''isplatin, '''<u>V</u>'''inblastine<br />
<br />
===Regimen {{#subobject:ca6708|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract Hagan et al. 2003 (RTOG 97-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Begins 8 weeks after consolidation. Note that only 45% of patients in RTOG 97-06 were able to complete all 3 cycles of MCV.''<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 2 to 4<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. [http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14529770 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==PGC {{#subobject:22e1d2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PGC: '''<u>P</u>'''aclitaxel, '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin<br />
<br>PCG: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''isplatin, '''<u>G</u>'''emcitabine<br />
===Regimen variant #1 {{#subobject:ad1bc8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2010.28.18_suppl.lba4518 Paz-Ares et al 2010 (SOGUG 99/01)]<br />
|2000-2007<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#Observation_2|Observation]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Patients in SOGUG 99/01 had pT3-4 and/or pN positive disease with adequate renal function (CrCl greater than 50 mL/min/1.73m<sup>2</sup>). The study prematurely closed due to poor recruitment and lacks adequate power to make firm conclusions, and has never been published in manuscript format.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Cystectomy|Cystectomy]]; the median time treatment started post-cystectomy was 48 days<br />
<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 80 mg mg/2 IV once per day on days 1 & 8<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:29bee9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response, adjuvant chemotherapy began 12 weeks after [[#Cisplatin.2C_Paclitaxel.2C_RT_2|cisplatin, paclitaxel, RT]] versus [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|cisplatin, 5-FU, RT]] or 8 weeks after [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#'''Abstract:''' L. G. Paz-Ares, E. Solsona, E. Esteban, A. Saez, J. Gonzalez-Larriba, A. Anton, M. Hevia, F. de la Rosa, V. Guillem, and J. Bellmunt. Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study. ASCO MEETING ABSTRACTS Jun 22, 2010:LBA4518. [https://doi.org/10.1200/jco.2010.28.18_suppl.lba4518 link to abstract] '''contains verified protocol'''<br />
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
=Locally advanced or metastatic disease, first-line, platinum-ineligible=<br />
==Atezolizumab monotherapy {{#subobject:1d9e29|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:764948|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |Years of enrollment<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568632/ Balar et al. 2016 (IMvigor210)]<br />
|2014-2015<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#88419d; color:white " |ORR: 23% (95% CI 16-31)<br />
|-<br />
|}<br />
<big>'''On 8/16/2018 the FDA updated the prescribing information for atezolizumab to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are cisplatin-ineligible.'''</big><br />
<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''IMvigor210:''' Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, Dawson NA, van der Heijden MS, Dreicer R, Srinivas S, Retz MM, Joseph RW, Drakaki A, Vaishampayan UN, Sridhar SS, Quinn DI, Durán I, Shaffer DR, Eigl BJ, Grivas PD, Yu EY, Li S, Kadel EE 3rd, Boyd Z, Bourgon R, Hegde PS, Mariathasan S, Thåström A, Abidoye OO, Fine GD, Bajorin DF; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017 Jan 7;389(10064):67-76. Epub 2016 Dec 8. [http://thelancet.com/journals/lancet/article/PIIS0140-6736(16)32455-2/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568632/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27939400 PubMed] NCT02951767<br />
<br />
<br /><br />
<br />
==Pembrolizumab monotherapy {{#subobject:7fc2f6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:946aec|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |Years of enrollment<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30616-2/fulltext Balar et al. 2017 (KEYNOTE-052)]<br />
|2015-2016<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#88419d; color:white " |ORR: 24% (95% CI 20-29)<br />
|-<br />
|} <br />
<big>'''On 5/18/2018 the FDA released a warning that patients in the monotherapy arms of the ongoing KEYNOTE-361 trial with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy.'''</big><br />
<br />
<big>'''On 8/16/2018 the FDA updated the prescribing information for pembrolizumab to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are cisplatin-ineligible.'''</big><br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''KEYNOTE-052:''' Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, Savage MJ, Perini RF, Keefe SM, Bajorin D, Bellmunt J. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Nov;18(11):1483-1492. Epub 2017 Sep 26. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30616-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28967485 PubMed] NCT02335424<br />
<br />
=Locally advanced or metastatic disease, first-line, platinum-eligible=<br />
<br />
==Atezolizumab monotherapy {{#subobject:1d9e29|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:764948|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]<br />
| rowspan="2" |2016-2018<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|1. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]<br> 2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|3. [[#GCb_.26_Atezolizumab|GCb & Atezolizumab]]<br> 4. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Atezolizumab|GC & Atezolizumab]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''IMvigor130:''' Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636<br />
<br />
==Carboplatin & Gemcitabine (GCb) {{#subobject:8855e5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GCb: '''<u>G</u>'''emcitabine & '''<u>C</u>'''ar'''<u>b</u>'''oplatin<br />
===Regimen variant #1, AUC 4.5/1000 {{#subobject:5f00b7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792956 De Santis et al. 2009 (EORTC 30986)]<br />
|2001-2005<br />
| style="background-color:#1a9851" |Randomized Phase II/III (E-de-esc)<br />
|M-CAVI<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#1a9851" |Lower toxicity than M-CAVI<br />
|Intention to treat: <br>38% (2009)<br>41.2% (2012)<br />
|Intention to treat: <br>20% (2009)<br>30.3% (2012)<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]<br />
| rowspan="2" |2015-2017<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Durvalumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]])<br />
| style="background-color:#d73027" |(Grouped with [[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]]) More toxic<br />
|Intention to treat (Cisplatin-ineligible): 46%<br />
|Intention to treat (Cisplatin-ineligible): 24%<br />
|-<br />
|2. Durvalumab & Tremelimumab, then Durvalumab maintenance<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
| style="background-color:#ffffbf" |(Grouped with [[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]]) Not more toxic<br />
|Intention to treat (Cisplatin-ineligible): 46%<br />
|Intention to treat (Cisplatin-ineligible): 36%<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]<br />
| rowspan="2" |2016-2018<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|<br />
|<br />
|-<br />
|2. [[#GCb_.26_Atezolizumab|GCb & Atezolizumab]]<br> 3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Atezolizumab|GC & Atezolizumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|<br />
|<br />
|<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 4.5 IV over 60 minutes once on day 1, '''given second'''<br />
**''In DANUBE trial, AUC was 4.5-5 IV.''<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given first'''<br />
<br />
'''21-day cycles''' <br />
<br />
''Patients who achieved complete response were given two additional cycles of treatment.''<br />
<br>''Patients on the DANUBE trial received up to 6 cycles.''<br />
<br />
===Regimen variant #2, AUC 5/1250 {{#subobject:4f0596|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext Dogliotti et al. 2006]<br />
|2000-2002<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|Intention to treat: 40% (95% CI NR)<br>Evaluable patients only: 56%<br>(95% CI: 40–72)<br />
|Intention to treat: 49% (95% CI NR)<br>Evaluable patients only: 66%<br>(95% CI: 49–80)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 30 to 60 minutes once on day 2<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. [https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17207911 PubMed]<br />
#'''EORTC 30986:''' De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Skoneczna I, Marreaud S, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol. 2009 Nov 20;27(33):5634-9. [https://doi.org/10.1200/JCO.2008.21.4924 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792956/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19786668 PubMed] NCT00111787<br />
##'''Update:''' De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Gil T, Marreaud S, Daugaard G, Skoneczna I, Collette S, Lorent J, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012 Jan 10;30(2):191-9. [https://doi.org/10.1200/JCO.2011.37.3571 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255563/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22162575 PubMed]<br />
#'''IMvigor130:''' Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636<br />
#'''DANUBE:''' Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Sep 21:S1470-2045(20)30541-6. Epub ahead of print. [https://doi.org/10.1016/s1470-2045(20)30541-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32971005 PubMed] NCT02516241<br />
<br />
==Carboplatin & Paclitaxel (CP) {{#subobject:b33fe7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5d481c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.10782/full Vaughn et al. 2002 (ECOG E2896)]<br />
|1996-1999<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#3d3d3d; color:white" |ORR: 24% (95% CI 12-42)<br />
|-<br />
|[https://doi.org/10.1002/cncr.20123 Dreicer et al. 2004]<br />
|1998-2001<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: Dreicer et al. 2004 was closed early due to poor accrual.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''ECOG E2896:''' Vaughn DJ, Manola J, Dreicer R, See W, Levitt R, Wilding G. Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a trial of the Eastern Cooperative Oncology Group. Cancer. 2002 Sep 1;95(5):1022-7. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.10782/full link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12209686 PubMed]<br />
#Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. [https://doi.org/10.1002/cncr.20123 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15073851/ PubMed]<br />
<br />
==CISCA {{#subobject:b60f2a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CISCA: '''<u>CIS</u>'''platin, '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''driamycin (Doxorubicin)<br />
===Regimen {{#subobject:2d0b5e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/article-abstract/356753 Sternberg et al. 1977]<br />
|1976-1977<br />
| style="background-color:#ffffbe" |Non-randomized, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|<br />
|<br />
|-<br />
|[https://doi.org/10.1200/jco.1990.8.6.1050 Logothetis et al. 1990]<br />
|1985-1989<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|46% (95% CI 32-62)<br />
|65% (95% CI 52-77)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 2<br />
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 2<br />
<br />
====Supportive medications====<br />
<br />
*Forced mannitol diuresis with [[Cisplatin (Platinol)]]<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Sternberg JJ, Bracken RB, Handel PB, Johnson DE. Combination chemotherapy (CISCA) for advanced urinary tract carcinoma: a preliminary report. JAMA. 1977 Nov 21;238(21):2282-7. [https://jamanetwork.com/journals/jama/article-abstract/356753 link to original article] [https://pubmed.ncbi.nlm.nih.gov/578848 PubMed]<br />
#Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. [https://doi.org/10.1200/jco.1990.8.6.1050 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2189954 PubMed]<br />
<br />
==Cisplatin monotherapy {{#subobject:1af7a9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:71bd05|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19830901)52:5%3C767::AID-CNCR2820520502%3E3.0.CO;2-P Soloway et al. 1983]<br />
|1978-NR<br />
| style="background-color:#1a9851" |Randomized (C)<br />
|Cisplatin & Cyclophosphamide<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[https://doi.org/10.1200/JCO.1985.3.4.539 Khandekar et al. 1985]<br />
|1978-1981<br />
| style="background-color:#1a9851" |Randomized (C)<br />
|[[Stub#CAD|CAD]]<br />
| style="background-color:#fee08b" |Might have inferior ORR<br />
|-<br />
|[https://doi.org/10.1016/s0022-5347(17)44167-x Troner et al. 1987]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#CAD|CAD]]<br />
| style="background-color:#ffffbf" |Did not meet endpoint of ORR<br />
|-<br />
|[https://doi.org/10.1200/JCO.1989.7.6.706 Hillcoat et al. 1989]<br />
|1982-1986<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Cisplatin_.26_Methotrexate|Cisplatin & Methotrexate]]<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
|-<br />
|[https://doi.org/10.1200/JCO.1992.10.7.1066 Loehrer et al. 1992]<br />
|1984-1989<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''For historic reference. To our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]]<br />
<br />
===References===<br />
<br />
#Soloway MS, Einstein A, Corder MP, Bonney W, Prout GR Jr, Coombs J; National Bladder Cancer Collaborative Group A. A comparison of cisplatin and the combination of cisplatin and cyclophosphamide in advanced urothelial cancer: a National Bladder Cancer Collaborative Group A study. Cancer. 1983 Sep 1;52(5):767-72. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19830901)52:5%3C767::AID-CNCR2820520502%3E3.0.CO;2-P link to original article] [https://pubmed.ncbi.nlm.nih.gov/6347356 PubMed]<br />
#Khandekar JD, Elson PJ, DeWys WD, Slayton RE, Harris DT. Comparative activity and toxicity of cis-diamminedichloroplatinum (DDP) and a combination of doxorubicin, cyclophosphamide, and DDP in disseminated transitional cell carcinomas of the urinary tract. J Clin Oncol. 1985 Apr;3(4):539-45. [https://doi.org/10.1200/JCO.1985.3.4.539 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3884746 PubMed]<br />
#Troner M, Birch R, Omura GA, Williams S; Southeastern Cancer Study Group. Phase III comparison of cisplatin alone versus cisplatin, doxorubicin and cyclophosphamide in the treatment of bladder (urothelial) cancer: a Southeastern Cancer Study Group trial. J Urol. 1987 Apr;137(4):660-2. [https://doi.org/10.1016/s0022-5347(17)44167-x link to original article] [https://pubmed.ncbi.nlm.nih.gov/3550148 PubMed]<br />
#Hillcoat BL, Raghavan D, Matthews J, Kefford R, Yuen K, Woods R, Olver I, Bishop J, Pearson B, Coorey G, Levi J, Abbott RL, Aroney R, Gill PG, McLennan R. A randomized trial of cisplatin versus cisplatin plus methotrexate in advanced cancer of the urothelial tract. J Clin Oncol. 1989 Jun;7(6):706-9. [https://doi.org/10.1200/JCO.1989.7.6.706 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2654329 PubMed]<br />
#Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, Blumenstein B, Trump D. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. [https://doi.org/10.1200/JCO.1992.10.7.1066 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/1607913 PubMed]<br />
##'''Update:''' Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, Loehrer PJ Sr, Trump D. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997 Jul;15(7):2564-9. [https://doi.org/10.1200/JCO.1997.15.7.2564 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9215826 PubMed]<br />
<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:5cbd83|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GC: '''<u>G</u>'''emcitabine & '''<u>C</u>'''isplatin<br />
<br>GP: '''<u>G</u>'''emcitabine & '''<u>P</u>'''latinol (Cisplatin)<br />
===Regimen variant #1, 70/1000, q3wk {{#subobject:69fea8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdf186 Soto Parra et al. 2002]<br />
|1998-2000<br />
| style="background-color:#ffffbe" |Randomized Phase II, <20 pts in this subgroup (E-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]; q4wk<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]<br />
| rowspan="2" |2015-2017<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Durvalumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
|-<br />
|2. Durvalumab & Tremelimumab, then Durvalumab maintenance<br />
| style="background-color:#fee08b" |Might have inferior OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]<br />
| rowspan="2" |2016-2018<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#GCb_.26_Atezolizumab|GCb & Atezolizumab]]<br> 3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Atezolizumab|GC & Atezolizumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 1 or 2<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*2 liters of fluid and "appropriate antiemetic therapy" given with [[Cisplatin (Platinol)]]<br />
*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"<br />
<br />
'''21-day cycles (up to 6 cycles in DANUBE)'''<br />
<br />
===Regimen variant #2, 70/1000, q4wk {{#subobject:53ad73|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2000.18.17.3068 von der Maase et al. 2000]<br />
|1996-1998<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdf186 Soto Parra et al. 2002]<br />
|1998-2000<br />
| style="background-color:#ffffbe" |Randomized Phase II, <20 pts in this subgroup (E-de-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]; q3wk<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ Bellmunt et al. 2012 (EORTC 30987)]<br />
|2001-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#PGC_2|PCG]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.karger.com/Article/Abstract/354085 Sternberg et al. 2013 (CILAB)]<br />
|2008-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Larotaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]<br />
| rowspan="2" |2015-2017<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Durvalumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
|-<br />
|2. Durvalumab & Tremelimumab, then Durvalumab maintenance<br />
| style="background-color:#fee08b" |Might have inferior OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
|-<br />
|}<br />
''Only a minority of patients in Soto Parra et al. 2002 had bladder cancer. The majority of patients had [[non-small cell lung cancer]].''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 2<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
<br />
*Per Soto Parra et al. 2002:<br />
*2 liters of fluid and "appropriate antiemetic therapy" given with [[Cisplatin (Platinol)]]<br />
*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #3, 70/1250, q3wk {{#subobject:44c03b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext Dogliotti et al. 2006]<br />
|2000-2002<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Carboplatin_.26_Gemcitabine_.28GCb.29|Carboplatin & Gemcitabine]]<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of reduced toxicity<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]<br />
| rowspan="2" |2015-2017<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Durvalumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
| style="background-color:#d73027" |(Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]]) More toxic<br />
|-<br />
|2. Durvalumab & Tremelimumab, then Durvalumab maintenance<br />
| style="background-color:#fee08b" |Might have inferior OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
| style="background-color:#ffffbf" |(Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]]) Not more toxic<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
**''In DANUBE, Cisplatin given on day 1.''<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. [https://doi.org/10.1200/jco.2000.18.17.3068 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11001674 PubMed]<br />
##'''Update:''' von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. [https://doi.org/10.1200/JCO.2005.07.757 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16034041 PubMed]<br />
#Soto Parra H, Cavina R, Latteri F, Sala A, Dambrosio M, Antonelli G, Morenghi E, Alloisio M, Ravasi G, Santoro A. Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study. Ann Oncol. 2002 Jul;13(7):1080-6. [https://doi.org/10.1093/annonc/mdf186 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12176787 PubMed]<br />
#Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. [https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17207911 PubMed]<br />
#'''EORTC 30987:''' Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. [https://doi.org/10.1200/JCO.2011.38.6979 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22370319 PubMed] NCT00022191<br />
#'''CILAB:''' Sternberg CN, Skoneczna IA, Castellano D, Theodore C, Blais N, Voog E, Bellmunt J, Peters F, Le-Guennec S, Cerbone L, Risse ML, Machiels JP. Larotaxel with cisplatin in the first-line treatment of locally advanced/metastatic urothelial tract or bladder cancer: a randomized, active-controlled, phase III trial (CILAB). Oncology. 2013;85(4):208-15. Epub 2013 Sep 24. [https://www.karger.com/Article/Abstract/354085 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24080920 PubMed] NCT00625664<br />
#'''IMvigor130:''' Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636<br />
#'''DANUBE:''' Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Sep 21:S1470-2045(20)30541-6. Epub ahead of print. [https://doi.org/10.1016/s1470-2045(20)30541-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32971005 PubMed] NCT02516241<br />
<br />
==Cisplatin & Gemcitabine (GC) & Atezolizumab {{#subobject:8gajcz|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GC & Atezolizumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin, Atezolizumab<br />
===Regimen {{#subobject:80ihjx8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]<br />
| rowspan="2" |2016-2018<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]<br> 3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''IMvigor130:''' Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636<br />
<br />
==GCb & Atezolizumab {{#subobject:8tqccz|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GCb & Atezolizumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''ar'''<u>b</u>'''oplatin, Atezolizumab<br />
===Regimen {{#subobject:8q1jx8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]<br />
| rowspan="2" |2016-2018<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]<br> 3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 4.5 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''IMvigor130:''' Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636<br />
<br />
==Gemcitabine & Paclitaxel {{#subobject:385447|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1 {{#subobject:af7c37|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.24313/full Calabrò et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#5e5e5e; color:white" |ORR: 37%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 2500 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 150 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycle for 6 to 12 cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:b840fe|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2001.19.12.3018 Meluch et al. 2001]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#8a8a8a" |ORR: 54% (95% CI 40-67)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. [https://doi.org/10.1200/jco.2001.19.12.3018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11408496 PubMed]<br />
#Calabrò F, Lorusso V, Rosati G, Manzione L, Frassineti L, Sava T, Di Paula ED, Alonso S, Sternberg CN. Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer. 2009 Jun 15;115(12):2652-9. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.24313/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19396817 PubMed]<br />
<br />
==MVAC {{#subobject:d2ea09|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin<br />
===Regimen variant #1, standard {{#subobject:33db41|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1992.10.7.1066 Loehrer et al. 1992]<br />
|1984-1989<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_monotherapy|Cisplatin]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://doi.org/10.1200/jco.1990.8.6.1050 Logothetis et al. 1990]<br />
|1985-1989<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#CISCA|CISCA]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2002.20.5.1361 Siefker-Radtke et al. 2002]<br />
|1992-1999<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#FAP|FAP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%<br />
|-<br />
|[https://doi.org/10.1200/jco.2001.19.10.2638 Sternberg et al. 2001 (EORTC 30924)]<br />
|1993-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MVAC.2C_dose-dense_2|Dose-dense MVAC]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup><br />
|-<br />
|[https://doi.org/10.1200/jco.2000.18.17.3068 von der Maase et al. 2000]<br />
|1996-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1002/cncr.20123 Dreicer et al. 2004]<br />
|1998-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29|CP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for EORTC 30924 is based on the 2005 update.''<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once over 120 minutes on day 1 or 2<br />
<br />
'''28-day cycles''' (number of cycles and criteria to continue therapy varies depending on reference)<br />
<br />
===Regimen variant #2, with G-CSF support {{#subobject:72266e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2004.02.152 Bamias et al. 2003]<br />
|1997-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Docetaxel<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[Filgrastim (Neupogen)]] (dose not specified) SC once per day on days 7, 8, 9, 25, 26<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. [https://doi.org/10.1200/jco.1990.8.6.1050 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2189954 PubMed]<br />
#Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, Blumenstein B, Trump D. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. [https://doi.org/10.1200/JCO.1992.10.7.1066 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/1607913 PubMed]<br />
##'''Update:''' Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, Loehrer PJ Sr, Trump D. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997 Jul;15(7):2564-9. [https://doi.org/10.1200/JCO.1997.15.7.2564 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9215826 PubMed]<br />
#von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. [https://doi.org/10.1200/jco.2000.18.17.3068 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11001674 PubMed]<br />
##'''Update:''' von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. [https://doi.org/10.1200/JCO.2005.07.757 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16034041 PubMed]<br />
#'''EORTC 30924:''' Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [https://doi.org/10.1200/jco.2001.19.10.2638 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11352955 PubMed]<br />
##'''Update:''' Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. [https://www.ejcancer.com/article/S0959-8049(05)00874-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16330205 PubMed]<br />
#Siefker-Radtke AO, Millikan RE, Tu SM, Moore DF Jr, Smith TL, Williams D, Logothetis CJ. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol. 2002 Mar 1;20(5):1361-7. [https://doi.org/10.1200/JCO.2002.20.5.1361 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11870180 PubMed]<br />
#Bamias A, Aravantinos G, Deliveliotis C, Bafaloukos D, Kalofonos C, Xiros N, Zervas A, Mitropoulos D, Samantas E, Pectasides D, Papakostas P, Gika D, Kourousis C, Koutras A, Papadimitriou C, Bamias C, Kosmidis P, Dimopoulos MA; Hellenic Cooperative Oncology Group. Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. J Clin Oncol. 2004 Jan 15;22(2):220-8. Epub 2003 Dec 9. Erratum in: J Clin Oncol. 2004 May 1;22(9):1771. [https://doi.org/10.1200/JCO.2004.02.152 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14665607 PubMed]<br />
#Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. [https://doi.org/10.1002/cncr.20123 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15073851/ PubMed]<br />
<br />
==MVAC, dose-dense {{#subobject:c9beb1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ddMVAC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin<br />
===Regimen {{#subobject:daeb1c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://doi.org/10.1200/jco.2001.19.10.2638 Sternberg et al. 2001 (EORTC 30924)]<br />
|1993-1998<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br />
|62% (95% CI 54-70)<br />
|50% (95% CI 42-59)<br />
|-<br />
|[https://doi.org/10.1093/annonc/mds583 Bamias et al. 2012 (HE 16/03)]<br />
|2003-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|DD-GC<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for EORTC 30924 is based on the 2005 update.''<br><br />
''Note: In contrast to Sternberg et al. 2001, Sternberg et al. 2006 specified 15-day cycles.''<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once on day 2<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Granulocyte colony-stimulating factors|G-CSF]] (type not specified) 240 mcg/m<sup>2</sup> SC once per day on days 4 to 10 (additional use up to a total of 14 consecutive days if needed), injected at alternating sites, discontinued if ANC greater than 30,000/uL. <br />
**''In contrast to Sternberg et al. 2001, Sternberg et al. 2006 said G-CSF was given on days 3 to 7.''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''EORTC 30924:''' Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [https://doi.org/10.1200/jco.2001.19.10.2638 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11352955 PubMed]<br />
##'''Update:''' Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. [https://www.ejcancer.com/article/S0959-8049(05)00874-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16330205 PubMed]<br />
#'''HE 16/03:''' Bamias A, Dafni U, Karadimou A, Timotheadou E, Aravantinos G, Psyrri A, Xanthakis I, Tsiatas M, Koutoulidis V, Constantinidis C, Hatzimouratidis C, Samantas E, Visvikis A, Chrisophos M, Stravodimos K, Deliveliotis C, Eleftheraki A, Pectasides D, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol. 2013 Apr;24(4):1011-7. Epub 2012 Nov 7. [https://doi.org/10.1093/annonc/mds583 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23136231 PubMed] ACTRN12610000845033<br />
<br />
==PGC {{#subobject:393eb6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PGC: '''<u>P</u>'''aclitaxel, '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin<br />
<br>PCG: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''isplatin, '''<u>G</u>'''emcitabine<br />
===Regimen {{#subobject:837446|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ Bellmunt et al. 2012 (EORTC 30987)]<br />
|2001-2004<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|56% (95% CI NR)<br />
|44% (95% CI NR)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1 & 8, '''given first'''<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''EORTC 30987:''' Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. [https://doi.org/10.1200/JCO.2011.38.6979 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22370319 PubMed] NCT00022191<br />
<br />
=Locally advanced or metastatic disease, maintenance after platinum chemotherapy=<br />
<br />
==Avelumab monotherapy {{#subobject:efub4c|Regimen=1}}==<br />
{| class="wikitable sortable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:913o9g|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa2002788 Powles et al. 2020 (JAVELIN Bladder 100)]<br />
|2016-2019<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Best supportive care<br />
| style="background-color:#1a9851" |Superior OS<br />
| style="background-color:#d73027" |More toxic<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]] x 4 to 6 or [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]] x 4 to 6 cycles<br />
<br />
====Immunotherapy====<br />
<br />
*[[Avelumab (Bavencio)]] 10 mg/kg IV over 60 minutes once per day on days 1 & 15<br />
<br />
====Supportive Medications====<br />
Premedication with a histamine H1 receptor (H1) blocker and acetaminophen approximately 30 to 60 minutes prior to each dose of avelumab for the first 4 doses; for example:<br />
<br />
*[[Diphenhydramine (Benadryl)]] 25 to 50 mg IV or PO equivalent<br />
*[[Acetaminophen (Tylenol)]] 500 to 650 mg IV or PO equivalent<br />
<br />
'''28-day cycles'''<br />
===References===<br />
<br />
#'''JAVELIN Bladder 100:''' Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Kalofonos H, Radulović S, Demey W, Ullén A, Loriot Y, Sridhar SS, Tsuchiya N, Kopyltsov E, Sternberg CN, Bellmunt J, Aragon-Ching JB, Petrylak DP, Laliberte R, Wang J, Huang B, Davis C, Fowst C, Costa N, Blake-Haskins JA, di Pietro A, Grivas P. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020 Sep 24;383(13):1218-1230. Epub 2020 Sep 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa2002788 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32945632 PubMed] NCT02603432<br />
<br />
==Pembrolizumab monotherapy {{#subobject:gbzb4c|Regimen=1}}==<br />
{| class="wikitable sortable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9gia9g|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255983/ Galsky et al. 2020 (HCRN GU14-182)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
| style="background-color:#d73027" |More toxic<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*First-line platinum-based combination chemotherapy for up to 8 cycles without progression of disease<br />
<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
<!-- # Joaquim Bellmunt, Guru Sonpavde, Ronald De Wit, Toni K. Choueiri, Arlene O. Siefker-Radtke, Elizabeth R. Plimack, Nicole M. Lewis, Holly Brown, Yabing Mai, Christine K. Gause, David Ross Kaufman, Dean F. Bajorin. KEYNOTE-045: Randomized phase 3 trial of pembrolizumab (MK-3475) versus paclitaxel, docetaxel, or vinflunine for previously treated metastatic urothelial cancer. 2015 ASCO Annual Meeting abstract TPS4571. [http://meetinglibrary.asco.org/content/145993-156 link to abstract] --><br />
#'''HCRN GU14-182:''' Galsky MD, Mortazavi A, Milowsky MI, George S, Gupta S, Fleming MT, Dang LH, Geynisman DM, Walling R, Alter RS, Kassar M, Wang J, Gupta S, Davis N, Picus J, Philips G, Quinn DI, Haines GK 3rd, Hahn NM, Zhao Q, Yu M, Pal SK. Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer. J Clin Oncol. 2020 Jun 1;38(16):1797-1806. Epub 2020 Apr 9. [https://doi.org/10.1200/jco.19.03091 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255983/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32271672 PubMed] NCT02500121<br />
<br />
=Locally advanced or metastatic disease, after platinum chemotherapy=<br />
==Avelumab monotherapy {{#subobject:6C1497|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:D9FB6C|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |Years of enrollment<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493051/ Apolo et al. 2017 (JAVELIN)]<br />
|2014<br />
| style="background-color:#ffffbe" |Phase Ib (RT)<br />
|18% (95% CI 8-33)<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Avelumab (Bavencio)]] 10 mg/kg IV over 60 minutes once on day 1<br />
<br />
====Supportive medications====<br />
''Per Apolo et al. 2017 (JAVELIN):''<br />
<br />
*"All patients were premedicated with [[:Category:Antihistamines|an antihistamine]] and [[Acetaminophen (Tylenol)|acetaminophen]] (doses and routes not given)<br />
*The avelumab package insert suggests "Premedicate with acetaminophen and an antihistamine for the first 4 infusions and subsequently as needed."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Phase 1:''' Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, Mega AE, Britten CD, Ravaud A, Mita AC, Safran H, Stinchcombe TE, Srdanov M, Gelb AB, Schlichting M, Chin K, Gulley JL. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: Results from a multicenter, phase Ib study. J Clin Oncol. 2017 Jul 1;35(19):2117-2124. Epub 2017 Apr 4. [https://doi.org/10.1200/JCO.2016.71.6795 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493051/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28375787 PubMed] NCT01772004<br />
<br />
==Docetaxel monotherapy {{#subobject:385447|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b840fe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1997.15.5.1853 McCaffrey et al. 1997]<br />
|1993-1995<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ Choueiri et al. 2012 (DFCI 06-116)]<br />
|2007-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel & Vandetanib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2015.65.0218 Petrylak et al. 2016 (JCDC)]<br />
| rowspan="2" |2011-2014<br />
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (C)<br />
|1. Docetaxel & Icrucumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|2. [[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy_5|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<br />
|2015-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext Petrylak et al. 2017 (RANGE)]<br />
|2015-2017<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]<br />
| style="background-color:#d73027" |Inferior PFS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for RANGE is based on the 2019 update.''<br><br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7. [https://doi.org/10.1200/JCO.1997.15.5.1853 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9164195 PubMed]<br />
#'''DFCI 06-116:''' Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, Hahn NM, Hutson TE, Sonpavde G, Morrissey SC, Buckle GC, Kim WY, Petrylak DP, Ryan CW, Eisenberger MA, Mortazavi A, Bubley GJ, Taplin ME, Rosenberg JE, Kantoff PW. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012 Feb 10;30(5):507-12. [https://doi.org/10.1200/jco.2011.37.7002 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22184381 PubMed] NCT00880334<br />
#'''JCDC:''' Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. [https://doi.org/10.1200/JCO.2015.65.0218 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26926681 PubMed] NCT01282463<br />
<!-- # Joaquim Bellmunt, Guru Sonpavde, Ronald De Wit, Toni K. Choueiri, Arlene O. Siefker-Radtke, Elizabeth R. Plimack, Nicole M. Lewis, Holly Brown, Yabing Mai, Christine K. Gause, David Ross Kaufman, Dean F. Bajorin. KEYNOTE-045: Randomized phase 3 trial of pembrolizumab (MK-3475) versus paclitaxel, docetaxel, or vinflunine for previously treated metastatic urothelial cancer. 2015 ASCO Annual Meeting abstract TPS4571. [http://meetinglibrary.asco.org/content/145993-156 link to abstract] --><br />
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28212060 PubMed] NCT02256436<br />
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707 PubMed]<br />
#'''RANGE:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28916371 PubMed] NCT02426125<br />
##'''Update:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30668-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946880/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31753727 PubMed]<br />
#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29268948 PubMed] NCT02302807<br />
#'''TROPiCS-04:''' NCT04527991<br />
<br />
==Docetaxel & Ramucirumab {{#subobject:385447|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b840fe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2015.65.0218 Petrylak et al. 2016 (JCDC)]<br />
|2011-2014<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext Petrylak et al. 2017 (RANGE)]<br />
|2015-2017<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior PFS<sup>1</sup> <br>(HR 0.70, 95% CI 0.57-0.85)<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for RANGE is based on the 2019 update.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Targeted therapy====<br />
<br />
*[[Ramucirumab (Cyramza)]] 10 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''JCDC:''' Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. [https://doi.org/10.1200/JCO.2015.65.0218 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26926681 PubMed] NCT01282463<br />
#'''RANGE:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28916371 PubMed] NCT02426125<br />
##'''Update:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30668-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946880/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31753727 PubMed]<br />
<br />
==Erdafitinib monotherapy {{#subobject:dbc30d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:473057|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |Years of enrollment<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1817323 Loriot et al. 2019 (BLC2001)]<br />
|2015-2018<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#8c96c6" |ORR 40% (95% CI 31-50)<br />
|-<br />
|}<br />
====Biomarker eligibility criteria====<br />
<br />
*Alterations: FGFR3 mutation, FGFR2 fusion, or FGFR3 fusion<br />
<br />
====Targeted therapy====<br />
<br />
*[[Erdafitinib (Balversa)]] 8 mg PO once per day<br />
**If serum phosphorus level and tolerability are acceptable at days 14 to 21, increase to 9 mg PO once per day<br />
**Additional dose adjustments per package insert<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Arlene O. Siefker-Radtke, Andrea Necchi, Se Hoon Park, Jesus Garcia-Donas, Robert A Huddart, Earle Frederick Burgess, Mark T. Fleming, Arash Rezazadeh, Begona Mellado, Sergei Varlamov, Monika Joshi, Ignacio Duran, Scott T. Tagawa, Anne OHagan, Anjali Narayan Avadhani, Bob Zhong, Peter De Porre, Yohann Loriot, on behalf of the BLC2001 Study Group. First results from the primary analysis population of the phase 2 study of erdafitinib (ERDA; JNJ-42756493) in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt). 2018 ASCO Annual Meeting abstract 4503 [https://meetinglibrary.asco.org/record/160559/abstract link to abstract] '''contains verified protocol'''<br />
# '''BLC2001:''' [https://clinicaltrials.gov/ct2/show/NCT02365597 CT.gov] --><br />
<br />
#'''BLC2001:''' Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, Fleming M, Rezazadeh A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Zhong B, Stuyckens K, Santiago-Walker A, De Porre P, O'Hagan A, Avadhani A, Siefker-Radtke AO; BLC2001 Study Group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348. [https://www.nejm.org/doi/full/10.1056/NEJMoa1817323 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31340094 PubMed] NCT02365597<br />
<br />
==Gemcitabine & Paclitaxel {{#subobject:ecfc0d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GP: '''<u>G</u>'''emcitabine & '''<u>P</u>'''aclitaxel<br />
===Regimen variant #1, gemcitabine 2 out of 3 weeks {{#subobject:384057|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdq398 Albers et al. 2010 (AUO AB 20/99)]<br />
|2001-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_Paclitaxel_2|GP]]; prolonged<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #2, weekly gemcitabine {{#subobject:9aa3e0|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2001.19.12.3018 Meluch et al. 2001]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts in this subgroup<br />
| style="background-color:#8c96c6" |ORR: 47%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. [https://doi.org/10.1200/jco.2001.19.12.3018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11408496 PubMed]<br />
#'''AUO AB 20/99:''' Albers P, Park SI, Niegisch G, Fechner G, Steiner U, Lehmann J, Heimbach D, Heidenreich A, Fimmers R, Siener R; AUO Bladder Cancer Group. Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99]. Ann Oncol. 2011 Feb;22(2):288-94. Epub 2010 Aug 2. [https://doi.org/10.1093/annonc/mdq398 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20682548 PubMed]<br />
<br />
==MVAC {{#subobject:373ed3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin<br />
<br />
===Regimen {{#subobject:af2e64|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359702/ Han et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#8c6bb1" |ORR: 30%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
<br />
'''28-day cycles''' (number of cycles and criteria to continue therapy varies depending on reference)<br />
<br />
===References===<br />
<br />
#Han KS, Joung JY, Kim TS, Jeong IG, Seo HK, Chung J, Lee KH. Methotrexate, vinblastine, doxorubicin and cisplatin combination regimen as salvage chemotherapy for patients with advanced or metastatic transitional cell carcinoma after failure of gemcitabine and cisplatin chemotherapy. Br J Cancer. 2008 Jan 15;98(1):86-90. Epub 2007 Dec 18. [https://doi.org/10.1038/sj.bjc.6604113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359702/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18087289 PubMed]<br />
<br />
==Nivolumab monotherapy {{#subobject:86b89c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:beb7fa|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |Years of enrollment<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30065-7/fulltext Sharma et al. 2017 (CheckMate 275)]<br />
|2015<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|19.6% overall<br>PD-L1 expression ≥5%: 28.4%<br>PD-L1 expression ≥1%: 23.8%<br>PD-L1 expression <1%: 16.1%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*At least one [[Regimen_classes#Platinum-based_regimen|platinum-based therapy]], with progression<br />
<br />
====Immunotherapy====<br />
<br />
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1<br />
**''The FDA-approved dose which is listed in the package insert is 240 mg IV over 60 minutes once on day 1''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''CheckMate 275:''' Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S, Arranz JÁ, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017 Mar;18(3):312-322. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30065-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/28131785 PubMed] NCT02387996<br />
##'''Update:''' Galsky MD, Saci A, Szabo PM, Han GC, Grossfeld G, Collette S, Siefker-Radtke A, Necchi A, Sharma P. Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275. Clin Cancer Res. 2020 Jun 12. Epub ahead of print. [https://doi.org/10.1158/1078-0432.ccr-19-4162 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32532789 PubMed]<br />
<br />
==nab-Paclitaxel monotherapy {{#subobject:fec6dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7dc525|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70162-1/fulltext Ko et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#8c6bb1" |ORR: 28% (95% CI 17-44)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 260 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
====Dose modifications====<br />
<br />
*"Two dose reductions were permitted, to 240 mg/m<sup>2</sup> and then to 180 mg/m<sup>2</sup>. When further dose reductions were required, study treatment was discontinued. Patients with febrile neutropenia, or delay of cycle because of persistent neutropenia, ANC of less than 500/uL for 1 week, or grade 3 or 4 thrombocytopenia required dose reductions. When sensory neuropathy of grade 2 or higher occurred, study drug was withheld until resolution to grade 2 or better, then reinstituted at the next lower dose. When mucositis or diarrhea of grade 3 or higher occurred, study drug was withheld until resolution to grade 1 or better, then reinstituted at the next lower dose. Patients with mucositis or diarrhea of grade 4 were removed from the trial."<br />
<br />
===References===<br />
<br />
#Ko YJ, Canil CM, Mukherjee SD, Winquist E, Elser C, Eisen A, Reaume MN, Zhang L, Sridhar SS. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study. Lancet Oncol. 2013 Jul;14(8):769-76. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70162-1/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23706985 PubMed] NCT00683059<br />
<br />
==Paclitaxel monotherapy {{#subobject:fec6dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, q3wks {{#subobject:9fddc0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy_5|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<br />
|2015-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm. IMvigor211 allowed up to 2 prior lines of platinum-containing chemotherapy.''<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 3 out of 4 weeks {{#subobject:524ebf|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2002.20.4.937 Vaughn et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#6e016b; color:white" |ORR: 10% (95% CI 0-20)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. [https://doi.org/10.1200/jco.2002.20.4.937 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11844814 PubMed]<br />
#'''Retrospective:''' Sideris S, Aoun F, Zanaty M, Martinez NC, Latifyan S, Awada A, Gil T. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol Clin Oncol. 2016 Jun;4(6):1063-1067. Epub 2016 Mar 17. [https://doi.org/10.3892/mco.2016.821 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887921/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27284445 PubMed]<br />
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28212060 PubMed] NCT02256436<br />
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707 PubMed]<br />
#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29268948 PubMed] NCT02302807<br />
#'''TROPiCS-04:''' NCT04527991<br />
<br />
==Pembrolizumab monotherapy {{#subobject:b0cd2a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8aec07|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|Investigator's choice of:<br> 1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. [[#Paclitaxel_monotherapy|Paclitaxel]]<br> 3. [[#Vinflunine_monotherapy|Vinflunine]]<br />
| style="background-color:#1a9850" |Superior OS <br>Median OS: 10 mo vs 7 mo <br>(HR 0.73, 95% CI 0.59-0.91)<br />
|-<br />
|}<br />
====Biomarker eligibility criteria====<br />
<br />
For the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.<br />
<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28212060 PubMed] NCT02256436<br />
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707 PubMed]<br />
<br />
==Pemetrexed monotherapy {{#subobject:fec6dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7dc525|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.03.6699 Sweeney et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#8c6bb1" |ORR: 28% (95% CI 16-43)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, Nicol SJ, Kaufman DS. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006 Jul 20;24(21):3451-7. [https://doi.org/10.1200/jco.2005.03.6699 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16849761 PubMed]<br />
<br />
==Vinflunine monotherapy {{#subobject:e40f4c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b5b9b9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2008.20.5534 Bellmunt et al. 2009 (CA183004)]<br />
|2003-2006<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<sup>1</sup> <br>(HR 0.72, 95% CI 0.57-0.91)<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy_5|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<br />
|2015-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''<sup>1<sup>Reported efficacy for CA183004 is based on the 2013 update.''<br />
====Chemotherapy====<br />
<br />
*[[Vinflunine (Javlor)]] 320 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#'''CA183004:''' Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, Caty A, Carles J, Jagiello-Gruszfeld A, Karyakin O, Delgado FM, Hurteloup P, Winquist E, Morsli N, Salhi Y, Culine S, von der Maase H. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009 Sep 20;27(27):4454-61. Epub 2009 Aug 17. Erratum in: J Clin Oncol. 2010 Jan 1;28(1):182. Winquist, Eric [added]. [https://doi.org/10.1200/JCO.2008.20.5534 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19687335 PubMed] NCT00315237<br />
##'''Update:''' Bellmunt J, Fougeray R, Rosenberg JE, von der Maase H, Schutz FA, Salhi Y, Culine S, Choueiri TK. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. Ann Oncol. 2013 Jun;24(6):1466-72. Epub 2013 Feb 17. [https://doi.org/10.1093/annonc/mdt007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23419284 PubMed]<br />
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28212060 PubMed] NCT02256436<br />
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707 PubMed]<br />
#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29268948 PubMed] NCT02302807<br />
#'''TROPiCS-04:''' NCT04527991<br />
<br />
=Locally advanced or metastatic disease, after platinum chemotherapy and immune checkpoint inhibitor=<br />
==Enfortumab vedotin monotherapy {{#subobject:dbdcad|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:415bc7|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 15%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 15%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784850/ Rosenberg et al. 2018 (EV-201)]<br />
|2017-2018<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|None<br />
|N/A<br />
| style="background-color:#8c96c6" |44% (95% CI 35.2-53.2)<br />
|N/A<br />
|-<br />
|[https://doi.org/10.1056/NEJMoa2035807 Powles et al. 2021 (EV-301)]<br />
|2018-2020<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Investigator-chosen chemotherapy (standard [[Bladder_cancer#Docetaxel_monotherapy | Docetaxel]], [[Bladder_cancer#Paclitaxel_monotherapy | Paclitaxel]], or [[Bladder_cancer#Vinflunine_monotherapy | Vinflunine]])<br />
| style="background-color:#1a9851" |Superior OS<br />
|Intention to treat: 40.6%<br />
|Intention to treat: 17.9%<br />
|}<br />
====Antibody-drug conjugate therapy====<br />
<br />
*[[Enfortumab vedotin (Padcev)]] 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''EV-201:''' Rosenberg JE, O'Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, Galsky MD, Hahn NM, Gartner EM, Pinelli JM, Liang SY, Melhem-Bertrandt A, Petrylak DP. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Oct 10;37(29): 2592-2600. Epub 2019 Jul 29. [https://doi.org/10.1200/JCO.19.01140 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784850/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31356140 Pubmed] NCT03219333<br />
#'''EV-301:''' Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. [https://doi.org/10.1056/NEJMoa2035807 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33577729 Pubmed] NCT03474107<br />
<br />
==Sacituzumab govitecan monotherapy {{#subobject:d9gacd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:417gu7|Variant=1}}===<br />
{| class="wikitable sortable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
![[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://pubmed.ncbi.nlm.nih.gov/33929895/ Tagawa et al. 2021 (TROPHY-U-O1)]<br />
|2018-2019<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#8c96c6" |27% (95% CI 19.5-36.6) <br />
|-<br />
|}<br />
<br />
====Antibody-drug conjugate therapy====<br />
<br />
*[[Sacituzumab govitecan (Trodelvy)]] 10 mg/kg IV once per day on days 1 & 8<br />
<br />
'''21-day cycles''' until unaccaptable toxicity or loss of clinical benefit <br />
<br />
===References===<br />
<br />
#'''TROPHY-U-01''' Tagawa ST, Balar AV, Petrylak DP, Kalebasty AR, Loriot Y, Fléchon A, Jain RK, Agarwal N, Bupathi M, Barthelemy P, Beuzeboc P, Palmbos P, Kyriakopoulos CE, Pouessel D, Sternberg CN, Hong Q, Goswami T, Itri LM, Grivas P. TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. J Clin Oncol. 2021 Apr 30. Epub ahead of print. [https://ascopubs.org/doi/full/10.1200/JCO.20.03489 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33929895/ Pubmed] NCT03547973<br />
<br />
=Links=<br />
<br />
*[http://www.eortc.be/tools/bladdercalculator/ EORTC Risk Tables for Predicting Recurrence and Progression in Individual Patients with Stage Ta T1 Bladder Cancer] - predicts probability of recurrence and progression in 1 to 5 years<br />
<br />
=Urine assays=<br />
''These are assays intended/being investigated as adjuncts to urine cytology and cystoscopy.''<br />
<br />
*[https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=347921 Cxbladder (uRNA-2)], a "urine based bladder cancer test (uRNA-2) which detects RNA markers in urine."<br />
*[http://www.scimedx.com/products/bladder_cancer/bladder_cancer.php ImmunoCyt™/uCyt+™], a cell-based detection assay which "uses fluorescent-labeled antibodies to 3 markers that are commonly found on malignant exfoliated urothelial cells."<ref>Greene KL, Berry A, Konety BR. Diagnostic Utility of the ImmunoCyt/uCyt+ Test in Bladder Cancer. Rev Urol. 2006 Fall;8(4):190-7. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751037/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17192798 PubMed]</ref><br />
*[http://www.abbottmolecular.com/us/products/oncology/fish/bladder-cancer-urovysion.html UroVysion] (Abbott Molecular) "designed to detect aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus via fluorescence in situ hybridization (FISH) in urine specimens from persons with hematuria suspected of having bladder cancer."<br />
<br />
=References=<br />
<references /><br />
<br />
[[Category:Bladder cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Genitourinary cancers]]</div>Karinehttps://hemonc.org/w/index.php?title=Paroxysmal_nocturnal_hemoglobinuria&diff=49702Paroxysmal nocturnal hemoglobinuria2021-05-14T21:09:40Z<p>Karine: iptacopan Lancet study regimen and reference</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#31a354" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
=="How I Treat"==<br />
<br />
*'''2021:''' Brodsky [https://doi.org/10.1182/blood.2019003812 How I treat paroxysmal nocturnal hemoglobinuria]<br />
<br />
=All lines of therapy=<br />
==Eculizumab monotherapy {{#subobject:1 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 12-week course {{#subobject:4bb05f |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa031688 Hillmen et al. 2004]<br />
| style="background-color:#ffffbe" |Pilot, <20 pts<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Eculizumab (Soliris)]] as follows:<br />
**Cycle 1: 600 mg IV over 25 to 45 minutes once per day on days 1, 8, 15, 22<br />
**Cycles 2 & 3: 900 mg IV over 25 to 45 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===Regimen variant #2, 6-month course {{#subobject:1 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa061648 Hillmen et al. 2006 (TRIUMPH)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior stabilization of Hgb levels and QoL<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367644/ Lee et al. 2018 (ALXN1210-PNH-301)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ravulizumab_monotherapy|Ravulizumab]]<br />
| style="background-color:#eeee01" |Non-inferior efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201/ Kulasekararaj et al. 2018 (ALXN1210-PNH-302)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ravulizumab_monotherapy|Ravulizumab]]<br />
| style="background-color:#eeee01" |Non-inferior efficacy<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Eculizumab (Soliris)]] as follows:<br />
**Cycle 1: 600 mg IV over 25 to 45 minutes once per day on days 1, 8, 15, 22<br />
**Cycles 2 to 12: 900 mg IV over 25 to 45 minutes once on day 1<br />
<br />
====Supportive medications==== <br />
<br />
*Patients received Neisseria meningitidis meningococcal vaccination<br />
<br />
'''28-day cycle for 1 cycle, then 14-day cycle for 11 cycles'''<br />
<br />
===Regimen variant #3, 12-month course {{#subobject:2 |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/111/4/1840.long Brodsky et al. 2007 (SHEPHERD)]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Eculizumab (Soliris)]] as follows:<br />
**Cycle 1: 600 mg IV over 25 to 45 minutes once per day on days 1, 8, 15, 22<br />
**Cycles 2 to 25: 900 mg IV over 25 to 45 minutes once on day 1<br />
<br />
'''28-day cycle for 1 cycle, then 14-day cycle for 24 cycles'''<br />
<br />
===Regimen variant #4, indefinite {{#subobject:3 |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/117/25/6786.long Kelly et al. 2011]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Eculizumab (Soliris)]] as follows:<br />
**Cycle 1: 600 mg IV over at least 30 minutes once per day on days 1, 8, 15, 22<br />
**Cycle 2 onwards: 900 mg IV over at least 30 minutes once on day 1<br />
***Patients with return of PNH symptoms, such as red or black urine, abdominal discomfort, or increased LDH before the next dose of eculizumab received higher doses: [[Eculizumab (Soliris)]] 1200 mg IV once on day 1<br />
<br />
====Supportive medications==== <br />
<br />
*Meningitis prophylaxis: ''Neisseria meningitidis'' meningococcal vaccination<br />
*[[Penicillin V]] 500 mg PO twice per day<br />
**Patients with penicillin allergies instead received: [[Erythromycin]] 500 mg PO twice per day<br />
<br />
'''28-day cycle for 1 cycle, then 14-day cycles'''<br />
<br />
===References===<br />
<br />
#Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF, Rother RP. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2004 Feb 5;350(6):552-9. [https://www.nejm.org/doi/full/10.1056/NEJMoa031688 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14762182 PubMed]<br />
##'''Update:''' Hill A, Hillmen P, Richards SJ, Elebute D, Marsh JC, Chan J, Mojcik CF, Rother RP. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood. 2005 Oct 1;106(7):2559-65. Epub 2005 Jun 28. [http://www.bloodjournal.org/content/106/7/2559.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15985537 PubMed]<br />
#'''TRIUMPH:''' Hillmen P, Young NS, Schubert J, Brodsky RA, Socié G, Muus P, Röth A, Szer J, Elebute MO, Nakamura R, Browne P, Risitano AM, Hill A, Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP, Luzzatto L. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006 Sep 21;355(12):1233-43. [https://www.nejm.org/doi/full/10.1056/NEJMoa061648 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16990386 PubMed]<br />
##'''Update:''' Hillmen P, Muus P, Dührsen U, Risitano AM, Schubert J, Luzzatto L, Schrezenmeier H, Szer J, Brodsky RA, Hill A, Socié G, Bessler M, Rollins SA, Bell L, Rother RP, Young NS. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007 Dec 1;110(12):4123-8. Epub 2007 Aug 16. [http://www.bloodjournal.org/content/110/12/4123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17702897 PubMed]<br />
#'''SHEPHERD:''' Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, Gaya A, Coyle L, de Castro C, Fu CL, Maciejewski JP, Bessler M, Kroon HA, Rother RP, Hillmen P. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008 Feb 15;111(4):1840-7. Epub 2007 Nov 30. [http://www.bloodjournal.org/content/111/4/1840.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18055865 PubMed] <br />
##'''Update:''' Hillmen P, Muus P, Röth A, Elebute MO, Risitano AM, Schrezenmeier H, Szer J, Browne P, Maciejewski JP, Schubert J, Urbano-Ispizua A, de Castro C, Socié G, Brodsky RA. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2013 Jul;162(1):62-73. Epub 2013 Apr 25. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.12347/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744747/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23617322 PubMed]<br />
#Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M, Mitchell LD, Cohen DR, Gregory WM, Hillmen P. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood. 2011 Jun 23;117(25):6786-92. Epub 2011 Apr 1. [http://www.bloodjournal.org/content/117/25/6786.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21460245 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
##'''Update: Abstract:''' Anita Hill; Richard J Kelly; Austin G Kulasekararaj; Shreyans A Gandhi; Lindsay D Mitchell; Modupe Elebute; Stephen John Richards; Matthew Cullen; Louise M Arnold; Joanna Large; Alexandra Wood; Gemma L Brooksbank; Tracy Downing; Claire McKinley; Dena Cohen; Walter M Gregory; Judith C. W. Marsh; Ghulam J. Mufti; Peter Hillmen. Eculizumab in Paroxysmal Nocturnal Hemoglobinuria (PNH): A Report of All 153 Patients Treated in the UK. 2012 ASH Annual Meeting abstract 3472. [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/3472?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=3472&searchid=1&FIRSTINDEX=0&volume=120&issue=21&resourcetype=HWCIT link to abstract]<br />
#'''Retrospective:''' Kelly RJ, Höchsmann B, Szer J, Kulasekararaj A, de Guibert S, Röth A, Weitz IC, Armstrong E, Risitano AM, Patriquin CJ, Terriou L, Muus P, Hill A, Turner MP, Schrezenmeier H, Peffault de Latour R. Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2015 Sep 10;373(11):1032-1039. [https://www.nejm.org/doi/full/10.1056/NEJMoa1502950 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26352814 PubMed]<br />
#'''ALXN1210-PNH-301:''' Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S, Füreder W, Ptushkin V, Rottinghaus ST, Volles L, Shafner L, Aguzzi R, Pradhan R, Schrezenmeier H, Hill A. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019 Feb 7;133(6):530-539. Epub 2018 Dec 3. [http://www.bloodjournal.org/content/133/6/530.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367644/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30510080 PubMed] NCT02946463<br />
#'''ALXN1210-PNH-302:''' Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, Gaya A, Lee JW, Gutierrez EO, Piatek CI, Szer J, Risitano A, Nakao S, Bachman E, Shafner L, Damokosh AI, Ortiz S, Röth A, Peffault de Latour R. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019 Feb 7;133(6):540-549. Epub 2018 Dec 3. [http://www.bloodjournal.org/content/133/6/540.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30510079 PubMed] NCT03056040<br />
#'''PEGASUS:''' Hillmen P, Szer J, Weitz I, Röth A, Höchsmann B, Panse J, Usuki K, Griffin M, Kiladjian JJ, de Castro C, Nishimori H, Tan L, Hamdani M, Deschatelets P, Francois C, Grossi F, Ajayi T, Risitano A, de la Tour RP. Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2021 Mar 18;384(11):1028-1037. [https://doi.org/10.1056/nejmoa2029073 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33730455/ PubMed] NCT03500549<br />
<br />
==Iptacopan monotherapy {{#subobject:aa617d |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5f179e |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(21)00028-4/fulltext Risitano et al. 2021]<br />
| style="background-color:#91cf61" |Non-randomized, 10 patients <br />
|-<br />
|}<br />
<br />
====Immunosuppressive therapy====<br />
*[[Iptacopan (LNP023)]] 200 mg twice daily orally <br />
<br />
*[[Eculizumab (Soliris)]] as prior or concurrent therapy<br />
<br />
===References===<br />
#Risitano AM, Röth A, Soret J, Frieri C, de Fontbrune FS, Marano L, Alashkar F, Benajiba L, Marotta S, Rozenberg I, Milojevic J, End P, Nidamarthy PK, Junge G, Peffault de Latour R. Addition of iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, single-arm, phase 2, proof-of-concept trial. Lancet Haematol. 2021 May;8(5):e344-e354. Epub 2021 Mar 23. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(21)00028-4/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/33765419/ PubMed]<br />
<br />
==Placebo==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa061648 Hillmen et al. 2006 (TRIUMPH)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Eculizumab_monotherapy|Eculizumab]]<br />
| style="background-color:#d73027" |Inferior stabilization of Hgb levels and QoL<br />
|-<br />
|}<br />
''No active treatment. Used as a comparator arm in one or more trials; for reference purposes, only.''<br />
<br />
===References===<br />
<br />
#'''TRIUMPH:''' Hillmen P, Young NS, Schubert J, Brodsky RA, Socié G, Muus P, Röth A, Szer J, Elebute MO, Nakamura R, Browne P, Risitano AM, Hill A, Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP, Luzzatto L. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006 Sep 21;355(12):1233-43. [https://www.nejm.org/doi/full/10.1056/NEJMoa061648 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16990386 PubMed]<br />
##'''Update:''' Hillmen P, Muus P, Dührsen U, Risitano AM, Schubert J, Luzzatto L, Schrezenmeier H, Szer J, Brodsky RA, Hill A, Socié G, Bessler M, Rollins SA, Bell L, Rother RP, Young NS. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007 Dec 1;110(12):4123-8. Epub 2007 Aug 16. [http://www.bloodjournal.org/content/110/12/4123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17702897 PubMed]<br />
<br />
==Ravulizumab monotherapy {{#subobject:abd213 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ba93ab |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367644/ Lee et al. 2018 (ALXN1210-PNH-301)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Eculizumab_monotherapy|Eculizumab]]<br />
| style="background-color:#eeee01" |Non-inferior efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201/ Kulasekararaj et al. 2018 (ALXN1210-PNH-302)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Eculizumab_monotherapy|Eculizumab]]<br />
| style="background-color:#eeee01" |Non-inferior efficacy<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Ravulizumab (Ultomiris)]]<br />
<br />
'''6-month course'''<br />
===References===<br />
<br />
#'''ALXN1210-PNH-301:''' Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S, Füreder W, Ptushkin V, Rottinghaus ST, Volles L, Shafner L, Aguzzi R, Pradhan R, Schrezenmeier H, Hill A. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019 Feb 7;133(6):530-539. Epub 2018 Dec 3. [http://www.bloodjournal.org/content/133/6/530.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367644/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30510080 PubMed] NCT02946463<br />
#'''ALXN1210-PNH-302:''' Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, Gaya A, Lee JW, Gutierrez EO, Piatek CI, Szer J, Risitano A, Nakao S, Bachman E, Shafner L, Damokosh AI, Ortiz S, Röth A, Peffault de Latour R. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019 Feb 7;133(6):540-549. Epub 2018 Dec 3. [http://www.bloodjournal.org/content/133/6/540.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30510079 PubMed] NCT03056040<br />
<br />
=Investigational agents=<br />
''These are drugs under study with at least some promising results for this disease.''<br />
<br />
Pegcetacoplan<br />
<br />
Danicopan<br />
[[Category:Paroxysmal nocturnal hemoglobinuria regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Bone marrow failure syndromes]]<br />
[[Category:Complementopathies]]<br />
[[Category:Hemolytic process]]</div>Karinehttps://hemonc.org/w/index.php?title=Paroxysmal_nocturnal_hemoglobinuria&diff=49701Paroxysmal nocturnal hemoglobinuria2021-05-14T20:55:26Z<p>Karine: investigational agents for PNH</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#31a354" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
=="How I Treat"==<br />
<br />
*'''2021:''' Brodsky [https://doi.org/10.1182/blood.2019003812 How I treat paroxysmal nocturnal hemoglobinuria]<br />
<br />
=All lines of therapy=<br />
==Eculizumab monotherapy {{#subobject:1 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 12-week course {{#subobject:4bb05f |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa031688 Hillmen et al. 2004]<br />
| style="background-color:#ffffbe" |Pilot, <20 pts<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Eculizumab (Soliris)]] as follows:<br />
**Cycle 1: 600 mg IV over 25 to 45 minutes once per day on days 1, 8, 15, 22<br />
**Cycles 2 & 3: 900 mg IV over 25 to 45 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===Regimen variant #2, 6-month course {{#subobject:1 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa061648 Hillmen et al. 2006 (TRIUMPH)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior stabilization of Hgb levels and QoL<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367644/ Lee et al. 2018 (ALXN1210-PNH-301)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ravulizumab_monotherapy|Ravulizumab]]<br />
| style="background-color:#eeee01" |Non-inferior efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201/ Kulasekararaj et al. 2018 (ALXN1210-PNH-302)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ravulizumab_monotherapy|Ravulizumab]]<br />
| style="background-color:#eeee01" |Non-inferior efficacy<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Eculizumab (Soliris)]] as follows:<br />
**Cycle 1: 600 mg IV over 25 to 45 minutes once per day on days 1, 8, 15, 22<br />
**Cycles 2 to 12: 900 mg IV over 25 to 45 minutes once on day 1<br />
<br />
====Supportive medications==== <br />
<br />
*Patients received Neisseria meningitidis meningococcal vaccination<br />
<br />
'''28-day cycle for 1 cycle, then 14-day cycle for 11 cycles'''<br />
<br />
===Regimen variant #3, 12-month course {{#subobject:2 |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/111/4/1840.long Brodsky et al. 2007 (SHEPHERD)]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Eculizumab (Soliris)]] as follows:<br />
**Cycle 1: 600 mg IV over 25 to 45 minutes once per day on days 1, 8, 15, 22<br />
**Cycles 2 to 25: 900 mg IV over 25 to 45 minutes once on day 1<br />
<br />
'''28-day cycle for 1 cycle, then 14-day cycle for 24 cycles'''<br />
<br />
===Regimen variant #4, indefinite {{#subobject:3 |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/117/25/6786.long Kelly et al. 2011]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Eculizumab (Soliris)]] as follows:<br />
**Cycle 1: 600 mg IV over at least 30 minutes once per day on days 1, 8, 15, 22<br />
**Cycle 2 onwards: 900 mg IV over at least 30 minutes once on day 1<br />
***Patients with return of PNH symptoms, such as red or black urine, abdominal discomfort, or increased LDH before the next dose of eculizumab received higher doses: [[Eculizumab (Soliris)]] 1200 mg IV once on day 1<br />
<br />
====Supportive medications==== <br />
<br />
*Meningitis prophylaxis: ''Neisseria meningitidis'' meningococcal vaccination<br />
*[[Penicillin V]] 500 mg PO twice per day<br />
**Patients with penicillin allergies instead received: [[Erythromycin]] 500 mg PO twice per day<br />
<br />
'''28-day cycle for 1 cycle, then 14-day cycles'''<br />
<br />
===References===<br />
<br />
#Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF, Rother RP. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2004 Feb 5;350(6):552-9. [https://www.nejm.org/doi/full/10.1056/NEJMoa031688 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14762182 PubMed]<br />
##'''Update:''' Hill A, Hillmen P, Richards SJ, Elebute D, Marsh JC, Chan J, Mojcik CF, Rother RP. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood. 2005 Oct 1;106(7):2559-65. Epub 2005 Jun 28. [http://www.bloodjournal.org/content/106/7/2559.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15985537 PubMed]<br />
#'''TRIUMPH:''' Hillmen P, Young NS, Schubert J, Brodsky RA, Socié G, Muus P, Röth A, Szer J, Elebute MO, Nakamura R, Browne P, Risitano AM, Hill A, Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP, Luzzatto L. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006 Sep 21;355(12):1233-43. [https://www.nejm.org/doi/full/10.1056/NEJMoa061648 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16990386 PubMed]<br />
##'''Update:''' Hillmen P, Muus P, Dührsen U, Risitano AM, Schubert J, Luzzatto L, Schrezenmeier H, Szer J, Brodsky RA, Hill A, Socié G, Bessler M, Rollins SA, Bell L, Rother RP, Young NS. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007 Dec 1;110(12):4123-8. Epub 2007 Aug 16. [http://www.bloodjournal.org/content/110/12/4123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17702897 PubMed]<br />
#'''SHEPHERD:''' Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, Gaya A, Coyle L, de Castro C, Fu CL, Maciejewski JP, Bessler M, Kroon HA, Rother RP, Hillmen P. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008 Feb 15;111(4):1840-7. Epub 2007 Nov 30. [http://www.bloodjournal.org/content/111/4/1840.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18055865 PubMed] <br />
##'''Update:''' Hillmen P, Muus P, Röth A, Elebute MO, Risitano AM, Schrezenmeier H, Szer J, Browne P, Maciejewski JP, Schubert J, Urbano-Ispizua A, de Castro C, Socié G, Brodsky RA. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2013 Jul;162(1):62-73. Epub 2013 Apr 25. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.12347/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744747/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23617322 PubMed]<br />
#Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M, Mitchell LD, Cohen DR, Gregory WM, Hillmen P. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood. 2011 Jun 23;117(25):6786-92. Epub 2011 Apr 1. [http://www.bloodjournal.org/content/117/25/6786.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21460245 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
##'''Update: Abstract:''' Anita Hill; Richard J Kelly; Austin G Kulasekararaj; Shreyans A Gandhi; Lindsay D Mitchell; Modupe Elebute; Stephen John Richards; Matthew Cullen; Louise M Arnold; Joanna Large; Alexandra Wood; Gemma L Brooksbank; Tracy Downing; Claire McKinley; Dena Cohen; Walter M Gregory; Judith C. W. Marsh; Ghulam J. Mufti; Peter Hillmen. Eculizumab in Paroxysmal Nocturnal Hemoglobinuria (PNH): A Report of All 153 Patients Treated in the UK. 2012 ASH Annual Meeting abstract 3472. [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/3472?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=3472&searchid=1&FIRSTINDEX=0&volume=120&issue=21&resourcetype=HWCIT link to abstract]<br />
#'''Retrospective:''' Kelly RJ, Höchsmann B, Szer J, Kulasekararaj A, de Guibert S, Röth A, Weitz IC, Armstrong E, Risitano AM, Patriquin CJ, Terriou L, Muus P, Hill A, Turner MP, Schrezenmeier H, Peffault de Latour R. Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2015 Sep 10;373(11):1032-1039. [https://www.nejm.org/doi/full/10.1056/NEJMoa1502950 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26352814 PubMed]<br />
#'''ALXN1210-PNH-301:''' Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S, Füreder W, Ptushkin V, Rottinghaus ST, Volles L, Shafner L, Aguzzi R, Pradhan R, Schrezenmeier H, Hill A. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019 Feb 7;133(6):530-539. Epub 2018 Dec 3. [http://www.bloodjournal.org/content/133/6/530.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367644/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30510080 PubMed] NCT02946463<br />
#'''ALXN1210-PNH-302:''' Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, Gaya A, Lee JW, Gutierrez EO, Piatek CI, Szer J, Risitano A, Nakao S, Bachman E, Shafner L, Damokosh AI, Ortiz S, Röth A, Peffault de Latour R. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019 Feb 7;133(6):540-549. Epub 2018 Dec 3. [http://www.bloodjournal.org/content/133/6/540.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30510079 PubMed] NCT03056040<br />
#'''PEGASUS:''' Hillmen P, Szer J, Weitz I, Röth A, Höchsmann B, Panse J, Usuki K, Griffin M, Kiladjian JJ, de Castro C, Nishimori H, Tan L, Hamdani M, Deschatelets P, Francois C, Grossi F, Ajayi T, Risitano A, de la Tour RP. Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2021 Mar 18;384(11):1028-1037. [https://doi.org/10.1056/nejmoa2029073 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33730455/ PubMed] NCT03500549<br />
<br />
==Placebo==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa061648 Hillmen et al. 2006 (TRIUMPH)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Eculizumab_monotherapy|Eculizumab]]<br />
| style="background-color:#d73027" |Inferior stabilization of Hgb levels and QoL<br />
|-<br />
|}<br />
''No active treatment. Used as a comparator arm in one or more trials; for reference purposes, only.''<br />
<br />
===References===<br />
<br />
#'''TRIUMPH:''' Hillmen P, Young NS, Schubert J, Brodsky RA, Socié G, Muus P, Röth A, Szer J, Elebute MO, Nakamura R, Browne P, Risitano AM, Hill A, Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP, Luzzatto L. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006 Sep 21;355(12):1233-43. [https://www.nejm.org/doi/full/10.1056/NEJMoa061648 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16990386 PubMed]<br />
##'''Update:''' Hillmen P, Muus P, Dührsen U, Risitano AM, Schubert J, Luzzatto L, Schrezenmeier H, Szer J, Brodsky RA, Hill A, Socié G, Bessler M, Rollins SA, Bell L, Rother RP, Young NS. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007 Dec 1;110(12):4123-8. Epub 2007 Aug 16. [http://www.bloodjournal.org/content/110/12/4123.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17702897 PubMed]<br />
<br />
==Ravulizumab monotherapy {{#subobject:abd213 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ba93ab |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367644/ Lee et al. 2018 (ALXN1210-PNH-301)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Eculizumab_monotherapy|Eculizumab]]<br />
| style="background-color:#eeee01" |Non-inferior efficacy<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201/ Kulasekararaj et al. 2018 (ALXN1210-PNH-302)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Eculizumab_monotherapy|Eculizumab]]<br />
| style="background-color:#eeee01" |Non-inferior efficacy<br />
|-<br />
|}<br />
====Immunosuppressive therapy====<br />
<br />
*[[Ravulizumab (Ultomiris)]]<br />
<br />
'''6-month course'''<br />
===References===<br />
<br />
#'''ALXN1210-PNH-301:''' Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S, Füreder W, Ptushkin V, Rottinghaus ST, Volles L, Shafner L, Aguzzi R, Pradhan R, Schrezenmeier H, Hill A. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019 Feb 7;133(6):530-539. Epub 2018 Dec 3. [http://www.bloodjournal.org/content/133/6/530.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367644/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30510080 PubMed] NCT02946463<br />
#'''ALXN1210-PNH-302:''' Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, Gaya A, Lee JW, Gutierrez EO, Piatek CI, Szer J, Risitano A, Nakao S, Bachman E, Shafner L, Damokosh AI, Ortiz S, Röth A, Peffault de Latour R. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019 Feb 7;133(6):540-549. Epub 2018 Dec 3. [http://www.bloodjournal.org/content/133/6/540.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30510079 PubMed] NCT03056040<br />
<br />
=Investigational agents=<br />
''These are drugs under study with at least some promising results for this disease.''<br />
<br />
Pegcetacoplan<br />
<br />
Danicopan<br />
[[Category:Paroxysmal nocturnal hemoglobinuria regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Bone marrow failure syndromes]]<br />
[[Category:Complementopathies]]<br />
[[Category:Hemolytic process]]</div>Karinehttps://hemonc.org/w/index.php?title=Iptacopan_(LNP-023)&diff=49700Iptacopan (LNP-023)2021-05-14T20:48:58Z<p>Karine: Iptacopan drug index info continued</p>
<hr />
<div>==General information==<br />
Class/mechanism: orally bioavailable, highly potent and highly selective factor B inhibitor. Blocks the alternative pathway of complement upstream of both CD55 and CD59. Iptacopan is used in diseases involving abnormal complement-mediated activity, such as paroxysmal nocturnal hemoglobinuria (PNH).<br />
<br>Route: oral<br />
<br />
For conciseness and simplicity, HemOnc.org currently will focus on treatment regimens and not list information such as: renal/hepatic dose adjustments, metabolism (including CYP450), excretion, monitoring parameters (although this will be considered for checklists), or manufacturer. Instead, for the most current information, please refer to your preferred pharmacopeias such as [http://www.thomsonhc.com/home/dispatch Micromedex], [http://online.lexi.com/ Lexicomp], [http://reference.medscape.com/drug/soliris-eculizumab-342875 Medscape], [http://www.utdol.com/online/content/search.do UpToDate (courtesy of Lexicomp)]<br />
<br />
==Diseases for which it is used==<br />
*[[Paroxysmal_nocturnal_hemoglobinuria]]<br />
<br />
==Patient drug information==<br />
<br />
==History of changes in FDA indication==<br />
* 12/16/2020: FDA breakthrough therapy designation for patients with paroxysmal nocturnal hemoglobinuria (PNH) and Rare Pediatric Disease (RPD) Designation in C3 glomerulopathy (C3G</div>Karinehttps://hemonc.org/w/index.php?title=Iptacopan_(LNP-023)&diff=49699Iptacopan (LNP-023)2021-05-14T20:43:00Z<p>Karine: Iptacopan drug index info</p>
<hr />
<div>==General information==<br />
Class/mechanism: orally bioavailable, highly potent and highly selective factor B inhibitor. Blocks the alternative pathway of complement upstream of both CD55 and CD59. Iptacopan is used in diseases involving abnormal complement-mediated activity, such as paroxysmal nocturnal hemoglobinuria (PNH).<br />
<br>Route: oral<br />
<br />
For conciseness and simplicity, HemOnc.org currently will focus on treatment regimens and not list information such as: renal/hepatic dose adjustments, metabolism (including CYP450), excretion, monitoring parameters (although this will be considered for checklists), or manufacturer. Instead, for the most current information, please refer to your preferred pharmacopeias such as [http://www.thomsonhc.com/home/dispatch Micromedex], [http://online.lexi.com/ Lexicomp], [http://reference.medscape.com/drug/soliris-eculizumab-342875 Medscape], [http://www.utdol.com/online/content/search.do UpToDate (courtesy of Lexicomp)]</div>Karinehttps://hemonc.org/w/index.php?title=Drug_index&diff=49698Drug index2021-05-14T20:30:33Z<p>Karine: iptacopan added to drug index</p>
<hr />
<div><br />
=Guidelines=<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
'''Other [[#Interesting_and_Helpful_Links|interesting and helpful links]] can be found by clicking the link.'''<br />
==Chemotherapy safety standards==<br />
<br />
*'''2020:''' Dillmon et al. [https://doi.org/10.1200/JCO.19.02297 Patient-Centered Standards for Medically Integrated Dispensing: ASCO/NCODA Standards] [https://pubmed.ncbi.nlm.nih.gov/31815576 PubMed]<br />
*'''2019:''' Celano et al. [https://doi.org/10.1200/JCO.18.01616 Safe handling of hazardous drugs: ASCO standards] [https://pubmed.ncbi.nlm.nih.gov/30620670 PubMed]<br />
*'''2016:''' Neuss et al. [https://doi.org/10.1200/JOP.2016.017905 2016 Updated American Society of Clinical Oncology/Oncology Nursing Society chemotherapy administration safety standards, including standards for pediatric oncology]<br />
*'''2010:''' Carrington et al. [https://onlinelibrary.wiley.com/doi/10.1111/j.1743-7563.2010.01321.x/full The Clinical Oncological Society of Australia (COSA) guidelines for the safe prescribing, dispensing and administration of cancer chemotherapy] [https://pubmed.ncbi.nlm.nih.gov/20887505 PubMed]<br />
<br />
==Dose adjustments==<br />
<br />
*'''2012:''' [https://doi.org/10.1200/jco.2011.39.9436 Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology Clinical Practice Guideline]<ref>Griggs JJ, Mangu PB, Anderson H, Balaban EP, Dignam JJ, Hryniuk WM, Morrison VA, Pini TM, Runowicz CD, Rosner GL, Shayne M, Sparreboom A, Sucheston LE, Lyman GH. Appropriate chemotherapy dosing for obese adult patients with cancer: american society of clinical oncology clinical practice guideline. J Clin Oncol. 2012 May 1;30(13):1553-61. Epub 2012 Apr 2. [https://doi.org/10.1200/jco.2011.39.9436 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22473167 PubMed]</ref><br />
<br />
==Antimicrobials==<br />
<br />
*'''2013:''' [https://doi.org/10.1200/JCO.2012.45.8661 Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology Clinical Practice Guideline]<br />
<br />
==Growth factors==<br />
<br />
*'''2015:''' [https://doi.org/10.1200/jco.2015.62.3488 Update of ASCO Clinical Practice Guideline recommendations for the use of WBC growth factors]<ref>Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, Goldberg JM, Khatcheressian JL, Leighl NB, Perkins CL, Somlo G, Wade JL, Wozniak AJ, Armitage JO. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015 Oct 1;33(28):3199-212. Epub 2015 Jul 13. [https://doi.org/10.1200/jco.2015.62.3488 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26169616/ PubMed]</ref><br />
<br />
=Antineoplastics=<br />
<br />
==A==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
*[[Abarelix (Plenaxis)]]<br />
*[[Abemaciclib (Verzenio)]]<br />
*[[Abexinostat (PCI-24781)]] '''in clinical trials'''<br />
*[[Abiraterone (Zytiga)]]<br />
*[[Acalabrutinib (Calquence)]]<br />
*[[Aclarubicin (Aclacinomycin)]]<br />
*[[Actinium Ac 225 lintuzumab (Actimab-A)]] '''in clinical trials'''<br />
*[[Adavosertib (MK-1775)]] '''in clinical trials'''<br />
*[[Adenovirus-interferon-γ (TG1042)]] '''in clinical trials'''<br />
*[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
*[[Afatinib (Gilotrif)]]<br />
*[[Afuresertib (GSK2110183)]] '''in clinical trials'''<br />
*[[Aldesleukin (Proleukin)]]<br />
*[[Alectinib (Alecensa)]]<br />
*[[Alemtuzumab (Campath)]]<br />
*[[Alisertib (MLN8237)]] '''in clinical trials'''<br />
*[[Alitretinoin (Panretin)]]<br />
*[[All-trans retinoic acid (ATRA)]]<br />
*[[Alpelisib (Piqray)]]<br />
*[[Altretamine (Hexalen)]]<br />
*[[Alvocidib (Flavopiridol)]]<br />
*[[Amatuximab (MORAb-009)]] '''in clinical trials'''<br />
*[[AMG 330]] '''in clinical trials'''<br />
*[[Amifostine (Ethyol)]]<br />
*[[Aminoglutethimide (Cytadren)]]<br />
*[[Aminopterin]] '''discontinued'''<br />
*[[Amonafide (Quinamed)]] '''in clinical trials'''<br />
*[[Amrubicin (Calsed)]]<br />
*[[Amsacrine (Amsidine)]]<br />
*[[Anastrozole (Arimidex)]]<br />
*[[Ancestim (Stemgen)]]<br />
*[[Apalutamide (Erleada)]]<br />
*[[Apatinib (Aitan)]]<br />
*[[Apocept (APG101)]] '''in clinical trials'''<br />
*[[Arsenic trioxide (Trisenox)]]<br />
*[[Asciminib (ABL001)]] '''in clinical trials'''<br />
*[[Asparaginase (Elspar)]] '''discontinued'''<br />
*[[Asparaginase Erwinia chrysanthemi (Erwinaze)]]<br />
*[[Astuprotimut-R (GSK1572932A)]] '''in clinical trials'''<br />
*[[Atezolizumab (Tecentriq)]]<br />
*[[Avapritinib (Ayvakit)]] '''FDA approved 1/9/2020'''<br />
*[[Avelumab (Bavencio)]]<br />
*[[Axicabtagene ciloleucel (Yescarta)]]<br />
*[[Axitinib (Inlyta)]]<br />
*[[Azacitidine (Onureg)]] '''FDA approved 9/1/2020'''<br />
*[[Azacitidine (Vidaza)]]<br />
<br />
==B==<br />
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<br />
*[[Bacillus Calmette-Guérin (BCG)]]<br />
*[[Barasertib (AZD1152)]] '''in clinical trials'''<br />
*[[Bavituximab (PGN401)]] '''in clinical trials'''<br />
*[[Belagenpumatucel-L (Lucanix)]] '''in clinical trials'''<br />
*[[Belantamab mafodotin (Blenrep)]] '''FDA approved 8/6/2020'''<br />
*[[Belinostat (Beleodaq)]]<br />
*[[Belotecan (Camptobell)]]<br />
*[[Bendamustine]]<br />
*[[Benralizumab (Fasenra)]]<br />
*[[Bevacizumab (Avastin)]]<br />
**[[Bevacizumab-awwb (Mvasi)]]<br />
**[[Bevacizumab-bvzr (Zirabev)]]<br />
*[[Bexarotene (Targretin)]]<br />
*[[Bicalutamide (Casodex)]]<br />
*[[Binimetinib (MEK162)]] '''in clinical trials'''<br />
*[[BHQ880]] '''in clinical trials'''<br />
*[[BL22 immunotoxin (CAT-3888)]] '''in clinical trials'''<br />
*[[Bleomycin (Blenoxane)]]<br />
*[[Blinatumomab (Blincyto)]]<br />
*[[Bortezomib (Velcade)]]<br />
*[[Bosutinib (Bosulif)]]<br />
*[[Brentuximab vedotin (Adcetris)]]<br />
*[[Brexucabtagene autoleucel (Tecartus)]] '''FDA approved 7/24/2020'''<br />
*[[Brigatinib (Alunbrig)]]<br />
*[[Buparlisib (BKM120)]] '''in clinical trials'''<br />
*[[Buserelin (Suprefact)]]<br />
*[[Busulfan (Myleran)]]<br />
<br />
==C==<br />
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<br />
*[[Cabazitaxel (Jevtana)]]<br />
*[[Cabozantinib (Cabometyx)]]<br />
*[[Cabozantinib (Cometriq)]]<br />
*[[Calaspargase (Asparlas)]]<br />
*[[Capecitabine (Xeloda)]]<br />
*[[Capivasertib (AZD5363)]] '''in clinical trials'''<br />
*[[Caplacizumab (Cablivi)]]<br />
*[[Capmatinib (Tabrecta)]] '''FDA approved 5/6/2020'''<br />
*[[Carboplatin (Paraplatin)]]<br />
*[[Carfilzomib (Kyprolis)]]<br />
*[[Carmustine (BCNU)]]<br />
*[[Carmustine wafer, polifeprosan 20 (Gliadel)]]<br />
*[[Caspofungin (Cancidas)]]<br />
*[[Catumaxomab (Removab)]] '''in US clinical trials'''<br />
*[[Cediranib (Recentin)]] '''in clinical trials'''<br />
*[[Cemiplimab (Libtayo)]]<br />
*[[Ceritinib (Zykadia)]]<br />
*[[Cetuximab (Erbitux)]]<br />
*[[Chidamide (Epidaza)]]<br />
*[[Chlorambucil (Leukeran)]]<br />
*[[Chlorozotocin (DCNU)]]<br />
*[[Cisplatin (Platinol)]]<br />
*[[Cixutumumab (IMC-A12)]] '''in clinical trials'''<br />
*[[Cladribine (Leustatin)]]<br />
*[[Clofarabine (Clolar)]]<br />
*[[Cobimetinib (Cotellic)]]<br />
*[[Coltuximab ravtansine (CoR, SAR3419)]] '''in clinical trials'''<br />
*[[Copanlisib (Aliqopa)]]<br />
*[[Cortisone]]<br />
*[[Crenolanib (CP-868,596)]] '''in clinical trials'''<br />
*[[Crizotinib (Xalkori)]]<br />
*[[Custirsen (OGX-011)]] '''in clinical trials'''<br />
*[[Cyclophosphamide (Cytoxan)]]<br />
*[[Cyproterone acetate (Androcur)]]<br />
*[[Cytarabine (Ara-C)]]<br />
*[[Cytarabine and daunorubicin liposomal (Vyxeos)]]<br />
*[[Cytarabine liposomal (DepoCyt)]]<br />
<br />
==D==<br />
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<br />
*[[Dabrafenib (Tafinlar)]]<br />
*[[Dacarbazine (DTIC)]]<br />
*[[Dacomitinib (Vizimpro)]]<br />
*[[Dactinomycin (Cosmegen)]]<br />
*[[Daratumumab (Darzalex)]]<br />
*[[Daratumumab and hyaluronidase (Darzalex Faspro)]] '''FDA approved 5/1/2020'''<br />
*[[Darolutamide (Nubeqa)]]<br />
*[[Dasatinib (Sprycel)]]<br />
*[[Daunorubicin (Cerubidine)]]<br />
*[[Daunorubicin liposomal (DaunoXome)]]<br />
*[[Decitabine (Dacogen)]]<br />
*[[Decitabine and cedazuridine (Inqovi)]] '''FDA approved 7/7/2020'''<br />
*[[Degarelix (Firmagon)]]<br />
*[[Denileukin diftitox (Ontak)]]<br />
*[[Denintuzumab mafodotin (SGN-CD19A)]] '''in clinical trials'''<br />
*[[Dexamethasone (Decadron)]]<br />
*[[Diethylstilbestrol (DES)]]<br />
*[[Dinaciclib (SCH 727965)]] '''in clinical trials'''<br />
*[[Dinutuximab (Unituxin)]]<br />
*[[Discodermolide (XAA296)]] '''in clinical trials'''<br />
*[[DMUC5754A]] '''in clinical trials'''<br />
*[[Docetaxel (Taxotere)]]<br />
*[[Dostarlimab (Jemperli)]] '''FDA approved 4/22/2021'''<br />
*[[Dovitinib (TKI-258)]] '''in clinical trials'''<br />
*[[Doxifluridine (Didox)]]<br />
*[[Doxorubicin (Adriamycin)]]<br />
*[[Pegylated liposomal doxorubicin (Doxil)]]<br />
*[[Durvalumab (Imfinzi)]]<br />
*[[Dutasteride (Avodart)]]<br />
*[[Duvelisib (Copiktra)]]<br />
<br />
==E==<br />
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<br />
*[[Edrecolomab (Panorex)]] '''discontinued'''<br />
*[[Elotuzumab (Empliciti)]]<br />
*[[Emapalumab (Gamifant)]]<br />
*[[Emepepimut-S (Stimuvax)]] '''in clinical trials'''<br />
*[[Enasidenib (Idhifa)]]<br />
*[[Encorafenib (LGX818)]] '''in clinical trials'''<br />
*[[Enfortumab vedotin (Padcev)]]<br />
*[[Ensartinib (X-396)]] '''in clinical trials'''<br />
*[[Entinostat (SNDX-275)]] '''in clinical trials'''<br />
*[[Entospletinib (GS-9973)]] '''in clinical trials'''<br />
*[[Entrectinib (Rozlytrek)]]<br />
*[[Enzalutamide (Xtandi)]]<br />
*[[Epirubicin (Ellence)]]<br />
*[[Epratuzumab (LymphoCide)]] '''in clinical trials'''<br />
*[[Erdafitinib (Balversa)]]<br />
*[[Eribulin (Halaven)]]<br />
*[[Erlotinib (Tarceva)]]<br />
*[[Estradiol]]<br />
*[[Estramustine (Emcyt)]]<br />
*[[Etirinotecan pegol (NKTR-102)]] '''in clinical trials'''<br />
*[[Etoposide (Vepesid)]]<br />
*[[Everolimus (Afinitor)]]<br />
*[[Exemestane (Aromasin)]]<br />
<br />
==F==<br />
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<br />
*[[Fam-trastuzumab deruxtecan (Enhertu)]]<br />
*[[Fedratinib (Inrebic)]]<br />
*[[Filanesib (ARRY-520)]] '''in clinical trials'''<br />
*[[Fluorouracil (5-FU)]]<br />
*[[Floxuridine (FUDR)]]<br />
*[[Fludarabine (Fludara)]]<br />
*[[Flumatinib (HH-GV-678)]] '''in clinical trials'''<br />
*[[Fluoxymesterone (Halotestin)]]<br />
*[[Flutamide (Eulexin)]]<br />
*[[Folinic acid (Leucovorin)]]<br />
*[[Formestane (Lentaron)]]<br />
*[[Forodesine (Fodosine)]] '''in clinical trials'''<br />
*[[Fostamatinib (Tavalisse)]]<br />
*[[Fotemustine (Muphoran)]] '''in clinical trials'''<br />
*[[Fruquintinib (HMPL-013)]] '''in clinical trials'''<br />
*[[Fulvestrant (Faslodex)]]<br />
*[[Futibatinib (TAS-120)]] '''in clinical trials'''<br />
<br />
==G==<br />
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<br />
*[[G207]] '''in clinical trials'''<br />
*[[Galeterone (TOK-001)]] '''in clinical trials'''<br />
*[[Galunisertib (LY2157299)]] '''in clinical trials'''<br />
*[[Ganetespib (STA-9090)]] '''in clinical trials'''<br />
*[[Ganitumab (AMG 479)]] '''in clinical trials'''<br />
*[[Gefitinib (Iressa)]]<br />
*[[Gemcitabine (Gemzar)]]<br />
*[[Gemcitabine elaidate (CP-4126, CO-101)]] '''in clinical trials'''<br />
*[[Gemtuzumab ozogamicin (Mylotarg)]]<br />
*[[Gilteritinib (Xospata)]]<br />
*[[Glasdegib (Daurismo)]]<br />
*[[Glembatumumab vedotin (CDX-011)]]] '''in clinical trials'''<br />
*[[Goserelin (Zoladex)]]<br />
*[[Guadecitabine (SGI-110)]] '''in clinical trials'''<br />
<br />
==H==<br />
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<br />
*[[Heptaplatin (Sunpla)]]<br />
*[[HER2 peptide vaccine (AE37)]] '''in clinical trials'''<br />
*[[Histrelin (Vantas)]]<br />
*[[Hu5F9-G4]] '''in clinical trials'''<br />
*[[Hydrocortisone (Cortef)]]<br />
*[[Hydroxyurea (Hydrea)]]<br />
<br />
==I==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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<br />
*[[Ibritumomab tiuxetan (Zevalin)]]<br />
*[[Ibrutinib (Imbruvica)]]<br />
*[[Icotinib (Conmana)]]<br />
*[[Idarubicin (Idamycin)]]<br />
*[[Idasanutlin (RG7388)]] '''in clinical trials'''<br />
*[[Idecabtagene vicleucel (Abecma)]] '''FDA approved 3/26/2021'''<br />
*[[Idelalisib (Zydelig)]]<br />
*[[Ifosfamide (Ifex)]]<br />
*[[IMA901]] '''in clinical trials'''<br />
*[[Imatinib (Gleevec)]]<br />
*[[Imetelstat (GRN163L)]] '''in clinical trials'''<br />
*[[Indatuximab ravtansine (BT062)]] '''in clinical trials'''<br />
*[[Infigratinib (BGJ398)]] '''in clinical trials'''<br />
*[[Inotuzumab ozogamicin (Besponsa)]]<br />
*[[Interferon alfa-2a (Roferon-A)]]<br />
*[[Interferon alfa-2b (Intron-A)]]<br />
*[[Interferon gamma-1b (Actimmune)]]<br />
*[[Iobenguane I 131 (Azedra)]]<br />
*[[Iodine-131]]<br />
*[[Ipatasertib (GDC-0068)]] '''in clinical trials'''<br />
*[[IPH 2101]] '''in clinical trials'''<br />
*[[Ipilimumab (Yervoy)]]<br />
*[[Iptacopan (LNP023)]]<br />
*[[Irinotecan (Camptosar)]]<br />
*[[Irinotecan liposome (Onivyde)]]<br />
*[[Isatuximab (Sarclisa)]] '''FDA approved 3/2/2020'''<br />
*[[Isotretinoin (Accutane)]]<br />
*[[Ivosidenib (Tibsovo)]]<br />
*[[Ixabepilone (Ixempra)]]<br />
*[[Ixazomib (Ninlaro)]]<br />
<br />
==J==<br />
<br />
*[[JCAR015]] '''in clinical trials'''<br />
<br />
==K==<br />
<br />
*[[Ketoconazole (Nizoral)]]<br />
<br />
==L==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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*[[Lanreotide (Somatuline)]]<br />
*[[Lapatinib (Tykerb)]]<br />
*[[Lapuleucel-T (DN24-02)]] '''in clinical trials'''<br />
*[[Larotrectinib (Vitrakvi)]]<br />
*[[Lasofoxifene (Fablyn)]] '''not FDA approved'''<br />
*[[Lenalidomide (Revlimid)]]<br />
*[[Lenvatinib (Lenvima)]]<br />
*[[Lestaurtinib (CEP-701)]] '''in clinical trials'''<br />
*[[Letermovir (Prevymis)]]<br />
*[[Letrozole (Femara)]]<br />
*[[Leuprolide (Lupron)]]<br />
*[[Levamisole (Ergamisol)]] '''discontinued'''<br />
*[[Levoleucovorin (Fusilev)]]<br />
*[[Linifanib (ABT-869)]] '''in clinical trials'''<br />
*[[Linsitinib (OSI-906)]] '''in clinical trials'''<br />
*[[Lisocabtagene maraleucel (Breyanzi)]] '''FDA approved 2/5/2021'''<br />
*[[Lobaplatin (D-19466)]]<br />
*[[Lomustine (CCNU)]]<br />
*[[Loncastuximab tesirine (Zynlonta)]] '''FDA approved 4/23/2021'''<br />
*[[Lorlatinib (Lorbrena)]]<br />
*[[Lorvotuzumab mertansine (BB-10901)]] '''in clinical trials'''<br />
*[[Lurbinectedin (Zepzelca)]] '''FDA approved 6/15/2020'''<br />
*[[Lutetium Lu 177 dotatate (Lutathera)]]<br />
*[[LY3023414]] '''in clinical trials'''<br />
<br />
==M==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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*[[Margetuximab (Margenza)]] '''FDA approved on 12/16/2020'''<br />
*[[Mapatumumab (HGS-ETR1)]] '''in clinical trials'''<br />
*[[Masitinib (AB1010)]] '''in clinical trials'''<br />
*[[Mechlorethamine (Mustargen)]]<br />
*[[Medroxyprogesterone (MPA)]]<br />
*[[Megestrol (Megace)]]<br />
*[[Melphalan (Alkeran)]]<br />
*[[Melphalan flufenamide (Pepaxto)]] '''FDA approved on 2/26/2021'''<br />
*[[Mepolizumab (Nucala)]]<br />
*[[Mercaptopurine (6-MP)]]<br />
*[[Methotrexate (MTX)]]<br />
*[[Methoxsalen (Uvadex)]]<br />
*[[Methylprednisolone (Solumedrol)]]<br />
*[[Midostaurin (Rydapt)]]<br />
*[[Mifamurtide (Mepact)]]<br />
*[[Milataxel (TL139)]] '''in clinical trials'''<br />
*[[Mirvetuximab soravtansine (IMGN853)]] '''in clinical trials'''<br />
*[[Mitomycin (Jelmyto)]] '''FDA approved on 4/15/2020'''<br />
*[[Mitomycin (Mutamycin)]]<br />
*[[Mitotane (Lysodren)]]<br />
*[[Mitoxantrone (Novantrone)]]<br />
*[[MK2206]] '''in clinical trials'''<br />
*[[Mocetinostat (MGCD0103)]] '''in clinical trials'''<br />
*[[Mogamulizumab (Poteligeo)]]<br />
*[[Momelotinib (CYT387)]] '''in clinical trials'''<br />
*[[MOR208]] '''in clinical trials'''<br />
*[[Motesanib (AMG 706)]] '''in clinical trials'''<br />
*[[Moxetumomab pasudotox (Lumoxiti)]]<br />
<br />
==N==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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<br />
*[[Naxitamab-gqgk (Danyelza)]] '''FDA approved 11/24/2020'''<br />
*[[Necitumumab (Portrazza)]]<br />
*[[Nedaplatin (Aqupla)]]<br />
*[[Nelarabine (Arranon)]]<br />
*[[NEOD001]]<br />
*[[Neratinib (Nerlynx)]]<br />
*[[Nilotinib (Tasigna)]]<br />
*[[Nilutamide (Nilandron)]]<br />
*[[Nimotuzumab (Theraloc)]]<br />
*[[Nimustine (ACNU)]]<br />
*[[Nintedanib (Vargatef)]]<br />
*[[Niraparib (Zejula)]]<br />
*[[Nivolumab (Opdivo)]]<br />
*[[Nolatrexed (Thymitaq)]]<br />
*[[Non-pegylated liposomal doxorubicin (Myocet)]]<br />
*[[Norethandrolone (Nilevar)]]<br />
*[[NovoTTF-100A system (Optune)]]<br />
<br />
==O==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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<br />
*[[Obinutuzumab (Gazyva)]]<br />
*[[Octreotide (Sandostatin)]]<br />
*[[Octreotide LAR (Sandostatin LAR)]]<br />
*[[Ofatumumab (Arzerra)]]<br />
*[[Olaparib (Lynparza)]]<br />
*[[Olaptesed pegol (NOX-A12)]] '''in clinical trials'''<br />
*[[Olaratumab (Lartruvo)]] '''discontinued'''<br />
*[[Omacetaxine (Synribo)]]<br />
*[[Onartuzumab (MetMAb)]] '''in clinical trials'''<br />
*[[Oprozomib (ONX 0912)]] '''in clinical trials'''<br />
*[[Orteronel (TAK-700)]] '''in clinical trials'''<br />
*[[Osimertinib (Tagrisso)]]<br />
*[[Osocimab (BAY 1213790)]] '''in clinical trials'''<br />
*[[Otlertuzumab (TRU-016)]] '''in clinical trials'''<br />
*[[Oxaliplatin (Eloxatin)]]<br />
<br />
==P==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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<br />
*[[Paclitaxel (Taxol)]]<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
*[[Paclitaxel, polymeric micelle-bound (Genexol-PM)]]<br />
*[[Pacritinib (SB1518)]] '''in clinical trials'''<br />
*[[Palbociclib (Ibrance)]]<br />
*[[Panitumumab (Vectibix)]]<br />
*[[Panobinostat (Farydak)]]<br />
*[[Pazopanib (Votrient)]]<br />
*[[Pegaspargase (Oncaspar)]]<br />
*[[Peginterferon alfa-2a (Pegasys)]]<br />
*[[Peginterferon alfa-2b (Sylatron)]]<br />
*[[Pembrolizumab (Keytruda)]]<br />
*[[Pemetrexed (Alimta)]]<br />
*[[Pemigatinib (Pemazyre)]] '''FDA approved 4/17/2020'''<br />
*[[Pentostatin (Nipent)]]<br />
*[[Pentraxin 2 (PRM-151)]] '''in clinical trials'''<br />
*[[Perifosine (KRX-0401)]] '''in clinical trials'''<br />
*[[Pertuzumab (Perjeta)]]<br />
*[[Pexidartinib (Turalio)]]<br />
*[[Phosphomannopentaose sulfate (PI-88)]] '''in clinical trials'''<br />
*[[Pictilisib (GDC-0941)]] '''in clinical trials'''<br />
*[[Pidilizumab (CT-011)]] '''in clinical trials'''<br />
*[[Pinatuzumab vedotin (DCDT2980S)]] '''in clinical trials'''<br />
*[[Pirarubicin (THP)]]<br />
*[[Pirtobrutinib (LOXO-305)]] '''in clinical trials'''<br />
*[[Pixantrone (Pixuvri)]]<br />
*[[Plicamycin (Mithracin)]]<br />
*[[Plinabulin (NPI-2358)]] '''in clinical trials'''<br />
*[[Polatuzumab vedotin (Polivy)]]<br />
*[[Pomalidomide (Pomalyst)]]<br />
*[[Ponatinib (Iclusig)]]<br />
*[[Porfimer (Photofrin)]]<br />
*[[Pracinostat (SB939)]] '''in clinical trials'''<br />
*[[Pralatrexate (Folotyn)]]<br />
*[[Pralsetinib (Gavreto)]] '''FDA approved 9/4/2020'''<br />
*[[Prednisone (Sterapred)]]<br />
*[[Prednisolone (Millipred)]]<br />
*[[Procarbazine (Matulane)]]<br />
<br />
==Q==<br />
*[[Quisinostat (JNJ-26481585)]] '''in clinical trials'''<br />
*[[Quizartinib (AC220)]] '''in clinical trials'''<br />
<br />
==R==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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<br />
*[[Radium Ra 223 (Xofigo)]]<br />
*[[Radotinib (Supect)]]<br />
*[[Raltitrexed (Tomudex)]]<br />
*[[Ramucirumab (Cyramza)]]<br />
*[[Ranimustine (Cymerin)]]<br />
*[[Ravulizumab (Ultomiris)]]<br />
*[[Realgar-Indigo naturalis formulation]]<br />
*[[Refametinib (BAY 869766)]] '''in clinical trials'''<br />
*[[Regorafenib (Stivarga)]]<br />
*[[Relugolix (Orgovyx)]] '''FDA approved 12/18/2020'''<br />
*[[Reovirus (Reolysin)]] '''in clinical trials'''<br />
*[[Retaspimycin (IPI-504)]] '''in clinical trials'''<br />
*[[Ribociclib (Kisqali)]]<br />
*[[Ricolinostat (ACY-1215, Rocilinostat)]] '''in clinical trials'''<br />
*[[Ridaforolimus (AP23573)]] '''in clinical trials'''<br />
*[[Rilotumumab (AMG 102)]] '''in clinical trials'''<br />
*[[Ripretinib (Qinlock)]] '''FDA approved 5/15/2020'''<br />
*[[Rituximab (Rituxan)]]<br />
**[[Rituximab-abbs (Truxima)]]<br />
**[[Rituximab-pvvr (Ruxience)]]<br />
*[[Rituximab and hyaluronidase human (Rituximab Hycela)]]<br />
*[[Rociletinib (CO-1686)]] '''in clinical trials'''<br />
*[[Romidepsin (Istodax)]]<br />
*[[Ropeginterferon alfa-2b (AOP2014)]] '''in clinical trials'''<br />
*[[Rucaparib (Rubraca)]]<br />
*[[Ruxolitinib (Jakafi)]]<br />
<br />
==S==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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<br />
*[[Sacituzumab govitecan (Trodelvy)]] '''FDA approved 4/22/2020'''<br />
*[[Samarium-153 (Quadramet)]]<br />
*[[Sapacitabine (CS-682)]] '''in clinical trials'''<br />
*[[Sapanisertib (MLN0128)]] '''in clinical trials'''<br />
*[[Seliciclib (CYC202)]] '''in clinical trials'''<br />
*[[Selinexor (Xpovio)]]<br />
*[[Selpercatinib (Retevmo)]] '''FDA approved 5/8/2020'''<br />
*[[Selumetinib (Koselugo)]] '''FDA approved 4/10/2020'''<br />
*[[Semuloparin (AVE5026)]] '''in clinical trials'''<br />
*[[Semustine (MeCCNU)]]<br />
*[[Sintilimab (IBI 308)]] '''in clinical trials'''<br />
*[[Sipuleucel-T (Provenge)]]<br />
*[[Sonidegib (Odomzo)]]<br />
*[[Sorafenib (Nexavar)]]<br />
*[[Sotorasib (AMG 510)]] '''in clinical trials'''<br />
*[[Spebrutinib (CC-292)]] '''in clinical trials'''<br />
*[[Stilbamidine]]<br />
*[[Streptozocin (Zanosar)]]<br />
*[[Strontium-89 (Metastron)]]<br />
*[[Sunitinib (Sutent)]]<br />
*[[Surufatinib (HMPL-012)]] '''in clinical trials'''<br />
*[[Sutimlimab (BIVV009)]] '''in clinical trials'''<br />
<br />
==T==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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<br />
*[[Tabalumab (LY2127399)]] '''in clinical trials'''<br />
*[[Tafasitamab (Monjuvi)]] '''FDA approved 7/31/2020'''<br />
*[[Tagraxofusp (Elzonris)]]<br />
*[[Talazoparib (Talzenna)]]<br />
*[[Talimogene laherparepvec (Imlygic)]]<br />
*[[Tamibarotene (Amnoid)]] '''in clinical trials'''<br />
*[[Tamoxifen (Nolvadex)]]<br />
*[[Tazemetostat (Tazverik)]] '''FDA approved 1/23/2020'''<br />
*[[Tegafur and uracil (UFT)]]<br />
*[[Tegafur, gimeracil, oteracil (Teysuno, S-1)]]<br />
*[[Telotristat (Xermelo)]]<br />
*[[Temozolomide (Temodar)]]<br />
*[[Temsirolimus (Torisel)]]<br />
*[[Teniposide (Vumon)]]<br />
*[[Tepotinib (Tepmetko)]] '''FDA approved 2/3/2021'''<br />
*[[Tesetaxel (DJ-927)]] '''in clinical trials'''<br />
*[[Tesevatinib (XL647)]] '''in clinical trials'''<br />
*[[Testolactone (Teslac)]] '''discontinued'''<br />
*[[Thalidomide (Thalomid)]]<br />
*[[Thioguanine (Tabloid)]]<br />
*[[Thiotepa (Tepadina)]]<br />
*[[Thiotepa (Thioplex)]]<br />
*[[Tigatuzumab (CS-1008)]] '''in clinical trials'''<br />
*[[Tipifarnib (Zarnestra)]] '''in clinical trials'''<br />
*[[Tirabrutinib (GS-4059)]] '''in clinical trials'''<br />
*[[Tisagenlecleucel (Kymriah)]]<br />
*[[Tisotumab vedotin (HuMax-TF-ADC)]] '''in clinical trials'''<br />
*[[Tivantinib (ARQ 197)]] '''in clinical trials'''<br />
*[[Tivozanib (AV-951)]] '''in clinical trials'''<br />
*[[Topotecan (Hycamtin)]]<br />
*[[Toremifene (Fareston)]]<br />
*[[Tosedostat (CHR-2797)]] '''in clinical trials'''<br />
*[[Tositumomab and I-131 (Bexxar)]]<br />
*[[Trabectedin (Yondelis)]]<br />
*[[Trametinib (Mekinist)]]<br />
*[[Trastuzumab (Herceptin)]]<br />
**[[Trastuzumab-anns (Kanjinti)]]<br />
**[[Trastuzumab-dkst (Ogivri)]]<br />
**[[Trastuzumab-dttb (Ontruzant)]]<br />
**[[Trastuzumab-pkrb (Herzuma)]]<br />
**[[Trastuzumab-qyyp (Trazimera)]]<br />
*[[Trastuzumab and hyaluronidase (Herceptin Hylecta)]]<br />
*[[Trebananib (AMG 386)]] '''in clinical trials'''<br />
*[[Tremelimumab (ticilimumab)]] '''in clinical trials'''<br />
*[[Treosulfan (Ovastat)]]<br />
*[[Trifluridine and tipiracil (Lonsurf)]]<br />
*[[Trilostane (Vetoryl)]]<br />
*[[Trimetrexate (Neutrexin)]]<br />
*[[Triptorelin (Trelstar LA)]]<br />
*[[Tucatinib (Tukysa)]] '''FDA approved 4/17/2020'''<br />
<br />
==U==<br />
<br />
*[[Ublituximab (TG-1101)]] '''in clinical trials'''<br />
*[[UCART19]] '''in clinical trials'''<br />
*[[Umbralisib (Ukoniq)]] '''FDA approved 2/5/2021'''<br />
*[[Uracil mustard]]<br />
*[[Urethane]]<br />
<br />
==V==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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<br />
*[[Vadastuximab talirine (SGN-CD33A)]] '''in clinical trials'''<br />
*[[Valrubicin (Valstar)]]<br />
*[[Vandetanib (Caprelsa)]]<br />
*[[Varlilumab (CDX-1127)]] '''in clinical trials'''<br />
*[[Veliparib (ABT-888)]] '''in clinical trials'''<br />
*[[Veltuzumab (hA20)]] '''in clinical trials'''<br />
*[[Vemurafenib (Zelboraf)]]<br />
*[[Venetoclax (Venclexta)]]<br />
*[[Vinblastine (Velban)]]<br />
*[[Vincristine (Oncovin)]]<br />
*[[Vincristine liposomal (Marqibo)]]<br />
*[[Vindesine (Eldisine)]]<br />
*[[Vinflunine (Javlor)]]<br />
*[[Vinorelbine (Navelbine)]]<br />
*[[Vismodegib (Erivedge)]]<br />
*[[Volasertib (BI 6727)]] '''in clinical trials'''<br />
*[[Vorinostat (Zolinza)]]<br />
*[[Vosaroxin (SNS 595)]] '''in clinical trials'''<br />
*[[Voxelotor (Oxbryta)]]<br />
*[[Voxtalisib (XL765)]] '''in clinical trials'''<br />
<br />
==Z==<br />
*[[Zandelisib (ME-401)]] '''in clinical trials'''<br />
*[[Zanubrutinib (Brukinsa)]]<br />
*[[Ziv-aflibercept (Zaltrap)]]<br />
<br />
=Supportive and other medications=<br />
<br />
==A==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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*[[Abciximab (ReoPro)]]<br />
*[[Acetaminophen (Tylenol)]]<br />
*[[Acetazolamide (Diamox)]]<br />
*[[Acyclovir (Zovirax)]]<br />
*[[Alendronate (Fosamax)]]<br />
*[[Alizapride (Litican)]]<br />
*[[Allopurinol (Zyloprim)]]<br />
*[[Alprazolam (Xanax)]]<br />
*[[Aminocaproic acid (Amicar)]]<br />
*[[Amoxicillin]]<br />
*[[Anagrelide (Agrylin)]]<br />
*[[Anti-inhibitor coagulant complex (FEIBA NF)]]<br />
*[[Antithrombin III (human and recombinant)]]<br />
*[[Antithymocyte globulin, horse ATG (Atgam)]]<br />
*[[Antithymocyte globulin, rabbit ATG (Grafalon)]]<br />
*[[Antithymocyte globulin, rabbit ATG (Thymoglobulin)]]<br />
*[[Apixaban (Eliquis)]]<br />
*[[Aprepitant (Emend)]]<br />
*[[Argatroban (Acova)]]<br />
*[[Aripiprazole (Abilify)]]<br />
*[[Ascorbic acid (Vitamin C)]]<br />
*[[Aspirin]]<br />
*[[Aspirin and dipyridamole (Aggrenox)]]<br />
*[[Atropine (Atropen)]]<br />
*[[Atovaquone (Mepron)]]<br />
*[[Avatrombopag (Doptelet)]]<br />
*[[Azathioprine (Imuran)]]<br />
<br />
==B==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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*[[Betrixaban (Bevyxxa)]]<br />
*[[Bismuth subsalicylate (Pepto-Bismol)]]<br />
*[[Bivalirudin (Angiomax)]]<br />
<br />
==C==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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*[[Cangrelor (Kengreal)]]<br />
*[[Calcium phosphate rinse (Caphosol)]]<br />
*[[Cetirizine (Zyrtec)]]<br />
*[[Chlorpheniramine (Chlor-Trimeton)]]<br />
*[[Cilostazol (Pletal)]]<br />
*[[Cimetidine (Tagamet)]]<br />
*[[Ciprofloxacin (Cipro)]]<br />
*[[Clarithromycin (Biaxin)]]<br />
*[[Clemastine (Tavist)]]<br />
*[[Clodronate (Bonefos)]]<br />
*[[Clopidogrel (Plavix)]]<br />
*[[Crizanlizumab (Adakveo)]]<br />
*[[Cyanocobalamin (Vitamin B12)]]<br />
*[[Cyclosporine modified (Neoral)]]<br />
*[[Cyclosporine non-modified (Sandimmune)]]<br />
*[[Cytomegalovirus Immune Globulin (Cytogam)]]<br />
<br />
==D==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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*[[Dabigatran (Pradaxa)]]<br />
*[[Dalteparin (Fragmin)]]<br />
*[[Danazol (Danocrine)]]<br />
*[[Dapsone (Aczone)]]<br />
*[[Darbepoetin alfa (Aranesp)]]<br />
*[[Deferasirox (Exjade)]]<br />
*[[Deferasirox (Jadenu)]]<br />
*[[Deferiprone (Ferriprox)]]<br />
*[[Deferoxamine (Desferal)]]<br />
*[[Defibrotide (Defitelio)]]<br />
*[[Denosumab (Xgeva)]]<br />
*[[Desmopressin (DDAVP)]]<br />
*[[Dexchlorpheniramine (Polaramine)]]<br />
*[[Dexrazoxane (Zinecard)]]<br />
*[[Diphenhydramine (Benadryl)]]<br />
*[[Dipyridamole (Persantine)]]<br />
*[[Docusate (Colace)]]<br />
*[[Dolasetron (Anzemet)]]<br />
*[[Domperidone (Motilium)]]<br />
*[[Doxycycline]]<br />
*[[Dronabinol (Marinol)]]<br />
<br />
==E==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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*[[Eculizumab (Soliris)]]<br />
*[[Edoxaban (Savaysa)]]<br />
*[[Eltrombopag (Promacta)]]<br />
*[[Emicizumab-kxwh (Hemlibra)]]<br />
*[[Enoxaparin (Lovenox)]]<br />
*[[Epoetin alfa (Procrit)]]<br />
*[[Epoetin alfa-epbx (Retacrit)]]<br />
*[[Eptifibatide (Integrilin)]]<br />
<br />
==F==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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*[[Factor VIIa, recombinant (NovoSeven RT)]]<br />
*[[Factor VIII, human]]<br />
*[[Factor VIII, recombinant]]<br />
*[[Factor IX, human]]<br />
*[[Factor IX, recombinant]]<br />
*[[Factor IX, recombinant, Fc fusion protein (Alprolix)]]<br />
*[[Factor X, human (Coagadex)]]<br />
*[[Factor Xa, recombinant, inactivated-zhzo (Andexxa)]]<br />
*[[Factor XIII concentrate, human (Corifact)]]<br />
*[[Famciclovir (Famvir)]]<br />
*[[Famotidine (Pepcid)]]<br />
*[[Ferric carboxymaltose (Injectafer)]]<br />
*[[Ferric gluconate (Ferrlecit)]]<br />
*[[Ferrous sulfate (Feosol)]]<br />
*[[Ferumoxytol (Feraheme)]]<br />
*[[Fibrinogen concentrate, human (RiaSTAP)]]<br />
*[[Filgrastim (Neupogen)]]<br />
**[[Filgrastim-aafi (Nivestym)]]<br />
**[[Filgrastim-sndz (Zarxio)]]<br />
*[[Finasteride (Proscar)]]<br />
*[[Fluconazole (Diflucan)]]<br />
*[[Folic acid (Folate)]]<br />
*[[Fondaparinux (Arixtra)]]<br />
*[[Fosaprepitant (Emend for Injection)]]<br />
*[[Furosemide (Lasix)]]<br />
<br />
==G==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
*[[Glucarpidase (Voraxaze)]]<br />
*[[Granisetron (Kytril)]]<br />
*[[Granisetron (Sancuso)]]<br />
*[[Granisetron (Sustol)]]<br />
<br />
==H==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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*[[Haloperidol (Haldol)]]<br />
*[[Hematopoetic progenitor cells, cord blood (Hemacord)]]<br />
<br />
==I==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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*[[Ibandronate (Boniva)]]<br />
*[[Idarucizumab (Praxbind)]]<br />
*[[Indomethacin (Indocin)]]<br />
*[[Iron dextran (INFeD)]]<br />
*[[Iron sucrose (Venofer)]]<br />
*[[Itraconazole (Sporanox)]]<br />
<br />
==L==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
*[[Lactulose]]<br />
*[[Lamivudine (Epivir)]]<br />
*[[Lansoprazole (Prevacid)]]<br />
*[[Lenograstim (Granocyte)]]<br />
*[[Lepirudin (Refludan)]] '''discontinued'''<br />
*[[Levofloxacin (Levaquin)]]<br />
*[[L-glutamine (Endari)]]<br />
*[[Lipefilgrastim (XM22)]] '''in clinical trials'''<br />
*[[Loperamide (Imodium)]]<br />
*[[Lorazepam (Ativan)]]<br />
*[[Luspatercept (Reblozyl)]]<br />
*[[Lusutrombopag (Mulpleta)]]<br />
<br />
==M==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<br />
*[[Mannitol]]<br />
*[[Meperidine (Demerol)]]<br />
*[[Mesna (Mesnex)]]<br />
*[[Methyltesterone (Android)]]<br />
*[[Metoclopramide (Reglan)]]<br />
*[[Mycophenolate mofetil (CellCept)]]<br />
<br />
==N==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<br />
*[[Nabilone (Cesamet)]]<br />
*[[Netupitant and palonosetron (Akynzeo)]]<br />
<br />
==O==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
*[[Olanzapine (Zyprexa)]]<br />
*[[Omeprazole (Prilosec)]]<br />
*[[Ondansetron (Zofran)]]<br />
*[[Oprelvekin (Neumega)]]<br />
<br />
==P==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<br />
*[[Palifermin (Kepivance)]]<br />
*[[Palonosetron (Aloxi)]]<br />
*[[Pamidronate (Aredia)]]<br />
*[[Pantoprazole (Protonix)]]<br />
*[[Pegfilgrastim (Neulasta)]]<br />
**[[Pegfilgrastim-bmez (Ziextenzo)]]<br />
**[[Pegfilgrastim-cbqv (Udenyca)]]<br />
**[[Pegfilgrastim-jmdb (Fulphila)]]<br />
*[[Penicillin V]]<br />
*[[Pentamidine (Nebupent)]]<br />
*[[Phenytoin (Dilantin)]]<br />
*[[Phytonadione (Vitamin K)]]<br />
*[[Plerixafor (Mozobil)]]<br />
*[[Prasugrel (Effient)]]<br />
*[[Pravastatin (Pravachol)]]<br />
*[[Prochlorperazine (Compazine)]]<br />
*[[Promethazine (Phenergan)]]<br />
*[[Protamine sulfate]]<br />
*[[Prothrombin Complex Concentrate, human]]<br />
<br />
==Q==<br />
<br />
*[[Quinine (Qualaquin)]]<br />
<br />
==R==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
<br />
*[[Rabeprazole (Aciphex)]]<br />
*[[Raloxifene (Evista)]]<br />
*[[Ramosetron (Iribo)]]<br />
*[[Ranitidine (Zantac)]]<br />
*[[Rasburicase (Elitek)]]<br />
*[[Rho(D) immune globulin (RhoGAM)]]<br />
*[[Risedronate (Actonel)]]<br />
*[[Rivaroxaban (Xarelto)]]<br />
*[[Rolapitant (Varubi)]]<br />
*[[Romiplostim (Nplate)]]<br />
<br />
==S==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
*[[Sargramostim (Leukine)]]<br />
*[[Scopolamine (Scopoderm)]]<br />
*[[Sennosides (Senna)]]<br />
*[[Siltuximab (Sylvant)]]<br />
*[[Sirolimus (Rapamune)]]<br />
<br />
==T==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
*[[Tacrolimus (Prograf)]]<br />
*[[Tbo-filgrastim (Granix)]]<br />
*[[Ticagrelor (Brilinta)]]<br />
*[[Ticlodipine (Ticlid)]]<br />
*[[Tinzaparin (Innohep)]]<br />
*[[Tirofiban (Aggrastat)]]<br />
*[[Tocilizumab (Actemra)]]<br />
*[[Tofacitinib (Xeljanz)]]<br />
*[[Tranexamic acid (Cyklokapron)]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]]<br />
*[[Tropisetron (Navoban)]]<br />
<br />
==U==<br />
*[[Unfractionated heparin (UFH)]]<br />
*[[Uridine triacetate (Vistogard)]]<br />
<br />
==V==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
*[[Valacyclovir (Valtrex)]]<br />
*[[Valganciclovir (Valcyte)]]<br />
*[[Valproate (Depakote)]]<br />
*[[von Willebrand factor and factor VIII complex, human]]<br />
*[[von Willebrand factor, recombinant]]<br />
*[[Vorapaxar (Zontivity)]]<br />
*[[Voriconazole (Vfend)]]<br />
<br />
==W==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
<br />
*[[Warfarin (Coumadin)]]<br />
<br />
==Z==<br />
*[[Zoledronic acid (Zometa)]]<br />
<br />
=By Category=<br />
''Selecting a category here will take you to a new page listing all drugs in that category (note: drug categorization is still in process so not all of these links are active).''<br />
<br />
==[[:Category:REMS_program|Drugs in a REMS program]]==<br />
<br />
==Cytotoxic Chemotherapy==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<br />
*[[:Category:Alkylating agents|Alkylating agents]]<br />
*[[:Category:Anthracyclines|Anthracyclines]]<br />
*[[:Category:Antimetabolites|Antimetabolites]]<br />
*[[:Category:Human DNA synthesis inhibitors|DNA synthesis inhibitors]]<br />
*[[:Category:Microtubule inhibitors|Microtubule inhibitors]]<br />
*[[:Category:Nitrogen mustards|Nitrogen mustards]]<br />
*[[:Category:Nitrosureas|Nitrosureas]]<br />
*[[:Category:Platinum agents|Platinum agents]]<br />
*[[:Category:Proteasome inhibitors|Proteasome inhibitors]]<br />
*[[:Category:Taxanes|Taxanes]]<br />
*[[:Category:Topoisomerase inhibitors|Topoisomerase inhibitors]]<br />
*[[:Category:Vinca alkaloids|Vinca alkaloids]]<br />
<br />
==[[:Category:Kinase inhibitors|Kinase inhibitors]]==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<div style="column-count:2;-moz-column-count:2;-webkit-column-count:2"><br />
*[[:Category:AKT1 inhibitors|AKT1 inhibitors]]<br />
*[[:Category:ALK inhibitors|ALK inhibitors]]<br />
*[[:Category:Aurora kinase inhibitors|Aurora kinase inhibitors]]<br />
*[[:Category:AXL inhibitors|AXL inhibitors]]<br />
*[[:Category:Bcr-Abl inhibitors|Bcr-Abl inhibitors]]<br />
*[[:Category:BRAF inhibitors|BRAF inhibitors]]<br />
*[[:Category:BTK inhibitors|BTK inhibitors]]<br />
*[[:Category:CDK inhibitors|CDK inhibitors]]<br />
*[[:Category:EGFR inhibitors|EGFR inhibitors]]<br />
*[[:Category:ERBB2 inhibitors|ERBB2 inhibitors]]<br />
*[[:Category:ERBB4 inhibitors|ERBB4 inhibitors]]<br />
*[[:Category:FGFR inhibitors|FGFR inhibitors]]<br />
*[[:Category:FLT3 inhibitors|FLT3 inhibitors]]<br />
*[[:Category:IGFR inhibitors|IGFR inhibitors]]<br />
*[[:Category:JAK inhibitors|JAK inhibitors]]<br />
*[[:Category:KIT inhibitors|KIT inhibitors]]<br />
*[[:Category:MEK inhibitors|MEK inhibitors]]<br />
*[[:Category:MET inhibitors|MET inhibitors]]<br />
*[[:Category:mTOR inhibitors|mTOR inhibitors]]<br />
*[[:Category:PDGFR inhibitors|PDGFR inhibitors]]<br />
*[[:Category:PI3K inhibitors|PI3K inhibitors]]<br />
*[[:Category:PLK1 inhibitors|PLK1 inhibitors]]<br />
*[[:Category:RET inhibitors|RET inhibitors]]<br />
*[[:Category:ROS1 inhibitors|ROS1 inhibitors]]<br />
*[[:Category:SRC inhibitors|SRC inhibitors]]<br />
*[[:Category:SYK inhibitors|SYK inhibitors]]<br />
*[[:Category:TEK inhibitors|TEK inhibitors]]<br />
*[[:Category:TRK inhibitors|TRK inhibitors]]<br />
*[[:Category:VEGFR inhibitors|VEGF inhibitors]]<br />
</div><br />
<br />
==[[:Category:Endocrine therapeutic|Endocrine therapy]]==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<br />
*[[:Category:Antiandrogens|Antiandrogens]]<br />
*[[:Category:Steroid synthesis inhibitors|Steroid synthesis inhibitors]]<br />
*[[:Category:Androgen receptor inhibitors|Androgen receptor inhibitors]]<br />
*[[:Category:5 alpha-reductase inhibitors|5 alpha-reductase inhibitors]]<br />
*[[:Category:GnRH agonists|GnRH agonists]]<br />
*[[:Category:GnRH antagonists|GnRH antagonists]]<br />
*[[:Category:Aromatase inhibitors|Aromatase inhibitors]]<br />
*[[:Category:Selective estrogen receptor modulators|Selective estrogen receptor modulators]]<br />
*[[:Category:Steroids|Steroids]]<br />
*[[:Category:Somatostatin analogs|Somatostatin analogs]]<br />
<br />
==Investigational and Discontinued==<br />
<br />
*[[:Category:Investigational_drugs|Investigational]]<br />
*[[:Category:Discontinued_drugs|Discontinued]]<br />
<br />
==Biologics==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<br />
*[[:Category:Antibody medications|Antibody medications]]<br />
*[[:Category:Antibody-drug conjugates|Antibody-drug conjugates]]<br />
*[[:Category:Anti-HER2 medications|Anti-HER2 medications]]<br />
*[[:Category:IL-6 inhibitors|IL-6 inhibitors]]<br />
*[[:Category:Enzymes|Enzymes]]<br />
*[[:Category:Immunotherapeutic|Immunotherapy]]<br />
*[[:Category:Immunomodulatory drugs (IMiDs)|Immunomodulatory drugs (IMiDs)]]<br />
<br />
==Supportive Medications==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
*[[:Category:Antibacterials|Antibacterials]]<br />
*[[:Category:Antidiarrheals|Antidiarrheals]]<br />
*[[:Category:Antifungals|Antifungals]]<br />
*[[:Category:Antihistamines|Antihistamines]]<br />
*[[:Category:Antivirals|Antivirals]]<br />
*[[:Category:Bisphosphonates|Bisphosphonates]]<br />
*[[:Category:Chemotherapy protective agents|Chemotherapy protective agents]]<br />
*[[:Category:Emesis prevention|Emesis prevention]]<br />
*[[:Category:PCP prophylaxis|PCP prophylaxis]]<br />
*[[:Category:RANK ligand inhibitors|RANK ligand inhibitors]]<br />
*[[:Category:Steroids|Steroids]]<br />
<br />
==[[:Category:Radioactive agents|Radioactive agents]]==<br />
<br />
*[[:Category:Alpha emitters|Alpha emitters]]<br />
*[[:Category:Radioimmunotherapy|Radioimmunotherapy]]<br />
<br />
==[[:Category:Hematology medications|Benign Hematology Medications]]==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<br />
*[[:Category:Anticoagulants|Anticoagulants]]<br />
**[[:Category:Direct thrombin inhibitors|Direct thrombin inhibitors (DTI)]]<br />
**[[:Category:Factor Xa inhibitors|Factor Xa inhibitors]]<br />
**[[:Category:Heparins|Heparins]]<br />
**[[:Category:Low molecular weight heparins|Low molecular weight heparins (LMWH)]]<br />
**[[:Category:Vitamin K antagonists|Vitamin K antagonists (VKA)]]<br />
*[[:Category:Antiplatelet agents|Antiplatelet agents (APA)]]<br />
**[[:Category:Phosphodiesterase inhibitors|Phosphodiesterase inhibitors]]<br />
**[[:Category:Cyclooxygenase inhibitors|Cyclooxygenase inhibitors]]<br />
**[[:Category:P2Y12 ADP inhibitors|P2Y12 ADP inhibitors]]<br />
*[[:Category:Hemostasis medications|Hemostasis medications]]<br />
**[[:Category:Coagulation factors|Coagulation factors]]<br />
**[[:Category:Fibrinolysis inhibitors|Fibrinolysis inhibitors]]<br />
**[[:Category:Vasopressin analogs|Vasopressin analogs]]<br />
*[[:Category:Chelators|Chelators]]<br />
<br />
==[[:Category:Hematopoietic growth factors|Hematopoietic Growth Factors]]==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<br />
*[[:Category:Erythrocyte growth factors|Erythrocyte growth factors]]<br />
*[[:Category:Granulocyte colony-stimulating factors|Granulocyte growth factors]]<br />
*[[:Category:Megakaryocyte growth factors|Megakaryocyte growth factors]]<br />
<br />
==Miscellaneous==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<br />
*[[:Category:REMS_program|Drugs in a REMS program]]<br />
*[[:Category:HDAC inhibitors|HDAC inhibitors]]<br />
*[[:Category:Hypomethylating agents|Hypomethylating agents]]<br />
*[[:Category:Retinoids|Retinoids]]<br />
*[[:Category:WHO_Essential_Cancer_Medicine|WHO Essential Cancer Medicines]]<br />
<br />
==Medications by Condition==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<div style="column-count:3;-moz-column-count:3;-webkit-column-count:3"><br />
*[[:Category:B-cell acute lymphoblastic leukemia medications|Acute lymphocytic leukemia medications]]<br />
*[[:Category:Acute myeloid leukemia medications|Acute myeloid leukemia medications]]<br />
*[[:Category:Acute promyelocytic leukemia medications|Acute promyelocytic leukemia medications]]<br />
*[[:Category:Anal cancer medications|Anal cancer medications]]<br />
*[[:Category:Anaplastic large cell lymphoma medications|Anaplastic large cell lymphoma medications]]<br />
*[[:Category:Basal cell and squamous cell skin cancer medications|Basal cell and squamous cell skin cancer medications]]<br />
*[[:Category:Bladder cancer medications|Bladder cancer medications]]<br />
*[[:Category:Bone cancer medications |Bone cancer medications]]<br />
*[[:Category:Breast cancer medications|Breast cancer medications]]<br />
*[[:Category:Burkitt lymphoma medications|Burkitt lymphoma medications]]<br />
*[[:Category:Cancer of unknown primary medications |Cancer of unknown primary medications]]<br />
*[[:Category:Castleman’s disease medications|Castleman’s disease medications]]<br />
*[[:Category:Central nervous system (CNS) cancer medications|Central nervous system (CNS) cancer medications]]<br />
*[[:Category:CNS lymphoma medications|Central nervous system (CNS) lymphoma medications]]<br />
*[[:Category:Cervical cancer medications|Cervical cancer medications]]<br />
*[[:Category:Chronic lymphocytic leukemia medications|Chronic lymphocytic leukemia (CLL/SLL) medications]]<br />
*[[:Category:Chronic myelogenous leukemia medications|Chronic myelogenous leukemia medications]]<br />
*[[:Category:Chronic myelomonocytic leukemia medications|Chronic myelomonocytic leukemia medications]]<br />
*[[:Category:Colon cancer medications|Colon cancer medications]]<br />
*[[:Category:Cutaneous T-cell lymphoma medications|Cutaneous T-cell lymphoma medications]]<br />
*[[:Category:Diffuse large B-cell lymphoma medications|Diffuse large B-cell lymphoma medications]]<br />
*[[:Category:Endometrial cancer medications|Endometrial cancer medications]]<br />
*[[:Category:Esophageal cancer medications|Esophageal cancer medications]]<br />
*[[:Category:Essential thrombocythemia medications|Essential thrombocythemia medications]]<br />
*[[:Category:Extranodal NK- and T-cell lymphoma, nasal type medications|Extranodal NK/T-cell lymphoma, nasal type lymphoma medications]]<br />
*[[:Category:Follicular lymphoma medications|Follicular lymphoma medications]]<br />
*[[:Category:Gastric cancer medications|Gastric cancer medications]]<br />
*[[:Category:Hairy cell leukemia medications|Hairy cell leukemia medications]]<br />
*[[:Category:Head and neck cancer medications|Head and neck cancer medications]]<br />
*[[:Category:Hepatobiliary cancer medications|Hepatobiliary cancer medications]]<br />
*[[:Category:HIV-associated lymphoma medications|HIV-associated lymphoma medications]]<br />
*[[:Category:Hodgkin lymphoma medications|Hodgkin lymphoma medications]]<br />
*[[:Category:Hodgkin lymphoma, nodular lymphocyte-predominant medications|Hodgkin lymphoma, nodular lymphocyte-predominant medications]]<br />
*[[:Category:Immune thrombocytopenia medications|Immune thrombocytopenic purpura (ITP) medications]]<br />
*[[:Category:Light-chain (AL) amyloidosis medications|Light-chain (AL) amyloidosis medications]]<br />
*[[:Category:Mantle cell lymphoma medications|Mantle cell lymphoma medications]]<br />
*[[:Category:Marginal zone lymphoma medications|Marginal zone lymphoma medications]]<br />
*[[:Category:Mediastinal gray-zone lymphoma medications|Mediastinal gray-zone lymphoma medications]]<br />
*[[:Category:Melanoma medications |Melanoma medications]]<br />
*[[:Category:Mesothelioma medications|Mesothelioma medications]]<br />
*[[:Category:Multiple myeloma medications|Multiple myeloma medications]]<br />
*[[:Category:Myelodysplastic syndrome medications|Myelodysplastic syndrome medications]]<br />
*[[:Category:Myelofibrosis medications|Myelofibrosis medications]]<br />
*[[:Category:NK- and T-cell lymphoma medications|NK/T-cell lymphoma medications]]<br />
*[[:Category:Non-small cell lung cancer medications|Non-small cell lung cancer medications]]<br />
*[[:Category:Neuroendocrine tumor medications|Neuroendocrine tumor medications]]<br />
*[[:Category:Ovarian cancer medications|Ovarian cancer medications]]<br />
*[[:Category:Pancreatic cancer medications |Pancreatic cancer medications]]<br />
*[[:Category:Paroxysmal nocturnal hemoglobinuria medications|Paroxysmal nocturnal hemoglobinuria (PNH) medications]]<br />
*[[:Category:Penile cancer medications |Penile cancer medications]]<br />
*[[:Category:Peripheral T-cell lymphoma medications|Peripheral T-cell lymphoma medications]]<br />
*[[:Category:Plasma cell leukemia medications|Plasma cell leukemia medications]]<br />
*[[:Category:Polycythemia vera medications|Polycythemia vera medications]]<br />
*[[:Category:Primary mediastinal B-cell lymphoma medications|Primary mediastinal B-cell lymphoma medications]]<br />
*[[:Category:Prostate cancer medications|Prostate cancer medications]]<br />
*[[:Category:Rectal cancer medications|Rectal cancer medications]]<br />
*[[:Category:Renal cell carcinoma medications|Renal cell carcinoma medications]]<br />
*[[:Category:Sarcoma medications |Sarcoma medications]]<br />
*[[:Category:Sickle cell anemia medications|Sickle cell anemia medications]]<br />
*[[:Category:Small cell lung cancer medications|Small cell lung cancer medications]]<br />
*[[:Category:T-cell lymphoma medications|T-cell lymphoma medications]]<br />
*[[:Category:Testicular cancer medications|Testicular cancer medications]]<br />
*[[:Category:Thymoma medications|Thymoma medications]]<br />
*[[:Category:Thyroid cancer medications|Thyroid cancer medications]]<br />
*[[:Category:Transformed lymphoma medications|Transformed lymphoma medications]]<br />
*[[:Category:Transplant medications|Transplant medications]]<br />
*[[:Category:Waldenström macroglobulinemia medications|Waldenström macroglobulinemia medications]]<br />
</div><br />
<br />
==[[:Category:Routed medications|Medications by Route of Administration]]==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
<br />
*[[:Category:Intra-arterial medications|Intraarterial (IA) medications]]<br />
*[[:Category:Intracavitary medications|Intracavitary medications]]<br />
*[[:Category:Intramuscular medications|Intramuscular (IM) medications]]<br />
*[[:Category:Intrathecal medications|Intrathecal (IT) medications]]<br />
*[[:Category:Intravenous medications|Intravenous (IV) medications]]<br />
*[[:Category:Intravesical medications|Intravesicular medications]]<br />
*[[:Category:Oral medications|Oral (PO) medications]]<br />
*[[:Category:Subcutaneous medications|Subcutaneous (SC) medications]]<br />
<br />
==Medications by Year of Approval==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<div style="column-count:3;-moz-column-count:3;-webkit-column-count:3"><br />
*[[:Category:FDA approved in 1939|FDA approved in 1939]]<br />
*[[:Category:FDA approved in 1941|FDA approved in 1941]]<br />
*[[:Category:FDA approved in 1946|FDA approved in 1946]]<br />
*[[:Category:FDA approved in 1949|FDA approved in 1949]]<br />
*[[:Category:FDA approved in 1951|FDA approved in 1951]]<br />
*[[:Category:FDA approved in 1952|FDA approved in 1952]]<br />
*[[:Category:FDA approved in 1953|FDA approved in 1953]]<br />
*[[:Category:FDA approved in 1954|FDA approved in 1954]]<br />
*[[:Category:FDA approved in 1955|FDA approved in 1955]]<br />
*[[:Category:FDA approved in 1956|FDA approved in 1956]]<br />
*[[:Category:FDA approved in 1957|FDA approved in 1957]]<br />
*[[:Category:FDA approved in 1958|FDA approved in 1958]]<br />
*[[:Category:FDA approved in 1959|FDA approved in 1959]]<br />
*[[:Category:FDA approved in 1962|FDA approved in 1962]]<br />
*[[:Category:FDA approved in 1963|FDA approved in 1963]]<br />
*[[:Category:FDA approved in 1964|FDA approved in 1964]]<br />
*[[:Category:FDA approved in 1965|FDA approved in 1965]]<br />
*[[:Category:FDA approved in 1966|FDA approved in 1966]]<br />
*[[:Category:FDA approved in 1967|FDA approved in 1967]]<br />
*[[:Category:FDA approved in 1968|FDA approved in 1968]]<br />
*[[:Category:FDA approved in 1969|FDA approved in 1969]]<br />
*[[:Category:FDA approved in 1970|FDA approved in 1970]]<br />
*[[:Category:FDA approved in 1971|FDA approved in 1971]]<br />
*[[:Category:FDA approved in 1973|FDA approved in 1973]]<br />
*[[:Category:FDA approved in 1974|FDA approved in 1974]]<br />
*[[:Category:FDA approved in 1975|FDA approved in 1975]]<br />
*[[:Category:FDA approved in 1976|FDA approved in 1976]]<br />
*[[:Category:FDA approved in 1977|FDA approved in 1977]]<br />
*[[:Category:FDA approved in 1978|FDA approved in 1978]]<br />
*[[:Category:FDA approved in 1979|FDA approved in 1979]]<br />
*[[:Category:FDA approved in 1980|FDA approved in 1980]]<br />
*[[:Category:FDA approved in 1981|FDA approved in 1981]]<br />
*[[:Category:FDA approved in 1982|FDA approved in 1982]]<br />
*[[:Category:FDA approved in 1983|FDA approved in 1983]]<br />
*[[:Category:FDA approved in 1984|FDA approved in 1984]]<br />
*[[:Category:FDA approved in 1985|FDA approved in 1985]]<br />
*[[:Category:FDA approved in 1986|FDA approved in 1986]]<br />
*[[:Category:FDA approved in 1987|FDA approved in 1987]]<br />
*[[:Category:FDA approved in 1988|FDA approved in 1988]]<br />
*[[:Category:FDA approved in 1989|FDA approved in 1989]]<br />
*[[:Category:FDA approved in 1990|FDA approved in 1990]]<br />
*[[:Category:FDA approved in 1991|FDA approved in 1991]]<br />
*[[:Category:FDA approved in 1992|FDA approved in 1992]]<br />
*[[:Category:FDA approved in 1993|FDA approved in 1993]]<br />
*[[:Category:FDA approved in 1994|FDA approved in 1994]]<br />
*[[:Category:FDA approved in 1995|FDA approved in 1995]]<br />
*[[:Category:FDA approved in 1996|FDA approved in 1996]]<br />
*[[:Category:FDA approved in 1997|FDA approved in 1997]]<br />
*[[:Category:FDA approved in 1998|FDA approved in 1998]]<br />
*[[:Category:FDA approved in 1999|FDA approved in 1999]]<br />
*[[:Category:FDA approved in 2000|FDA approved in 2000]]<br />
*[[:Category:FDA approved in 2001|FDA approved in 2001]]<br />
*[[:Category:FDA approved in 2002|FDA approved in 2002]]<br />
*[[:Category:FDA approved in 2003|FDA approved in 2003]]<br />
*[[:Category:FDA approved in 2004|FDA approved in 2004]]<br />
*[[:Category:FDA approved in 2005|FDA approved in 2005]]<br />
*[[:Category:FDA approved in 2006|FDA approved in 2006]]<br />
*[[:Category:FDA approved in 2007|FDA approved in 2007]]<br />
*[[:Category:FDA approved in 2008|FDA approved in 2008]]<br />
*[[:Category:FDA approved in 2009|FDA approved in 2009]]<br />
*[[:Category:FDA approved in 2010|FDA approved in 2010]]<br />
*[[:Category:FDA approved in 2011|FDA approved in 2011]]<br />
*[[:Category:FDA approved in 2012|FDA approved in 2012]]<br />
*[[:Category:FDA approved in 2013|FDA approved in 2013]]<br />
*[[:Category:FDA approved in 2014|FDA approved in 2014]]<br />
*[[:Category:FDA approved in 2015|FDA approved in 2015]]<br />
*[[:Category:FDA approved in 2016|FDA approved in 2016]]<br />
*[[:Category:FDA approved in 2017|FDA approved in 2017]]<br />
*[[:Category:FDA approved in 2018|FDA approved in 2018]]<br />
*[[:Category:FDA approved in 2019|FDA approved in 2019]]<br />
</div><br />
<br />
=Interesting and Helpful Links=<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
*[[Antidepressants and other psychiatric medications in cancer care]]<br />
*[[Antiemesis|Antiemetic support]]<br />
*[https://doi.org/10.1200/JCO.2012.45.8661 Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology Clinical Practice Guideline (2013)]<br />
*[https://doi.org/10.1200/JOP.2016.017905 2016 Updated American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards, Including Standards for Pediatric Oncology]<br />
*[http://issuu.com/theoncologypharmacist/docs/jhop_march2011/1?mode=a_p Chemotherapy Administration Sequence]<ref>Mancini R, Modlin J. Chemotherapy Administration Sequence: A Review of the Literature and Creation of a Sequencing Chart. J Hematol Oncol Pharm. 2011;1(1):17-25. [http://issuu.com/theoncologypharmacist/docs/jhop_march2011/1?mode=a_p link to original article]</ref> - with chemotherapy sequencing chart<br />
*[https://onlinelibrary.wiley.com/doi/10.1111/j.1743-7563.2010.01321.x/full The Clinical Oncological Society of Australia (COSA) guidelines for the safe prescribing, dispensing and administration of cancer chemotherapy.] [https://pubmed.ncbi.nlm.nih.gov/20887505 PubMed]<br />
*[https://crediblemeds.org/ CredibleMeds.org] - lists of QT-prolonging drugs; requires free registration to see full list<br />
*[http://www.accessdata.fda.gov/scripts/drugshortages/default.cfm FDA drug shortages list]<br />
*[http://www.ashp.org/menu/DrugShortages ASHP drug shortages list] - also includes information about discontinued drugs<br />
*[http://dailymed.nlm.nih.gov/dailymed/index.cfm DailyMed] - a comprehensive NLM portal to all FDA-approved drugs<br />
*[http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ Drugs@FDA] - the main portal into the FDA drug database<br />
*[http://www.cancer.gov/drugdictionary The NCI Drug Dictionary] - an extensive resource with most antineoplastics (approved and in clinical trials) listed<br />
*[http://blogs.sciencemag.org/pipeline/ In the Pipeline] - a blog from a veteran of the pharmaceutical industry, Derek Lowe. General but much is cancer-relevant. The [http://www.pipeline.corante.com/ old home] of this blog is no longer active.<br />
*[[Steroid conversions]]<br />
*[[Vesicant & irritant chemotherapy]]<br />
*[http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers]<br />
*[https://www.pharmgkb.org/view/dosing-guidelines.do?source=CPIC# CPIC Guidelines] The Clinical Pharmacogenetics Implementation Consortium provides guidelines for a small set of drugs with pharmacogenetically-guided dosing implications, some of which are oncologics<br />
<br />
==References==<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Clinical pharmacology]]</div>Karinehttps://hemonc.org/w/index.php?title=Non-small_cell_lung_cancer&diff=49697Non-small cell lung cancer2021-05-14T16:33:51Z<p>Karine: Paz-Ares 2021 new regimen, chemo part</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Amit_Kulkarni.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Akulkarni|Amit Kulkarni, MBBS]]<br>University of Minnesota<br>Minneapolis, MN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/AmitKulkarniMD AmitKulkarniMD]<br />
| style="background-color:#F0F0F0" |[[File:TravisOsterman.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Travisosterman|Travis Osterman, DO, MS, FAMIA]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/TravisOsterman TravisOsterman]<br>[https://www.linkedin.com/in/travis-osterman-1850b236/ LinkedIn]<br />
|-<br />
|}<br />
''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Non-small cell lung cancer_-_historical|historical regimens page]]. If you still can't find it, please let us know so we can add it!''.<br />
<br>There are several related dedicated pages:<br />
<br />
*'''Histology-specific:'''<br />
**'''[[Non-small_cell_lung_cancer,_Nonsquamous|NSCLC, Nonsquamous]]'''<br />
**'''[[Non-small_cell_lung_cancer,_Squamous|NSCLC, Squamous]]'''<br />
*'''Biomarker-specific:'''<br />
**'''[[Non-small_cell_lung_cancer,_ALK-positive|NSCLC, ALK-positive]]'''<br />
**'''[[Non-small_cell_lung_cancer,_BRAF-mutated|NSCLC, BRAF-mutated]]'''<br />
**'''[[Non-small_cell_lung_cancer,_EGFR-mutated|NSCLC, EGFR-mutated]]'''<br />
**'''[[Non-small_cell_lung_cancer,_KRAS-mutated|NSCLC, KRAS-mutated]]'''<br />
**'''[[Non-small cell lung cancer, MET-mutated|NSCLC, MET-mutated]]'''<br />
**'''[[Non-small cell lung cancer, RET-positive|NSCLC, RET-positive]]'''<br />
**'''[[Non-small_cell_lung_cancer,_ROS1-positive|NSCLC, ROS1-positive]]'''<br />
*'''[[CNS carcinoma]]'''<br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
<br />
*'''2020:''' Schneider et al. [https://doi.org/10.1200/jco.19.02748 Lung Cancer Surveillance After Definitive Curative-Intent Therapy: ASCO Guideline]<br />
<br />
===Older===<br />
*'''2017:''' Hanna et al. [https://doi.org/10.1200/JCO.2017.74.6065 Systemic therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update] [https://pubmed.ncbi.nlm.nih.gov/28806116 PubMed]<br />
*'''2015:''' Masters et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019421/ Systemic therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update]<br />
*'''2009:''' Azzoli et al. [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2793036/ American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non–Small-Cell Lung Cancer]<br />
<br />
==ASCO/CCO==<br />
===Current===<br />
*'''2021:''' Hanna et al. [https://doi.org/10.1200/jco.20.03570 Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update]<br />
*'''2020:''' Hanna et al. [https://doi.org/10.1200/jco.19.03022 Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update]<br />
*'''2017:''' Kris et al. [https://doi.org/10.1200/JCO.2017.72.4401 Adjuvant systemic therapy and adjuvant radiation therapy for stage I to IIIA completely resected non–small-cell lung cancers: American Society of Clinical Oncology/Cancer Care Ontario clinical practice guideline update] [https://pubmed.ncbi.nlm.nih.gov/28437162 PubMed]<br />
<br />
===Older===<br />
*'''2007:''' Pisters et al. [https://doi.org/10.1200/JCO.2007.14.1226 Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline] [https://pubmed.ncbi.nlm.nih.gov/17954710 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2018:''' Planchard et al. [https://doi.org/10.1093/annonc/mdy275 Metastatic Non-Small-Cell Lung Cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
*'''2015:''' Eberhardt et al. [https://doi.org/10.1093/annonc/mdv187 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer]<br />
<br />
===Older===<br />
*'''2016:''' Novello et al. [https://doi.org/10.1093/annonc/mdw326 Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
*'''2014:''' Vansteenkiste et al. [https://doi.org/10.1093/annonc/mdu089 2nd ESMO Consensus Conference on Lung Cancer: early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up]<br />
*'''2014:''' Besse et al. [https://doi.org/10.1093/annonc/mdu123 2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and further lines of treatment in advanced disease]<br />
*'''2014:''' Kerr et al. [https://doi.org/10.1093/annonc/mdu145 Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer]<br />
*'''2013:''' Vansteenkiste et al. [https://doi.org/10.1093/annonc/mdt241 Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
<br />
==KSMO/ESMO==<br />
*'''2020:''' Park et al. [https://doi.org/10.1016/j.annonc.2019.10.026 Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with locally-advanced unresectable non-small-cell lung cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf NCCN Guidelines - Non-Small Cell Lung Cancer]<br />
<br />
=Neoadjuvant therapy=<br />
==Cisplatin & Docetaxel (DC) {{#subobject:cab6b8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e8cc0c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60294-X/fulltext Pless et al. 2015 (SAKK 16/00)]<br />
|2001-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Docetaxel, then RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS<br />
|-<br />
|}<br />
''This trial included patients with Stage IIIA or N2 NSCLC.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]]<br />
*[[Docetaxel (Taxotere)]]<br />
<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Surgical_resection|Complete resection]]<br />
<br />
===References===<br />
<br />
#'''SAKK 16/00:''' Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S, Gerard MA, Xyrafas A, Früh M, Cathomas R, Zippelius A, Roth A, Bijelovic M, Ochsenbein A, Meier UR, Mamot C, Rauch D, Gautschi O, Betticher DC, Mirimanoff RO, Peters S; SAKK Lung Cancer Project Group. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015 Sep 12;386(9998):1049-56. Epub 2015 Aug 11. Erratum in: Lancet. 2015 Sep 12;386(9998):1040. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60294-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/26275735 PubMed] NCT00030771<br />
<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:c567c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b0097e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2010.33.7089 Scagliotti et al. 2011 (CHEST)]<br />
|2000-2004<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_neoadjuvant_therapy|Surgery alone]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''This trial included patients with Stage IB to IIIA NSCLC.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1, '''given at least 4 hours after gemcitabine'''<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Surgical_resection|Complete resection]], 2 to 6 weeks after last dose of chemotherapy<br />
<br />
===References===<br />
<br />
#'''CHEST:''' Scagliotti GV, Pastorino U, Vansteenkiste JF, Spaggiari L, Facciolo F, Orlowski TM, Maiorino L, Hetzel M, Leschinger M, Visseren-Grul C, Torri V. Randomized phase III study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to IIIA non-small-cell lung cancer. J Clin Oncol. 2012 Jan 10;30(2):172-8. Epub 2011 Nov 28. [https://doi.org/10.1200/JCO.2010.33.7089 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22124104 PubMed]<br />
<br />
=Adjuvant therapy=<br />
==Carboplatin & Paclitaxel (CP) {{#subobject:3a6ad9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:59db47|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652093/ Strauss et al. 2008 (CALGB 9633)]<br />
|1996-2003<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Lobectomy|Lobectomy]] or [[Surgery#Pneumonectomy|pneumonectomy]], within 4 to 8 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 45 to 60 minutes once on day 1<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<!-- Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA, and at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA. --><br />
<br />
#'''CALGB 9633:''' Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, Gillenwater HH, Watson DM, Sugarbaker DJ, Schilsky RL, Vokes EE, Green MR. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008 Nov 1;26(31):5043-51. Epub 2008 Sep 22. [https://doi.org/10.1200/jco.2008.16.4855 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652093/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18809614 PubMed]<br />
<br />
==Cisplatin & Docetaxel (DC) {{#subobject:211cca|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
DC: '''<u>D</u>'''ocetaxel & '''<u>C</u>'''isplatin<br />
===Regimen {{#subobject:bc45d4|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[http://icvts.oxfordjournals.org/content/20/6/783.long Barlesi et al. 2015]<br />
|2004-2007<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_2|Cisplatin & Gemcitabine]]<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of QoL<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30691-5/fulltext Wakelee et al. 2017 (ECOG-ACRIN E1505)]<br />
|2007-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Cisplatin, Docetaxel, Bevacizumab<br> 2. Cisplatin, Gemcitabine, Bevacizumab<br> 3. Cisplatin, Pemetrexed, Bevacizumab<br> 4. Cisplatin, Vinorelbine, Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Barlesi et al. 2015: Complete R0 [[Surgery#Lung_cancer_surgery|resection]], within 8 weeks<br />
*ECOG-ACRIN E1505: Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 6 to 12 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 3 cycles (Barlesi et al. 2015) or 4 cycles (ECOG-ACRIN E1505)'''<br />
<br />
===References===<br />
<br />
#Barlesi F, Chouaid C, Crequit J, Le Caer H, Pujol JL, Legodec J, Vergnenegre A, Le Treut J, Fabre-Guillevin E, Loundou A, Auquier P, Simeoni MC, Thomas PA. A randomized trial comparing adjuvant chemotherapy with gemcitabine plus cisplatin with docetaxel plus cisplatin in patients with completely resected non-small-cell lung cancer with quality of life as the primary objective. Interact Cardiovasc Thorac Surg. 2015 Jun;20(6):783-90. Epub 2015 Mar 11. [http://icvts.oxfordjournals.org/content/20/6/783.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25765952 PubMed]<br />
#'''ECOG-ACRIN E1505:''' Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30691-5/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29129443 PubMed] NCT00324805<br />
<br />
==Cisplatin & Etoposide (EP) {{#subobject:dbad67|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a211c5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa031644 Arriagada et al. 2004 (IALT)]<br />
|1995-2000<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 60 days<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#'''IALT:''' Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. [https://www.nejm.org/doi/full/10.1056/NEJMoa031644 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14736927 PubMed]<br />
##'''Update:''' Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. [https://doi.org/10.1200/JCO.2009.23.2272 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19933916 PubMed]<br />
<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:289ea6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GC: '''<u>G</u>'''emcitabine & '''<u>C</u>'''isplatin<br />
===Regimen variant #1, 75/1200 x 4 {{#subobject:4cd112|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30691-5/fulltext Wakelee et al. 2017 (ECOG-ACRIN E1505)]<br />
|2007-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Cisplatin, Docetaxel, Bevacizumab<br> 2. Cisplatin, Gemcitabine, Bevacizumab<br> 3. Cisplatin, Pemetrexed, Bevacizumab<br> 4. Cisplatin, Vinorelbine, Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 6 to 12 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1200 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #2, 75/1250 x 3 {{#subobject:22cb4c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[http://icvts.oxfordjournals.org/content/20/6/783.long Barlesi et al. 2015]<br />
|2004-2007<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Docetaxel_.28DC.29_2|Cisplatin & Docetaxel]]<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of QoL<br />
|-<br />
|}<br />
''This trial included patients with Stage IB–III NSCLC.''<br />
====Preceding treatment====<br />
<br />
*Complete R0 [[Surgery#Lung_cancer_surgery|resection]], within 8 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#Barlesi F, Chouaid C, Crequit J, Le Caer H, Pujol JL, Legodec J, Vergnenegre A, Le Treut J, Fabre-Guillevin E, Loundou A, Auquier P, Simeoni MC, Thomas PA. A randomized trial comparing adjuvant chemotherapy with gemcitabine plus cisplatin with docetaxel plus cisplatin in patients with completely resected non-small-cell lung cancer with quality of life as the primary objective. Interact Cardiovasc Thorac Surg. 2015 Jun;20(6):783-90. Epub 2015 Mar 11. [http://icvts.oxfordjournals.org/content/20/6/783.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25765952 PubMed]<br />
#'''ECOG-ACRIN E1505:''' Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30691-5/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29129443 PubMed] NCT00324805<br />
<br />
==Cisplatin & Pemetrexed {{#subobject:1caad6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CPx: '''<u>C</u>'''isplatin & '''<u>P</u>'''emetre'''<u>x</u>'''ed<br />
===Regimen {{#subobject:73f03b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mds578 Kreuter et al. 2013 (TREAT)]<br />
|2006-2009<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin_.26_Vinorelbine|Cisplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet secondary endpoint of OS<sup>1</sup><br />
| style="background-color:#1a9850" |Superior clinical feasibility rate<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30691-5/fulltext Wakelee et al. 2017 (ECOG-ACRIN E1505)]<br />
|2007-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Cisplatin, Docetaxel, Bevacizumab<br> 2. Cisplatin, Gemcitabine, Bevacizumab<br> 3. Cisplatin, Pemetrexed, Bevacizumab<br> 4. Cisplatin, Vinorelbine, Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://www.nature.com/articles/s41416-019-0533-3 Groen et al. 2019 (NVALT-8)]<br />
|2007-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CPx & Nadroparin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS<br />
|<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for TREAT is based on the 2016 update.''<br><br />
''Note: In TREAT, this treatment was intended for pathologically confirmed NSCLC stages (according to the TNM staging system version 6) IB, IIA, IIB or T3N1.''<br />
====Preceding treatment====<br />
<br />
*TREAT & NVALT-8: Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 4 to 6 weeks<br />
*ECOG-ACRIN E1505: Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 6 to 12 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#'''TREAT:''' Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt W, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Zuna I, Griesinger F, Thomas M; TREAT investigators; AIO Lung Cancer Study Group; LLCG Leuven Lung Cancer Group. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study. Ann Oncol. 2013 Apr;24(4):986-92. Epub 2012 Nov 15. [https://doi.org/10.1093/annonc/mds578 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23161898 PubMed] NCT00349089<br />
##'''Update:''' Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt WE, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Griesinger F, Thomas M; TREAT investigators. Three-year follow-up of a randomized phase II trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine (the TREAT study). J Thorac Oncol. 2016 Jan;11(1):85-93. [http://www.jto.org/article/S1556-0864(15)00023-4/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/26762743 PubMed]<br />
#'''ECOG-ACRIN E1505:''' Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30691-5/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29129443 PubMed] NCT00324805<br />
#'''NVALT-8:''' Groen HJM, van der Heijden EHFM, Klinkenberg TJ, Biesma B, Aerts J, Verhagen A, Kloosterziel C, Pieterman R, van den Borne B, Smit HJM, Hoekstra O, Schramel FMNH, van der Noort V, van Tinteren H, Smit EF, Dingemans AC; NVALT Study Group. Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study. Br J Cancer. 2019 Aug;121(5):372-377. Epub 2019 Jul 24. [https://www.nature.com/articles/s41416-019-0533-3 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/31337877 PubMed] NTR1250/1217<br />
<br />
==Cisplatin & Vinblastine {{#subobject:af5cc1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1d592|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa031644 Arriagada et al. 2004 (IALT)]<br />
|1995-2000<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: Exact days for parts of the regimen were not specified by Arriagada et al. 2004. This vinblastine schedule is extrapolated from regimen information in Table 1 in which vinblastine is said to be given "weekly from days 1 to 29" and "then every 2 weeks after day 43 until last cisplatin administration.''<br />
====Preceding treatment====<br />
<br />
*Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 60 days<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 22, 43, 64<br />
*[[Vinblastine (Velban)]] 4 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 43, 57<br />
<br />
'''12-week course'''<br />
<br />
===References===<br />
<br />
#'''IALT:''' Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. [https://www.nejm.org/doi/full/10.1056/NEJMoa031644 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14736927 PubMed]<br />
##'''Update:''' Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. [https://doi.org/10.1200/JCO.2009.23.2272 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19933916 PubMed]<br />
<br />
==Cisplatin & Vindesine {{#subobject:80fe2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:2d16cd|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa031644 Arriagada et al. 2004 (IALT)]<br />
|1995-2000<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: Exact days for parts of the regimen were not specified by Arriagada et al. 2004. This vindesine schedule is extrapolated from regimen information in Table 1 in which vindesine is said to be given "weekly from days 1 to 29" and "then every 2 weeks after day 43 until last cisplatin administration.''<br />
====Preceding treatment====<br />
<br />
*Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 60 days<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 22, 43, 64<br />
*[[Vindesine (Eldisine)]] 3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 43, 57<br />
<br />
'''12-week course'''<br />
<br />
===References===<br />
<br />
#'''IALT:''' Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. [https://www.nejm.org/doi/full/10.1056/NEJMoa031644 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14736927 PubMed]<br />
##'''Update:''' Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. [https://doi.org/10.1200/JCO.2009.23.2272 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19933916 PubMed]<br />
<br />
==Cisplatin & Vinorelbine {{#subobject:ab1b88|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CVb: '''<u>C</u>'''isplatin & '''<u>V</u>'''inorel'''<u>b</u>'''ine<br />
===Regimen variant #1, cisplatin 50 mg/m<sup>2</sup>, 2 weeks out of 4 {{#subobject:c1a368|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa043623 Winton et al. 2005 (JBR.10)]<br />
|1994-2001<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|<br />
|-<br />
|[https://doi.org/10.1093/annonc/mds578 Kreuter et al. 2013 (TREAT)]<br />
|2006-2009<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Cisplatin_.26_Pemetrexed|Cisplatin & Pemetrexed]]<br />
| style="background-color:#ffffbf" |Did not meet secondary endpoint of OS<sup>1</sup><br />
| style="background-color:#1a9850" |Superior clinical feasibility rate<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for TREAT is based on the 2016 update.''<br />
====Preceding treatment====<br />
<br />
*JBR.10: Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 6 weeks<br />
*TREAT: Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 4 to 6 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 4 cycles'''<br />
===Regimen variant #2, cisplatin 75 mg/m<sup>2</sup>, q3wk {{#subobject:04b3e6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30691-5/fulltext Wakelee et al. 2017 (ECOG-ACRIN E1505)]<br />
|2007-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Cisplatin, Docetaxel, Bevacizumab<br> 2. Cisplatin, Gemcitabine, Bevacizumab<br> 3. Cisplatin, Pemetrexed, Bevacizumab<br> 4. Cisplatin, Vinorelbine, Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 6 to 12 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #3, cisplatin 100 mg/m<sup>2</sup>, q4wk {{#subobject:6edee|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(06)70804-X/fulltext Douillard et al. 2006 (ANITA)]<br />
|1994-2000<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa031644 Arriagada et al. 2004 (IALT)]<br />
|1995-2000<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*IALT: Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 60 days<br />
*ANITA: Complete [[Surgery#Lung_cancer_surgery|surgical resection]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#'''IALT:''' Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. [https://www.nejm.org/doi/full/10.1056/NEJMoa031644 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14736927 PubMed]<br />
##'''Update:''' Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. [https://doi.org/10.1200/JCO.2009.23.2272 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19933916 PubMed]<br />
#'''JBR.10:''' Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao MS, Gandara D, Kesler K, Demmy T, Shepherd F; National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin vs observation in resected non-small-cell lung cancer. N Engl J Med. 2005 Jun 23;352(25):2589-97. [https://www.nejm.org/doi/full/10.1056/NEJMoa043623 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15972865 PubMed]<br />
##'''Update:''' Butts CA, Ding K, Seymour L, Twumasi-Ankrah P, Graham B, Gandara D, Johnson DH, Kesler KA, Green M, Vincent M, Cormier Y, Goss G, Findlay B, Johnston M, Tsao MS, Shepherd FA. Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol. 2010 Jan 1;28(1):29-34. Epub 2009 Nov 23. [https://doi.org/10.1200/JCO.2009.24.0333 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799232/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19933915 PubMed]<br />
#'''ANITA:''' Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Rodrigues Pereira J, Le Groumellec A, Lorusso V, Clary C, Torres AJ, Dahabreh J, Souquet PJ, Astudillo J, Fournel P, Artal-Cortes A, Jassem J, Koubkova L, His P, Riggi M, Hurteloup P. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006 Sep;7(9):719-27. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(06)70804-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/16945766 PubMed] ISRCTN95053737<br />
#'''TREAT:''' Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt W, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Zuna I, Griesinger F, Thomas M; TREAT investigators; AIO Lung Cancer Study Group; LLCG. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study. Ann Oncol. 2013 Apr;24(4):986-92. Epub 2012 Nov 15. [https://doi.org/10.1093/annonc/mds578 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23161898 PubMed] NCT00349089<br />
##'''Update:''' Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt WE, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Griesinger F, Thomas M; TREAT investigators. Three-year follow-up of a randomized phase II trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine (the TREAT study). J Thorac Oncol. 2016 Jan;11(1):85-93. [http://www.jto.org/article/S1556-0864(15)00023-4/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/26762743 PubMed]<br />
#'''ECOG-ACRIN E1505:''' Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30691-5/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29129443 PubMed] NCT00324805<br />
<br />
=Induction chemotherapy for locally advanced disease=<br />
==Carboplatin & Paclitaxel (CP) {{#subobject:b2de53|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PC: '''<u>P</u>'''aclitaxel & '''<u>C</u>'''arboplatin<br />
===Regimen variant #1, 6/200 {{#subobject:4d4e46|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.05.4163 Huber et al. 2006 (CTRT99/97)]<br />
|1997-2002<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.55.405 Belani et al. 2005 (LAMP)]<br />
|1998-2001<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/JCO.2006.07.3569 Vokes et al. 2007 (CALGB 39801)]<br />
|1998-2002<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 30 minutes once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''21-day cycle for 2 cycles'''<br />
<br />
====Subsequent treatment====<br />
<br />
*LAMP: [[#Radiation_therapy|RT]] x 63 Gy<br />
*CTRT99/97: Paclitaxel & RT versus [[#Radiation_therapy|RT]]<br />
*CALGB 39801: [[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_RT|Carboplatin, Paclitaxel, RT]]<br />
<br />
===Regimen variant #2, 6/225 {{#subobject:1ec13b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295560/ Hoang et al. 2012 (ECOG 3598)]<br />
|2000-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#ECOG_3598|See link]]<br />
| style="background-color:#ffffbf" |[[Complex_multipart_regimens#ECOG_3598|See link]]<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 2 cycles'''<br />
<br />
====Subsequent treatment====<br />
<br />
*[[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_RT|Carboplatin, Paclitaxel, RT]]<br />
<br />
===References===<br />
<br />
#'''LAMP:''' Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. [https://doi.org/10.1200/jco.2005.55.405 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16087941 PubMed]<br />
#'''CTRT99/97:''' Huber RM, Flentje M, Schmidt M, Pöllinger B, Gosse H, Willner J, Ulm K; Bronchial Carcinoma Therapy Group. Simultaneous chemoradiotherapy compared with radiotherapy alone after induction chemotherapy in inoperable stage IIIA or IIIB non-small-cell lung cancer: study CTRT99/97 by the Bronchial Carcinoma Therapy Group. J Clin Oncol. 2006 Sep 20;24(27):4397-404. [https://doi.org/10.1200/JCO.2005.05.4163 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16983107 PubMed]<br />
#'''CALGB 39801:''' Vokes EE, Herndon JE 2nd, Kelley MJ, Cicchetti MG, Ramnath N, Neill H, Atkins JN, Watson DM, Akerley W, Green MR; [[Study_Groups#CALGB|CALGB]]. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol. 2007 May 1;25(13):1698-704. Epub 2007 Apr 2. [https://doi.org/10.1200/JCO.2006.07.3569 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17404369 PubMed]<br />
#'''ECOG 3598:''' Hoang T, Dahlberg SE, Schiller JH, Mehta MP, Fitzgerald TJ, Belinsky SA, Johnson DH. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol. 2012 Feb 20;30(6):616-22. Epub 2012 Jan 23. [https://doi.org/10.1200/JCO.2011.36.9116 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295560/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22271472 PubMed] NCT00004859<br />
<br />
==Cisplatin & Vinblastine {{#subobject:6b4fa8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:2433e7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199010043231403 Dillman et al. 1990 (CALGB 8433)]<br />
|1984-1987<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br />
|-<br />
|[https://academic.oup.com/jnci/article-abstract/87/3/198/932006 Sause et al. 1995 (RTOG 88-08)]<br />
|1989-1992<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ Curran et al. 2011 (RTOG 9410)]<br />
|1994-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#RTOG_9410|See link]]<br />
| style="background-color:#fc8d59" |[[Complex_multipart_regimens#RTOG_9410|See link]]<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for CALGB 8433 is based on the 1996 update.''<br><br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 29<br />
*[[Vinblastine (Velban)]] 5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29<br />
<br />
'''5-week course'''<br />
<br />
====Subsequent treatment====<br />
<br />
*[[#Radiation_therapy|RT]] x 60 to 63 Gy<br />
<br />
===References===<br />
<br />
#'''CALGB 8433:''' Dillman RO, Seagren SL, Propert KJ, Guerra J, Eaton WL, Perry MC, Carey RW, Frei EF 3rd, Green MR. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med. 1990 Oct 4;323(14):940-5. [https://www.nejm.org/doi/full/10.1056/NEJM199010043231403 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/2169587 PubMed]<br />
##'''Update:''' Dillman RO, Herndon J, Seagren SL, Eaton WL Jr, Green MR. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst. 1996 Sep 4;88(17):1210-5. [https://academic.oup.com/jnci/article/88/17/1210/911128 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8780630 PubMed]<br />
#'''RTOG 88-08:''' Sause WT, Scott C, Taylor S, Johnson D, Livingston R, Komaki R, Emami B, Curran WJ, Byhardt RW, Turrisi AT, Dar AR, Cox JD. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst. 1995 Feb 1;87(3):198-205. [https://academic.oup.com/jnci/article-abstract/87/3/198/932006 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/7707407 PubMed]<br />
##'''Update:''' Sause W, Kolesar P, Taylor S IV, Johnson D, Livingston R, Komaki R, Emami B, Curran W Jr, Byhardt R, Dar AR, Turrisi A 3rd. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest. 2000 Feb;117(2):358-64. [https://journal.chestnet.org/article/S0012-3692(15)48622-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/10669675 PubMed]<br />
#'''RTOG 9410:''' Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. [http://jnci.oxfordjournals.org/content/103/19/1452.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21903745 PubMed]<br />
<br />
=Definitive therapy for locally advanced disease=<br />
==Carboplatin & Paclitaxel (CP) & RT {{#subobject:899399|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PC & RT: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''arboplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen variant #1, 2/40/60 {{#subobject:5d3a16|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.24.5050 Yamamoto et al. 2010 (WJTOG0105)]<br />
|2001-2005<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. MVP & RT<br> 2. Carboplatin, Irinotecan, RT<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Paclitaxel (Taxol)]] 40 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 60 Gy<br />
<br />
'''6-week course'''<br />
<br />
===Regimen variant #2, 2/45/60 {{#subobject:5d4d16|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902826/ Lu et al. 2010 (ID99-303)]<br />
|2000-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PC, AE-941, RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295560/ Hoang et al. 2012 (ECOG 3598)]<br />
|2000-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#ECOG_3598|See link]]<br />
| style="background-color:#ffffbf" |[[Complex_multipart_regimens#ECOG_3598|See link]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419359/ Bradley et al. 2015 (RTOG 0617)]<br />
| rowspan="2" |2007-2011<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Carboplatin, Paclitaxel, Cetuximab, concurrent RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. Carboplatin, Paclitaxel, high-dose RT<br> 3. Carboplatin, Paclitaxel, Cetuximab, high-dose RT<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdx009 Liang et al. 2017]<br />
|2007-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin.2C_Etoposide.2C_RT|EP & RT]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Preceding treatment====<br />
<br />
*ECOG 3598: [[#Carboplatin_.26_Paclitaxel_.28CP.29_2|PC]] induction x 2<br />
<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 2 IV over 30 minutes once per day on days 1, 8, 15, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 45 mg/m<sup>2</sup> IV over 1 to 3 hours once per day on days 1, 8, 15, '''given first'''<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 2 Gy fractions x 30 fractions (total of 60 Gy)<br />
<br />
'''6-week course'''<br />
====Subsequent treatment====<br />
<br />
*RTOG 0617: [[#Carboplatin_.26_Paclitaxel_.28CP.29_3|PC]] consolidation x 2<br />
<br />
===Regimen variant #3, 2/45/63 {{#subobject:59d765|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.55.405 Belani et al. 2005 (LAMP)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Carboplatin_.26_Paclitaxel_.28CP.29_2|PC induction]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 2 IV over 30 minutes once per day on days 1, 8, 15, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 45 mg/m<sup>2</sup> IV over 1 to 3 hours once per day on days 1, 8, 15, '''given first'''<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 1.8 Gy fractions x 25 fractions, then 2 Gy fractions x 9 fractions<br />
<br />
'''7-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[#Carboplatin_.26_Paclitaxel_.28CP.29_3|PC]] consolidation x 2<br />
<br />
===Regimen variant #4, 2/50/66 {{#subobject:c54de8|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2006.07.3569 Vokes et al. 2007 (CALGB 39801)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Carboplatin_.26_Paclitaxel_.28CP.29_2|PC]] x 2 versus [[#No_induction|no induction]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 2 IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36, 43, '''given first'''<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 66 Gy<br />
<br />
'''7-week course'''<br />
===References===<br />
<br />
#'''LAMP:''' Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. [https://doi.org/10.1200/jco.2005.55.405 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16087941 PubMed]<br />
#'''CALGB 39801:''' Vokes EE, Herndon JE 2nd, Kelley MJ, Cicchetti MG, Ramnath N, Neill H, Atkins JN, Watson DM, Akerley W, Green MR; [[Study_Groups#CALGB|CALGB]]. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol. 2007 May 1;25(13):1698-704. Epub 2007 Apr 2. [https://doi.org/10.1200/JCO.2006.07.3569 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17404369 PubMed]<br />
#'''ID99-303:''' Lu C, Lee JJ, Komaki R, Herbst RS, Feng L, Evans WK, Choy H, Desjardins P, Esparaz BT, Truong MT, Saxman S, Kelaghan J, Bleyer A, Fisch MJ. Chemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer: a randomized phase III trial. J Natl Cancer Inst. 2010 Jun 16;102(12):859-65. Epub 2010 May 26. [https://academic.oup.com/jnci/article/102/12/859/2568981 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902826/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20505152 PubMed] NCT00005838<br />
#'''WJTOG0105:''' Yamamoto N, Nakagawa K, Nishimura Y, Tsujino K, Satouchi M, Kudo S, Hida T, Kawahara M, Takeda K, Katakami N, Sawa T, Yokota S, Seto T, Imamura F, Saka H, Iwamoto Y, Semba H, Chiba Y, Uejima H, Fukuoka M. Phase III study comparing second- and third-generation regimens with concurrent thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer: West Japan Thoracic Oncology Group WJTOG0105. J Clin Oncol. 2010 Aug 10;28(23):3739-45. Epub 2010 Jul 12. [https://doi.org/10.1200/JCO.2009.24.5050 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20625120 PubMed]<br />
#'''ECOG 3598:''' Hoang T, Dahlberg SE, Schiller JH, Mehta MP, Fitzgerald TJ, Belinsky SA, Johnson DH. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol. 2012 Feb 20;30(6):616-22. Epub 2012 Jan 23. [https://doi.org/10.1200/JCO.2011.36.9116 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295560/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22271472 PubMed] NCT00004859<br />
#'''RTOG 0617:''' Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. Epub 2015 Jan 16. [https://doi.org/10.1016/s1470-2045(14)71207-0 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419359/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25601342 PubMed] NCT00533949<br />
##'''Update:''' Bradley JD, Hu C, Komaki RR, Masters GA, Blumenschein GR, Schild SE, Bogart JA, Forster KM, Magliocco AM, Kavadi VS, Narayan S, Iyengar P, Robinson CG, Wynn RB, Koprowski CD, Olson MR, Meng J, Paulus R, Curran WJ Jr, Choy H. Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Mar 1;38(7):706-714. Epub 2019 Dec 16. [https://doi.org/10.1200/jco.19.01162 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048161/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31841363 PubMed]<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/236 Project Data Sphere]<br />
<!-- Note: This study was previously oral presented as: 15th World Conference on Lung Cancer, Sydney, 27–30 October 2013. --><br />
#Liang J, Bi N, Wu S, Chen M, Lv C, Zhao L, Shi A, Jiang W, Xu Y, Zhou Z, Wang W, Chen D, Hui Z, Lv J, Zhang H, Feng Q, Xiao Z, Wang X, Liu L, Zhang T, Du L, Chen W, Shyr Y, Yin W, Li J, He J, Wang L. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial. Ann Oncol. 2017 Apr 1;28(4):777-783. [https://doi.org/10.1093/annonc/mdx009 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28137739 PubMed] NCT01494558<br />
<br />
==Carboplatin, Vinorelbine, RT {{#subobject:c9edfa|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a0fcb6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776981/ Strøm et al. 2013 (Conrad)]<br />
|2006-2011<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Carboplatin_.26_Vinorelbine|Carboplatin & Vinorelbine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 60 minutes once on day 1<br />
*[[Vinorelbine (Navelbine)]] 60 mg/m<sup>2</sup> PO once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 42 Gy in 15 fractions<br />
<br />
===References===<br />
<br />
#'''Conrad:''' Strøm HH, Bremnes RM, Sundstrøm SH, Helbekkmo N, Fløtten O, Aasebø U; Norwegian Lung Cancer Study Group. Concurrent palliative chemoradiation leads to survival and quality of life benefits in poor prognosis stage III non-small-cell lung cancer: a randomised trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2013 Sep 17;109(6):1467-75. Epub 2013 Aug 20. [https://www.nature.com/articles/bjc2013466 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776981/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23963145 PubMed] ISRCTN63778716<br />
<br />
==Carboplatin & RT {{#subobject:f563a8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Carboplatin & RT: Carboplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:6b0bae|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70139-0/fulltext Atagi et al. 2012 (JCOG0301)]<br />
|2003-2010<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Radiation_therapy|RT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 60 Gy, details not available in abstract<br />
<br />
===References===<br />
<br />
#'''JCOG0301:''' Atagi S, Kawahara M, Yokoyama A, Okamoto H, Yamamoto N, Ohe Y, Sawa T, Ishikura S, Shibata T, Fukuda H, Saijo N, Tamura T; [[Study_Groups#JCOG|JCOG]] Lung Cancer Study Group. Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Lancet Oncol. 2012 Jul;13(7):671-8. Epub 2012 May 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70139-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22622008 PubMed] NCT00132665<br />
<br />
==Cisplatin & RT {{#subobject:e6b41e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Cisplatin & RT: Cisplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:6b0bae|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199202203260805 Schaake-Koning et al. 1992]<br />
|rowspan=2|1984-1989<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Cisplatin_.26_RT|Cisplatin & RT]]; weekly cisplatin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Radiation_therapy|RT]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 6 mg/m<sup>2</sup> IV once per day on days of radiation<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] as follows:<br />
**Weeks 1 & 2: 3 Gy fractions, five fractions per week<br />
**Weeks 3 to 5: no radiation<br />
**Weeks 6 & 7: 2.5 Gy fractions, five fractions per week<br />
<br />
'''7-week course'''<br />
<br />
===References===<br />
<br />
#Schaake-Koning C, van den Bogaert W, Dalesio O, Festen J, Hoogenhout J, van Houtte P, Kirkpatrick A, Koolen M, Maat B, Nijs A, Renaud A, Rodrigus P, Schuster-Uitterhoeve L, Sculier JP, van Zandwijk N, Bartelink H. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med. 1992 Feb 20;326(8):524-30. [https://www.nejm.org/doi/full/10.1056/NEJM199202203260805 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/1310160 PubMed]<br />
<br />
==Cisplatin, Docetaxel, RT {{#subobject:6d901b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
DC & RT: '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
<br>DP & RT: '''<u>D</u>'''ocetaxel, '''<u>P</u>'''latinol (Cisplatin), '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen variant #1, 20/20 {{#subobject:fdef61|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2308-5 Oh et al. 2013 (KASLC 0401)]<br />
|2005-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. TP & RT<br> 2. GP & RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[https://doi.org/10.1200/JCO.2014.60.0130 Ahn et al. 2015 (KCSG-LU05-04)]<br />
|2005-2011<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''In KCSG-LU05-04, no benefit was observed to giving post-definitive consolidation.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Docetaxel (Taxotere)]] 20 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 33 fractions (total dose: 66 Gy)<br />
<br />
'''6-week course'''<br />
====Subsequent treatment====<br />
<br />
*KCSG-LU05-04: [[#Cisplatin_.26_Docetaxel_.28DC.29_3|Cisplatin & Docetaxel]] consolidation versus no further treatment<br />
<br />
===Regimen variant #2, 40/40 {{#subobject:6a7064|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.24.7577 Segawa et al. 2010 (OLCSG 0007)]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|MVP & RT<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''28-day cycle for 2 cycles'''<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]]<br />
<br />
===References===<br />
<br />
#'''OLCSG 0007:''' Segawa Y, Kiura K, Takigawa N, Kamei H, Harita S, Hiraki S, Watanabe Y, Sugimoto K, Shibayama T, Yonei T, Ueoka H, Takemoto M, Kanazawa S, Takata I, Nogami N, Hotta K, Hiraki A, Tabata M, Matsuo K, Tanimoto M. Phase III trial comparing docetaxel and cisplatin combination chemotherapy with mitomycin, vindesine, and cisplatin combination chemotherapy with concurrent thoracic radiotherapy in locally advanced non-small-cell lung cancer: OLCSG 0007. J Clin Oncol. 2010 Jul 10;28(20):3299-306. Epub 2010 Jun 7. [https://doi.org/10.1200/JCO.2009.24.7577 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20530281 PubMed] UMIN000000085<br />
#'''KASLC 0401:''' Oh IJ, Kim KS, Kim YC, Ban HJ, Kwon YS, Kim YI, Lim SC, Chung WK, Nam TK, Song JY, Yoon MS, Ahn SJ. A phase III concurrent chemoradiotherapy trial with cisplatin and paclitaxel or docetaxel or gemcitabine in unresectable non-small cell lung cancer: KASLC 0401. Cancer Chemother Pharmacol. 2013 Dec;72(6):1247-54. Epub 2013 Oct 5. [https://link.springer.com/article/10.1007%2Fs00280-013-2308-5 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24091849 PubMed]<br />
#'''KCSG-LU05-04:''' Ahn JS, Ahn YC, Kim JH, Lee CG, Cho EK, Lee KC, Chen M, Kim DW, Kim HK, Min YJ, Kang JH, Choi JH, Kim SW, Zhu G, Wu YL, Kim SR, Lee KH, Song HS, Choi YL, Sun JM, Jung SH, Ahn MJ, Park K. Multinational randomized phase III trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small-cell lung cancer: KCSG-LU05-04. J Clin Oncol. 2015 Aug 20;33(24):2660-6. Epub 2015 Jul 6. [https://doi.org/10.1200/JCO.2014.60.0130 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26150444 PubMed] NCT00326378<br />
<br />
==Cisplatin, Etoposide, RT {{#subobject:743aa8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
EP & RT: '''<u>E</u>'''toposide, '''<u>P</u>'''latinol (Cisplatin), '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen variant #1, 45 Gy with response-adapted treatment {{#subobject:dcb6c1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2002.03.055 Albain et al. 2002 (SWOG 9019)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407808/ Albain et al. 2009 (RTOG 93-09)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Etoposide (Vepesid)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''28-day cycle for 2 cycles'''<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions (total dose: 45 Gy), to start within 24 hours of cycle 1 day 1<br />
<br />
'''5-week course'''<br />
====Subsequent treatment====<br />
<br />
*SWOG 9019: Patients were re-imaged with CT scan (bone scan and head imaging were only done if patients had new symptoms), and those without progression or new metastatic disease received an additional 2 Gy per day x 8 fractions for a total of 61 Gy administered overall<br />
*RTOG 93-09: Additional radiation to 61 Gy, then [[#Cisplatin_.26_Etoposide_.28EP.29_2|cisplatin & etoposide consolidation]] versus surgery, then [[#Cisplatin_.26_Etoposide_.28EP.29_2|cisplatin & etoposide consolidation]]<br />
<br />
===Regimen variant #2, 60 to 66 Gy {{#subobject:426dfc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2007.14.4824 Kelly et al. 2008 (SWOG S0023)]<br />
|2001-2005<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/JCO.2008.17.7840 Hanna et al. 2008 (HOG Lun 01-24)]<br />
|2002-2006<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdx009 Liang et al. 2017]<br />
|2007-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_RT|PC & RT]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Etoposide (Vepesid)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 to 2 Gy fractions x 30 to 33 fractions (total dose: 60 to 66 Gy)<br />
<br />
'''6- to 6.5-week course'''<br />
<br />
====Subsequent treatment====<br />
<br />
*SWOG S0023: Docetaxel x 3, then gefitinib versus [[Non-small_cell_lung_cancer_-_null_regimens#Placebo|placebo]]<br />
*HOG Lun 01-24: Docetexal consolidation versus [[Non-small_cell_lung_cancer_-_null_regimens#Observation_2|observation]]<br />
*Liang et al. 2017: Optional consolidation chemotherapy<br />
<br />
===Regimen variant #3, 66 Gy, split cisplatin {{#subobject:f35aaa|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.03.070 Fournel et al. 2005 (NPC 95-01)]<br />
|1996-2000<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|Cisplatin & Vinorelbine, then [[#Radiation_therapy|RT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: this is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
*[[Etoposide (Vepesid)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 33 fractions (total dose: 66 Gy)<br />
<br />
'''6.5-week course'''<br />
<br />
====Subsequent treatment====<br />
<br />
*[[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine consolidation]]<br />
<br />
===Regimen variant #4, 69.6 Gy (hyperfractionated) {{#subobject:3ea5c6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ Curran et al. 2011 (RTOG 9410)]<br />
|rowspan=2|1994-1998<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Cisplatin.2C_Vinblastine.2C_RT|Cisplatin, Vinblastine, RT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Cisplatin_.26_Vinblastine_2|Cisplatin & Vinblastine]], then [[#Radiation_therapy|RT]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Etoposide (Vepesid)]] 50 mg PO twice per day on days 1 to 5, 8 to 12<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.2 Gy fractions (total dose: 69.6 Gy), given twice per day for 5 days per week, starting on cycle 1 day 1<br />
<br />
===References===<br />
<br />
#'''SWOG 9019:''' Albain KS, Crowley JJ, Turrisi AT 3rd, Gandara DR, Farrar WB, Clark JI, Beasley KR, Livingston RB. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol. 2002 Aug 15;20(16):3454-60. [https://doi.org/10.1200/jco.2002.03.055 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12177106 PubMed]<br />
#'''NPC 95-01:''' Fournel P, Robinet G, Thomas P, Souquet PJ, Léna H, Vergnenégre A, Delhoume JY, Le Treut J, Silvani JA, Dansin E, Bozonnat MC, Daurés JP, Mornex F, Pérol M; Groupe Lyon-Saint-Etienne d'Oncologie Thoracique; Groupe Français de Pneumo-Cancérologie. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol. 2005 Sep 1;23(25):5910-7. Epub 2005 Aug 8. [https://doi.org/10.1200/JCO.2005.03.070 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16087956/ PubMed]<br />
#'''SWOG S0023:''' Kelly K, Chansky K, Gaspar LE, Albain KS, Jett J, Ung YC, Lau DH, Crowley JJ, Gandara DR. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol. 2008 May 20;26(15):2450-6. Epub 2008 Mar 31. [https://doi.org/10.1200/JCO.2007.14.4824 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18378568 PubMed]<br />
#'''HOG Lun 01-24:''' Hanna N, Neubauer M, Yiannoutsos C, McGarry R, Arseneau J, Ansari R, Reynolds C, Govindan R, Melnyk A, Fisher W, Richards D, Bruetman D, Anderson T, Chowhan N, Nattam S, Mantravadi P, Johnson C, Breen T, White A, Einhorn L; Hoosier Oncology Group; US Oncology. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol. 2008 Dec 10;26(35):5755-60. Epub 2008 Nov 10. [https://doi.org/10.1200/JCO.2008.17.7840 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19001323 PubMed]<br />
#'''RTOG 93-09:''' Albain KS, Swann RS, Rusch VW, Turrisi AT 3rd, Shepherd FA, Smith C, Chen Y, Livingston RB, Feins RH, Gandara DR, Fry WA, Darling G, Johnson DH, Green MR, Miller RC, Ley J, Sause WT, Cox JD. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009 Aug 1;374(9687):379-86. Epub 2009 Jul 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60737-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407808/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19632716 PubMed]<br />
#'''RTOG 9410:''' Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. [http://jnci.oxfordjournals.org/content/103/19/1452.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21903745 PubMed]<br />
#Liang J, Bi N, Wu S, Chen M, Lv C, Zhao L, Shi A, Jiang W, Xu Y, Zhou Z, Wang W, Chen D, Hui Z, Lv J, Zhang H, Feng Q, Xiao Z, Wang X, Liu L, Zhang T, Du L, Chen W, Shyr Y, Yin W, Li J, He J, Wang L. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial. Ann Oncol. 2017 Apr 1;28(4):777-783. [https://doi.org/10.1093/annonc/mdx009 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28137739 PubMed] NCT01494558<br />
<br />
==Cisplatin, Vinblastine, RT {{#subobject:54c5c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c057fe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ Curran et al. 2011 (RTOG 9410)]<br />
|rowspan=2|1994-1998<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Cisplatin.2C_Etoposide.2C_RT|Cisplatin, Etoposide, RT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Cisplatin_.26_Vinblastine_2|Cisplatin & Vinblastine]], then [[#Radiation_therapy|RT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 29<br />
*[[Vinblastine (Velban)]] 5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]]<br />
<br />
'''5-week course'''<br />
<br />
===References===<br />
<br />
#'''RTOG 9410:''' Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. [http://jnci.oxfordjournals.org/content/103/19/1452.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21903745 PubMed]<br />
<br />
==Cisplatin, Vinorelbine, RT {{#subobject:59gcc4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c8ygfe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2015.62.6812 Eberhardt et al. 2015 (ESPATUE)]<br />
|2004-2013<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|Surgery<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Cisplatin & Paclitaxel<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]]<br />
*[[Vinorelbine (Navelbine)]]<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]]<br />
<br />
===References===<br />
<br />
#'''ESPATUE:''' Eberhardt WE, Pöttgen C, Gauler TC, Friedel G, Veit S, Heinrich V, Welter S, Budach W, Spengler W, Kimmich M, Fischer B, Schmidberger H, De Ruysscher D, Belka C, Cordes S, Hepp R, Lütke-Brintrup D, Lehmann N, Schuler M, Jöckel KH, Stamatis G, Stuschke M. Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE). J Clin Oncol. 2015 Dec 10;33(35):4194-201. Epub 2015 Nov 2. [https://doi.org/10.1200/JCO.2015.62.6812 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26527789 PubMed]<br />
<br />
==Radiation therapy {{#subobject:6a90fb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen variant #1, 20 Gy {{#subobject:1g2326|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063335/ Ball et al. 1997]<br />
|1988-1993<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & RT<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] 4 Gy in 5 fractions (20 Gy total)<br />
<br />
'''5-day course'''<br />
<br />
===Regimen variant #2, 45 Gy + 18 Gy boost (63 Gy total) {{#subobject:5d7861|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ Curran et al. 2011 (RTOG 9410)]<br />
|1994-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#RTOG_9410|See link]]<br />
|[[Complex_multipart_regimens#RTOG_9410|See link]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.55.405 Belani et al. 2005 (LAMP)]<br />
|1998-2001<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*LAMP: [[#Carboplatin_.26_Paclitaxel_.28CP.29_2|Carboplatin & Paclitaxel]] x 2<br />
*RTOG 9410: [[#Cisplatin_.26_Vinblastine_2|Cisplatin & Vinblastine]] x 5 wk<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] 45 Gy in 1.8 Gy fractions x 25 fractions, then 18 Gy boost in 2 Gy fractions x 9 fractions<br />
<br />
'''7-week course'''<br />
<br />
===Regimen variant #3, 60 Gy {{#subobject:12f326|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://annals.org/aim/article-abstract/705110/thoracic-radiation-therapy-alone-compared-combined-chemoradiotherapy-locally-unresectable-non Morton et al. 1991]<br />
|1983-1987<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MACC & RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.1999.17.1.4 Clamon et al. 1999 (CALGB 9130)]<br />
|1991-NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_RT|Carboplatin & RT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.redjournal.org/article/S0360-3016(01)02797-3/fulltext Bradley et al. 2002 (RTOG 93-04)]<br />
|1994-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Beta-interferon & RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdh100 Groen et al. 2004]<br />
|1995-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_RT|Carboplatin & RT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS24<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70139-0/fulltext Atagi et al. 2012 (JCOG0301)]<br />
|2003-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_RT|Carboplatin & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*CALGB 9130: [[#Cisplatin_.26_Vinblastine_2|Cisplatin & Vinblastine]] x 5 wk<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] 60 Gy<br />
<br />
'''One course'''<br />
===References===<br />
<br />
#Morton RF, Jett JR, McGinnis WL, Earle JD, Therneau TM, Krook JE, Elliott TE, Mailliard JA, Nelimark RA, Maksymiuk AW, Drummond RG, Laurie JA, Kugler JW, Anderson RT. Thoracic radiation therapy alone compared with combined chemoradiotherapy for locally unresectable non-small cell lung cancer: a randomized, phase III trial. Ann Intern Med. 1991 Nov 1;115(9):681-6. [https://annals.org/aim/article-abstract/705110/thoracic-radiation-therapy-alone-compared-combined-chemoradiotherapy-locally-unresectable-non link to original article] [https://pubmed.ncbi.nlm.nih.gov/1656827 PubMed]<br />
#Ball D, Smith J, Bishop J, Olver I, Davis S, O'Brien P, Bernshaw D, Ryan G, Millward M. A phase III study of radiotherapy with and without continuous-infusion fluorouracil as palliation for non-small-cell lung cancer. Br J Cancer. 1997;75(5):690-7. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063335/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/9043026 PubMed]<br />
#'''CALGB 9130:''' Clamon G, Herndon J, Cooper R, Chang AY, Rosenman J, Green MR; [[Study_Groups#CALGB|CALGB]]; [[Study_Groups#ECOG|ECOG]]. Radiosensitization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol. 1999 Jan;17(1):4-11. [https://doi.org/10.1200/JCO.1999.17.1.4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10458211 PubMed]<br />
#'''RTOG 93-04:''' Bradley JD, Scott CB, Paris KJ, Demas WF, Machtay M, Komaki R, Movsas B, Rubin P, Sause WT. A phase III comparison of radiation therapy with or without recombinant beta-interferon for poor-risk patients with locally advanced non-small-cell lung cancer (RTOG 93-04). Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1173-9. [https://www.redjournal.org/article/S0360-3016(01)02797-3/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11955727 PubMed]<br />
#Groen HJ, van der Leest AH, Fokkema E, Timmer PR, Nossent GD, Smit WJ, Nabers J, Hoekstra HJ, Hermans J, Otter R, van Putten JW, de Vries EG, Mulder NH. Continuously infused carboplatin used as radiosensitizer in locally unresectable non-small-cell lung cancer: a multicenter phase III study. Ann Oncol. 2004 Mar;15(3):427-32. [https://doi.org/10.1093/annonc/mdh100 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14998844 PubMed]<br />
#'''LAMP:''' Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. [https://doi.org/10.1200/jco.2005.55.405 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16087941 PubMed]<br />
#'''RTOG 9410:''' Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. [http://jnci.oxfordjournals.org/content/103/19/1452.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21903745 PubMed]<br />
#'''JCOG0301:''' Atagi S, Kawahara M, Yokoyama A, Okamoto H, Yamamoto N, Ohe Y, Sawa T, Ishikura S, Shibata T, Fukuda H, Saijo N, Tamura T; [[Study_Groups#JCOG|JCOG]] Lung Cancer Study Group. Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Lancet Oncol. 2012 Jul;13(7):671-8. Epub 2012 May 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70139-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22622008 PubMed] NCT00132665<br />
<br />
=Consolidation or maintenance after definitive therapy for inoperable disease=<br />
<br />
==Carboplatin & Paclitaxel (CP) {{#subobject:81d5a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d729a8|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.55.405 Belani et al. 2005 (LAMP)]<br />
|1998-2001<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419359/ Bradley et al. 2015 (RTOG 0617)]<br />
|2007-2011<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_RT|Carboplatin, Paclitaxel, RT]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 30 minutes once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''21-day cycle for 2 cycles'''<br />
<br />
===References===<br />
<br />
#'''LAMP:''' Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. [https://doi.org/10.1200/jco.2005.55.405 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16087941 PubMed]<br />
#'''RTOG 0617:''' Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. Epub 2015 Jan 16. [https://doi.org/10.1016/s1470-2045(14)71207-0 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419359/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25601342 PubMed] NCT00533949<br />
##'''Update:''' Bradley JD, Hu C, Komaki RR, Masters GA, Blumenschein GR, Schild SE, Bogart JA, Forster KM, Magliocco AM, Kavadi VS, Narayan S, Iyengar P, Robinson CG, Wynn RB, Koprowski CD, Olson MR, Meng J, Paulus R, Curran WJ Jr, Choy H. Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Mar 1;38(7):706-714. Epub 2019 Dec 16. [https://doi.org/10.1200/jco.19.01162 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048161/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31841363 PubMed]<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/272 Project Data Sphere]<br />
<br />
==Durvalumab monotherapy {{#subobject:6f72e5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:04242b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1709937 Antonia et al. 2017 (PACIFIC)]<br />
|2014-2016<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Placebo_2|Placebo]]<br />
| style="background-color:#1a9850" |Superior OS<sup>1</sup> <br>Median OS: Not reached vs 29.1 mo <br>(HR 0.69, 95% CI 0.55-0.86)<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2019 update.''<br />
====Preceding treatment====<br />
<br />
*"Two or more cycles (defined according to local practice) of platinum-based chemotherapy (containing etoposide, vinblastine, vinorelbine, a taxane [paclitaxel or docetaxel], or pemetrexed) concurrently with definitive radiation therapy (54 to 66 Gy), in which the mean dose to the lung was less than 20 Gy, the V20 (the volume of lung parenchyma that received 20 Gy or more) was less than 35%, or both."<br />
<br />
====Immunotherapy====<br />
<br />
*[[Durvalumab (Imfinzi)]] 10 mg/kg IV once on day 1<br />
<br />
'''14-day cycle for up to 26 cycles (1 year)'''<br />
<br />
===References===<br />
<br />
#'''PACIFIC:''' Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. Epub 2017 Sep 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1709937 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28885881 PubMed] NCT02125461<br />
##'''Update:''' Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Faivre-Finn C, Reck M, Vansteenkiste J, Spigel DR, Wadsworth C, Melillo G, Taboada M, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018 Dec 13;379(24):2342-2350. Epub 2018 Sep 25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1709937 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30280658 PubMed]<br />
##'''Update:''' Gray JE, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, Cho BC, Planchard D, Paz-Ares L, Faivre-Finn C, Vansteenkiste JF, Spigel DR, Wadsworth C, Taboada M, Dennis PA, Özgüroğlu M, Antonia SJ. Three-Year Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC-Update from PACIFIC. J Thorac Oncol. 2020 Feb;15(2):288-293. Epub 2019 Oct 14. [https://doi.org/10.1016/j.jtho.2019.10.002 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7244187/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31622733 PubMed]<br />
#'''KEYLYNK-012:''' NCT04380636<br />
<br />
=Advanced or metastatic disease, first-line=<br />
<br />
==Carboplatin & Docetaxel {{#subobject:bdce59|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
DCb: '''<u>D</u>'''ocetaxel & '''<u>C</u>'''ar'''<u>b</u>'''oplatin<br />
===Regimen {{#subobject:bce236|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/jco.2003.12.046 Fossella et al. 2003 (TAX 326)]<br />
| rowspan="2" |1998-2000<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Cisplatin_.26_Docetaxel_.28DC.29_3|Cisplatin & Docetaxel]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdl078 Booton et al. 2006 (BTOG1)]<br />
|2001-2002<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[Non-small_cell_lung_cancer_-_historical#MIC_3|MIC]]<br> 2. [[Non-small_cell_lung_cancer_-_historical#MVP_.28Vinblastine.29|MVP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2011.35.5214 Groen et al. 2011 (NVALT-4)]<br />
|2003-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Carboplatin, Docetaxel, Celecoxib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.21.9618 Lynch et al. 2010 (BMS099)]<br />
|2005-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Carboplatin, Docetaxel, Cetuximab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for up to 5 cycles (NVALT-4), 6 cycles (BMS099), or indefinitely'''<br />
<br />
===References===<br />
<!-- Previously presented in part at the Annual Meeting of the American Society of Clinical Oncology (ASCO), San Francisco, CA, May 12–15, 2001; the Annual Meeting of ASCO, Orlando, FL, May 18–21, 2002; and the Congress of the European Society for Medical Oncology, Nice, France, October 18–22, 2002. --><br />
<br />
#'''TAX 326:''' Fossella F, Rodrigues Pereira J, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. [https://doi.org/10.1200/jco.2003.12.046 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12837811 PubMed]<br />
#'''BTOG1:''' Booton R, Lorigan P, Anderson H, Baka S, Ashcroft L, Nicolson M, O'Brien M, Dunlop D, O'Byrne K, Laurence V, Snee M, Dark G, Thatcher N. A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer: a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1). Ann Oncol. 2006 Jul;17(7):1111-9. Epub 2006 Apr 7. [https://doi.org/10.1093/annonc/mdl078 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16603599 PubMed]<br />
#'''BMS099:''' Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, Paschold E, Iannotti NO, Dakhil S, Gorton S, Pautret V, Weber MR, Woytowitz D. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol. 2010 Feb 20;28(6):911-7. Epub 2010 Jan 25. [https://doi.org/10.1200/JCO.2009.21.9618 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20100966 PubMed] NCT00112294<br />
<!-- Presented in part at the 45th Annual Meeting of the American Society of Clinical Oncology, May 29-June 2, 2009, Orlando, FL. --><br />
#'''NVALT-4:''' Groen HJ, Sietsma H, Vincent A, Hochstenbag MM, van Putten JW, van den Berg A, Dalesio O, Biesma B, Smit HJ, Termeer A, Hiltermann TJ, van den Borne BE, Schramel FM. Randomized, placebo-controlled phase III study of docetaxel plus carboplatin with celecoxib and cyclooxygenase-2 expression as a biomarker for patients with advanced non-small-cell lung cancer: the NVALT-4 study. J Clin Oncol. 2011 Nov 10;29(32):4320-6. Epub 2011 Oct 11. [https://doi.org/10.1200/JCO.2011.35.5214 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21990410 PubMed] NTR1703<br />
<br />
==Carboplatin & Etoposide (CE) {{#subobject:4c2ff5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f920ac|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1990.8.9.1556 Klastersky et al. 1990 (EORTC 07861)]<br />
|1987-1989<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Etoposide_.28EP.29_2|Cisplatin & Etoposide]]<br />
| style="background-color:#fee08b" |Might have inferior ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] 325 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''3- to 4-week cycles'''<br />
<br />
===References===<br />
<br />
#'''EORTC 07861:''' Klastersky J, Sculier JP, Lacroix H, Dabouis G, Bureau G, Libert P, Richez M, Ravez P, Vandermoten G, Thiriaux J, Cordier R, Finet C, Berchier MC, Sergysels R, Mommen P, Paesmans M. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organisation for Research and Treatment of Cancer Protocol 07861. J Clin Oncol. 1990 Sep;8(9):1556-62. [https://doi.org/10.1200/JCO.1990.8.9.1556 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2167953 PubMed]<br />
<br />
==Carboplatin & Gemcitabine (GCb) {{#subobject:8669e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GC: '''<u>G</u>'''emcitabine & '''<u>C</u>'''arboplatin<br />
<br>GCa: '''<u>G</u>'''emcitabine & '''<u>Ca</u>'''rboplatin<br />
<br>GCb: '''<u>G</u>'''emcitabine & '''<u>C</u>'''ar'''<u>b</u>'''oplatin<br />
===Regimen variant #1, 4/1000 {{#subobject:fa3601|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360329/ Helbekkmo et al. 2007]<br />
|2003-2004<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Carboplatin_.26_Vinorelbine|VC]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: AUC was calculated using the Chatelut formula.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 4 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===Regimen variant #2, 5/1000 q3wk {{#subobject:cfb199|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2008.20.9114 Grønberg et al. 2009]<br />
|2005-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Pemetrexed|Carboplatin & Pemetrexed]]<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRQoL<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 4 cycles'''<br />
<br />
===Regimen variant #3, 5/1000 q4wk {{#subobject:82e4e7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.11535/abstract Danson et al. 2003]<br />
|1997-2001<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[Non-small_cell_lung_cancer_-_historical#MIC_3|MIC]]<br> 2. [[Non-small_cell_lung_cancer_-_historical#MVP_.28Vinblastine.29|MVP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #4, 5/1200 {{#subobject:58b47e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(03)00233-2/fulltext Zatloukal et al. 2003]<br />
|1999-2001<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of grade 3/4 toxicity<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.03.037 Rudd et al. 2005]<br />
|1999-2001<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Non-small_cell_lung_cancer_-_historical#MIC_3|MIC]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1200 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #5, 5/1250 q3wk {{#subobject:4bca29|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.01.2781 Sederholm et al. 2005]<br />
|1998-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691357/ Bepler et al. 2013 (MCC-15005)]<br />
|2007-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ERCC1 and RRM1 expression-based chemotherapy<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS6<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
| style="background-color:#d73027" |Inferior HRQoL<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 to 6 cycles'''<br />
<br />
===Regimen variant #6, 5/1250 q4wk {{#subobject:7e79d9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70254-7/fulltext Wu et al. 2013 (FASTACT-2)]<br />
|2009-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer,_EGFR-mutated#Carboplatin_.26_Gemcitabine_.28GCb.29.2FErlotinib|Carboplatin & Gemcitabine/Erlotinib]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm.'' <br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #7, 6/1000 {{#subobject:c7aefa|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdm430 Kosmidis et al. 2007]<br />
|2000-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_Paclitaxel|Gemcitabine & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #8, 6/1250 ("GCb6") {{#subobject:afcfd9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.ejcancer.com/article/S0959-8049(17)31001-8/fulltext Ferry et al. 2017 (BTOG2)]<br />
| rowspan="2" |2005-2009<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]; GC50<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|<br />
|-<br />
|2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]; GC80<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
| style="background-color:#d73027" |Inferior HRQoL<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 to 6 cycles'''<br />
<br />
===Regimen variant #9, 300/1000 {{#subobject:9c94c9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(01)00493-7/fulltext Grigorescu et al. 2002]<br />
|1997-2000<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Non-small_cell_lung_cancer_-_historical#Cisplatin_.26_Vinblastine|Cisplatin & Vinblastine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Grigorescu AC, Draghici IN, Nitipir C, Gutulescu N, Corlan E. Gemcitabine (GEM) and carboplatin (CBDCA) versus cisplatin (CDDP) and vinblastine (VLB) in advanced non-small-cell lung cancer (NSCLC) stages III and IV: a phase III randomised trial. Lung Cancer. 2002 Jul;37(1):9-14. [https://www.lungcancerjournal.info/article/S0169-5002(01)00493-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12057861 PubMed]<br />
#Danson S, Middleton MR, O'Byrne KJ, Clemons M, Ranson M, Hassan J, Anderson H, Burt PA, Fairve-Finn C, Stout R, Dowd I, Ashcroft L, Beresford C, Thatcher N. Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer. 2003 Aug 1;98(3):542-53. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.11535/abstract link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12879472 PubMed]<br />
#Zatloukal P, Petruzelka L, Zemanová M, Kolek V, Skricková J, Pesek M, Fojtů H, Grygárková I, Sixtová D, Roubec J, Horenková E, Havel L, Průsa P, Nováková L, Skácel T, Kůta M. Gemcitabine plus cisplatin vs gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial. Lung Cancer. 2003 Sep;41(3):321-31. [https://www.lungcancerjournal.info/article/S0169-5002(03)00233-2/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12928123 PubMed]<br />
#Rudd RM, Gower NH, Spiro SG, Eisen TG, Harper PG, Littler JA, Hatton M, Johnson PW, Martin WM, Rankin EM, James LE, Gregory WM, Qian W, Lee SM; London Lung Cancer Group. Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer Group. J Clin Oncol. 2005 Jan 1;23(1):142-53. [https://doi.org/10.1200/JCO.2005.03.037 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15625369 PubMed]<br />
#Sederholm C, Hillerdal G, Lamberg K, Kölbeck K, Dufmats M, Westberg R, Gawande SR; Swedish Lung Cancer Study Group. Phase III trial of gemcitabine plus carboplatin versus single-agent gemcitabine in the treatment of locally advanced or metastatic non-small-cell lung cancer: the Swedish Lung Cancer Study Group. J Clin Oncol. 2005 Nov 20;23(33):8380-8. [https://doi.org/10.1200/jco.2005.01.2781 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16293868 PubMed]<br />
#Helbekkmo N, Sundstrøm SH, Aasebø U, Brunsvig PF, von Plessen C, Hjelde HH, Garpestad OK, Bailey A, Bremnes RM; Norwegian Lung Cancer Study Group. Vinorelbine/carboplatin vs gemcitabine/carboplatin in advanced NSCLC shows similar efficacy, but different impact of toxicity. Br J Cancer. 2007 Aug 6;97(3):283-9. Epub 2007 Jun 26. [https://www.nature.com/articles/6603869 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360329/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17595658 PubMed]<br />
#Kosmidis PA, Kalofonos HP, Christodoulou C, Syrigos K, Makatsoris T, Skarlos D, Bakogiannis C, Nicolaides C, Bafaloukos D, Bamias A, Samantas E, Xiros N, Boukovinas I, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group. Ann Oncol. 2008 Jan;19(1):115-22. Epub 2007 Oct 15. [https://doi.org/10.1093/annonc/mdm430 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17938425 PubMed]<br />
<!-- Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL; and the International Association for the Study of Lung Cancer 12th World Conference on Lung Cancer, September 2-6, 2007, Seoul, Korea. --><br />
#Grønberg BH, Bremnes RM, Fløtten O, Amundsen T, Brunsvig PF, Hjelde HH, Kaasa S, von Plessen C, Stornes F, Tollåli T, Wammer F, Aasebø U, Sundstrøm S; Norwegian Lung Cancer Study Group. Phase III study by the Norwegian Lung Cancer Study Group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Jul 1;27(19):3217-24. Epub 2009 May 11. [https://doi.org/10.1200/jco.2008.20.9114 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19433683 PubMed]<br />
#'''ALPHA A1-99002L:''' Treat JA, Gonin R, Socinski MA, Edelman MJ, Catalano RB, Marinucci DM, Ansari R, Gillenwater HH, Rowland KM, Comis RL, Obasaju CK, Belani CP; Alpha Oncology Research Network. A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2010 Mar;21(3):540-7. Epub 2009 Oct 15. [https://doi.org/10.1093/annonc/mdp352 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19833819 PubMed] NCT00054392<br />
#'''MCC-15005:''' Bepler G, Williams C, Schell MJ, Chen W, Zheng Z, Simon G, Gadgeel S, Zhao X, Schreiber F, Brahmer J, Chiappori A, Tanvetyanon T, Pinder-Schenck M, Gray J, Haura E, Antonia S, Fischer JR. Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2013 Jul 1;31(19):2404-12. Epub 2013 May 20. [https://doi.org/10.1200/JCO.2012.46.9783 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691357/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23690416 PubMed] NCT00499109<br />
#'''FASTACT-2:''' Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, Srimuninnimit V, Sriuranpong V, Sandoval-Tan J, Zhu Y, Liao M, Zhou C, Pan H, Lee V, Chen YM, Sun Y, Margono B, Fuerte F, Chang GC, Seetalarom K, Wang J, Cheng A, Syahruddin E, Qian X, Ho J, Kurnianda J, Liu HE, Jin K, Truman M, Bara I, Mok T. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013 Jul;14(8):777-86. Epub 2013 Jun 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70254-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23782814 PubMed] NCT00883779<br />
#'''KEYNOTE-024:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1606774/suppl_file/nejmoa1606774_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27718847 PubMed] NCT02142738<br />
##'''HRQoL analysis:''' Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30690-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29129441 PubMed]<br />
##'''Update:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. [https://doi.org/10.1200/JCO.18.00149 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30620668 PubMed]<br />
#'''BTOG2:''' Ferry D, Billingham L, Jarrett H, Dunlop D, Woll PJ, Nicolson M, Shah R, Thompson J, Spicer J, Muthukumar D, Skailes G, Leonard P, Chetiyawardana AD, Wells P, Lewanski C, Crosse B, Hill M, Gaunt P, O'Byrne K; British Thoracic Oncology Group. Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: results from a British Thoracic Oncology Group randomised phase III trial. Eur J Cancer. 2017 Sep;83:302-312. Epub 2017 Aug 4. [https://www.ejcancer.com/article/S0959-8049(17)31001-8/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28780466 PubMed] NCT00112710<br />
<br />
==Carboplatin & Paclitaxel (CP) {{#subobject:c5fbdf|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CP: '''<u>C</u>'''arboplatin & '''<u>P</u>'''aclitaxel<br />
<br>PC: '''<u>P</u>'''aclitaxel & '''<u>C</u>'''arboplatin<br />
<br>TC: '''<u>T</u>'''axol (Paclitaxel) & '''<u>C</u>'''arboplatin<br />
===Regimen variant #1, 5/200 {{#subobject:5g4ff1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
| style="background-color:#d73027" |Inferior HRQoL<br />
|-<br />
|rowspan=2|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7146551/ Rizvi et al. 2020 (MYSTIC)]<br />
|rowspan=2|2015-2016<br />
|rowspan=2 style="background-color:#1a9851" |Phase III (C)<br />
|Durvalumab<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|<br />
|-<br />
|Durvalumab & Tremelimumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS<br />
|<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 15 to 60 minutes once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''21-day cycle for 4 to 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*KEYNOTE-024: Patients with nonsquamous histology could optionally proceed to [[#Pemetrexed_monotherapy_2|pemetrexed switch maintenance]]<br />
<br />
===Regimen variant #2, 6/175 {{#subobject:e3545d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962260/ Stathopoulos et al. 2004]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Paclitaxel & Vinorelbine<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of ORR/OS<br />
|-<br />
|[https://doi.org/10.1200/jco.2011.38.4032 Lynch et al. 2012 (CA184-041)]<br />
|2008-2009<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Ipilimumab|CP & Ipilimumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Steroids|Corticosteroids]] could be used as premedication for [[Paclitaxel (Taxol)]] infusion.<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #3, 6/200 {{#subobject:5f5ff1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2002.20.5.1335 Socinski et al. 2002]<br />
|1998-2000<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|CP]]; indefinite<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of QoL<br />
|-<br />
|[https://doi.org/10.1200/JCO.2002.12.112 Kosmidis et al. 2002]<br />
|1998-2000<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Gemcitabine_.26_Paclitaxel|Gemcitabine & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdf332 Rosell et al. 2002]<br />
|1996-1997<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/jco.2004.11.022 Johnson et al. 2004]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Bevacizumab|PacCBev]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.04.044 Leighl et al. 2005 (NCIC-CTG BR.18)]<br />
|2000-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CP & BMS-275291<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
| style="background-color:#1a9850" |Less toxic<br />
|-<br />
| rowspan="3" |[https://doi.org/10.1093/annonc/mdl377 Ohe et al. 2006 (FACS)]<br />
| rowspan="3" |2000-2002<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|<br />
|-<br />
|2. [[#Cisplatin_.26_Irinotecan_.28IC.29|Cisplatin & Irinotecan]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|<br />
|-<br />
|3. [[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.02.840 Herbst et al. 2005 (TRIBUTE)]<br />
|2001-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Erlotinib|CP & Erlotinib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://www.clinical-lung-cancer.com/article/S1525-7304(11)70705-7/pdf Schuette et al. 2006]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|CP]]; weekly<br />
| style="background-color:#ffffbf" |Seems to have non-inferior ORR<br />
| style="background-color:#ffffbf" |Mixed toxicity<br />
|-<br />
|[https://doi.org/10.1200/JCO.2007.12.2689 Blumenschein et al. 2008 (SPIRIT II)]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Bexarotene|CP & Bexarotene]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2010.32.8971 Hirsh et al. 2011 (A8501001)]<br />
|2005-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CP & Agatolimod<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.26.1321 Scagliotti et al. 2010 (ESCAPE)]<br />
|2006-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Sorafenib|CP & Sorafenib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2010.31.0326 Okamoto et al. 2010 (LETS)]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Carboplatin & S-1<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/jco.2011.39.5848 Socinski et al. 2012 (CA031)]<br />
|2007-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_nab-Paclitaxel|Carboplatin & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior ORR<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2011.35.0660 Lara et al. 2011 (ATTRACT-1)]<br />
|2008-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CP & Vadimezan<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067944/ Langer et al. 2014 (A4021016)]<br />
|2008-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CP & Figitumumab<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(13)01028-9/fulltext Laurie et al. 2013 (NCIC-CTG BR.29)]<br />
|2008-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Cediranib|CP & Cediranib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
| style="background-color:#1a9850" |Less toxic<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30694-0/fulltext Herbst et al. 2017 (SWOG S0819)]<br />
|2009-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Cetuximab|CP & Cetuximab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS<br />
|<br />
|-<br />
|[http://clincancerres.aacrjournals.org/content/23/8/1937.full Ramalingam et al. 2016 (M10-898)]<br />
|2012-2013<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Veliparib|CP & Veliparib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
| style="background-color:#d73027" |Inferior HRQoL<br />
|-<br />
|rowspan=2|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7146551/ Rizvi et al. 2020 (MYSTIC)]<br />
|rowspan=2|2015-2016<br />
|rowspan=2 style="background-color:#1a9851" |Phase III (C)<br />
|Durvalumab<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|<br />
|-<br />
|Durvalumab & Tremelimumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS<br />
|<br />
|-<br />
|}<br />
''Note: Patients in TRIBUTE received a maximum of 6 cycles. Patients in SWOG S0819 were EGFR FISH positive.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 15 to 60 minutes once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''21-day cycle for 3 or more cycles'''<br />
====Subsequent treatment====<br />
<br />
*Socinski et al. 2002, upon progression: Paclitaxel<br />
*KEYNOTE-024: Patients with nonsquamous histology could optionally proceed, after 4 to 6 cycles, to [[#Pemetrexed_monotherapy_2|pemetrexed switch maintenance]]<br />
<br />
===Regimen variant #4, 6/225 {{#subobject:847441|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2001.19.13.3210 Kelly et al. 2001 (SWOG 9509)]<br />
|1996-1998<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
| rowspan="3" |[https://www.nejm.org/doi/full/10.1056/NEJMoa011954 Schiller et al. 2002 (ECOG E1594)]<br />
| rowspan="3" |1996-1999<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Cisplatin_.26_Docetaxel_.28DC.29_3|Cisplatin & Docetaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|3. [[#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.07.172 Lilenbaum et al. 2005 (CALGB 9730)]<br />
|1997-2000<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Paclitaxel<br />
| style="background-color:#1a9850" |Superior FFS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2004.07.215 Herbst et al. 2004 (INTACT 2)]<br />
|2000-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CP & Gefitinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.01.3771 Williamson et al. 2005 (SWOG S0003)]<br />
|2000-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CP & Tirapazamine<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2007.13.1912 Belani et al. 2008]<br />
|2000-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|CP]]; weekly paclitaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdp352 Treat et al. 2009 (ALPHA A1-99002L)]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|Carboplatin & Gemcitabine]]<br> 2. Gemcitabine & Paclitaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(08)70261-4/fulltext Kubota et al. 2008 (JMTO LC00-03)]<br />
|2001-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Vinorelbine, then Docetaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.jto.org/article/S1556-0864(15)31941-9/fulltext Weissman et al. 2011]<br />
|2004-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GEMOX<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.21.9618 Lynch et al. 2010 (BMS099)]<br />
|2005-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CP & Cetuximab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''21-day cycle for up to 4 cycles (Belani et al. 2008), 6 cycles (Weissman et al. 2011), 10 cycles (SWOG 9509), or indefinitely (ECOG E1594)'''<br />
====Subsequent treatment====<br />
<br />
*Belani et al. 2008: Paclitaxel maintenance<br />
<br />
===References===<br />
<br />
#'''SWOG 9509:''' Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, Ramsey SD, Wozniak AJ, Weiss GR, Moore DF, Israel VK, Livingston RB, Gandara DR. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol. 2001 Jul 1;19(13):3210-8. [https://doi.org/10.1200/JCO.2001.19.13.3210 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11432888 PubMed]<br />
#'''ECOG E1594:''' Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; [[Study_Groups#ECOG|ECOG]]. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. [https://www.nejm.org/doi/full/10.1056/NEJMoa011954 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11784875 PubMed]<br />
#Socinski MA, Schell MJ, Peterman A, Bakri K, Yates S, Gitten R, Unger P, Lee J, Lee JH, Tynan M, Moore M, Kies MS. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol. 2002 Mar 1;20(5):1335-43. [https://doi.org/10.1200/JCO.2002.20.5.1335 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11870177 PubMed]<br />
#Kosmidis P, Mylonakis N, Nicolaides C, Kalophonos C, Samantas E, Boukovinas J, Fountzilas G, Skarlos D, Economopoulos T, Tsavdaridis D, Papakostas P, Bacoyiannis C, Dimopoulos M. Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol. 2002 Sep 1;20(17):3578-85. [https://doi.org/10.1200/JCO.2002.12.112 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12202657 PubMed]<br />
#Rosell R, Gatzemeier U, Betticher DC, Keppler U, Macha HN, Pirker R, Berthet P, Breau JL, Lianes P, Nicholson M, Ardizzoni A, Chemaissani A, Bogaerts J, Gallant G. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol. 2002 Oct;13(10):1539-49. [https://doi.org/10.1093/annonc/mdf332 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12377641 PubMed]<br />
#'''INTACT 2:''' Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, Wolf MK, Krebs AD, Averbuch SD, Ochs JS, Grous J, Fandi A, Johnson DH. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. J Clin Oncol. 2004 Mar 1;22(5):785-94. [https://doi.org/10.1200/JCO.2004.07.215 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/14990633 PubMed]<br />
#Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004 Jun 1;22(11):2184-91. [https://doi.org/10.1200/jco.2004.11.022 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15169807 PubMed]<br />
#Stathopoulos GP, Veslemes M, Georgatou N, Antoniou D, Giamboudakis P, Katis K, Tsavdaridis D, Rigatos SK, Dimitroulis I, Bastani S, Loukides S, Vergos K, Marossis K, Grigoratou T, Kalatzi E, Charalambatou M, Paspalli A, Michalopoulou P, Stoka M, Gerogianni A. Front-line paclitaxel-vinorelbine versus paclitaxel-carboplatin in patients with advanced non-small-cell lung cancer: a randomized phase III trial. Ann Oncol. 2004 Jul;15(7):1048-55. [https://doi.org/10.1093/annonc/mdq234 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962260/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15205198 PubMed]<br />
#'''CALGB 9730:''' Lilenbaum RC, Herndon JE 2nd, List MA, Desch C, Watson DM, Miller AA, Graziano SL, Perry MC, Saville W, Chahinian P, Weeks JC, Holland JC, Green MR. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the Cancer and Leukemia Group B (study 9730). J Clin Oncol. 2005 Jan 1;23(1):190-6. [https://doi.org/10.1200/JCO.2005.07.172 link to original article]'''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15625373 PubMed]<br />
#'''NCIC-CTG BR.18:''' Leighl NB, Paz-Ares L, Douillard JY, Peschel C, Arnold A, Depierre A, Santoro A, Betticher DC, Gatzemeier U, Jassem J, Crawford J, Tu D, Bezjak A, Humphrey JS, Voi M, Galbraith S, Hann K, Seymour L, Shepherd FA. Randomized phase III study of matrix metalloproteinase inhibitor BMS-275291 in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR18. J Clin Oncol. 2005 Apr 20;23(12):2831-9. [https://doi.org/10.1200/JCO.2005.04.044 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15837997 PubMed]<br />
#'''TRIBUTE:''' Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, Tran HT, Klein P, Li X, Ramies D, Johnson DH, Miller VA; TRIBUTE Investigator Group. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005 Sep 1;23(25):5892-9. Epub 2005 Jul 25. [https://doi.org/10.1200/JCO.2005.02.840 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16043829 PubMed]<br />
#'''SWOG S0003:''' Williamson SK, Crowley JJ, Lara PN Jr, McCoy J, Lau DH, Tucker RW, Mills GM, Gandara DR; [[Study_Groups#SWOG|SWOG]]. Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003. J Clin Oncol. 2005 Dec 20;23(36):9097-104. [https://doi.org/10.1200/JCO.2005.01.3771 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16361616 PubMed]<br />
#Schuette W, Blankenburg T, Guschall W, Dittrich I, Schroeder M, Schweisfurth H, Chemaissani A, Schumann C, Dickgreber N, Appel T, Ukena D. Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin. Clin Lung Cancer. 2006 Mar;7(5):338-43. [https://www.clinical-lung-cancer.com/article/S1525-7304(11)70705-7/pdf link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16640806 PubMed]<br />
#'''FACS:''' Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. [https://doi.org/10.1093/annonc/mdl377 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17079694 PubMed]<br />
#Belani CP, Ramalingam S, Perry MC, LaRocca RV, Rinaldi D, Gable PS, Tester WJ. Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol. 2008 Jan 20;26(3):468-73. [https://doi.org/10.1200/JCO.2007.13.1912 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18202422 PubMed]<br />
#'''SPIRIT II:''' Blumenschein GR Jr, Khuri FR, von Pawel J, Gatzemeier U, Miller WH Jr, Jotte RM, Le Treut J, Sun SL, Zhang JK, Dziewanowska ZE, Negro-Vilar A. Phase III trial comparing carboplatin, paclitaxel, and bexarotene with carboplatin and paclitaxel in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT II. J Clin Oncol. 2008 Apr 10;26(11):1879-85. [https://doi.org/10.1200/JCO.2007.12.2689 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18398153 PubMed]<br />
#'''JMTO LC00-03:''' Kubota K, Kawahara M, Ogawara M, Nishiwaki Y, Komuta K, Minato K, Fujita Y, Teramukai S, Fukushima M, Furuse K; Japan Multi-National Trial Organisation. Vinorelbine plus gemcitabine followed by docetaxel versus carboplatin plus paclitaxel in patients with advanced non-small-cell lung cancer: a randomised, open-label, phase III study. Lancet Oncol. 2008 Dec;9(12):1135-42. Epub 2008 Nov 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(08)70261-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19013107 PubMed] NCT00079287<br />
#'''ALPHA A1-99002L:''' Treat JA, Gonin R, Socinski MA, Edelman MJ, Catalano RB, Marinucci DM, Ansari R, Gillenwater HH, Rowland KM, Comis RL, Obasaju CK, Belani CP; Alpha Oncology Research Network. A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2010 Mar;21(3):540-7. Epub 2009 Oct 15. [https://doi.org/10.1093/annonc/mdp352 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19833819 PubMed] NCT00054392<br />
#'''BMS099:''' Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, Paschold E, Iannotti NO, Dakhil S, Gorton S, Pautret V, Weber MR, Woytowitz D. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol. 2010 Feb 20;28(6):911-7. Epub 2010 Jan 25. [https://doi.org/10.1200/JCO.2009.21.9618 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20100966 PubMed] NCT00112294<br />
#'''ESCAPE:''' Scagliotti G, Novello S, von Pawel J, Reck M, Rodrigues Pereira J, Thomas M, Abrão Miziara JE, Balint B, De Marinis F, Keller A, Arén O, Csollak M, Albert I, Barrios CH, Grossi F, Krzakowski M, Cupit L, Cihon F, Dimatteo S, Hanna N. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol. 2010 Apr 10;28(11):1835-42. Epub 2010 Mar 8. [https://doi.org/10.1200/JCO.2009.26.1321 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20212250 PubMed] NCT00300885<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/274 Project Data Sphere]<br />
#'''LETS:''' Okamoto I, Yoshioka H, Morita S, Ando M, Takeda K, Seto T, Yamamoto N, Saka H, Asami K, Hirashima T, Kudoh S, Satouchi M, Ikeda N, Iwamoto Y, Sawa T, Miyazaki M, Tamura K, Kurata T, Fukuoka M, Nakagawa K; West Japan Oncology Group. Phase III trial comparing oral S-1 plus carboplatin with paclitaxel plus carboplatin in chemotherapy-naïve patients with advanced non-small-cell lung cancer: results of a West Japan Oncology Group study. J Clin Oncol. 2010 Dec 20;28(36):5240-6. Epub 2010 Nov 15. [https://doi.org/10.1200/JCO.2010.31.0326 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21079147 PubMed] UMIN000000503<br />
#Weissman CH, Reynolds CH, Neubauer MA, Pritchard S, Kobina S, Asmar L. A phase III randomized trial of gemcitabine-oxaliplatin versus carboplatin-paclitaxel as first-line therapy in patients with advanced non-small cell lung cancer. J Thorac Oncol. 2011 Feb;6(2):358-64. [https://www.jto.org/article/S1556-0864(15)31941-9/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/21206386 PubMed]<br />
<!-- Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL. --><br />
#'''A8501001:''' Hirsh V, Paz-Ares L, Boyer M, Rosell R, Middleton G, Eberhardt WE, Szczesna A, Reiterer P, Saleh M, Arrieta O, Bajetta E, Webb RT, Raats J, Benner RJ, Fowst C, Meech SJ, Readett D, Schiller JH. Randomized phase III trial of paclitaxel/carboplatin with or without PF-3512676 (Toll-like receptor 9 agonist) as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2011 Jul 1;29(19):2667-74. Epub 2011 May 31. [https://doi.org/10.1200/JCO.2010.32.8971 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21632509 PubMed] NCT00254891<br />
#'''ATTRACT-1:''' Lara PN Jr, Douillard JY, Nakagawa K, von Pawel J, McKeage MJ, Albert I, Losonczy G, Reck M, Heo DS, Fan X, Fandi A, Scagliotti G. Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. J Clin Oncol. 2011 Aug 1;29(22):2965-71. Epub 2011 Jun 27. [https://doi.org/10.1200/JCO.2011.35.0660 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21709202 PubMed] NCT00662597<br />
<!-- Presented in part at The Chicago Multidisciplinary Symposium in Thoracic Oncology, Chicago, IL, December 9-11, 2010, and the 14th World Congress on Lung Cancer, Amsterdam, the Netherlands, July 3-7, 2011. --><br />
#'''CA184-041:''' Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. [https://doi.org/10.1200/jco.2011.38.4032 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22547592 PubMed] NCT00527735<br />
<!-- Presented at the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago, IL, June 4-8, 2010; the 47th Annual Meeting of ASCO, Chicago, IL, June 2-7, 2011, and 14th World Conference on Lung Cancer, Amsterdam Rai, the Netherlands, July 3-7, 2011. --><br />
#'''CA031:''' Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, Hon JK, Hirsh V, Bhar P, Zhang H, Iglesias JL, Renschler MF. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2055-62. Epub 2012 Apr 30. [https://doi.org/10.1200/jco.2011.39.5848 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22547591 PubMed] NCT00540514<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/108 Project Data Sphere]<br />
#'''NCIC-CTG BR.29:''' Laurie SA, Solomon BJ, Seymour L, Ellis PM, Goss GD, Shepherd FA, Boyer MJ, Arnold AM, Clingan P, Laberge F, Fenton D, Hirsh V, Zukin M, Stockler MR, Lee CW, Chen EX, Montenegro A, Ding K, Bradbury PA. Randomised, double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC Clinical Trials Group study BR29. Eur J Cancer. 2014 Mar;50(4):706-12. Epub 2013 Dec 17. [https://www.ejcancer.com/article/S0959-8049(13)01028-9/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24360368 PubMed] NCT00795340<br />
<!-- Presented in part at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. --><br />
#'''A4021016:''' Langer CJ, Novello S, Park K, Krzakowski M, Karp DD, Mok T, Benner RJ, Scranton JR, Olszanski AJ, Jassem J. Randomized, phase III trial of first-line figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2014 Jul 1;32(19):2059-66. Epub 2014 Jun 2. [https://doi.org/10.1200/jco.2013.54.4932 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067944/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24888810 PubMed] NCT00596830<br />
#'''KEYNOTE-024:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1606774/suppl_file/nejmoa1606774_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27718847 PubMed] NCT02142738<br />
##'''HRQoL analysis:''' Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30690-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29129441 PubMed]<br />
##'''Update:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. [https://doi.org/10.1200/JCO.18.00149 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30620668 PubMed]<br />
#'''M10-898:''' Ramalingam SS, Blais N, Mazieres J, Reck M, Jones CM, Juhasz E, Urban L, Orlov S, Barlesi F, Kio E, Keiholz U, Qin Q, Qian J, Nickner C, Dziubinski J, Xiong H, Ansell P, McKee M, Giranda V, Gorbunova V. Randomized, placebo-controlled, phase II study of veliparib in combination with carboplatin and paclitaxel for advanced/metastatic non-small cell lung cancer. Clin Cancer Res. 2017 Apr 15;23(8):1937-1944. Epub 2016 Oct 10. [http://clincancerres.aacrjournals.org/content/23/8/1937.full link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/27803064 PubMed] NCT01560104<br />
#'''SWOG S0819:''' Herbst RS, Redman MW, Kim ES, Semrad TJ, Bazhenova L, Masters G, Oettel K, Guaglianone P, Reynolds C, Karnad A, Arnold SM, Varella-Garcia M, Moon J, Mack PC, Blanke CD, Hirsch FR, Kelly K, Gandara DR. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol. 2018 Jan;19(1):101-114. Epub 2017 Nov 20. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30694-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29169877 PubMed] NCT00946712<br />
#'''MYSTIC:''' Rizvi NA, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn MJ, van den Heuvel MM, Cobo M, Vicente D, Smolin A, Moiseyenko V, Antonia SJ, Le Moulec S, Robinet G, Natale R, Schneider J, Shepherd FA, Geater SL, Garon EB, Kim ES, Goldberg SB, Nakagawa K, Raja R, Higgs BW, Boothman AM, Zhao L, Scheuring U, Stockman PK, Chand VK, Peters S; MYSTIC Investigators. Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 May 1;6(5):661-674. [https://doi.org/10.1001/jamaoncol.2020.0237 link to original article] '''contains verified protocol in supplement''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7146551/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32271377 PubMed] NCT02453282<br />
<br />
==Carboplatin & nab-Paclitaxel {{#subobject:413b7d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:bcb4af|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2011.39.5848 Socinski et al. 2012 (CA031)]<br />
|2007-2009<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#1a9850" |Superior ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 mg/mL/min (per Calvert formula) IV once on day 1, '''given second'''<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, '''given first'''<br />
<br />
'''21-day cycle for 6 cycles'''; treatment could continue at physician's discretion if there was no progressive disease or unacceptable toxicity<br />
<br />
===References===<br />
<br />
#'''CA031:''' Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, Hon JK, Hirsh V, Bhar P, Zhang H, Iglesias JL, Renschler MF. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2055-62. Epub 2012 Apr 30. [https://doi.org/10.1200/jco.2011.39.5848 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22547591 PubMed] NCT00540514<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/108 Project Data Sphere]<br />
<br />
==Carboplatin & Paclitaxel (CP) & Bevacizumab {{#subobject:1c2c25|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PacCBev: '''<u>Pac</u>'''litaxel, '''<u>C</u>'''arboplatin, '''<u>Bev</u>'''acizumab <br />
<br>B+CP: '''<u>B</u>'''evacizumab, '''<u>C</u>'''arboplatin, '''<u>Pac</u>'''litaxel<br />
<br>BCP: '''<u>B</u>'''evacizumab, '''<u>C</u>'''arboplatin, '''<u>Pac</u>'''litaxel<br />
===Regimen {{#subobject:7df5c3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2004.11.022 Johnson et al. 2004]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30694-0/fulltext Herbst et al. 2017 (SWOG S0819)]<br />
|2009-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Carboplatin, Paclitaxel, Bevacizumab, Cetuximab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS<br />
|-<br />
|}<br />
====Biomarker eligibility criteria====<br />
*SWOG S0819: EGFR FISH positive<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 15 to 30 minutes once on day 1, '''given second, starting 60 minutes after the completion of paclitaxel'''<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
====Targeted therapy====<br />
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1, '''given third, starting 60 minutes after the completion of carboplatin'''<br />
**Infusion time per Johnson, et al. 2004 was over 90 minutes for cycle 1; if tolerated, given over 30 to 60 minutes for cycles 2 and later<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004 Jun 1;22(11):2184-91. [https://doi.org/10.1200/jco.2004.11.022 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15169807 PubMed]<br />
#'''SWOG S0819:''' Herbst RS, Redman MW, Kim ES, Semrad TJ, Bazhenova L, Masters G, Oettel K, Guaglianone P, Reynolds C, Karnad A, Arnold SM, Varella-Garcia M, Moon J, Mack PC, Blanke CD, Hirsch FR, Kelly K, Gandara DR. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol. 2018 Jan;19(1):101-114. Epub 2017 Nov 20. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30694-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29169877 PubMed] NCT00946712<br />
<br />
==Carboplatin & Paclitaxel (CP) & Ipilimumab {{#subobject:e8ba81|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f70cfc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2011.38.4032 Lynch et al. 2012 (CA184-041)]<br />
|2008-2009<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
''Note: this is the "phased" approach to this regimen.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Immunotherapy====<br />
<br />
*[[Ipilimumab (Yervoy)]] as follows:<br />
**Cycles 3 to 6: 10 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Steroids|Corticosteroids]] could be used as premedication for [[Paclitaxel (Taxol)]] infusion or for toxicity management.<br />
<br />
'''21-day cycle for up to 6 cycles''' <br />
====Subsequent treatment====<br />
<br />
*[[#Ipilimumab_monotherapy|Maintenance ipilimumab]]<br />
<br />
===References===<br />
<!-- Presented in part at The Chicago Multidisciplinary Symposium in Thoracic Oncology, Chicago, IL, December 9-11, 2010, and the 14th World Congress on Lung Cancer, Amsterdam, the Netherlands, July 3-7, 2011. --><br />
<br />
#'''CA184-041:''' Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. [https://doi.org/10.1200/jco.2011.38.4032 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22547592 PubMed] NCT00527735<br />
<br />
==Carboplatin & Pemetrexed {{#subobject:920f46|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CP: '''<u>C</u>'''arboplatin & '''<u>P</u>'''emetrexed<br />
<br>Carbo-Pem: '''<u>Carbo</u>'''platin & '''<u>Pem</u>'''etrexed<br />
===Example orders===<br />
<br />
*[[Example orders for Carboplatin (Paraplatin) and Pemetrexed (Alimta) in non-small cell lung cancer]]<br />
<br />
===Regimen variant #1, 5/500 x 6 {{#subobject:f0cdea|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
| style="background-color:#d73027" |Inferior HRQoL<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 15 to 60 minutes once on day 1, '''given second'''<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*(Ardizzoni et al. 2012 contained more details):<br />
*[[Dexamethasone (Decadron)]] 4 mg or [[steroid conversions|equivalent corticosteroid]] PO twice per day on the day before, the day of, and day after each dose of [[Pemetrexed (Alimta)]]<br />
*[[Folic acid (Folate)]] 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be taken throughout pemetrexed therapy<br />
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be given throughout pemetrexed therapy<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*Optional [[#Pemetrexed_monotherapy_2|pemetrexed maintenance]]<br />
<br />
===Regimen variant #2, 6/500 x 4 {{#subobject:ecc998|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2008.20.9114 Grønberg et al. 2009]<br />
|2005-2006<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Carboplatin_.26_Gemcitabine_.28GCb.29|Carboplatin & Gemcitabine]]<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRQoL<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 15 to 60 minutes once on day 1, '''given second'''<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*(Ardizzoni et al. 2012 contained more details):<br />
*[[Dexamethasone (Decadron)]] 4 mg or [[steroid conversions|equivalent corticosteroid]] PO twice per day on the day before, the day of, and day after each dose of [[Pemetrexed (Alimta)]]<br />
*[[Folic acid (Folate)]] 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be taken throughout pemetrexed therapy<br />
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be given throughout pemetrexed therapy<br />
<br />
'''21-day cycle for up to 4 cycles'''<br />
<br />
===Regimen variant #3, 6/500 x 6 {{#subobject:8aad39|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
| style="background-color:#d73027" |Inferior HRQoL<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM once every 9 weeks, first dose prior to [[Pemetrexed (Alimta)]]<br />
*[[Folic acid (Folate)]] 1 mg PO once per day<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*Optional [[#Pemetrexed_monotherapy_2|pemetrexed maintenance]]<br />
<br />
===References===<br />
<!-- Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL; and the International Association for the Study of Lung Cancer 12th World Conference on Lung Cancer, September 2-6, 2007, Seoul, Korea. --><br />
<br />
#Grønberg BH, Bremnes RM, Fløtten O, Amundsen T, Brunsvig PF, Hjelde HH, Kaasa S, von Plessen C, Stornes F, Tollåli T, Wammer F, Aasebø U, Sundstrøm S; Norwegian Lung Cancer Study Group. Phase III study by the Norwegian Lung Cancer Study Group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Jul 1;27(19):3217-24. Epub 2009 May 11. [https://doi.org/10.1200/jco.2008.20.9114 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19433683 PubMed]<br />
#'''KEYNOTE-024:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1606774/suppl_file/nejmoa1606774_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27718847 PubMed] NCT02142738<br />
##'''HRQoL analysis:''' Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30690-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29129441 PubMed]<br />
##'''Update:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. [https://doi.org/10.1200/JCO.18.00149 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30620668 PubMed]<br />
<br />
==Carboplatin & Vinorelbine {{#subobject:e7a434|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VC: '''<u>V</u>'''inorelbine & '''<u>C</u>'''arboplatin<br />
===Regimen variant #1, IV vinorelbine {{#subobject:a9c41c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.lungcancerjournal.info/article/S0169-5002(05)00119-4/fulltext Tan et al. 2005 (GLOB 2)]<br />
|2000-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_Vinorelbine|Gemcitabine & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #2, PO vinorelbine {{#subobject:bd4ba1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405221/ Fløtten et al. 2012]<br />
|2007-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_Vinorelbine|Gemcitabine & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 60 mg/m<sup>2</sup> PO once per day on days 1 & 8<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''GLOB 2:''' Tan EH, Szczesna A, Krzakowski M, Macha HN, Gatzemeier U, Mattson K, Wernli M, Reiterer P, Hui R, Pawel JV, Bertetto O, Pouget JC, Burillon JP, Parlier Y, Abratt R; GLOB 2 group. Randomized study of vinorelbine--gemcitabine versus vinorelbine--carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer. 2005 Aug;49(2):233-40. [http://www.lungcancerjournal.info/article/S0169-5002(05)00119-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16022917 PubMed]<br />
#Fløtten Ø, Grønberg BH, Bremnes R, Amundsen T, Sundstrøm S, Rolke H, Hornslien K, Wentzel-Larsen T, Aasebø U, von Plessen C; Norwegian Lung Cancer Study Group. Vinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC: a phase III randomised controlled trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2012 Jul 24;107(3):442-7. Epub 2012 Jul 3. [https://www.nature.com/articles/bjc2012284 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405221/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22759880 PubMed]<br />
<br />
==Cemiplimab monotherapy {{#subobject:179ig6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:igjaze|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/s0140-6736(21)00228-2 Sezer et al. 2021 (EMPOWER-Lung 1)]<br />
|2017-2020<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|1. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|Carboplatin & Gemcitabine]]<br> 2. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br> 3. [[#Carboplatin_.26_Pemetrexed|Carboplatin & Pemetrexed]]<br> 4. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br> 5. [[#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]]<br> 6. Cisplatin & Pemetrexed<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: some of the comparator platinum doublets appear to be histology-specific, but this is not specified in the manuscript or protocol. We have reached out to the authors for clarification. Per Sanofi, "it was strongly recommended that patients with squamous NSCLC do not receive pemetrexed-containing regimens"; otherwise, no histology-specific guidance was provided to the investigator.''<br />
====Biomarker eligibility criteria====<br />
*PD-L1 expressed in at least 50% of tumor cells<br />
====Immunotherapy====<br />
*[[Cemiplimab (Libtayo)]] 350 mg IV over 30 minutes once on day 1<br />
<br />
'''21-day cycle for up to 36 cycles (2 years)'''<br />
===References===<br />
#'''EMPOWER-Lung 1:''' Sezer A, Kilickap S, Gümüş M, Bondarenko I, Özgüroğlu M, Gogishvili M, Turk HM, Cicin I, Bentsion D, Gladkov O, Clingan P, Sriuranpong V, Rizvi N, Gao B, Li S, Lee S, McGuire K, Chen CI, Makharadze T, Paydas S, Nechaeva M, Seebach F, Weinreich DM, Yancopoulos GD, Gullo G, Lowy I, Rietschel P. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet. 2021 Feb 13;397(10274):592-604. [https://doi.org/10.1016/s0140-6736(21)00228-2 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33581821/ PubMed] NCT03088540<br />
<br />
==Cisplatin & Docetaxel (DC) {{#subobject:179d86|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
DC: '''<u>D</u>'''ocetaxel & '''<u>C</u>'''isplatin<br />
<br>DP: '''<u>D</u>'''ocetaxel & '''<u>P</u>'''latinol (Cisplatin)<br />
<br>Doc-Cis: '''<u>Doc</u>'''etaxel & '''<u>Cis</u>'''platin<br />
===Regimen variant #1, 50/75 {{#subobject:c60a4e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://ar.iiarjournals.org/content/33/12/5477.long Berghmans et al. 2013 (ELCWP-01041)]<br />
|2003-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[Non-small_cell_lung_cancer_-_historical#GIP|GIP]]<br> 2. [[Non-small_cell_lung_cancer_-_historical#Ifosfamide_.26_Gemcitabine|IG]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 75/75 {{#subobject:154c29|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="3" |[https://www.nejm.org/doi/full/10.1056/NEJMoa011954 Schiller et al. 2002 (ECOG E1594)]<br />
| rowspan="3" |1996-1999<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|3. [[#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/jco.2003.12.046 Fossella et al. 2003 (TAX 326)]<br />
| rowspan="2" |1998-2000<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Docetaxel]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2006.09.7915 Cobo et al. 2007]<br />
|2001-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ERCC1 mRNA-guided therapy<br />
| style="background-color:#fc8d59" |Seems to have inferior ORR<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdn774 Tan et al. 2009 (GLOB3)]<br />
|2004-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTF<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles (GLOB3) or indefinitely (E1594, TAX326)'''<br />
<br />
===Regimen variant #3, 80/60 {{#subobject:5a7d3b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2004.06.114 Kubota et al. 2004]<br />
|1998-2000<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Non-small_cell_lung_cancer_-_historical#Cisplatin_.26_Vindesine|Cisplatin & Vindesine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.23.3445 Takeda et al. 2009 (WJTOG0203)]<br />
|2003-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Regimen_classes#Platinum_doublet|Platinum doublet]] x 3, then Gefitinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478975/ Kubota et al. 2015 (TCOG0701 CATS)]<br />
|2007-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & S-1<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given second'''<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''<br />
<br />
'''21-day cycle for 3 to 6 cycles'''<br />
<br />
===Regimen variant #4, 80/100 {{#subobject:b1a602|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)04644-4/fulltext Georgoulias et al. 2001]<br />
|1997-1999<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Docetaxel_.26_Gemcitabine|Docetaxel & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of ORR/TTP<br />
|-<br />
|[https://doi.org/10.3816/clc.2003.n.008 Georgoulias et al. 2003]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 2<br />
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#Georgoulias V, Papadakis E, Alexopoulos A, Tsiafaki X, Rapti A, Veslemes M, Palamidas P, Vlachonikolis I; Greek Oncology Cooperative Group (GOCG) for Lung Cancer. Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet. 2001 May 12;357(9267):1478-84. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)04644-4/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/11377599 PubMed]<br />
#'''ECOG E1594:''' Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; [[Study_Groups#ECOG|ECOG]]. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. [https://www.nejm.org/doi/full/10.1056/NEJMoa011954 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11784875 PubMed]<br />
#Georgoulias V, Pallis AG, Kourousis C, Alexopoulos A, Ardavanis A, Agelidou A, Agelidou M, Toumbis M, Tzannes S, Pavlakou G, Ziotopoulos P, Tzelepatiotis E, Samaras N; Hellenic Oncology Research Group. Docetaxel versus docetaxel/cisplatin in patients with advanced non-small-cell lung cancer: preliminary analysis of a multicenter, randomized phase III study. Clin Lung Cancer. 2003 Mar;4(5):288-93. [https://doi.org/10.3816/clc.2003.n.008 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14609446 PubMed]<br />
##'''Update:''' Georgoulias V, Ardavanis A, Agelidou A, Agelidou M, Chandrinos V, Tsaroucha E, Toumbis M, Kouroussis C, Syrigos K, Polyzos A, Samaras N, Papakotoulas P, Christofilakis C, Ziras N, Alegakis A. Docetaxel versus docetaxel plus cisplatin as front-line treatment of patients with advanced non-small-cell lung cancer: a randomized, multicenter phase III trial. J Clin Oncol. 2004 Jul 1;22(13):2602-9. [https://doi.org/10.1200/JCO.2004.11.004 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15226327 PubMed]<br />
<!-- Previously presented in part at the Annual Meeting of the American Society of Clinical Oncology (ASCO), San Francisco, CA, May 12–15, 2001; the Annual Meeting of ASCO, Orlando, FL, May 18–21, 2002; and the Congress of the European Society for Medical Oncology, Nice, France, October 18–22, 2002. --><br />
#'''TAX 326:''' Fossella F, Rodrigues Pereira J, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. [https://doi.org/10.1200/jco.2003.12.046 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12837811 PubMed]<br />
#Kubota K, Watanabe K, Kunitoh H, Noda K, Ichinose Y, Katakami N, Sugiura T, Kawahara M, Yokoyama A, Yokota S, Yoneda S, Matsui K, Kudo S, Shibuya M, Isobe T, Segawa Y, Nishiwaki Y, Ohashi Y, Niitani H; Japanese Taxotere Lung Cancer Study Group. Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group. J Clin Oncol. 2004 Jan 15;22(2):254-61. [https://doi.org/10.1200/JCO.2004.06.114 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/14722033 PubMed]<br />
#Cobo M, Isla D, Massuti B, Montes A, Sanchez JM, Provencio M, Viñolas N, Paz-Ares L, Lopez-Vivanco G, Muñoz MA, Felip E, Alberola V, Camps C, Domine M, Sanchez JJ, Sanchez-Ronco M, Danenberg K, Taron M, Gandara D, Rosell R. Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in non-small-cell lung cancer. J Clin Oncol. 2007 Jul 1;25(19):2747-54. [https://doi.org/10.1200/JCO.2006.09.7915 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17602080 PubMed]<br />
#Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, Yang SH, Choi JH, Heo DS, Park SY, Shin SW, Ahn MJ, Lee JS, Yun YH, Lee JW, Park K. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007 Nov 20;25(33):5233-9. [https://doi.org/10.1200/JCO.2007.10.8134 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18024869 PubMed]<br />
#'''GLOB3:''' Tan EH, Rolski J, Grodzki T, Schneider CP, Gatzemeier U, Zatloukal P, Aitini E, Carteni G, Riska H, Tsai YH, Abratt R. Global Lung Oncology Branch trial 3 (GLOB3): final results of a randomised multinational phase III study alternating oral and iv vinorelbine plus cisplatin versus docetaxel plus cisplatin as first-line treatment of advanced non-small-cell lung cancer. Ann Oncol. 2009 Jul;20(7):1249-56. Epub 2009 Mar 10. [https://doi.org/10.1093/annonc/mdn774 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19276396 PubMed]<br />
#'''WJTOG0203:''' Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. [https://doi.org/10.1200/JCO.2009.23.3445 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20038730 PubMed]<br />
#'''ELCWP-01041:''' Berghmans T, Lafitte JJ, Scherpereel A, Paesmans M, Lecomte J, Marco VG, Meert AP, Leclercq N, Sculier JP; European Lung Cancer Working Party. An ELCWP phase III trial comparing ifosfamide and cisplatin regimens in advanced NSCLC. Anticancer Res. 2013 Dec;33(12):5477-82. [http://ar.iiarjournals.org/content/33/12/5477.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24324084 PubMed] NCT00622349<br />
#'''TCOG0701 CATS:''' Kubota K, Sakai H, Katakami N, Nishio M, Inoue A, Okamoto H, Isobe H, Kunitoh H, Takiguchi Y, Kobayashi K, Nakamura Y, Ohmatsu H, Sugawara S, Minato K, Fukuda M, Yokoyama A, Takeuchi M, Michimae H, Gemma A, Kudoh S; Tokyo Cooperative Oncology Group. A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial. Ann Oncol. 2015 Jul;26(7):1401-8. Epub 2015 Apr 23. [https://doi.org/10.1093/annonc/mdv190 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478975/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/25908605 PubMed] UMIN000000608<br />
<br />
==Cisplatin & Etoposide (EP) {{#subobject:0d191d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PE: '''<u>P</u>'''latinol (Cisplatin) & '''<u>E</u>'''toposide<br />
<br>EC: '''<u>E</u>'''toposide & '''<u>C</u>'''isplatin<br />
===Regimen variant #1, 60/360 {{#subobject:2888e6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1986.4.1.14 Ruckdeschel et al. 1986 (ECOG E1581)]<br />
|1981-1983<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[Non-small_cell_lung_cancer_-_historical#CAMP|CAMP]]<br> 2. [[Non-small_cell_lung_cancer_-_historical#Cisplatin_.26_Vindesine|Cisplatin & Vindesine]]<br> 3. [[Non-small_cell_lung_cancer_-_historical#MVP_.28Vinblastine.29|MVP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint<br />
|-<br />
|}<br />
''Note: this is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Etoposide (Vepesid)]] 120 mg/m<sup>2</sup> IV once per day on days 4, 6, 8<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 75/300 {{#subobject:5151cf|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.3.623 Bonomi et al. 2000 (ECOG E5592)]<br />
|1993-1994<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdi216 Belani et al. 2005]<br />
|1995-1996<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 45 minutes once per day on days 1 to 3<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #3, 100/300 {{#subobject:5281cf|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1999.17.1.12 Cardenal et al. 1999]<br />
|1995-1996<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior TTP<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #4, 105/600 {{#subobject:5a56cf|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819990215%2985%3A4%3C855%3A%3AAID-CNCR12%3E3.0.CO%3B2-R Font et al. 1999]<br />
|1993-1995<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Etoposide_.28EP.29_2|PE]]; dose-dense<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Etoposide (Vepesid)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #5, 120/300 {{#subobject:d94e47|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1990.8.9.1556 Klastersky et al. 1990 (EORTC 07861)]<br />
|1987-1989<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Etoposide_.28CE.29|Carboplatin & Etoposide]]<br />
| style="background-color:#d9ef8b" |Might have superior ORR<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2077209/ Comella et al. 1996]<br />
|1993-1995<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Carboplatin, Cisplatin, Etoposide, Vinorelbine<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 120 mg/m<sup>2</sup> IV once on day 1<br />
**Comella et al. 1996 gave 40 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''3- to 4-week cycles'''<br />
<br />
===References===<br />
<br />
#'''ECOG E1581:''' Ruckdeschel JC, Finkelstein DM, Ettinger DS, Creech RH, Mason BA, Joss RA, Vogl S. A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer. J Clin Oncol. 1986 Jan;4(1):14-22. [https://doi.org/10.1200/JCO.1986.4.1.14 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/3510278 PubMed]<br />
#'''EORTC 07861:''' Klastersky J, Sculier JP, Lacroix H, Dabouis G, Bureau G, Libert P, Richez M, Ravez P, Vandermoten G, Thiriaux J, Cordier R, Finet C, Berchier MC, Sergysels R, Mommen P, Paesmans M. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organisation for Research and Treatment of Cancer Protocol 07861. J Clin Oncol. 1990 Sep;8(9):1556-62. [https://doi.org/10.1200/JCO.1990.8.9.1556 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2167953 PubMed]<br />
#Comella P, Frasci G, De Cataldis G, Panza N, Cioffi R, Curcio C, Belli M, Bianco A, Ianniello G, Maiorino L, Della Vittoria M, Perchard J, Comella G; Gruppo Oncologico Campano. Cisplatin/carboplatin + etoposide + vinorelbine in advanced non-small-cell lung cancer: a multicentre randomised trial. Br J Cancer. 1996 Dec;74(11):1805-11. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2077209/ link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/8956797 PubMed]<br />
#Cardenal F, López-Cabrerizo MP, Antón A, Alberola V, Massuti B, Carrato A, Barneto I, Lomas M, García M, Lianes P, Montalar J, Vadell C, González-Larriba JL, Nguyen B, Artal A, Rosell R. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 1999 Jan;17(1):12-8. [https://doi.org/10.1200/JCO.1999.17.1.12 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10458212 PubMed]<br />
#Font A, Moyano AJ, Puerto JM, Tres A, Garcia-Giron C, Barneto I, Anton A, Sanchez JJ, Salvador A, Rosell R; Spanish Lung Cancer Group. Increasing dose intensity of cisplatin-etoposide in advanced nonsmall cell lung carcinoma: a phase III randomized trial of the Spanish Lung Cancer Group. Cancer. 1999 Feb 15;85(4):855-63. [https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819990215%2985%3A4%3C855%3A%3AAID-CNCR12%3E3.0.CO%3B2-R link to original article] [https://pubmed.ncbi.nlm.nih.gov/10091762 PubMed]<br />
#'''ECOG E5592:''' Bonomi P, Kim K, Fairclough D, Cella D, Kugler J, Rowinsky E, Jiroutek M, Johnson D. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000 Feb;18(3):623-31. [https://doi.org/10.1200/JCO.2000.18.3.623 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10653877 PubMed]<br />
#Belani CP, Lee JS, Socinski MA, Robert F, Waterhouse D, Rowland K, Ansari R, Lilenbaum R, Natale RB. Randomized phase III trial comparing cisplatin-etoposide to carboplatin-paclitaxel in advanced or metastatic non-small cell lung cancer. Ann Oncol. 2005 Jul;16(7):1069-75. Epub 2005 Apr 28. [https://doi.org/10.1093/annonc/mdi216 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15860487 PubMed]<br />
<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:fb3ee0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GC: '''<u>G</u>'''emcitabine & '''<u>C</u>'''isplatin<br />
<br>GP: '''<u>G</u>'''emcitabine & '''<u>P</u>'''latinol (Cisplatin)<br />
===Regimen variant #1, 70/1000 {{#subobject:b0126d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2007.10.8134 Park et al. 2007]<br />
|2002-2004<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]; 6 cycles<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #2, 75/1250 q3wk {{#subobject:0e126e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.03.170 Bissett et al. 2005]<br />
|1999-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GC & Prinomastat<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdm061 Novello et al. 2007]<br />
|2001-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]] x 2, then gemcitabine x 3<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdr030 Manegold et al. 2011]<br />
|2005-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GC & PF-3512676<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
| style="background-color:#d73027" |Inferior HRQoL<br />
|-<br />
|}<br />
''Note: Patients in Novello et al. 2007 received 5 cycles. Patients in KEYNOTE-024 received 4 to 6 cycles.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 30 minutes once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles (see note)'''<br />
<br />
===Regimen variant #3, 75/1250 q4wk {{#subobject:64837d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70254-7/fulltext Wu et al. 2013 (FASTACT-2)]<br />
|2009-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer,_EGFR-mutated#Cisplatin_.26_Gemcitabine.2FErlotinib|GC/Erlotinib]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm.'' <br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #4, 80/1000 {{#subobject:816a83|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="3" |[https://doi.org/10.1093/annonc/mdl377 Ohe et al. 2006 (FACS)]<br />
| rowspan="3" |2000-2002<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|2. [[#Cisplatin_.26_Irinotecan_.28IC.29|Cisplatin & Irinotecan]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|3. [[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.23.3445 Takeda et al. 2009 (WJTOG0203)]<br />
|2003-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Regimen_classes#Platinum_doublet|Platinum doublet]] x 3, then Gefitinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 6 cycles (WJTOG0203) or indefinitely (FACS)'''<br />
<br />
===Regimen variant #5, 80/1125 {{#subobject:10bc56|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394313/ Wachters et al. 2003]<br />
|1998-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Epirubicin & Gemcitabine<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 2<br />
*[[Gemcitabine (Gemzar)]] 1125 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 5 cycles'''<br />
<br />
===Regimen variant #6, 80/1200 x 6 {{#subobject:744a8d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2003.06.099 Gridelli et al. 2003]<br />
|1998-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_Vinorelbine|Gemcitabine & Vinorelbine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70146-8/fulltext Gridelli et al. 2007 (GECO)]<br />
|2003-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. GC & Rofecoxib<br> 2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]; PCI<br> 3. Cisplatin, PCI Gemcitabine, Rofecoxib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2011.41.2056 Gridelli et al. 2012 (TORCH)]<br />
|2006-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Erlotinib<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1200 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*TORCH, at progression: [[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
<br />
===Regimen variant #7, 80/1250 x 4 {{#subobject:f2149d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ejcancer.com/article/S0959-8049(17)31001-8/fulltext Ferry et al. 2017 (BTOG2)]<br />
|rowspan=2|2005-2009<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]; GC50<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|2. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb6]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2011.39.9782 Pérol et al. 2012 (IFCT-GFPC 0502)]<br />
|2006-2009<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
<br />
*IFCT-GFPC 0502: [[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy|Erlotinib switch maintenance]] versus [[#Gemcitabine_monotherapy_2|gemcitabine maintenance]] versus [[Non-small_cell_lung_cancer_-_null_regimens#Observation_3|observation]]<br />
<br />
===Regimen variant #8, 80/1250 x 6 {{#subobject:646326|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2004.08.001 Giaccone et al. 2004 (INTACT 1)]<br />
|2000-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GC & Gefitinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.05.1474 Gatzemeier et al. 2007 (TALENT)]<br />
|2001-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GC & Erlotinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322957/ Boni et al. 2012 (FAST)]<br />
|rowspan=2|2001-2006<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. GIN<br> 2. GN<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|3. [[Non-small_cell_lung_cancer_-_historical#GIP|GIP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.04.3299 Paz-Ares et al. 2006]<br />
|2002-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GC & Aprinocarsen<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #9, 100/1000 q3wk {{#subobject:ec88d3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.spandidos-publications.com/ijo/39/4/1011 Ridolfi et al. 2011]<br />
|2000-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GC & LD IL-2<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #10, 100/1000 q4wk {{#subobject:a352e8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1999.17.11.3522 Crinò et al. 1999]<br />
|1995-1997<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Non-small_cell_lung_cancer_-_historical#MIC_2|MIC]]<br />
| style="background-color:#91cf60" |Seems to have superior ORR<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.1.122 Sandler et al. 2000]<br />
|1995-1997<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Non-small_cell_lung_cancer_-_historical#Cisplatin_monotherapy|Cisplatin]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
| rowspan="3" |[https://www.nejm.org/doi/full/10.1056/NEJMoa011954 Schiller et al. 2002 (ECOG E1594)]<br />
| rowspan="3" |1996-1999<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Cisplatin_.26_Docetaxel_.28DC.29_3|Cisplatin & Docetaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|3. [[#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://doi.org/10.1200/jco.2007.15.0375 Scagliotti et al. 2008 (JMDB)]<br />
|2004-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Cisplatin_.26_Pemetrexed|Cisplatin & Pemetrexed]]<br />
| style="background-color:#eeee01" |Seems to have non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #11, 100/1250 {{#subobject:8bb0be|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1999.17.1.12 Cardenal et al. 1999]<br />
|1995-1996<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Cisplatin_.26_Etoposide_.28EP.29_2|Cisplatin & Etoposide]]<br />
| style="background-color:#1a9850" |Superior TTP<br />
|-<br />
|[https://doi.org/10.1200/JCO.2003.12.038 Alberola et al. 2003]<br />
|1998-2000<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[Stub#PGV|CGV]]<br> 2. GV-VI<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 6 cycles (Alberola et al. 2003) or indefinitely (Cardenal et al. 1999)'''<br />
<br />
===Regimen variant #12, 100/1400 {{#subobject:b9409e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(02)00444-0/fulltext Gebbia et al. 2003]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1400 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''28-day cycles'''<br />
===References===<br />
<br />
#Cardenal F, López-Cabrerizo MP, Antón A, Alberola V, Massuti B, Carrato A, Barneto I, Lomas M, García M, Lianes P, Montalar J, Vadell C, González-Larriba JL, Nguyen B, Artal A, Rosell R. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 1999 Jan;17(1):12-8. [https://doi.org/10.1200/JCO.1999.17.1.12 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10458212 PubMed]<br />
#Crinò L, Scagliotti GV, Ricci S, De Marinis F, Rinaldi M, Gridelli C, Ceribelli A, Bianco R, Marangolo M, Di Costanzo F, Sassi M, Barni S, Ravaioli A, Adamo V, Portalone L, Cruciani G, Masotti A, Ferrara G, Gozzelino F, Tonato M. Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol. 1999 Nov;17(11):3522-30. [https://doi.org/10.1200/JCO.1999.17.11.3522 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10550150 PubMed]<br />
#Sandler AB, Nemunaitis J, Denham C, von Pawel J, Cormier Y, Gatzemeier U, Mattson K, Manegold C, Palmer MC, Gregor A, Nguyen B, Niyikiza C, Einhorn LH. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2000 Jan;18(1):122-30. [https://doi.org/10.1200/JCO.2000.18.1.122 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10623702 PubMed]<br />
#'''ECOG E1594:''' Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; [[Study_Groups#ECOG|ECOG]]. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. [https://www.nejm.org/doi/full/10.1056/NEJMoa011954 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11784875 PubMed]<br />
#Gebbia V, Galetta D, Caruso M, Verderame F, Pezzella G, Valdesi M, Borsellino N, Pandolfo G, Durini E, Rinaldi M, Loizzi M, Gebbia N, Valenza R, Tirrito ML, Varvara F, Colucci G; Gruppo Ocologico Italia Meridionale. Gemcitabine and cisplatin versus vinorelbine and cisplatin versus ifosfamide+gemcitabine followed by vinorelbine and cisplatin versus vinorelbine and cisplatin followed by ifosfamide and gemcitabine in stage IIIB-IV non small cell lung carcinoma: a prospective randomized phase III trial of the Gruppo Oncologico Italia Meridionale. Lung Cancer. 2003 Feb;39(2):179-89. [https://www.lungcancerjournal.info/article/S0169-5002(02)00444-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12581571 PubMed]<br />
#Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B, Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava S, Hirsh V, Bezjak A, Seymour L, Perrone F; Italian GEMVIN Investigators; NCIC-CTG. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Aug 15;21(16):3025-34. Epub 2003 Jul 1. [https://doi.org/10.1200/JCO.2003.06.099 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12837810 PubMed]<br />
#Alberola V, Camps C, Provencio M, Isla D, Rosell R, Vadell C, Bover I, Ruiz-Casado A, Azagra P, Jiménez U, González-Larriba JL, Diz P, Cardenal F, Artal A, Carrato A, Morales S, Sanchez JJ, de las Peñas R, Felip E, López-Vivanco G; Spanish Lung Cancer Group. Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial. J Clin Oncol. 2003 Sep 1;21(17):3207-13. [https://doi.org/10.1200/JCO.2003.12.038 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12947054 PubMed]<br />
#Zatloukal P, Petruzelka L, Zemanová M, Kolek V, Skricková J, Pesek M, Fojtů H, Grygárková I, Sixtová D, Roubec J, Horenková E, Havel L, Průsa P, Nováková L, Skácel T, Kůta M. Gemcitabine plus cisplatin vs gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial. Lung Cancer. 2003 Sep;41(3):321-31. [https://www.lungcancerjournal.info/article/S0169-5002(03)00233-2/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12928123 PubMed]<br />
#Wachters FM, Van Putten JW, Kramer H, Erjavec Z, Eppinga P, Strijbos JH, de Leede GP, Boezen HM, de Vries EG, Groen HJ. First-line gemcitabine with cisplatin or epirubicin in advanced non-small-cell lung cancer: a phase III trial. Br J Cancer. 2003 Oct 6;89(7):1192-9. [https://www.nature.com/articles/6601283 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394313/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/14520444 PubMed]<br />
#'''INTACT 1:''' Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A, Johnson DH. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol. 2004 Mar 1;22(5):777-84. [https://doi.org/10.1200/JCO.2004.08.001 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/14990632 PubMed]<br />
#Bissett D, O'Byrne KJ, von Pawel J, Gatzemeier U, Price A, Nicolson M, Mercier R, Mazabel E, Penning C, Zhang MH, Collier MA, Shepherd FA. Phase III study of matrix metalloproteinase inhibitor prinomastat in non-small-cell lung cancer. J Clin Oncol. 2005 Feb 1;23(4):842-9. [https://doi.org/10.1200/JCO.2005.03.170 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15681529 PubMed]<br />
#Paz-Ares L, Douillard JY, Koralewski P, Manegold C, Smit EF, Reyes JM, Chang GC, John WJ, Peterson PM, Obasaju CK, Lahn M, Gandara DR. Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase C-alpha antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2006 Mar 20;24(9):1428-34. [https://doi.org/10.1200/JCO.2005.04.3299 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16549837 PubMed]<br />
#'''FACS:''' Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. [https://doi.org/10.1093/annonc/mdl377 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17079694 PubMed]<br />
#Novello S, Bruzzi P, Barone C, Buosi R, Masotti A, Michetti G, Fioretti M, Barbera S, Spatafora M, Garetto L, Mazzanti P, Dongiovanni V, Selvaggi G, Crinò L, Scagliotti GV. Phase III study in stage IV non-small-cell lung cancer patients treated with two courses of cisplatin/gemcitabine followed by a randomization to three additional courses of the same combination or gemcitabine alone. Ann Oncol. 2007 May;18(5):903-8. Epub 2007 Mar 9. [https://doi.org/10.1093/annonc/mdm061 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17351253 PubMed]<br />
#'''TALENT:''' Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, Milanowski J, Karnicka-Mlodkowski H, Pesek M, Serwatowski P, Ramlau R, Janaskova T, Vansteenkiste J, Strausz J, Manikhas GM, Von Pawel J. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol. 2007 Apr 20;25(12):1545-52. [https://doi.org/10.1200/JCO.2005.05.1474 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17442998 PubMed]<br />
#'''GECO:''' Gridelli C, Gallo C, Ceribelli A, Gebbia V, Gamucci T, Ciardiello F, Carozza F, Favaretto A, Daniele B, Galetta D, Barbera S, Rosetti F, Rossi A, Maione P, Cognetti F, Testa A, Di Maio M, Morabito A, Perrone F; GECO investigators. Factorial phase III randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study. Lancet Oncol. 2007 Jun;8(6):500-12. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70146-8/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17513173 PubMed] NCT00385606<br />
#Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, Yang SH, Choi JH, Heo DS, Park SY, Shin SW, Ahn MJ, Lee JS, Yun YH, Lee JW, Park K. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007 Nov 20;25(33):5233-9. [https://doi.org/10.1200/JCO.2007.10.8134 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18024869 PubMed]<br />
#'''JMDB:''' Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. Epub 2008 May 27. [https://doi.org/10.1200/jco.2007.15.0375 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18506025 PubMed]<br />
#'''WJTOG0203:''' Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. [https://doi.org/10.1200/JCO.2009.23.3445 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20038730 PubMed]<br />
#Manegold C, van Zandwijk N, Szczesna A, Zatloukal P, Au JS, Blasinska-Morawiec M, Serwatowski P, Krzakowski M, Jassem J, Tan EH, Benner RJ, Ingrosso A, Meech SJ, Readett D, Thatcher N. A phase III randomized study of gemcitabine and cisplatin with or without PF-3512676 (TLR9 agonist) as first-line treatment of advanced non-small-cell lung cancer. Ann Oncol. 2012 Jan;23(1):72-7. Epub 2011 Apr 4. [https://doi.org/10.1093/annonc/mdr030 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/21464154 PubMed]<br />
#Ridolfi L, Bertetto O, Santo A, Naglieri E, Lopez M, Recchia F, Lissoni P, Galliano M, Testore F, Porta C, Maglie M, Dall'agata M, Fumagalli L, Ridolfi R. Chemotherapy with or without low-dose interleukin-2 in advanced non-small cell lung cancer: results from a phase III randomized multicentric trial. Int J Oncol. 2011 Oct;39(4):1011-7. Epub 2011 Jun 24. [https://www.spandidos-publications.com/ijo/39/4/1011 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/21720704 PubMed]<br />
#'''FAST:''' Boni C, Tiseo M, Boni L, Baldini E, Recchia F, Barone C, Grossi F, Germano D, Matano E, Marini G, Labianca R, Di Costanzo F, Bagnulo A, Pennucci C, Caroti C, Mencoboni M, Zanelli F, Prochilo T, Cafferata MA, Ardizzoni A; Gruppo Oncologico Italiano di Ricerca Clinica. Triplets versus doublets, with or without cisplatin, in the first-line treatment of stage IIIB-IV non-small cell lung cancer (NSCLC) patients: a multicenter randomised factorial trial (FAST). Br J Cancer. 2012 Feb 14;106(4):658-65. Epub 2012 Jan 12. [https://www.nature.com/articles/bjc2011606 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322957/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22240782 PubMed]<br />
#'''TORCH:''' Gridelli C, Ciardiello F, Gallo C, Feld R, Butts C, Gebbia V, Maione P, Morgillo F, Genestreti G, Favaretto A, Leighl N, Wierzbicki R, Cinieri S, Alam Y, Siena S, Tortora G, Felletti R, Riccardi F, Mancuso G, Rossi A, Cantile F, Tsao MS, Saieg M, da Cunha Santos G, Piccirillo MC, Di Maio M, Morabito A, Perrone F. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: the TORCH randomized trial. J Clin Oncol. 2012 Aug 20;30(24):3002-11. Epub 2012 Jul 9. [https://doi.org/10.1200/JCO.2011.41.2056 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22778317 PubMed] NCT00349219<br />
##'''HRQoL analysis:''' Di Maio M, Leighl NB, Gallo C, Feld R, Ciardiello F, Butts C, Maione P, Gebbia V, Morgillo F, Wierzbicki R, Favaretto A, Alam Y, Cinieri S, Siena S, Bianco R, Riccardi F, Spatafora M, Ravaioli A, Felletti R, Fregoni V, Genestreti G, Rossi A, Mancuso G, Fasano M, Morabito A, Tsao MS, Signoriello S, Perrone F, Gridelli C. Quality of life analysis of TORCH, a randomized trial testing first-line erlotinib followed by second-line cisplatin/gemcitabine chemotherapy in advancednon-small-cell lung cancer. J Thorac Oncol. 2012 Dec;7(12):1830-1844. [https://www.jto.org/article/S1556-0864(15)33167-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/23154555 PubMed]<br />
#'''IFCT-GFPC 0502:''' Pérol M, Chouaid C, Pérol D, Barlési F, Gervais R, Westeel V, Crequit J, Léna H, Vergnenègre A, Zalcman G, Monnet I, Le Caer H, Fournel P, Falchero L, Poudenx M, Vaylet F, Ségura-Ferlay C, Devouassoux-Shisheboran M, Taron M, Milleron B. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2012 Oct 1;30(28):3516-24. Epub 2012 Sep 4. [https://doi.org/10.1200/JCO.2011.39.9782 link to original article]'''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22949150 PubMed] NCT00300586<br />
#'''FASTACT-2:''' Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, Srimuninnimit V, Sriuranpong V, Sandoval-Tan J, Zhu Y, Liao M, Zhou C, Pan H, Lee V, Chen YM, Sun Y, Margono B, Fuerte F, Chang GC, Seetalarom K, Wang J, Cheng A, Syahruddin E, Qian X, Ho J, Kurnianda J, Liu HE, Jin K, Truman M, Bara I, Mok T. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013 Jul;14(8):777-86. Epub 2013 Jun 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70254-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23782814 PubMed] NCT00883779<br />
#'''KEYNOTE-024:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1606774/suppl_file/nejmoa1606774_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27718847 PubMed] NCT02142738<br />
##'''HRQoL analysis:''' Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30690-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29129441 PubMed]<br />
##'''Update:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. [https://doi.org/10.1200/JCO.18.00149 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30620668 PubMed]<br />
#'''BTOG2:''' Ferry D, Billingham L, Jarrett H, Dunlop D, Woll PJ, Nicolson M, Shah R, Thompson J, Spicer J, Muthukumar D, Skailes G, Leonard P, Chetiyawardana AD, Wells P, Lewanski C, Crosse B, Hill M, Gaunt P, O'Byrne K. Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: results from a British Thoracic Oncology Group randomised phase III trial. Eur J Cancer. 2017 Sep;83:302-312. Epub 2017 Aug 4. [https://www.ejcancer.com/article/S0959-8049(17)31001-8/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28780466 PubMed] NCT00112710<br />
<br />
==Cisplatin & Gemcitabine (GC) & Cetuximab {{#subobject:fb3990|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b02hcd|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2007.13.0856 Butts et al. 2008]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|-<br />
|}<br />
''Note: this was a non-comparative study.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
====Targeted therapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**Cycle 1: 400 mg/m<sup>2</sup> IV once on day 1, then 250 mg/m<sup>2</sup> IV once per day on days 8 & 15<br />
**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Butts CA, Bodkin D, Middleman EL, Englund CW, Ellison D, Alam Y, Kreisman H, Graze P, Maher J, Ross HJ, Ellis PM, McNulty W, Kaplan E, Pautret V, Weber MR, Shepherd FA. Randomized phase II study of gemcitabine plus cisplatin or carboplatin [corrected], with or without cetuximab, as first-line therapy for patients with advanced or metastatic non small-cell lung cancer. J Clin Oncol. 2007 Dec 20;25(36):5777-84. Erratum in: J Clin Oncol. 2008 Jul 1;26(19): 3295. [https://doi.org/10.1200/jco.2007.13.0856 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18089875 PubMed]<br />
<br />
==Cisplatin & Irinotecan (IC) {{#subobject:c1250d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
IP: '''<u>I</u>'''rinotecan & '''<u>P</u>'''latinol (Cisplatin)<br />
===Regimen {{#subobject:4cf321|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747545/ Negoro et al. 2003]<br />
| rowspan="2" |1995-1998<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Non-small_cell_lung_cancer_-_historical#Cisplatin_.26_Vindesine|Cisplatin & Vindesine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|Irinotecan<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
| rowspan="3" |[https://doi.org/10.1093/annonc/mdl377 Ohe et al. 2006 (FACS)]<br />
| rowspan="3" |2000-2002<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|3. [[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.23.3445 Takeda et al. 2009 (WJTOG0203)]<br />
|2003-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Regimen_classes#Platinum_doublet|Platinum doublet]] x 3, then Gefitinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Irinotecan (Camptosar)]] 60 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles (WJTOG0203) or indefinitely (FACS)'''<br />
<br />
===References===<br />
<br />
#Negoro S, Masuda N, Takada Y, Sugiura T, Kudoh S, Katakami N, Ariyoshi Y, Ohashi Y, Niitani H, Fukuoka M; CPT-11 Lung Cancer Study Group West. Randomised phase III trial of irinotecan combined with cisplatin for advanced non-small-cell lung cancer. Br J Cancer. 2003 Feb 10;88(3):335-41. [https://www.nature.com/articles/6600725 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747545/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12569373 PubMed]<br />
#'''FACS:''' Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. [https://doi.org/10.1093/annonc/mdl377 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17079694 PubMed]<br />
#'''WJTOG0203:''' Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. [https://doi.org/10.1200/JCO.2009.23.3445 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20038730 PubMed]<br />
<br />
==Cisplatin & Paclitaxel {{#subobject:7f19fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PC: '''<u>P</u>'''aclitaxel & '''<u>C</u>'''isplatin<br />
===Regimen variant #1, 70/175 x 4 {{#subobject:a142cf|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2007.10.8134 Park et al. 2007]<br />
|2002-2004<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]] x 6<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #2, 70/175 x 6 {{#subobject:a16yqf|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2007.10.8134 Park et al. 2007]<br />
|2002-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]] x 4<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|[https://doi.org/10.1016/j.annonc.2020.10.479 Shi et al. 2020 (PM-03-2015)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Paclitaxel micellar<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #3, 75/135, q2wk {{#subobject:df98d7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962260/ Stathopoulos et al. 2010a]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Liposomal Cisplatin & Paclitaxel<br />
| style="background-color:#ffffbf" |Did not meet secondary endpoints<br />
| style="background-color:#d73027" |More toxic<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 135 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycle for up to 9 cycles'''<br />
<br />
===Regimen variant #4, 75/135, q3wk {{#subobject:5f385|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.3.623 Bonomi et al. 2000 (ECOG E5592)]<br />
|1993-1994<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Cisplatin_.26_Etoposide_.28EP.29_2|Cisplatin & Etoposide]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
| rowspan="3" |[https://www.nejm.org/doi/full/10.1056/NEJMoa011954 Schiller et al. 2002 (ECOG E1594)]<br />
| rowspan="3" |1996-1999<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Cisplatin_.26_Docetaxel_.28DC.29_3|Cisplatin & Docetaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 2, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 135 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1, '''given first'''<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #5, 80/175 {{#subobject:2730a0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.19.3390 Gatzemeier et al. 2000]<br />
|1995-1996<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_historical#Cisplatin_monotherapy|Cisplatin]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://doi.org/10.1200/JCO.2003.03.195 Smit et al. 2003 (EORTC 08975)]<br />
|1998-2000<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br> 2. Gemcitabine & Paclitaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #6, 80/200 {{#subobject:96cd6e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdf332 Rosell et al. 2002]<br />
|1996-1997<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#'''ECOG E5592:''' Bonomi P, Kim K, Fairclough D, Cella D, Kugler J, Rowinsky E, Jiroutek M, Johnson D. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000 Feb;18(3):623-31. [https://doi.org/10.1200/JCO.2000.18.3.623 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10653877 PubMed]<br />
#Gatzemeier U, von Pawel J, Gottfried M, ten Velde GP, Mattson K, de Marinis F, Harper P, Salvati F, Robinet G, Lucenti A, Bogaerts J, Gallant G. Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000 Oct 1;18(19):3390-9. [https://doi.org/10.1200/JCO.2000.18.19.3390 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11013280 PubMed]<br />
#'''ECOG E1594:''' Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; [[Study_Groups#ECOG|ECOG]]. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. [https://www.nejm.org/doi/full/10.1056/NEJMoa011954 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11784875 PubMed]<br />
#Rosell R, Gatzemeier U, Betticher DC, Keppler U, Macha HN, Pirker R, Berthet P, Breau JL, Lianes P, Nicholson M, Ardizzoni A, Chemaissani A, Bogaerts J, Gallant G. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol. 2002 Oct;13(10):1539-49. [https://doi.org/10.1093/annonc/mdf332 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12377641 PubMed]<br />
#'''EORTC 08975:''' Smit EF, van Meerbeeck JP, Lianes P, Debruyne C, Legrand C, Schramel F, Smit H, Gaafar R, Biesma B, Manegold C, Neymark N, Giaccone G; [[Study_Groups#EORTC|EORTC]] Lung Cancer Group. Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organisation for Research and Treatment of Cancer Lung Cancer Group--EORTC 08975. J Clin Oncol. 2003 Nov 1;21(21):3909-17. [https://doi.org/10.1200/JCO.2003.03.195 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/14581415 PubMed]<br />
#Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, Yang SH, Choi JH, Heo DS, Park SY, Shin SW, Ahn MJ, Lee JS, Yun YH, Lee JW, Park K. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007 Nov 20;25(33):5233-9. [https://doi.org/10.1200/JCO.2007.10.8134 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18024869 PubMed]<br />
#Stathopoulos GP, Antoniou D, Dimitroulis J, Michalopoulou P, Bastas A, Marosis K, Stathopoulos J, Provata A, Yiamboudakis P, Veldekis D, Lolis N, Georgatou N, Toubis M, Pappas Ch, Tsoukalas G. Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial. Ann Oncol. 2010 Nov;21(11):2227-32. Epub 2010 May 3. [https://doi.org/10.1093/annonc/mdq234 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962260/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20439345 PubMed]<br />
#'''PM-03-2015:''' Shi M, Gu A, Tu H, Huang C, Wang H, Yu Z, Wang X, Cao L, Shu Y, Wang H, Yang R, Li X, Chang J, Hu Y, Shen P, Hu Y, Guo Z, Tao M, Zhang Y, Liu X, Sun Q, Zhang X, Jiang Z, Zhao J, Chen F, Yu H, Zhang W, Sun J, Li D, Zhou J, Han B, Wu YL. Comparing nanoparticle polymeric micellar paclitaxel and solvent-based paclitaxel as first-line treatment of advanced non-small-cell lung cancer: an open-label, randomized, multicenter, phase III trial. Ann Oncol. 2021 Jan;32(1):85-96. Epub 2020 Oct 29. [https://doi.org/10.1016/j.annonc.2020.10.479 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/33130217 PubMed] NCT02667743<br />
<br />
==Cisplatin & Vinorelbine {{#subobject:bdd6b2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CV: '''<u>C</u>'''isplatin & '''<u>V</u>'''inorelbine<br />
<br>NP: '''<u>N</u>'''avelbine (Vinorelbine) & '''<u>P</u>'''latinol (Cisplatin)<br />
<br>PV: '''<u>P</u>'''latinol (Cisplatin) & '''<u>V</u>'''inorelbine<br />
<br>VC: '''<u>V</u>'''inorelbine & '''<u>C</u>'''isplatin<br />
===Regimen variant #1, 75/25 {{#subobject:21f9be|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(04)00772-5/fulltext Martoni et al. 2005]<br />
|1998-2003<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*Vinorelbine maintenance<br />
<br />
===Regimen variant #2, 80/25 {{#subobject:daeaf6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="3" |[https://doi.org/10.1093/annonc/mdl377 Ohe et al. 2006 (FACS)]<br />
| rowspan="3" |2000-2002<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|3. [[#Cisplatin_.26_Irinotecan_.28IC.29|Cisplatin & Irinotecan]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.23.3445 Takeda et al. 2009 (WJTOG0203)]<br />
|2003-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Regimen_classes#Platinum_doublet|Platinum doublet]] x 3, then Gefitinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60569-9/fulltext Pirker et al. 2009 (FLEX)]<br />
|2004-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin.2C_Vinorelbine.2C_Cetuximab|Cisplatin, Vinorelbine, Cetuximab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles (FLEX; WJTOG0203) or indefinitely (FACS)'''<br />
<br />
===Regimen variant #3, 80/30, 2 out of 3 weeks vinorelbine {{#subobject:6c3243|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2003.06.099 Gridelli et al. 2003]<br />
|1998-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_Vinorelbine|Gemcitabine & Vinorelbine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.04.016 Georgoulias et al. 2005]<br />
|1999-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Docetaxel_.26_Gemcitabine|Docetaxel & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(08)00009-3/fulltext Gebbia et al. 2008]<br />
|2003-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]; 3 out of 4 weeks<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
| style="background-color:#1a9850" |Less toxic<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 8<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 6 cycles (Gridelli et al. 2003) or up to 9 cycles (Georgoulias et al. 2005)'''<br />
<br />
===Regimen variant #4, 80/30, weekly vinorelbine {{#subobject:6c3243|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/oxfordjournals.annonc.a058687 Depierre et al. 1994]<br />
|1989-1991<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Vinorelbine<br />
| style="background-color:#1a9850" |Superior TTP<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdf316 Souquet et al. 2002 (GLOB-1)]<br />
|1998-1999<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#NIP|NIP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS1<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #5, 100/25 {{#subobject:45998f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1998.16.7.2459 Wozniak et al. 1998]<br />
|1993-1995<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Non-small_cell_lung_cancer_-_historical#Cisplatin_monotherapy|Cisplatin]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2001.19.13.3210 Kelly et al. 2001 (SWOG 9509)]<br />
|1996-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2002.02.068 Scagliotti et al. 2002]<br />
|1998-2000<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br> 2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/jco.2003.12.046 Fossella et al. 2003 (TAX 326)]<br />
| rowspan="2" |1998-2000<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Carboplatin_.26_Docetaxel|Carboplatin & Docetaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Cisplatin_.26_Docetaxel_.28DC.29_3|Cisplatin & Docetaxel]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2007.12.2614 Ramlau et al. 2008 (SPIRIT I)]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CV & Bexarotene<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 10 cycles (SWOG 9509) or indefinitely (TAX 326, SPIRIT I)'''<br />
<br />
===Regimen variant #6, 100/30 {{#subobject:cda93a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1023/a:1008338312647 Robinet et al. 2001 (GFPC 95-1)]<br />
|1995-1997<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CV & concurrent WBRT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdi126 Pujol et al. 2005]<br />
|1999-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Docetaxel_.26_Gemcitabine|Docetaxel & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: patients in GFPC 95-1 had intracranial metastases.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 60 to 120 minutes once on day 1<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV over 10 to 20 minutes once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*GFPC 95-1: [[External_beam_radiotherapy|WBRT]]<br />
<br />
===Regimen variant #7, 120/30 {{#subobject:2bf191|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.1994.12.2.360 Le Chevalier et al. 1994]<br />
| rowspan="2" |1989-1991<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|1. Cisplatin & Vindesine<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|2. Vinorelbine<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2000.18.7.1451 Comella et al. 2000]<br />
| rowspan="2" |1997-1999<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[Stub#PGV|PGV]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Note: in Comella et al. 2000, vinorelbine was given for a total of 10 weeks.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 120 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] as follows:<br />
**Cycle 1: 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Cycle 2 onwards: 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
'''28-day cycle for 1 cycle, then 42-day cycles (see note)'''<br />
<br />
===References===<br />
<br />
#Depierre A, Chastang C, Quoix E, Lebeau B, Blanchon F, Paillot N, Lemarie E, Milleron B, Moro D, Clavier J, Herman D, Tuchais E, Jacoulet P, Brechot JM, Cordier JF, Solal-Celigny P, Badri N, Besenval M. Vinorelbine versus vinorelbine plus cisplatin in advanced non-small cell lung cancer: a randomized trial. Ann Oncol. 1994 Jan;5(1):37-42. [https://doi.org/10.1093/oxfordjournals.annonc.a058687 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/8172790 PubMed]<br />
#Le Chevalier T, Brisgand D, Douillard JY, Pujol JL, Alberola V, Monnier A, Riviere A, Lianes P, Chomy P, Cigolari S, Gottfried M, Ruffle P, Panizo A, Gaspard MH, Ravaioli A, Besenval M, Besson F, Martinez A, Berthaud P, Tursz T. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol. 1994 Feb;12(2):360-7. [https://doi.org/10.1200/JCO.1994.12.2.360 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/8113844 PubMed]<br />
#Wozniak AJ, Crowley JJ, Balcerzak SP, Weiss GR, Spiridonidis CH, Baker LH, Albain KS, Kelly K, Taylor SA, Gandara DR, Livingston RB; [[Study_Groups#SWOG|SWOG]]. Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol. 1998 Jul;16(7):2459-65. [https://doi.org/10.1200/JCO.1998.16.7.2459 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9667264 PubMed]<br />
#Comella P, Frasci G, Panza N, Manzione L, De Cataldis G, Cioffi R, Maiorino L, Micillo E, Lorusso V, Di Rienzo G, Filippelli G, Lamberti A, Natale M, Bilancia D, Nicolella G, Di Nota A, Comella G; Southern Italy Cooperative Oncology Group. Randomized trial comparing cisplatin, gemcitabine, and vinorelbine with either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non-small-cell lung cancer: interim analysis of a phase III trial of the Southern Italy Cooperative Oncology Group. J Clin Oncol. 2000 Apr;18(7):1451-7. [https://doi.org/10.1200/JCO.2000.18.7.1451 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10735892 PubMed]<br />
#'''GFPC 95-1:''' Robinet G, Thomas P, Breton JL, Léna H, Gouva S, Dabouis G, Bennouna J, Souquet PJ, Balmes P, Thiberville L, Fournel P, Quoix E, Riou R, Rebattu P, Pérol M, Paillotin D, Mornex F. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Français de Pneumo-Cancérologie (GFPC) Protocol 95-1. Ann Oncol. 2001 Jan;12(1):59-67. [https://doi.org/10.1023/a:1008338312647 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11249050 PubMed]<br />
#'''SWOG 9509:''' Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, Ramsey SD, Wozniak AJ, Weiss GR, Moore DF, Israel VK, Livingston RB, Gandara DR. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol. 2001 Jul 1;19(13):3210-8. [https://doi.org/10.1200/JCO.2001.19.13.3210 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11432888 PubMed]<br />
#Scagliotti GV, De Marinis F, Rinaldi M, Crinò L, Gridelli C, Ricci S, Matano E, Boni C, Marangolo M, Failla G, Altavilla G, Adamo V, Ceribelli A, Clerici M, Di Costanzo F, Frontini L, Tonato M; Italian Lung Cancer Project. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol. 2002 Nov 1;20(21):4285-91. [https://doi.org/10.1200/JCO.2002.02.068 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12409326 PubMed]<br />
#'''GLOB-1:''' Souquet PJ, Tan EH, Rodrigues Pereira J, Van Klaveren R, Price A, Gatzemeier U, Jaworski M, Burillon JP, Aubert D. GLOB-1: a prospective randomised clinical phase III trial comparing vinorelbine-cisplatin with vinorelbine-ifosfamide-cisplatin in metastatic non-small-cell lung cancer patients. Ann Oncol. 2002 Dec;13(12):1853-61. Erratum in: Ann Oncol. 2003 Feb;14(2):347. [https://doi.org/10.1093/annonc/mdf316 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12453852 PubMed]<br />
<!-- Previously presented in part at the Annual Meeting of the American Society of Clinical Oncology (ASCO), San Francisco, CA, May 12–15, 2001; the Annual Meeting of ASCO, Orlando, FL, May 18–21, 2002; and the Congress of the European Society for Medical Oncology, Nice, France, October 18–22, 2002. --><br />
#'''TAX 326:''' Fossella F, Rodrigues Pereira J, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. [https://doi.org/10.1200/jco.2003.12.046 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12837811 PubMed]<br />
#Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B, Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava S, Hirsh V, Bezjak A, Seymour L, Perrone F; Italian GEMVIN Investigators; NCIC-CTG. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Aug 15;21(16):3025-34. Epub 2003 Jul 1. [https://doi.org/10.1200/JCO.2003.06.099 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12837810 PubMed]<br />
#Martoni A, Marino A, Sperandi F, Giaquinta S, Di Fabio F, Melotti B, Guaraldi M, Palomba G, Preti P, Petralia A, Artioli F, Picece V, Farris A, Mantovani L. Multicentre randomised phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer. Eur J Cancer. 2005 Jan;41(1):81-92. [https://www.ejcancer.com/article/S0959-8049(04)00772-5/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15617993 PubMed]<br />
#Georgoulias V, Ardavanis A, Tsiafaki X, Agelidou A, Mixalopoulou P, Anagnostopoulou O, Ziotopoulos P, Toubis M, Syrigos K, Samaras N, Polyzos A, Christou A, Kakolyris S, Kouroussis C, Androulakis N, Samonis G, Chatzidaki D. Vinorelbine plus cisplatin versus docetaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol. 2005 May 1;23(13):2937-45. Epub 2005 Feb 22. [https://doi.org/10.1200/JCO.2005.04.016 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15728228 PubMed]<br />
#Pujol JL, Breton JL, Gervais R, Rebattu P, Depierre A, Morère JF, Milleron B, Debieuvre D, Castéra D, Souquet PJ, Moro-Sibilot D, Lemarié E, Kessler R, Janicot H, Braun D, Spaeth D, Quantin X, Clary C. Gemcitabine-docetaxel versus cisplatin-vinorelbine in advanced or metastatic non-small-cell lung cancer: a phase III study addressing the case for cisplatin. Ann Oncol. 2005 Apr;16(4):602-10. Epub 2005 Mar 1. [https://doi.org/10.1093/annonc/mdi126 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15741225 PubMed]<br />
#'''FACS:''' Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. [https://doi.org/10.1093/annonc/mdl377 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17079694 PubMed]<br />
#Gebbia V, Galetta D, Lorusso V, Caruso M, Verderame F, Pezzella G, Borsellino N, Durini E, Valenza R, Agostara B, Colucci G; Gruppo Oncologico Italia Meridionale. Cisplatin plus weekly vinorelbine versus cisplatin plus vinorelbine on days 1 and 8 in advanced non-small cell lung cancer: a prospective randomized phase III trial of the GOIM (Gruppo Oncologico Italia Meridionale). Lung Cancer. 2008 Sep;61(3):369-77. Epub 2008 Mar 4. [https://www.lungcancerjournal.info/article/S0169-5002(08)00009-3/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18308419 PubMed]<br />
#'''SPIRIT I:''' Ramlau R, Zatloukal P, Jassem J, Schwarzenberger P, Orlov SV, Gottfried M, Rodrigues Pereira J, Temperley G, Negro-Vilar R, Rahal S, Zhang JK, Negro-Vilar A, Dziewanowska ZE. Randomized phase III trial comparing bexarotene (L1069-49)/cisplatin/vinorelbine with cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT I. J Clin Oncol. 2008 Apr 10;26(11):1886-92. [https://doi.org/10.1200/JCO.2007.12.2614 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18398154 PubMed]<br />
#'''FLEX:''' Pirker R, Rodrigues Pereira J, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009 May 2;373(9674):1525-31. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60569-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19410716 PubMed] NCT00148798<br />
#'''WJTOG0203:''' Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. [https://doi.org/10.1200/JCO.2009.23.3445 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20038730 PubMed]<br />
<br />
==Cisplatin, Vinorelbine, Cetuximab {{#subobject:9c28e0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b4c5e3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60569-9/fulltext Pirker et al. 2009 (FLEX)]<br />
|2004-2006<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
====Targeted therapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**Cycle 1: 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, then 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 8 & 15<br />
**Cycles 2 to 6: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
====Subsequent treatment====<br />
<br />
*Cetuximab maintenance<br />
<br />
===References===<br />
<br />
#'''FLEX:''' Pirker R, Rodrigues Pereira J, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009 May 2;373(9674):1525-31. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60569-9/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19410716 PubMed] NCT00148798<br />
<br />
==Docetaxel & Vinorelbine {{#subobject:18h94c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:abi4b2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.6.1346 Miller et al. 2000]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]]<br />
*[[Vinorelbine (Navelbine)]]<br />
<br />
===References===<br />
<br />
#Miller VA, Krug LM, Ng KK, Pizzo B, Perez W, Heelan RT, Kris MG. Phase II trial of docetaxel and vinorelbine in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000 Mar;18(6):1346-50. [https://doi.org/10.1200/JCO.2000.18.6.1346 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10715307 PubMed]<br />
<br />
==Gemcitabine & Paclitaxel {{#subobject:29305d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GT: '''<u>G</u>'''emcitabine & '''<u>T</u>'''axol (Paclitaxel)<br />
<br />
===Regimen variant #1, 1000/125 {{#subobject:b3708b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2002.12.112 Kosmidis et al. 2002]<br />
|1998-2000<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdm430 Kosmidis et al. 2007]<br />
|2000-2004<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Carboplatin_.26_Gemcitabine_.28GCb.29|Carboplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdl396 Comella et al. 2006 (SICOG 0101)]<br />
|2001-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Gemcitabine_.26_Vinorelbine|GV]]<br> 2. [[Stub#PGT|PGT]]<br> 3. [[Stub#PGV|PGV]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Paclitaxel (Taxol)]] 125 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #2, 1000/200 {{#subobject:b9275b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdq445 Kosmidis et al. 2010]<br />
|2004-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Paclitaxel & Vinorelbine<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#Kosmidis PA, Kalofonos HP, Christodoulou C, Syrigos K, Makatsoris T, Skarlos D, Bakogiannis C, Nicolaides C, Bafaloukos D, Bamias A, Samantas E, Xiros N, Boukovinas I, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group. Ann Oncol. 2008 Jan;19(1):115-22. Epub 2007 Oct 15. [https://doi.org/10.1093/annonc/mdm430 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17938425 PubMed]<br />
#'''SICOG 0101:''' Comella P, Filippelli G, De Cataldis G, Massidda B, Frasci G, Maiorino L, Putzu C, Mancarella S, Palmeri S, Cioffi R, Roselli M, Buzzi F, Milia V, Gambardella A, Natale D, Bianco M, Ghiani M, Masullo P; Southern Italy Cooperative Oncology Group. Efficacy of the combination of cisplatin with either gemcitabine and vinorelbine or gemcitabine and paclitaxel in the treatment of locally advanced or metastatic non-small-cell lung cancer: a phase III randomised trial of the Southern Italy Cooperative Oncology Group (SICOG 0101). Ann Oncol. 2007 Feb;18(2):324-30. Epub 2006 Oct 27. [https://doi.org/10.1093/annonc/mdl396 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17071935 PubMed]<br />
#Kosmidis PA, Fountzilas G, Eleftheraki AG, Kalofonos HP, Pentheroudakis G, Skarlos D, Dimopoulos MA, Bafaloukos D, Pectasides D, Samantas E, Boukovinas J, Lambaki S, Katirtzoglou N, Bakogiannis C, Syrigos KN; Hellenic Cooperative Oncology Group. Paclitaxel and gemcitabine versus paclitaxel and vinorelbine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol. 2011 Apr;22(4):827-34. Epub 2010 Sep 29. [https://doi.org/10.1093/annonc/mdq445 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20880999 PubMed] ACTRN12609000946213<br />
<br />
==Gemcitabine & Vinorelbine {{#subobject:3c6eb0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VG: '''<u>V</u>'''inorelbine & '''<u>G</u>'''emcitabine<br />
<br>GV: '''<u>G</u>'''emcitabine & '''<u>V</u>'''inorelbine<br />
<br>G+V: '''<u>G</u>'''emcitabine & '''<u>V</u>'''inorelbine<br />
===Regimen variant #1, 1000/25, 2 weeks out of 3 (IV vinorelbine) {{#subobject:a01f58|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2004.10.576 Laack et al. 2004]<br />
|1999-2001<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[Stub#GVP|GVP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[http://www.lungcancerjournal.info/article/S0169-5002(05)00119-4/fulltext Tan et al. 2005 (GLOB 2)]<br />
|2000-2002<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Carboplatin_.26_Vinorelbine|Carboplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*"[[:Category:Emesis_prevention|Antiemetic]] agents and other supportive treatments were provided at the discretion of the treating physician."<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 1000/25, 3 weeks out of 4 (IV vinorelbine) {{#subobject:2c7f61|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.clinical-lung-cancer.com/article/S1525-7304(11)70825-7/pdf Greco et al. 2007]<br />
|1998-2005<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|PCG<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
| style="background-color:#1a9850" |Less toxic<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3, 1000/60 (PO vinorelbine) {{#subobject:c8251a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405221/ Fløtten et al. 2012]<br />
|2007-2009<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Carboplatin_.26_Vinorelbine|Carboplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Vinorelbine (Navelbine)]] 60 mg/m<sup>2</sup> PO once per day on days 1 & 8<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===Regimen variant #4, 1200/30 {{#subobject:c8uv1a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(01)00392-0/fulltext Frasci et al. 2001]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Vinorelbine_monotherapy|Vinorelbine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1200 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#Frasci G, Lorusso V, Panza N, Comella P, Nicolella G, Bianco A, DeCataldis G, Belli M, Iannelli N, Massidda B, Mascia V, Comella G, De Lena M; Southern Italy Cooperative Oncology Group. Gemcitabine plus vinorelbine yields better survival outcome than vinorelbine alone in elderly patients with advanced non-small cell lung cancer: a Southern Italy Cooperative Oncology Group (SICOG) phase III trial. Lung Cancer. 2001 Dec;34 Suppl 4:S65-9. [https://www.lungcancerjournal.info/article/S0169-5002(01)00392-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11742706 PubMed]<br />
#Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B, Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava S, Hirsh V, Bezjak A, Seymour L, Perrone F; Italian GEMVIN Investigators; NCIC-CTG. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Aug 15;21(16):3025-34. Epub 2003 Jul 1. [https://doi.org/10.1200/JCO.2003.06.099 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12837810 PubMed]<br />
#Laack E, Dickgreber N, Müller T, Knuth A, Benk J, Lorenz C, Gieseler F, Dürk H, Engel-Riedel W, Dalhoff K, Kortsik C, Graeven U, Burk M, Dierlamm T, Welte T, Burkholder I, Edler L, Hossfeld DK; German and Swiss Lung Cancer Study Group. Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung cancer: from the German and Swiss Lung Cancer Study Group. J Clin Oncol. 2004 Jun 15;22(12):2348-56. [https://doi.org/10.1200/JCO.2004.10.576 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15197195 PubMed]<br />
#'''GLOB 2:''' Tan EH, Szczesna A, Krzakowski M, Macha HN, Gatzemeier U, Mattson K, Wernli M, Reiterer P, Hui R, Pawel JV, Bertetto O, Pouget JC, Burillon JP, Parlier Y, Abratt R; GLOB 2 group. Randomized study of vinorelbine--gemcitabine versus vinorelbine--carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer. 2005 Aug;49(2):233-40. [http://www.lungcancerjournal.info/article/S0169-5002(05)00119-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16022917 PubMed]<br />
#Greco FA, Spigel DR, Kuzur ME, Shipley D, Gray JR, Thompson DS, Burris HA, Yardley DA, Pati A, Webb CD, Gandhi JG, Hainsworth JD. Paclitaxel/Carboplatin/gemcitabine versus gemcitabine/vinorelbine in advanced non-small-cell lung cancer: a phase II/III study of the Minnie Pearl Cancer Research Network. Clin Lung Cancer. 2007 Sep;8(8):483-7. [https://www.clinical-lung-cancer.com/article/S1525-7304(11)70825-7/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/17922972 PubMed]<br />
#Fløtten Ø, Grønberg BH, Bremnes R, Amundsen T, Sundstrøm S, Rolke H, Hornslien K, Wentzel-Larsen T, Aasebø U, von Plessen C; Norwegian Lung Cancer Study Group. Vinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC: a phase III randomised controlled trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2012 Jul 24;107(3):442-7. Epub 2012 Jul 3. [https://www.nature.com/articles/bjc2012284 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405221/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22759880 PubMed]<br />
<br />
==Ipilimumab & Nivolumab {{#subobject:517ff0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3a481c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1801946 Hellmann et al. 2018 (CheckMate 227)]<br />
|rowspan=2|2015-2016<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|1. [[#Nivolumab_monotherapy|Nivolumab]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[Regimen_classes#Platinum_doublet|Platinum doublet]]<br />
| style="background-color:#1a9850" |Superior OS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2019 update.''<br />
====Immunotherapy====<br />
<br />
*[[Ipilimumab (Yervoy)]] 1 mg/kg IV once on day 1<br />
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once per day on days 1, 15, 29<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<br />
#'''CheckMate 227:''' Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018 May 31;378(22):2093-2104. Epub 2018 Apr 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1801946 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29658845 PubMed] NCT02477826<br />
##'''Update:''' Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, Park K, Alexandru A, Lupinacci L, de la Mora Jimenez E, Sakai H, Albert I, Vergnenegre A, Peters S, Syrigos K, Barlesi F, Reck M, Borghaei H, Brahmer JR, O'Byrne KJ, Geese WJ, Bhagavatheeswaran P, Rabindran SK, Kasinathan RS, Nathan FE, Ramalingam SS. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019 Nov 21;381(21):2020-2031. Epub 2019 Sep 28. [https://www.nejm.org/doi/full/10.1056/NEJMoa1910231 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31562796 PubMed]<br />
<br />
==Ipilimumab & Nivolumab & Platinum doublet {{#subobject:#08c783|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:#c626c7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30641-0/fulltext Paz-Ares et al. 2021 (CheckMate 9LA)]<br />
|rowspan=2|2017-2019<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[Regimen_classes#Platinum_doublet|Platinum doublet]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Platinum doublet histology-based.''<br />
====Immunotherapy====<br />
<br />
*[[Ipilimumab (Yervoy)]] 1 mg/kg intravenously every 6 weeks<br />
*[[Nivolumab (Opdivo)]] 360 mg intravenously every 3 weeks<br />
<br />
continued until progression <br />
<br />
====Chemotherapy====<br />
''for patients with squamous cell histology''<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 2 cycles'''<br />
<br />
''for patients with non-squamous cell histology''<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 or 6 IV or [[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 2 cycles'''<br />
<br />
===References===<br />
<br />
#'''CheckMate 9LA''' Paz-Ares L, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Salman P, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, John T, Carbone DP, Meadows-Shropshire S, Agrawal S, Oukessou A, Yan J, Reck M. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):198-211. Epub 2021 Jan 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30641-0/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/33476593 PubMed] NCT02477826<br />
<br />
==Nivolumab monotherapy {{#subobject:PYR1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:PYV1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613493 Carbone et al. 2017 (CheckMate 026)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[Regimen_classes#Platinum_doublet|Platinum doublet]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''Note: control arm patients in CheckMate 026 received investigator's choice of platinum doublet; the most commonly used regimen was [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|carboplatin & paclitaxel]].''<br />
====Immunotherapy====<br />
<br />
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1<br />
**Notably, on 9/13/16 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''CheckMate 026:''' Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van den Heuvel MM, Ciuleanu TE, Badin F, Ready N, Hiltermann TJN, Nair S, Juergens R, Peters S, Minenza E, Wrangle JM, Rodriguez-Abreu D, Borghaei H, Blumenschein GR Jr, Villaruz LC, Havel L, Krejci J, Corral Jaime J, Chang H, Geese WJ, Bhagavatheeswaran P, Chen AC, Socinski MA; CheckMate 026 Investigators. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017 Jun 22;376(25):2415-2426. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613493 link to original article]'''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28636851 PubMed] NCT02041533<br />
#'''CheckMate 227:''' Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018 May 31;378(22):2093-2104. Epub 2018 Apr 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1801946 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29658845 PubMed] NCT02477826<br />
<br />
==Pembrolizumab monotherapy {{#subobject:430dc7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d2e0ab|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1501824 Garon et al. 2015 (KEYNOTE-001)]<br />
|2012-2014<br />
| style="background-color:#91cf61" |Phase 1, >20 pts in dosing cohort<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|1. [[#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]]<br> 2. [[#Carboplatin_.26_Paclitaxel_4 | Carboplatin & Paclitaxel]]<br> 3. [[#Carboplatin_.26_Pemetrexed | Carboplatin & Pemetrexed]]<br> 4. [[#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]]<br> 5. [[#Cisplatin_.26_Pemetrexed_2 | Cisplatin & Pemetrexed]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior HRQoL<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32409-7/fulltext Mok et al. 2019 (KEYNOTE-042)]<br />
|2014-2017<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|1. [[#Carboplatin_.26_Paclitaxel_6 | Carboplatin & Paclitaxel]]<br> 2. [[#Carboplatin_.26_Pemetrexed_2 | Carboplatin & Pemetrexed]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|<br />
|-<br />
|}<br />
''KEYNOTE-024 required PD-L1 to be expressed on at least '''50% of tumor cells''', no EGFR/ALK mutations. Treatment choice for patients in the comparator arm was up to the investigators; most with nonsquamous histology received carboplatin & pemetrexed, whereas most with squamous histology received carboplatin & gemcitabine. Patients could receive a maximum of 35 cycles. ORR was 45% (95% CI: 37-53).''<br />
<br>''KEYNOTE-042 required PD-L1 to be expressed on at least '''1% of tumor cells'''. Treatment choice for patients in the comparator arm was carboplatin & paclitaxel for patients with squamous histology, and carboplatin & pemetrexed for patients with nonsquamous histology.''<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Phase 1:''' Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28. Epub 2015 Apr 19. [https://www.nejm.org/doi/full/10.1056/NEJMoa1501824 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25891174 PubMed] NCT01295827<br />
#'''KEYNOTE-024:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1606774/suppl_file/nejmoa1606774_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27718847 PubMed] NCT02142738<br />
##'''HRQoL analysis:''' Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30690-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29129441 PubMed]<br />
##'''Update:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. [https://doi.org/10.1200/JCO.18.00149 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30620668 PubMed]<br />
<!-- # '''Abstract:''' Tony Mok, Yi-Long Wu, Patricia A, Watson, Jin Zhang, Reshma A. Rangwala, and Gilberto Lopes. Phase 3 KEYNOTE-042 trial of pembrolizumab (MK-3475) versus platinum doublet chemotherapy in treatment-naive patients (pts) with PD-L1–positive advanced non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2015 33:15_suppl, TPS8105-TPS8105 [https://doi.org/10.1200/jco.2015.33.15_suppl.tps8105 link to abstract] --><br />
#'''KEYNOTE-042:''' Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. Epub 2019 Apr 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32409-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/30955977 PubMed] NCT02220894<br />
<br />
=Advanced or metastatic disease, first-line, elderly or poor performance status=<br />
<br />
==Carboplatin & Gemcitabine (GCb) {{#subobject:2f045e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CG: '''<u>C</u>'''arboplatin & '''<u>G</u>'''emcitabine<br />
===Regimen {{#subobject:c4b462|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdq637 Biesma et al. 2011 (NVALT-3)]<br />
|2003-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_7|CP]]<br />
|<br />
| style="background-color:#ffffbf" |Similar QoL<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 4 cycles'''<br />
===References===<br />
<br />
#'''NVALT-3:''' Biesma B, Wymenga AN, Vincent A, Dalesio O, Smit HJ, Stigt JA, Smit EF, van Felius CL, van Putten JW, Slaets JP, Groen HJ; Dutch Chest Physician Study Group. Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study. Ann Oncol. 2011 Jul;22(7):1520-7. Epub 2011 Jan 20. [https://doi.org/10.1093/annonc/mdq637 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21252061 PubMed] NTR925<br />
<br />
==Carboplatin & Paclitaxel (CP) {{#subobject:050d96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TC: '''<u>T</u>'''axol (Paclitaxel) & '''<u>C</u>'''arboplatin<br />
<br>CP: '''<u>C</u>'''arboplatin & '''<u>P</u>'''aclitaxel<br />
===Regimen variant #1, 5/175 {{#subobject:5dd7ea|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdq637 Biesma et al. 2011 (NVALT-3)]<br />
|2003-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Gemcitabine_.28GCb.29_4|CG]]<br />
|<br />
| style="background-color:#ffffbf" |Similar QoL<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for up to 4 cycles'''<br />
<br />
===Regimen variant #2, 6/90 {{#subobject:bd42df|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960780-0/fulltext Quoix et al. 2011 (IFCT-0501)]<br />
|rowspan=2|2006-2009<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. [[#Vinorelbine_monotherapy|Vinorelbine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Study involved only patients 70 to 89 years old''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 90 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
<br />
*Growth factor support was not recommended as primary prophylaxis during cycle 1, but could be used if the patient develops grade 3-4 neutropenia<br />
<br />
'''28-day cycle for up to 4 cycles'''<br />
<br />
===Regimen variant #3, 6/200 {{#subobject:7ba15a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2007.13.2720 Lilenbaum et al. 2008]<br />
|2002-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Erlotinib<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 15 to 60 minutes once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''21-day cycle for up to 4 cycles'''<br />
<br />
===Regimen variant #4, 6/225 {{#subobject:e1af15|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.jto.org/article/S1556-0864(15)31485-4/fulltext Langer et al. 2008]<br />
|2002-2003<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Carboplatin & PPX<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Lilenbaum R, Axelrod R, Thomas S, Dowlati A, Seigel L, Albert D, Witt K, Botkin D. Randomized phase II trial of erlotinib or standard chemotherapy in patients with advanced non-small-cell lung cancer and a performance status of 2. J Clin Oncol. 2008 Feb 20;26(6):863-9. [https://doi.org/10.1200/jco.2007.13.2720 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18281658 PubMed]<br />
#Langer CJ, O'Byrne KJ, Socinski MA, Mikhailov SM, Leśniewski-Kmak K, Smakal M, Ciuleanu TE, Orlov SV, Dediu M, Heigener D, Eisenfeld AJ, Sandalic L, Oldham FB, Singer JW, Ross HJ. Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. J Thorac Oncol. 2008 Jun;3(6):623-30. [https://www.jto.org/article/S1556-0864(15)31485-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18520802 PubMed]<br />
#'''NVALT-3:''' Biesma B, Wymenga AN, Vincent A, Dalesio O, Smit HJ, Stigt JA, Smit EF, van Felius CL, van Putten JW, Slaets JP, Groen HJ; Dutch Chest Physician Study Group. Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study. Ann Oncol. 2011 Jul;22(7):1520-7. Epub 2011 Jan 20. [https://doi.org/10.1093/annonc/mdq637 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21252061 PubMed] NTR925<br />
#'''IFCT-0501:''' Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960780-0/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21831418 PubMed] NCT00298415<br />
<br />
==Carboplatin & Pemetrexed {{#subobject:fc1ec6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Carboplatin (Paraplatin) and Pemetrexed (Alimta) in non-small cell lung cancer]]<br />
<br />
===Regimen {{#subobject:b1cc1a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2012.48.1911 Zukin et al. 2013 (INCA-Lung001)]<br />
|2008-2011<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Pemetrexed_monotherapy|Pemetrexed]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 15 to 60 minutes once on day 1, '''given second'''<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*(Ardizzoni et al. 2012 contained more details):<br />
*[[Dexamethasone (Decadron)]] 4 mg or [[steroid conversions|equivalent corticosteroid]] PO twice per day on the day before, the day of, and day after each dose of [[Pemetrexed (Alimta)]]<br />
*[[Folic acid (Folate)]] 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be taken throughout pemetrexed therapy<br />
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be given throughout pemetrexed therapy<br />
<br />
'''21-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
<!-- Presented at the 48th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2012. --><br />
<br />
#'''INCA-Lung001:''' Zukin M, Barrios CH, Rodrigues Pereira J, De Albuquerque Ribeiro R, de Mendonça Beato CA, do Nascimento YN, Murad A, Franke FA, Precivale M, de Lima Araujo LH, Da Rocha Baldotto CS, Vieira FM, Small IA, Ferreira CG, Lilenbaum RC. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. 2013 Aug 10;31(23):2849-53. Epub 2013 Jun 17. [https://doi.org/10.1200/jco.2012.48.1911 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23775961 PubMed] NCT01836575<br />
<br />
==Carboplatin, Pemetrexed, Bevacizumab {{#subobject:03239b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8a4c4f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1002/cncr.30986 Spigel et al. 2018 (ToPPS)]<br />
|2009-2013<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|1. [[#Pemetrexed_monotherapy|Pemetrexed]]<br> 2. [[#Pemetrexed_.26_Bevacizumab|Pemetrexed & Bevacizumab]]<br />
|PFS: 4.8 mo<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] as follows:<br />
**Cycles 1 to 4: AUC 5 IV once on day 1<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*Premedications, [[Folic acid (Folate)]], and vitamin supplementation per standard guidelines<br />
*Antiemetics per standard guidelines<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ToPPS:''' Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. [https://doi.org/10.1002/cncr.30986 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29451696 PubMed] NCT00892710<br />
<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:21a22f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b72a5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(13)00155-4/fulltext Morabito et al. 2013 (CAPPA-2)]<br />
|2008-2012<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2017.76.8390 Gridelli et al. 2018 (MILES-3)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2017.76.8390 Gridelli et al. 2018 (MILES-4)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''MILES studies involved only patients at least 70 years old. CAPPA-2 allowed patients aged 18-70 with ECOG PS = 2.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]]<br />
*[[Gemcitabine (Gemzar)]]<br />
<br />
===References===<br />
<br />
#'''CAPPA-2:''' Morabito A, Gebbia V, Di Maio M, Cinieri S, Viganò MG, Bianco R, Barbera S, Cavanna L, De Marinis F, Montesarchio V, Costanzo R, Sandomenico C, Montanino A, Mancuso G, Russo P, Nacci A, Giordano P, Daniele G, Piccirillo MC, Rocco G, Gridelli C, Gallo C, Perrone F. Randomized phase III trial of gemcitabine and cisplatin vs gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study. Lung Cancer. 2013 Jul;81(1):77-83. Epub 2013 May 1. [https://www.lungcancerjournal.info/article/S0169-5002(13)00155-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23643177 PubMed] NCT00526643<br />
#'''MILES-3/MILES-4:''' Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. [https://doi.org/10.1200/JCO.2017.76.8390 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30028656 PubMed] NCT01405586; NCT01656551<br />
<br />
==Docetaxel monotherapy {{#subobject:17ba7f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Docetaxel (Taxotere) in non-small cell lung cancer]]<br />
<br />
===Regimen variant #1, 25 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:22a876|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/jjco/article/45/1/88/889067 Tsukada et al. 2014 (JCOG0207)]<br />
|2003-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Docetaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 36 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:110876|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1002/cncr.23019 Hainsworth et al. 2007]<br />
|2001-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Docetaxel_.26_Gemcitabine|Docetaxel & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 36 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3, 38 mg/m<sup>2</sup>, 2 out of 3 weeks {{#subobject:75b593|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.clinical-lung-cancer.com/article/S1525-7304(11)00016-7/fulltext Karampeazis et al. 2011]<br />
|2003-2008<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Vinorelbine_monotherapy|Vinorelbine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 38 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #4, 60 mg/m<sup>2</sup> q3wk {{#subobject:afca35|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2006.06.1044 Kudoh et al. 2006 (WJTOG 9904)]<br />
|2000-2003<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Vinorelbine_monotherapy|Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2014.55.8627 Abe et al. 2015 (JCOG0803/WJOG4307L)]<br />
|2008-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Docetaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''This is the PMDA-approved dose.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
'''21-day cycle for up to 4 cycles (WJTOG 9904) or indefinitely'''<br />
===References===<br />
<br />
#'''WJTOG 9904:''' Kudoh S, Takeda K, Nakagawa K, Takada M, Katakami N, Matsui K, Shinkai T, Sawa T, Goto I, Semba H, Seto T, Ando M, Satoh T, Yoshimura N, Negoro S, Fukuoka M. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol. 2006 Aug 1;24(22):3657-63. [https://doi.org/10.1200/JCO.2006.06.1044 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16877734 PubMed]<br />
#Hainsworth JD, Spigel DR, Farley C, Shipley DL, Bearden JD, Gandhi J, Houston GA, Greco FA. Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network. Cancer. 2007 Nov 1;110(9):2027-34. [https://onlinelibrary.wiley.com/doi/abs/10.1002/cncr.23019 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17823908 PubMed]<br />
#Karampeazis A, Vamvakas L, Agelidou A, Kentepozidis N, Chainis K, Chandrinos V, Vardakis N, Pallis AG, Christophyllakis C, Georgoulias V; Hellenic Oncology Research Group. Docetaxel vs vinorelbine in elderly patients with advanced non--small-cell lung cancer: a Hellenic Oncology Research Group randomized phase III study. Clin Lung Cancer. 2011 May;12(3):155-60. Epub 2011 Apr 27. [https://www.clinical-lung-cancer.com/article/S1525-7304(11)00016-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21663857 PubMed]<br />
#'''JCOG0207:''' Tsukada H, Yokoyama A, Goto K, Shinkai T, Harada M, Ando M, Shibata T, Ohe Y, Tamura T, Saijo N; Lung Cancer Study Group of the Japan Clinical Oncology Group (JCOG). Randomized controlled trial comparing docetaxel-cisplatin combination with weekly docetaxel alone in elderly patients with advanced non-small-cell lung cancer: Japan Clinical Oncology Group (JCOG) 0207. Jpn J Clin Oncol. 2015 Jan;45(1):88-95. Epub 2014 Nov 6. [https://academic.oup.com/jjco/article/45/1/88/889067 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/25378648 PubMed] UMIN C000000146<br />
#'''JCOG0803/WJOG4307L:''' Abe T, Takeda K, Ohe Y, Kudoh S, Ichinose Y, Okamoto H, Yamamoto N, Yoshioka H, Minato K, Sawa T, Iwamoto Y, Saka H, Mizusawa J, Shibata T, Nakamura S, Ando M, Yokoyama A, Nakagawa K, Saijo N, Tamura T. Randomized phase III trial comparing weekly docetaxel plus cisplatin versus docetaxel monotherapy every 3 weeks in elderly patients with advanced non-small-cell lung cancer: the intergroup trial JCOG0803/WJOG4307L. J Clin Oncol. 2015 Feb 20;33(6):575-81. Epub 2015 Jan 12. [https://doi.org/10.1200/JCO.2014.55.8627 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25584004 PubMed] UMIN000001424<br />
<br />
==Gemcitabine monotherapy {{#subobject:21a88f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 1000 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:137c9f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.jto.org/article/S1556-0864(15)33345-1/fulltext O'Brien et al. 2008]<br />
|2002-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Paclitaxel poliglumex<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #2, 1150 mg/m<sup>2</sup>, 2 out of 3 weeks {{#subobject:340c10|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960780-0/fulltext Quoix et al. 2011 (IFCT-0501)]<br />
|2006-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_7|Carboplatin & Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Study involved only patients 70 to 89 years old''<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1150 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*Growth factor support was not recommended as primary prophylaxis during cycle 1, but could be used if the patient develops grade 3 to 4 neutropenia<br />
<br />
'''21-day cycle for up to 5 cycles'''<br />
<br />
===Regimen variant #3, 1200 mg/m<sup>2</sup>, 2 out of 3 weeks {{#subobject:b8de5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[http://jnci.oxfordjournals.org/content/95/5/362.long Gridelli et al. 2003 (MILES)]<br />
|rowspan=2|1997-2000<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Gemcitabine_.26_Vinorelbine_2|Gemcitabine & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Vinorelbine_monotherapy|Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793001/ Reynolds et al. 2009 (USO-03012)]<br />
|2004-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Gemcitabine_.28GCb.29_2|Carboplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(13)00155-4/fulltext Morabito et al. 2013 (CAPPA-2)]<br />
|2008-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_6|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2017.76.8390 Gridelli et al. 2018 (MILES-3)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_6|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2017.76.8390 Gridelli et al. 2018 (MILES-4)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_6|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''MILES studies involved only patients at least 70 years old. CAPPA-2 allowed patients aged 18-70 with ECOG PS = 2.''<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1200 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*"[[:Category:Emesis_prevention|Antiemetic]] agents and other supportive treatments were provided at the discretion of the treating physician."<br />
<br />
'''21-day cycle for 4 to 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''MILES:''' Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. [http://jnci.oxfordjournals.org/content/95/5/362.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12618501 PubMed]<br />
#'''SICOG 9909:''' Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, Maiorino L, Guida M, Panza N, Mancarella S, Cioffi R. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004 Aug 2;91(3):489-97. [https://www.nature.com/articles/6602011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409832/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15266334 PubMed]<br />
#O'Brien ME, Socinski MA, Popovich AY, Bondarenko IN, Tomova A, Bilynsky BT, Hotko YS, Ganul VL, Kostinsky IY, Eisenfeld AJ, Sandalic L, Oldham FB, Bandstra B, Sandler AB, Singer JW. Randomized phase III trial comparing single-agent paclitaxel Poliglumex (CT-2103, PPX) with single-agent gemcitabine or vinorelbine for the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. J Thorac Oncol. 2008 Jul;3(7):728-34. [https://www.jto.org/article/S1556-0864(15)33345-1/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18594318 PubMed]<br />
#'''USO-03012:''' Reynolds C, Obasaju C, Schell MJ, Li X, Zheng Z, Boulware D, Caton JR, Demarco LC, O'Rourke MA, Shaw Wright G, Boehm KA, Asmar L, Bromund J, Peng G, Monberg MJ, Bepler G. Randomized phase III trial of gemcitabine-based chemotherapy with in situ RRM1 and ERCC1 protein levels for response prediction in non-small-cell lung cancer. J Clin Oncol. 2009 Dec 1;27(34):5808-15. Epub 2009 Nov 2. [https://doi.org/10.1200/JCO.2009.21.9766 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793001/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19884554 PubMed] NCT00190710<br />
#'''IFCT-0501:''' Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960780-0/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21831418 PubMed] NCT00298415<br />
#'''CAPPA-2:''' Morabito A, Gebbia V, Di Maio M, Cinieri S, Viganò MG, Bianco R, Barbera S, Cavanna L, De Marinis F, Montesarchio V, Costanzo R, Sandomenico C, Montanino A, Mancuso G, Russo P, Nacci A, Giordano P, Daniele G, Piccirillo MC, Rocco G, Gridelli C, Gallo C, Perrone F. Randomized phase III trial of gemcitabine and cisplatin vs gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study. Lung Cancer. 2013 Jul;81(1):77-83. Epub 2013 May 1. [https://www.lungcancerjournal.info/article/S0169-5002(13)00155-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23643177 PubMed] NCT00526643<br />
#'''MILES-3/MILES-4:''' Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. [https://doi.org/10.1200/JCO.2017.76.8390 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30028656 PubMed] NCT01405586; NCT01656551<br />
<br />
==Gemcitabine & Paclitaxel {{#subobject:fa1732|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GT: '''<u>G</u>'''emcitabine & '''<u>T</u>'''axol (Paclitaxel)<br />
===Regimen {{#subobject:a80095|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409832/ Comella et al. 2004 (SICOG 9909)]<br />
|rowspan=2|1999-2003<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Gemcitabine_monotherapy|Gemcitabine]]<br> 2. [[Non-small_cell_lung_cancer_-_historical#Paclitaxel_monotherapy|Paclitaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|3. [[#Gemcitabine_.26_Vinorelbine_2|GV]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''SICOG 9909:''' Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, Maiorino L, Guida M, Panza N, Mancarella S, Cioffi R. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004 Aug 2;91(3):489-97. [https://www.nature.com/articles/6602011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409832/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15266334 PubMed]<br />
<br />
==Gemcitabine & Vinorelbine {{#subobject:0e1f07|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GV: '''<u>G</u>'''emcitabine & '''<u>V</u>'''inorelbine<br />
<br>VG: '''<u>V</u>'''inorelbine & '''<u>G</u>'''emcitabine<br />
===Regimen variant #1, 1000/25 {{#subobject:4d6b82|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[http://jnci.oxfordjournals.org/content/95/5/362.long Gridelli et al. 2003 (MILES)]<br />
|rowspan=2|1997-2000<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Vinorelbine_monotherapy|Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''This study involved only patients at least 70 years old''<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*"[[:Category:Emesis_prevention|Antiemetic]] agents and other supportive treatments were provided at the discretion of the treating physician."<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #2, 1200/30 {{#subobject:07e5b2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.13.2529 Frasci et al. 2000]<br />
|1997-1999<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Vinorelbine_monotherapy|Vinorelbine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''This study involved only patients at least 70 years old''<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1200 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Frasci G, Lorusso V, Panza N, Comella P, Nicolella G, Bianco A, De Cataldis G, Iannelli A, Bilancia D, Belli M, Massidda B, Piantedosi F, Comella G, De Lena M. Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000 Jul;18(13):2529-36. [https://doi.org/10.1200/JCO.2000.18.13.2529 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10893283 PubMed]<br />
#'''MILES:''' Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. [http://jnci.oxfordjournals.org/content/95/5/362.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12618501 PubMed]<br />
#'''SICOG 9909:''' Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, Maiorino L, Guida M, Panza N, Mancarella S, Cioffi R. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004 Aug 2;91(3):489-97. [https://www.nature.com/articles/6602011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409832/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15266334 PubMed]<br />
<br />
==Pemetrexed monotherapy {{#subobject:615e55|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Pemetrexed (Alimta) in non-small cell lung cancer]]<br />
<br />
===Regimen {{#subobject:7f11b0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2012.48.1911 Zukin et al. 2013 (INCA-Lung001)]<br />
|2008-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Pemetrexed_3|Carboplatin & Pemetrexed]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2017.76.8390 Gridelli et al. 2018 (MILES-4)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Cisplatin & Gemcitabine<br> 2. Cisplatin & Pemetrexed<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1<br />
<br />
'''21-day cycle for up to 4 cycles (INCA-Lung001) or 6 cycles (MILES-4)'''<br />
<br />
===References===<br />
<!-- Presented at the 48th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2012. --><br />
<br />
#'''INCA-Lung001:''' Zukin M, Barrios CH, Rodrigues Pereira J, De Albuquerque Ribeiro R, de Mendonça Beato CA, do Nascimento YN, Murad A, Franke FA, Precivale M, de Lima Araujo LH, Da Rocha Baldotto CS, Vieira FM, Small IA, Ferreira CG, Lilenbaum RC. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. 2013 Aug 10;31(23):2849-53. Epub 2013 Jun 17. [https://doi.org/10.1200/jco.2012.48.1911 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23775961 PubMed] NCT01836575<br />
#'''ToPPS:''' Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. [https://doi.org/10.1002/cncr.30986 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29451696 PubMed] NCT00892710<br />
#'''MILES-4:''' Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. [https://doi.org/10.1200/JCO.2017.76.8390 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30028656 PubMed] NCT01405586; NCT01656551<br />
<br />
==Pemetrexed & Bevacizumab {{#subobject:3c119a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e31aed|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1002/cncr.30986 Spigel et al. 2018 (ToPPS)]<br />
|2009-2013<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|1. [[#Pemetrexed_monotherapy|Pemetrexed]]<br> 2. [[#Carboplatin.2C_Pemetrexed.2C_Bevacizumab_2|Carboplatin, Pemetrexed, Bevacizumab]]<br />
|PFS: 4.0 mo<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*Premedications, [[Folic acid (Folate)]], and vitamin supplementation per standard guidelines<br />
*Antiemetics per standard guidelines<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ToPPS:''' Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. [https://doi.org/10.1002/cncr.30986 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29451696 PubMed] NCT00892710<br />
<br />
==Vinorelbine monotherapy {{#subobject:aa0ce0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 25 mg/m<sup>2</sup> {{#subobject:5beb7a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2006.06.1044 Kudoh et al. 2006 (WJTOG 9904)]<br />
|2000-2003<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.clinical-lung-cancer.com/article/S1525-7304(11)00016-7/fulltext Karampeazis et al. 2011]<br />
|2003-2008<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960780-0/fulltext Quoix et al. 2011 (IFCT-0501)]<br />
|2006-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_7|Carboplatin & Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''IFCT-0501 involved only patients 70 to 89 years old''<br />
====Chemotherapy====<br />
<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*Growth factor support was not recommended as primary prophylaxis during cycle 1, but could be used if the patient develops grade 3 to 4 neutropenia<br />
<br />
'''21-day cycle for up to 4 cycles (WJTOG 9904), 5 cycles (IFCT-0501), or 6 cycles (Karampeazis et al. 2011)'''<br />
<br />
===Regimen variant #2, 30 mg/m<sup>2</sup> {{#subobject:408bee|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jnci.oxfordjournals.org/content/91/1/66.long Gridelli et al. 1999 (ELVIS)]<br />
|1996-1997<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
| rowspan="2" |[http://jnci.oxfordjournals.org/content/95/5/362.long Gridelli et al. 2003 (MILES)]<br />
|rowspan=2|1997-2000<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Gemcitabine_.26_Vinorelbine|Gemcitabine & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Study involved only patients at least 70 years old''<br />
====Chemotherapy====<br />
<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*(varies depending on reference):<br />
*ELVIS: [[Metoclopramide (Reglan)]] 20 mg IV bolus once per day on days 1 & 8, prior to [[Vinorelbine (Navelbine)]]<br />
*MILES: "[[:Category:Emesis_prevention|Antiemetic]] agents and other supportive treatments were provided at the discretion of the treating physician."<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''ELVIS:''' Gridelli C, Perrone F, Gallo C; Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 1999 Jan 6;91(1):66-72. [http://jnci.oxfordjournals.org/content/91/1/66.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9890172 PubMed]<br />
#'''MILES:''' Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. [http://jnci.oxfordjournals.org/content/95/5/362.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12618501 PubMed]<br />
#'''WJTOG 9904:''' Kudoh S, Takeda K, Nakagawa K, Takada M, Katakami N, Matsui K, Shinkai T, Sawa T, Goto I, Semba H, Seto T, Ando M, Satoh T, Yoshimura N, Negoro S, Fukuoka M. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol. 2006 Aug 1;24(22):3657-63. [https://doi.org/10.1200/JCO.2006.06.1044 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16877734 PubMed]<br />
#Karampeazis A, Vamvakas L, Agelidou A, Kentepozidis N, Chainis K, Chandrinos V, Vardakis N, Pallis AG, Christophyllakis C, Georgoulias V; Hellenic Oncology Research Group. Docetaxel vs vinorelbine in elderly patients with advanced non--small-cell lung cancer: a Hellenic Oncology Research Group randomized phase III study. Clin Lung Cancer. 2011 May;12(3):155-60. Epub 2011 Apr 27. [https://www.clinical-lung-cancer.com/article/S1525-7304(11)00016-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21663857 PubMed]<br />
#'''IFCT-0501:''' Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960780-0/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21831418 PubMed] NCT00298415<br />
<br />
=Maintenance after first-line therapy=<br />
<br />
==Bevacizumab monotherapy {{#subobject:75f589|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e01dd1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2012.47.3983 Johnson et al. 2013 (ATLAS-NSCLC)]<br />
|2006-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Erlotinib & Bevacizumab maintenance<br />
| style="background-color:#d73027" |Inferior PFS<sup>1</sup><br />
| style="background-color:#1a9850" |Less toxic<br />
|-<br />
|}<br />
''<sup>1</sup>While this arm was inferior in ATLAS, the authors note that, due to toxicity, the "two-drug maintenance regimen will not lead to a new postchemotherapy standard of care."''<br><br />
''Note: This trial should not be confused with the ones with the same name in breast cancer and in renal cell carcinoma.''<br />
====Preceding treatment====<br />
<br />
*Carboplatin, Docetaxel, Bevacizumab x 4 or Carboplatin, Gemcitabine, Bevacizumab x 4 or [[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Bevacizumab|PacCBev]] x 4 or Cisplatin, Docetaxel, Bevacizumab x 4 or [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Bevacizumab|Cisplatin, Gemcitabine, Bevacizumab]] x 4 or Cisplatin, Vinorelbine, Bevacizumab x 4<br />
<br />
====Targeted therapy====<br />
<br />
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ATLAS:''' Johnson BE, Kabbinavar F, Fehrenbacher L, Hainsworth J, Kasubhai S, Kressel B, Lin CY, Marsland T, Patel T, Polikoff J, Rubin M, White L, Yang JC, Bowden C, Miller V. ATLAS: randomized, double-blind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2013 Nov 1;31(31):3926-34. Epub 2013 Oct 7. [https://doi.org/10.1200/JCO.2012.47.3983 link to original article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/24101054 PubMed] NCT00257608<br />
<br />
==Gemcitabine monotherapy {{#subobject:5d1f99|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ce1f77|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(06)00060-2/fulltext Brodowicz et al. 2006]<br />
|1999-2002<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Observation_3|Observation]]<br />
| style="background-color:#1a9850" |Superior TTP<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2011.39.9782 Pérol et al. 2012 (IFCT-GFPC 0502)]<br />
|rowspan=2|2006-2009<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy|Erlotinib]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[Non-small_cell_lung_cancer_-_null_regimens#Observation_3|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]] x 4<br />
<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Brodowicz T, Krzakowski M, Zwitter M, Tzekova V, Ramlau R, Ghilezan N, Ciuleanu T, Cucevic B, Gyurkovits K, Ulsperger E, Jassem J, Grgic M, Saip P, Szilasi M, Wiltschke C, Wagnerova M, Oskina N, Soldatenkova V, Zielinski C, Wenczl M; Central European Cooperative Oncology Group. Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer. 2006 May;52(2):155-63. Epub 2006 Mar 29. [https://www.lungcancerjournal.info/article/S0169-5002(06)00060-2/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16569462 PubMed]<br />
#'''IFCT-GFPC 0502:''' Pérol M, Chouaid C, Pérol D, Barlési F, Gervais R, Westeel V, Crequit J, Léna H, Vergnenègre A, Zalcman G, Monnet I, Le Caer H, Fournel P, Falchero L, Poudenx M, Vaylet F, Ségura-Ferlay C, Devouassoux-Shisheboran M, Taron M, Milleron B. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2012 Oct 1;30(28):3516-24. Epub 2012 Sep 4. [https://doi.org/10.1200/JCO.2011.39.9782 link to original article]'''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22949150 PubMed] NCT00300586<br />
<br />
==Ipilimumab monotherapy {{#subobject:b19c3f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b4472a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2011.38.4032 Lynch et al. 2012 (CA184-041)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Ipilimumab|Carboplatin, Paclitaxel, Ipilimumab]] x 6<br />
<br />
====Immunotherapy====<br />
<br />
*[[Ipilimumab (Yervoy)]] 10 mg/kg IV once on day 1<br />
<br />
'''12-week cycles'''<br />
<br />
===References===<br />
<!-- Presented in part at The Chicago Multidisciplinary Symposium in Thoracic Oncology, Chicago, IL, December 9-11, 2010, and the 14th World Congress on Lung Cancer, Amsterdam, the Netherlands, July 3-7, 2011. --><br />
<br />
#'''CA184-041:''' Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. [https://doi.org/10.1200/jco.2011.38.4032 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22547592 PubMed] NCT00527735<br />
<br />
==Pembrolizumab monotherapy {{#subobject:0hg651|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d2e0eb|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|(ZEAL-1L)<br />
|2020-ongoing<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Niraparib & Pembrolizumab<br />
| style="background-color:#d3d3d3" |In progress<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Platinum-based induction therapy<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
#'''ZEAL-1L:''' NCT04475939<br />
<br />
==Pemetrexed monotherapy {{#subobject:ed7aa9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Pemetrexed (Alimta) in non-small cell lung cancer]]<br />
<br />
===Regimen {{#subobject:2b465b|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61497-5/fulltext Ciuleanu et al. 2009 (JMEN)]<br />
|2005-2007<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Placebo_5|Placebo]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32409-7/fulltext Mok et al. 2019 (KEYNOTE-042)]<br />
|2014-2017<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1801005 Gandhi et al. 2018 (KEYNOTE-189)]<br />
|2016-2017<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*JMEN: Platinum-based chemotherapy x 4<br />
*KEYNOTE-024: [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]] or [[#Carboplatin_.26_Pemetrexed|Carboplatin & Pemetrexed]] or [[#Cisplatin_.26_Pemetrexed_2 |Cisplatin & Pemetrexed]]<br />
*KEYNOTE-189 (control arm): [[#Carboplatin_.26_Pemetrexed_2|Carboplatin & Pemetrexed]] x 4 or [[#Cisplatin_.26_Pemetrexed_2 |Cisplatin & Pemetrexed]] x 4<br />
*KEYNOTE-189 (experimental arm): [[#Pemetrexed_.26_Pembrolizumab|Pemetrexed & Pembrolizumab maintenance]] x 2 y<br />
*KEYNOTE-042: [[#Carboplatin_.26_Pemetrexed_2|Carboplatin & Pemetrexed]] x 6<br />
<br />
====Chemotherapy====<br />
<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[Folic acid (Folate)]]<br />
*[[Cyanocobalamin (Vitamin B12)]]<br />
*[[Dexamethasone (Decadron)]]<br />
*"Investigators followed current American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) guidelines for use of colony-stimulating factors and erythropoiesis-stimulating agents."<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''JMEN:''' Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Rodrigues Pereira J, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009 Oct 24;374(9699):1432-40. Epub 2009 Sep 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61497-5/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19767093 PubMed]<br />
#'''KEYNOTE-024:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1606774/suppl_file/nejmoa1606774_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27718847 PubMed] NCT02142738<br />
##'''HRQoL analysis:''' Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30690-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29129441 PubMed]<br />
##'''Update:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. [https://doi.org/10.1200/JCO.18.00149 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30620668 PubMed]<br />
#'''KEYNOTE-189:''' Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1801005 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1801005/suppl_file/nejmoa1801005_protocol.pdf link to protocol] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29658856 PubMed] NCT02578680<br />
<!-- # '''Abstract:''' Tony Mok, Yi-Long Wu, Patricia A, Watson, Jin Zhang, Reshma A. Rangwala, and Gilberto Lopes. Phase 3 KEYNOTE-042 trial of pembrolizumab (MK-3475) versus platinum doublet chemotherapy in treatment-naive patients (pts) with PD-L1–positive advanced non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2015 33:15_suppl, TPS8105-TPS8105 [https://doi.org/10.1200/jco.2015.33.15_suppl.tps8105 link to abstract] --><br />
#'''KEYNOTE-042:''' Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. Epub 2019 Apr 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32409-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/30955977 PubMed] NCT02220894<br />
<br />
==Pemetrexed & Pembrolizumab {{#subobject:4f9073|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0365c3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1801005 Gandhi et al. 2018 (KEYNOTE-189)]<br />
|2016-2017<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Complex_multipart_regimens#KEYNOTE-189|See link]]<br />
|style="background-color:#1a9850"|[[Complex_multipart_regimens#KEYNOTE-189|See link]]<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Non-small_cell_lung_cancer#Carboplatin.2C_Pemetrexed.2C_Pembrolizumab|Carboplatin, Pemetrexed, Pembrolizumab]] x 4 or [[Non-small_cell_lung_cancer#Cisplatin.2C_Pemetrexed.2C_Pembrolizumab|Cisplatin, Pemetrexed, Pembrolizumab]] x 4<br />
====Immunotherapy====<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV over 30 minutes once on day 1, '''given first, at least 30 minutes prior to pemetrexed'''<br />
====Chemotherapy====<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1, '''given second'''<br />
<br />
====Supportive medications====<br />
*[[Folic acid (Folate)]] according to local guidelines<br />
*[[Cyanocobalamin (Vitamin B12)]] according to local guidelines<br />
*[[:Category:Steroids|Corticosteroids]] according to local guidelines<br />
<br />
'''21-day cycle for up to 2 years (35 cycles total, including induction)'''<br />
====Subsequent treatment====<br />
*[[Non-small_cell_lung_cancer#Pemetrexed_monotherapy_2|Pemetrexed maintenance]]<br />
<br />
===References===<br />
# '''KEYNOTE-189:''' Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1801005 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1801005/suppl_file/nejmoa1801005_protocol.pdf link to protocol] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29658856 PubMed] NCT02578680<br />
<br />
=Advanced or metastatic disease, second-line=<br />
<br />
==Cabozantinib monotherapy {{#subobject:47f237|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1276ee|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30561-7/fulltext Neal et al. 2016 (ECOG-ACRIN 1512)]<br />
|rowspan=2|2013-2014<br />
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|1. [[#Cabozantinib_.26_Erlotinib|Cabozantinib & Erlotinib]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
<br />
*[[Cabozantinib (Cometriq)]] 60 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''ECOG-ACRIN 1512:''' Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30561-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27825638 PubMed] NCT01708954<br />
<br />
==Cabozantinib & Erlotinib {{#subobject:d9d1c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:238161|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30561-7/fulltext Neal et al. 2016 (ECOG-ACRIN 1512)]<br />
|rowspan=2|2013-2014<br />
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|1. [[#Cabozantinib_monotherapy|Cabozantinib]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
<br />
*[[Cabozantinib (Cometriq)]] 40 mg PO once per day<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''ECOG-ACRIN 1512:''' Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30561-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27825638 PubMed] NCT01708954<br />
<br />
==Carboplatin & Pemetrexed {{#subobject:60fd1d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Carboplatin (Paraplatin) and Pemetrexed (Alimta) in non-small cell lung cancer]]<br />
<br />
===Regimen {{#subobject:95c37d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2012.43.6758 Ardizzoni et al. 2012 (GOIRC 02-2006)]<br />
|2007-2009<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Pemetrexed_monotherapy_3|Pemetrexed]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 15 to 60 minutes once on day 1, '''given second'''<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*(Ardizzoni et al. 2012 contained more details):<br />
*[[Dexamethasone (Decadron)]] 4 mg or [[steroid conversions|equivalent corticosteroid]] PO twice per day on the day before, the day of, and day after each dose of [[Pemetrexed (Alimta)]]<br />
*[[Folic acid (Folate)]] 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be taken throughout pemetrexed therapy<br />
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be given throughout pemetrexed therapy<br />
<br />
'''21-day cycle for 4 to 6 cycles'''<br />
<br />
===References===<br />
<!-- Presented at the 47th Annual Meeting of the American Society of Clinical Oncology, Chicago, June 3-7, 2011; 14th World Conference on Lung Cancer, Amsterdam, the Netherlands, July 3-7, 2011; and 13th National Congress of Medical Oncology, Bologna, Italy, November 5-7, 2011. --><br />
<br />
#'''GOIRC 02-2006:''' Ardizzoni A, Tiseo M, Boni L, Vincent AD, Passalacqua R, Buti S, Amoroso D, Camerini A, Labianca R, Genestreti G, Boni C, Ciuffreda L, Di Costanzo F, de Marinis F, Crinò L, Santo A, Pazzola A, Barbieri F, Zilembo N, Colantonio I, Tibaldi C, Mattioli R, Cafferata MA, Camisa R, Smit EF. Pemetrexed versus pemetrexed and carboplatin as second-line chemotherapy in advanced non-small-cell lung cancer: results of the GOIRC 02-2006 randomized phase II study and pooled analysis with the NVALT7 trial. J Clin Oncol. 2012 Dec 20;30(36):4501-7. Epub 2012 Oct 29. [https://doi.org/10.1200/jco.2012.43.6758 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23109689 PubMed] NCT00786331<br />
<br />
==Docetaxel monotherapy {{#subobject:ffa516|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Docetaxel (Taxotere) in non-small cell lung cancer]]<br />
<br />
===Regimen variant #1, 33.3 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:5b378|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(08)00307-3/fulltext Gebbia et al. 2008 (DISTAL-2)]<br />
|2005-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Capecitabine_.26_Docetaxel_.28TX.29|Capecitabine & Docetaxel]]<br> 2. Docetaxel & Gemcitabine<br> 3. [[#Docetaxel_.26_Vinorelbine|Docetaxel & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 33.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 35 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:5b296|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.02.3739 Schuette et al. 2005]<br />
|2000-2003<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Docetaxel_monotherapy_2|Docetaxel]]; 75 mg/m<sup>2</sup>, every 3 wks<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70310-3/fulltext Garassino et al. 2013 (TAILOR<sub>NSCLC</sub>)]<br />
|2007-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note that there is another trial named TAILOR in colorectal cancer.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**8 mg PO once per day on days 1, 8, 15; 12 hours prior to [[Docetaxel (Taxotere)]]<br />
**10 mg IV once per day on days 1, 8, 15; 30 minutes prior to [[Docetaxel (Taxotere)]]<br />
**8 mg PO once per day on days 1, 8, 15; 12 hours after [[Docetaxel (Taxotere)]]<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3, 50 mg/m<sup>2</sup> q2wk, limited duration {{#subobject:4cf20a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2994826/ Pallis et al. 2010 (HORG CT/04.14)]<br />
|2004-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Carboplatin & Docetaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''These patients had previously been treated with a platinum-free regimen.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #4, 60 mg/m<sup>2</sup> q3wk, limited duration {{#subobject:b90b5e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225192/ Herbst et al. 2010 (ZODIAC)]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Vandetanib|Docetaxel & Vandetanib]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|}<br />
''This is the PMDA-approved dose. While statistically inferior, the median PFS difference was only 0.8 months.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #5, 60 mg/m<sup>2</sup> q3wk, indefinite {{#subobject:3afa13|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdn705 Takeda et al. 2009 (JCOG 0104)]<br />
|2002-2003<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel & Gemcitabine<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2013.52.4694 Kawaguchi et al. 2014 (DELTA<sub>NSCLC</sub>)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2960845-X/fulltext Garon et al. 2014 (REVEL)]<br />
|2010-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440713 Gridelli et al. 2018 (AvaALL)]<br />
|2011-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Investigator's choice of:<br> 1. Docetaxel & Bevacizumab<br> 2. Erlotinib & Bevacizumab<br> 3. Pemetrexed & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''This is the PMDA-approved dose, the dose used for East Asian patients in REVEL, and the dose used in Japanese patients in EAST-LC. Note that there is another trial named DELTA in indolent lymphoma.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV over at least 60 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #6, 75 mg/m<sup>2</sup> q3wk, limited duration {{#subobject:500ace|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225192/ Herbst et al. 2010 (ZODIAC)]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Vandetanib|Docetaxel & Vandetanib]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|}<br />
''Note: while statistically inferior, the median PFS difference in ZODIAC was only 0.8 months.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #7, 75 mg/m<sup>2</sup> q3wk, indefinite {{#subobject:b495b6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409790/ Gridelli et al. 2004 (DISTAL 01)]<br />
|2000-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_monotherapy_2|Docetaxel]]; 33.3 mg/m<sup>2</sup>, 6 out of 8 wks<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of QoL<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.02.3739 Schuette et al. 2005]<br />
|2000-2003<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_monotherapy_2|Docetaxel]]; 35 mg/m<sup>2</sup>, 3 out of 4 wks<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2391114/ Paz-Ares et al. 2008 (STELLAR 2)]<br />
|2002-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Paclitaxel poliglumex<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.23.4146 Krzakowski et al. 2010]<br />
|2003-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Vinflunine<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(12)00616-2/fulltext Sun et al. 2012 (JMID)]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pemetrexed_monotherapy_3|Pemetrexed]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70385-0/fulltext Ciuleanu et al. 2012 (TITAN)]<br />
|2006-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70310-3/fulltext Garassino et al. 2013 (TAILOR<sub>NSCLC</sub>)]<br />
|2007-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2960845-X/fulltext Garon et al. 2014 (REVEL)]<br />
|2010-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440713 Gridelli et al. 2018 (AvaALL)]<br />
|2011-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Investigator's choice of:<br> 1. Docetaxel & Bevacizumab<br> 2. Erlotinib & Bevacizumab<br> 3. Pemetrexed & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.00816 Pillai et al. 2019 (GALAXY-2)]<br />
|2013-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel & Ganetespib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*Per JMEI: [[Dexamethasone (Decadron)]] 8 mg PO twice per day on days -1 to 2 (3 days)<br />
*Per Chem et al. 2006: [[Dexamethasone (Decadron)]] as follows:<br />
**8 mg PO once per day on days 1, 8, 15; 12 hours prior to [[Docetaxel (Taxotere)]]<br />
**10 mg IV once per day on days 1, 8, 15; 30 minutes prior to [[Docetaxel (Taxotere)]]<br />
**8 mg PO once per day on days 1, 8, 15; 12 hours after [[Docetaxel (Taxotere)]]<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''DISTAL 01:''' Gridelli C, Gallo C, Di Maio M, Barletta E, Illiano A, Maione P, Salvagni S, Piantedosi FV, Palazzolo G, Caffo O, Ceribelli A, Falcone A, Mazzanti P, Brancaccio L, Capuano MA, Isa L, Barbera S, Perrone F. A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer: the DISTAL 01 study. Br J Cancer. 2004 Dec 13;91(12):1996-2004. [https://www.nature.com/articles/6602241 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409790/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15558071 PubMed]<br />
#Schuette W, Nagel S, Blankenburg T, Lautenschlaeger C, Hans K, Schmidt EW, Dittrich I, Schweisfurth H, von Weikersthal LF, Raghavachar A, Reissig A, Serke M. Phase III study of second-line chemotherapy for advanced non-small-cell lung cancer with weekly compared with 3-weekly docetaxel. J Clin Oncol. 2005 Nov 20;23(33):8389-95. [https://doi.org/10.1200/JCO.2005.02.3739 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16293869 PubMed]<br />
#'''STELLAR 2:''' Paz-Ares L, Ross H, O'Brien M, Riviere A, Gatzemeier U, Von Pawel J, Kaukel E, Freitag L, Digel W, Bischoff H, García-Campelo R, Iannotti N, Reiterer P, Bover I, Prendiville J, Eisenfeld AJ, Oldham FB, Bandstra B, Singer JW, Bonomi P. Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer. Br J Cancer. 2008 May 20;98(10):1608-13. Epub 2008 May 13. [https://www.nature.com/articles/6604372 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2391114/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18475293 PubMed]<br />
#'''DISTAL-2:''' Gebbia V, Gridelli C, Verusio C, Frontini L, Aitini E, Daniele B, Gamucci T, Mancuso G, Di Maio M, Gallo C, Perrone F, Morabito A. Weekly docetaxel vs docetaxel-based combination chemotherapy as second-line treatment of advanced non-small-cell lung cancer patients: the DISTAL-2 randomized trial. Lung Cancer. 2009 Feb;63(2):251-8. Epub 2008 Jul 15. [https://www.lungcancerjournal.info/article/S0169-5002(08)00307-3/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18632181 PubMed] NCT00345059<br />
#'''JCOG 0104:''' Takeda K, Negoro S, Tamura T, Nishiwaki Y, Kudoh S, Yokota S, Matsui K, Semba H, Nakagawa K, Takada Y, Ando M, Shibata T, Saijo N. Phase III trial of docetaxel plus gemcitabine versus docetaxel in second-line treatment for non-small-cell lung cancer: results of a Japan Clinical Oncology Group trial (JCOG0104). Ann Oncol. 2009 May;20(5):835-41. Epub 2009 Jan 22. [https://doi.org/10.1093/annonc/mdn705 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19164456 PubMed]<br />
#Krzakowski M, Ramlau R, Jassem J, Szczesna A, Zatloukal P, Von Pawel J, Sun X, Bennouna J, Santoro A, Biesma B, Delgado FM, Salhi Y, Vaissiere N, Hansen O, Tan EH, Quoix E, Garrido P, Douillard JY. Phase III trial comparing vinflunine with docetaxel in second-line advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy. J Clin Oncol. 2010 May 1;28(13):2167-73. Epub 2010 Mar 29. [https://doi.org/10.1200/JCO.2009.23.4146 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20351334 PubMed]<br />
#'''ZODIAC:''' Herbst RS, Sun Y, Eberhardt WE, Germonpré P, Saijo N, Zhou C, Wang J, Li L, Kabbinavar F, Ichinose Y, Qin S, Zhang L, Biesma B, Heymach JV, Langmuir P, Kennedy SJ, Tada H, Johnson BE. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2010 Jul;11(7):619-26. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70132-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225192/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20570559 PubMed] NCT00312377<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/163 Project Data Sphere]<br />
#'''HORG CT/04.14:''' Pallis AG, Agelaki S, Agelidou A, Varthalitis I, Syrigos K, Kentepozidis N, Pavlakou G, Kotsakis A, Kontopodis E, Georgoulias V. A randomized phase III study of the docetaxel/carboplatin combination versus docetaxel single-agent as second line treatment for patients with advanced/metastatic non-small cell lung cancer. BMC Cancer. 2010 Nov 19;10:633. [https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-10-633 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2994826/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21092076 PubMed] NCT00430651<br />
#'''TITAN:''' Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, Johannsdottir HK, Klughammer B, Gonzalez EE. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. 2012 Mar;13(3):300-8. Epub 2012 Jan 24. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70385-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22277837 PubMed] NCT00556322<br />
#'''JMID:''' Sun Y, Wu YL, Zhou CC, Zhang L, Zhang L, Liu XY, Yu SY, Jiang GL, Li K, Qin SK, Ma SL, Han L, Quinlivan M, Orlando M, Zhang XQ. Second-line pemetrexed versus docetaxel in Chinese patients with locally advanced or metastatic non-small cell lung cancer: a randomized, open-label study. Lung Cancer. 2013 Feb;79(2):143-50. Epub 2012 Nov 20. [https://www.lungcancerjournal.info/article/S0169-5002(12)00616-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/23182660 PubMed] NCT00391274<br />
#'''TAILOR:''' Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, Bianchi F, Bettini A, Longo F, Moscetti L, Tomirotti M, Marabese M, Ganzinelli M, Lauricella C, Labianca R, Floriani I, Giaccone G, Torri V, Scanni A, Marsoni S; TAILOR trialists. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013 Sep;14(10):981-8. Epub 2013 Jul 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70310-3/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23883922 PubMed] NCT00637910<br />
#'''DELTA:''' Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol. 2014 Jun 20;32(18):1902-8. Epub 2014 May 19. [https://doi.org/10.1200/JCO.2013.52.4694 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24841974 PubMed]<br />
#'''REVEL:''' Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Pérol M. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23;384(9944):665-73. Epub 2014 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2960845-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24933332 PubMed] NCT01168973<br />
#'''AvaALL:''' Gridelli C, de Castro Carpeno J, Dingemans AC, Griesinger F, Grossi F, Langer C, Ohe Y, Syrigos K, Thatcher N, Das-Gupta A, Truman M, Donica M, Smoljanovic V, Bennouna J. Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):e183486. Epub 2018 Dec 13. Erratum in: JAMA Oncol. 2018 Dec 1;4(12):1792. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2698039 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440713 link to PMC article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/30177994 PubMed] NCT01351415<br />
#'''GALAXY-2:''' Pillai RN, Fennell DA, Kovcin V, Ciuleanu TE, Ramlau R, Kowalski D, Schenker M, Yalcin I, Teofilovici F, Vukovic VM, Ramalingam SS. Randomized Phase III Study of Ganetespib, a Heat Shock Protein 90 Inhibitor, With Docetaxel Versus Docetaxel in Advanced Non-Small-Cell Lung Cancer (GALAXY-2). J Clin Oncol. 2020 Feb 20;38(6):613-622. Epub 2019 Dec 12. [https://doi.org/10.1200/JCO.19.00816 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/31829907 PubMed]<br />
#'''DUBLIN-3:''' NCT02504489<br />
<br />
==Docetaxel & Ramucirumab {{#subobject:7b9570|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 60 mg/m<sup>2</sup> docetaxel {{#subobject:07d626|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2960845-X/fulltext Garon et al. 2014 (REVEL)]<br />
|2010-2013<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Docetaxel_monotherapy_2|Docetaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior OS <br>Median OS: 10.5 mo vs 9.1 mo <br>(HR 0.86, 95% CI 0.75-0.98)<br />
|-<br />
|}<br />
''Note: This is the PMDA-approved dose and the dose recommended for East Asians. The FDA only provides recommendations for ramucirumab dosing.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Ramucirumab (Cyramza)]] 10 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*Colony-stimulating factors and erythroid-stimulating factor use per investigator discretion.<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 75 mg/m<sup>2</sup> docetaxel {{#subobject:b3ec19|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2960845-X/fulltext Garon et al. 2014 (REVEL)]<br />
|2010-2013<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Docetaxel_monotherapy_2|Docetaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior OS <br>Median OS: 10.5 mo vs 9.1 mo <br>(HR 0.86, 95% CI 0.75-0.98)<br />
|-<br />
|}<br />
''Note: The FDA only provides recommendations for ramucirumab dosing.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Ramucirumab (Cyramza)]] 10 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*Colony-stimulating factors and erythroid-stimulating factor use per investigator discretion.<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''REVEL:''' Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Pérol M. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23;384(9944):665-73. Epub 2014 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2960845-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24933332 PubMed] NCT01168973<br />
<br />
==Docetaxel & Vandetanib {{#subobject:827eac|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 60 mg/m<sup>2</sup> docetaxel {{#subobject:c0b4c2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225192/ Herbst et al. 2010 (ZODIAC)]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Docetaxel_monotherapy_2|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
''This is the PMDA-approved dose of docetaxel. While statistically superior, the median PFS difference was only 0.8 months. Vandetanib is continued until disease progression, unacceptable toxicity, or withdrawal of consent.''<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] as follows:<br />
**Cycles 1 up to 6: 60 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Vandetanib (Caprelsa)]] 100 mg PO once per day<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 75 mg/m<sup>2</sup> docetaxel {{#subobject:10fe1c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225192/ Herbst et al. 2010 (ZODIAC)]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Docetaxel_monotherapy_2|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
''While statistically superior, the median PFS difference was only 0.8 months. Vandetanib is continued until disease progression, unacceptable toxicity, or withdrawal of consent.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Vandetanib (Caprelsa)]] 100 mg PO once per day<br />
<br />
'''21-day cycle for up to 6 cycles (see note)'''<br />
<br />
===References===<br />
<br />
#'''ZODIAC:''' Herbst RS, Sun Y, Eberhardt WE, Germonpré P, Saijo N, Zhou C, Wang J, Li L, Kabbinavar F, Ichinose Y, Qin S, Zhang L, Biesma B, Heymach JV, Langmuir P, Kennedy SJ, Tada H, Johnson BE. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2010 Jul;11(7):619-26. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70132-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225192/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20570559 PubMed] NCT00312377<br />
<br />
==Gefitinib monotherapy {{#subobject:ebfac2d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1b01c8f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.27630 Sun et al. 2012 (KCSG-LU08-01)]<br />
|2008-2010<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[#Pemetrexed_monotherapy_3|Pemetrexed]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
<br />
*[[Gefitinib (Iressa)]] 250 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''KCSG-LU08-01:''' Sun JM, Lee KH, Kim SW, Lee DH, Min YJ, Yun HJ, Kim HK, Song HS, Kim YH, Kim BS, Hwang IG, Lee K, Jo SJ, Lee JW, Ahn JS, Park K, Ahn MJ; Korean Cancer Study Group. Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial. Cancer. 2012 Dec 15;118(24):6234-42. Epub 2012 Jun 6. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.27630 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22674612 PubMed] NCT01066195<br />
<br />
==Gemcitabine monotherapy {{#subobject:b327a9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dac826|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1999.17.7.2081 Crinò et al. 1999a]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Crinò L, Mosconi AM, Scagliotti G, Selvaggi G, Novello S, Rinaldi M, Della Giulia M, Gridelli C, Rossi A, Calandri C, De Marinis F, Noseda M, Tonato M. Gemcitabine as second-line treatment for advanced non-small-cell lung cancer: a phase II trial. J Clin Oncol. 1999 Jul;17(7):2081-5. [https://doi.org/10.1200/JCO.1999.17.7.2081 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10561261 PubMed]<br />
<br />
==Pemetrexed monotherapy {{#subobject:24fa23b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Pemetrexed (Alimta) in non-small cell lung cancer]]<br />
<br />
===Regimen {{#subobject:4e0b1b|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdm592 Cullen et al. 2008]<br />
|2004-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pemetrexed_monotherapy_3|Pemetrexed]]; high-dose<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(12)00616-2/fulltext Sun et al. 2012 (JMID)]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70385-0/fulltext Ciuleanu et al. 2012 (TITAN)]<br />
|2006-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2010.29.5717 de Boer et al. 2011 (ZEAL)]<br />
|2007-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Pemetrexed_.26_Vandetanib|Pemetrexed & Vandetanib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://doi.org/10.1200/jco.2012.43.6758 Ardizzoni et al. 2012 (GOIRC 02-2006)]<br />
|2007-2009<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Carboplatin_.26_Pemetrexed_4|Carboplatin & Pemetrexed]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.27630 Sun et al. 2012 (KCSG-LU08-01)]<br />
|2008-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gefitinib_monotherapy_3|Gefitinib]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440713 Gridelli et al. 2018 (AvaALL)]<br />
|2011-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Investigator's choice of:<br> 1. Docetaxel & Bevacizumab<br> 2. Erlotinib & Bevacizumab<br> 3. Pemetrexed & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*(per Ardizzoni et al. 2012):<br />
*[[Dexamethasone (Decadron)]] 4 mg or [[steroid conversions|equivalent corticosteroid]] PO twice per day on the day before, the day of, and day after each dose of [[Pemetrexed (Alimta)]]<br />
*[[Folic acid (Folate)]] 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be taken throughout pemetrexed therapy<br />
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be given throughout pemetrexed therapy<br />
<br />
'''21-day cycles''' <br />
<br />
''GOIRC 02-2006 treated patients for up to 4 cycles or until progressive disease, unacceptable toxicity, or patient refusal.''<br />
<br />
===References===<br />
<br />
#Cullen MH, Zatloukal P, Sörenson S, Novello S, Fischer JR, Joy AA, Zereu M, Peterson P, Visseren-Grul CM, Iscoe N. A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2008 May;19(5):939-45. Epub 2008 Feb 17. [https://doi.org/10.1093/annonc/mdm592 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18283036 PubMed]<br />
<!-- Presented as a poster discussion at the 45th Annual Meeting of the American Society of Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and as an oral presentation at the 13th World Congress on Lung Cancer, July 31-August 4, 2009, San Francisco, CA, and at the European Cancer Organisation 15/34th European Society for Medical Oncology Congress, September 20-24, 2009, Berlin, Germany. --><br />
#'''ZEAL:''' de Boer RH, Arrieta Ó, Yang CH, Gottfried M, Chan V, Raats J, de Marinis F, Abratt RP, Wolf J, Blackhall FH, Langmuir P, Milenkova T, Read J, Vansteenkiste JF. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2011 Mar 10;29(8):1067-74. Epub 2011 Jan 31. [https://doi.org/10.1200/JCO.2010.29.5717 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/21282537 PubMed] NCT00418886<br />
#'''TITAN:''' Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, Johannsdottir HK, Klughammer B, Gonzalez EE. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. 2012 Mar;13(3):300-8. Epub 2012 Jan 24. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70385-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22277837 PubMed] NCT00556322<br />
#'''KCSG-LU08-01:''' Sun JM, Lee KH, Kim SW, Lee DH, Min YJ, Yun HJ, Kim HK, Song HS, Kim YH, Kim BS, Hwang IG, Lee K, Jo SJ, Lee JW, Ahn JS, Park K, Ahn MJ; Korean Cancer Study Group. Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial. Cancer. 2012 Dec 15;118(24):6234-42. Epub 2012 Jun 6. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.27630 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22674612 PubMed] NCT01066195<br />
<!-- Presented at the 47th Annual Meeting of the American Society of Clinical Oncology, Chicago, June 3-7, 2011; 14th World Conference on Lung Cancer, Amsterdam, the Netherlands, July 3-7, 2011; and 13th National Congress of Medical Oncology, Bologna, Italy, November 5-7, 2011. --><br />
#'''GOIRC 02-2006:''' Ardizzoni A, Tiseo M, Boni L, Vincent AD, Passalacqua R, Buti S, Amoroso D, Camerini A, Labianca R, Genestreti G, Boni C, Ciuffreda L, Di Costanzo F, de Marinis F, Crinò L, Santo A, Pazzola A, Barbieri F, Zilembo N, Colantonio I, Tibaldi C, Mattioli R, Cafferata MA, Camisa R, Smit EF. Pemetrexed versus pemetrexed and carboplatin as second-line chemotherapy in advanced non-small-cell lung cancer: results of the GOIRC 02-2006 randomized phase II study and pooled analysis with the NVALT7 trial. J Clin Oncol. 2012 Dec 20;30(36):4501-7. Epub 2012 Oct 29. [https://doi.org/10.1200/jco.2012.43.6758 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23109689 PubMed] NCT00786331<br />
#'''JMID:''' Sun Y, Wu YL, Zhou CC, Zhang L, Zhang L, Liu XY, Yu SY, Jiang GL, Li K, Qin SK, Ma SL, Han L, Quinlivan M, Orlando M, Zhang XQ. Second-line pemetrexed versus docetaxel in Chinese patients with locally advanced or metastatic non-small cell lung cancer: a randomized, open-label study. Lung Cancer. 2013 Feb;79(2):143-50. Epub 2012 Nov 20. [https://www.lungcancerjournal.info/article/S0169-5002(12)00616-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/23182660 PubMed] NCT00391274<br />
#'''AvaALL:''' Gridelli C, de Castro Carpeno J, Dingemans AC, Griesinger F, Grossi F, Langer C, Ohe Y, Syrigos K, Thatcher N, Das-Gupta A, Truman M, Donica M, Smoljanovic V, Bennouna J. Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):e183486. Epub 2018 Dec 13. Erratum in: JAMA Oncol. 2018 Dec 1;4(12):1792. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2698039 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440713 link to PMC article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/30177994 PubMed] NCT01351415<br />
<br />
=Advanced or metastatic disease, third-line=<br />
==Cabozantinib monotherapy {{#subobject:47f237|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1276ee|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30561-7/fulltext Neal et al. 2016 (ECOG-ACRIN 1512)]<br />
|rowspan=2|2013-2014<br />
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|1. [[#Cabozantinib_.26_Erlotinib|Cabozantinib & Erlotinib]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
<br />
*[[Cabozantinib (Cometriq)]] 60 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''ECOG-ACRIN 1512:''' Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30561-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27825638 PubMed] NCT01708954<br />
<br />
==Cabozantinib & Erlotinib {{#subobject:d9d1c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:238161|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30561-7/fulltext Neal et al. 2016 (ECOG-ACRIN 1512)]<br />
|rowspan=2|2013-2014<br />
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|1. [[#Cabozantinib_monotherapy|Cabozantinib]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
<br />
*[[Cabozantinib (Cometriq)]] 40 mg PO once per day<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''ECOG-ACRIN 1512:''' Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30561-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27825638 PubMed] NCT01708954<br />
<br />
==Docetaxel monotherapy {{#subobject:ff8fa6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Docetaxel (Taxotere) in non-small cell lung cancer]]<br />
<br />
===Regimen {{#subobject:3a685a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2013.52.4694 Kawaguchi et al. 2014 (DELTA<sub>NSCLC</sub>)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|}<br />
''This is the PMDA-approved dose. Note that there is another trial named DELTA in indolent lymphoma.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV over at least 60 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''DELTA:''' Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol. 2014 Jun 20;32(18):1902-8. Epub 2014 May 19. [https://doi.org/10.1200/JCO.2013.52.4694 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24841974 PubMed]<br />
<br />
=Advanced or metastatic disease, subsequent lines of therapy=<br />
''Note: this section includes regimens that were tested in second-line and beyond; those tested specifically in the [[#Advanced_or_metastatic_disease.2C_second-line|second-line]] or [[#Advanced_or_metastatic_disease.2C_third-line|third-line]] are to be found above.''<br />
==Afatinib monotherapy {{#subobject:1bf6db|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 30 mg/day {{#subobject:f69d3b|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
''This is the FDA-recommended dose for patients with "severe renal impairment".''<br />
====Targeted therapy====<br />
<br />
*[[Afatinib (Gilotrif)]] 30 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen variant #2, 50 mg/day {{#subobject:f109f9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70087-6/fulltext Miller et al. 2012 (LUX-Lung 1)]<br />
|2008-2009<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Placebo_5|Placebo]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://doi.org/10.1200/jco.2012.45.0981 Katakami et al. 2013 (LUX-Lung 4)]<br />
|2009-2011<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#6e016b; color:white " |ORR: 8% (95% CI: 3-18)<br />
|-<br />
|}<br />
''In LUX-Lung 4, 72.6% of patients were EGFR mutation positive. This was third or fourth line therapy for participants, who had progressed while receiving erlotinib and/or gefitinib and had received one or two previous lines of chemotherapy, including at least one platinum-based regimen.'' <br />
====Targeted therapy====<br />
<br />
*[[Afatinib (Gilotrif)]] 50 mg PO once per day, given 1 hour before eating food<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''LUX-Lung 1:''' Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang JC. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012 May;13(5):528-38. Epub 2012 Mar 26. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70087-6/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22452896 PubMed] NCT00656136<br />
##'''HRQoL analysis:''' Hirsh V, Cadranel J, Cong XJ, Fairclough D, Finnern HW, Lorence RM, Miller VA, Palmer M, Yang JC. Symptom and quality of life benefit of afatinib in advanced non-small-cell lung cancer patients previously treated with erlotinib or gefitinib: results of a randomized phase IIb/III trial (LUX-Lung 1). J Thorac Oncol. 2013 Feb;8(2):229-37. [https://www.jto.org/article/S1556-0864(15)32746-5/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/23328549 PubMed]<br />
#'''LUX-Lung 4:''' Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, Ichinose Y, Koboyashi K, Takeda K, Kiura K, Nishio K, Seki Y, Ebisawa R, Shahidi M, Yamamoto N. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013 Sep 20;31(27):3335-41. Epub 2013 Jul 1. [https://doi.org/10.1200/jco.2012.45.0981 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23816963 PubMed] NCT00711594<br />
<br />
==Afatinib & Paclitaxel {{#subobject:3d0a87|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0cb697|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769992/ Schuler et al. 2015 (LUX-Lung 5)]<br />
|2010-2011<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Single-agent chemotherapy<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Afatinib (Gilotrif)]] 40 mg PO once per day<br />
<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''LUX-Lung 5:''' Schuler M, Yang JC, Park K, Kim JH, Bennouna J, Chen YM, Chouaid C, De Marinis F, Feng JF, Grossi F, Kim DW, Liu X, Lu S, Strausz J, Vinnyk Y, Wiewrodt R, Zhou C, Wang B, Chand VK, Planchard D; LUX-Lung 5 Investigators. Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial. Ann Oncol. 2016 Mar;27(3):417-23. Epub 2015 Dec 8. [https://doi.org/10.1093/annonc/mdv597 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769992/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26646759 PubMed] NCT01085136<br />
<br />
==Amrubicin monotherapy {{#subobject:d1a9ba|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f264a4|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdw621 Yoshioka et al. 2017 (D0702035)]<br />
|2010-2012<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Amrubicin (Calsed)]] 35 mg/m<sup>2</sup> IV over 5 minutes once per day on days 1 to 3<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''D0702035:''' Yoshioka H, Katakami N, Okamoto H, Iwamoto Y, Seto T, Takahashi T, Sunaga N, Kudoh S, Chikamori K, Harada M, Tanaka H, Saito H, Saka H, Takeda K, Nogami N, Masuda N, Harada T, Kitagawa H, Horio H, Yamanaka T, Fukuoka M, Yamamoto N, Nakagawa K. A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer. Ann Oncol. 2017 Feb 1;28(2):285-291. [https://doi.org/10.1093/annonc/mdw621 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28426104 PubMed] NCT01207011<br />
<br />
==Atezolizumab monotherapy {{#subobject:412fc4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:9f357f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00587-0/fulltext Fehrenbacher et al. 2016 (POPLAR)]<br />
|2013-2014<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ooc)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32517-X/fulltext Rittmeyer et al. 2016 (OAK)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''POPLAR:''' Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30;387(10030):1837-46. Epub 2016 Mar 9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00587-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/26970723 PubMed] NCT01903993<br />
#'''OAK:''' Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32517-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/27979383 PubMed] NCT02008227<br />
##'''Update:''' Fehrenbacher L, von Pawel J, Park K, Rittmeyer A, Gandara DR, Ponce Aix S, Han JY, Gadgeel SM, Hida T, Cortinovis DL, Cobo M, Kowalski DM, De Marinis F, Gandhi M, Danner B, Matheny C, Kowanetz M, He P, Felizzi F, Patel H, Sandler A, Ballinger M, Barlesi F. Updated Efficacy Analysis Including Secondary Population Results for OAK: A Randomized Phase III Study of Atezolizumab versus Docetaxel in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer. J Thorac Oncol. 2018 Aug;13(8):1156-1170. Epub 2018 May 17. Erratum in: J Thorac Oncol. 2018 Nov;13(11):1800. [https://www.jto.org/article/S1556-0864(18)30611-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29777823 PubMed]<br />
##'''Update:''' von Pawel J, Bordoni R, Satouchi M, Fehrenbacher L, Cobo M, Han JY, Hida T, Moro-Sibilot D, Conkling P, Gandara DR, Rittmeyer A, Gandhi M, Yu W, Matheny C, Patel H, Sandler A, Ballinger M, Kowanetz M, Park K. Long-term survival in patients with advanced non-small-cell lung cancer treated with atezolizumab versus docetaxel: Results from the randomised phase III OAK study. Eur J Cancer. 2019 Jan;107:124-132. Epub 2018 Dec 17. [https://www.ejcancer.com/article/S0959-8049(18)31518-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/30562710 PubMed]<br />
<br />
==Docetaxel monotherapy {{#subobject:fd1716|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Docetaxel (Taxotere) in non-small cell lung cancer]]<br />
<br />
===Regimen variant #1, 35 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:5b296|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[http://journal.chestnet.org/article/S0012-3692(15)38821-8/fulltext Chen et al. 2006]<br />
| rowspan="2" |2002-2004<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Docetaxel_monotherapy_4|Docetaxel]]; 40 mg/m<sup>2</sup>, 2 out of 3 wks<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoint<br />
|-<br />
|2. [[#Docetaxel_monotherapy_4|Docetaxel]]; 75 mg/m<sup>2</sup>, every 3 wks<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoint<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**8 mg PO once per day on days 1, 8, 15; 12 hours prior to [[Docetaxel (Taxotere)]]<br />
**10 mg IV once per day on days 1, 8, 15; 30 minutes prior to [[Docetaxel (Taxotere)]]<br />
**8 mg PO once per day on days 1, 8, 15; 12 hours after [[Docetaxel (Taxotere)]]<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 60 mg/m<sup>2</sup> q3wk, indefinite {{#subobject:3a67f3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2007.15.0185 Maruyama et al. 2008 (V-15-32)]<br />
|2003-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gefitinib<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2013.52.4694 Kawaguchi et al. 2014 (DELTA<sub>NSCLC</sub>)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdw621 Yoshioka et al. 2017 (D0702035)]<br />
|2010-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Amrubicin_monotherapy|Amrubicin]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834128/ Nokihara et al. 2017 (EAST-LC)]<br />
|2010-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
''This is the PMDA-approved dose, the dose used for East Asian patients in REVEL, and the dose used in Japanese patients in EAST-LC.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV over at least 60 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #3, 75 mg/m<sup>2</sup> q3wk, indefinite {{#subobject:b495b6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.10.2095 Shepherd et al. 2000 (TAX 317)]<br />
|1994-1998<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Non-small_cell_lung_cancer_-_historical#Best_supportive_care_2|Best supportive care]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2000.18.12.2354 Fossella et al. 2000 (TAX 320)]<br />
| rowspan="2" |1995-1998<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Docetaxel_monotherapy_4|Docetaxel]]; 100 mg/m<sup>2</sup><br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. Ifosfamide<br> 3. [[#Vinorelbine_monotherapy_2|Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdj115 Camps et al. 2005]<br />
|2000-2003<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]; 36 mg/m<sup>2</sup>, 6 out of 8 wks<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[https://doi.org/10.1200/jco.2004.08.163 Hanna et al. 2004 (JMEI)]<br />
|2001-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pemetrexed_monotherapy_3|Pemetrexed]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.03.6491 Ramlau et al. 2006]<br />
|2001-2003<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Topotecan<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
| rowspan="2" |[http://journal.chestnet.org/article/S0012-3692(15)38821-8/fulltext Chen et al. 2006]<br />
| rowspan="2" |2002-2004<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Docetaxel_monotherapy_4|Docetaxel]]; 35 mg/m<sup>2</sup>, 3 out of 4 wks<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoint<br />
|-<br />
|2. [[#Docetaxel_monotherapy_4|Docetaxel]]; 40 mg/m<sup>2</sup>, 2 out of 3 wks<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoint<br />
|-<br />
|[https://doi.org/10.1200/JCO.2008.17.1405 Fidias et al. 2008]<br />
|2002-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel consolidation<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61758-4/fulltext Kim et al. 2008 (INTEREST)]<br />
|2004-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gefitinib_monotherapy_3|Gefitinib]]<br />
| style="background-color:#eeee01" |Seems to have non-inferior OS<br />
|-<br />
|[http://clincancerres.aacrjournals.org/content/16/4/1307.long Lee et al. 2010 (ISTANA)]<br />
|2005-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gefitinib_monotherapy_3|Gefitinib]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2012.42.6932 Ramlau et al. 2012 (EFC10261)]<br />
|2007-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel & ziv-Aflibercept<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70586-2/fulltext Reck et al. 2014 (LUME-Lung 1)]<br />
|2008-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Nintedanib|Docetaxel & Nintedanib]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834128/ Nokihara et al. 2017 (EAST-LC)]<br />
|2010-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ Katakami et al. 2017 (E7389-G000-302)]<br />
|2011-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Eribulin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00587-0/fulltext Fehrenbacher et al. 2016 (POPLAR)]<br />
|2013-2014<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01281-7/fulltext Herbst et al. 2015 (KEYNOTE-010)]<br />
|2013-2015<br />
| style="background-color:#1a9851" |Phase II/III (C)<br />
|[[#Pembrolizumab_monotherapy_3|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32517-X/fulltext Rittmeyer et al. 2016 (OAK)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://doi.org/10.1016/j.jtho.2019.01.006 Wu et al. 2019 (CheckMate 078)]<br />
|2015-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Nivolumab_monotherapy_2|Nivolumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30673-9/fulltext Barlesi et al. 2018 (JAVELIN Lung 200)]<br />
|2015-2017<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Avelumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*Per JMEI: [[Dexamethasone (Decadron)]] 8 mg PO twice per day on days -1 to 2 (3 days)<br />
*Per Chem et al. 2006: [[Dexamethasone (Decadron)]] as follows:<br />
**8 mg PO once per day on days 1, 8, 15; 12 hours prior to [[Docetaxel (Taxotere)]]<br />
**10 mg IV once per day on days 1, 8, 15; 30 minutes prior to [[Docetaxel (Taxotere)]]<br />
**8 mg PO once per day on days 1, 8, 15; 12 hours after [[Docetaxel (Taxotere)]]<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #4, 100 mg/m<sup>2</sup> q3wk {{#subobject:465aa0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1995.13.3.645 Fossella et al. 1995]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#Fossella FV, Lee JS, Shin DM, Calayag M, Huber M, Perez-Soler R, Murphy WK, Lippman S, Benner S, Glisson B, Chasen M, Hong WK, Raber M. Phase II study of docetaxel for advanced or metastatic platinum-refractory non-small-cell lung cancer. J Clin Oncol. 1995 Mar;13(3):645-51. [https://doi.org/10.1200/JCO.1995.13.3.645 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/7884425 PubMed]<br />
#'''TAX 317:''' Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, Levitan N, Gressot L, Vincent M, Burkes R, Coughlin S, Kim Y, Berille J. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000 May;18(10):2095-103. [https://doi.org/10.1200/JCO.2000.18.10.2095 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10811675 PubMed]<br />
#'''TAX 320:''' Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L; TAX 320 Non-Small Cell Lung Cancer Study Group. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol. 2000 Jun;18(12):2354-62. Erratum in: J Clin Oncol. 2004 Jan 1;22(1):209. [https://doi.org/10.1200/JCO.2000.18.12.2354 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10856094 PubMed]<br />
#'''JMEI:''' Hanna N, Shepherd FA, Fossella FV, Rodrigues Pereira J, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar M, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1;22(9):1589-97. [https://doi.org/10.1200/jco.2004.08.163 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15117980 PubMed]<br />
#Camps C, Massuti B, Jiménez A, Maestu I, Gómez RG, Isla D, González JL, Almenar D, Blasco A, Rosell R, Carrato A, Viñolas N, Batista N, Girón CG, Galán A, López M, Blanco R, Provencio M, Diz P, Felip E; Spanish Lung Cancer Group. Randomized phase III study of 3-weekly versus weekly docetaxel in pretreated advanced non-small-cell lung cancer: a Spanish Lung Cancer Group trial. Ann Oncol. 2006 Mar;17(3):467-72. Epub 2005 Dec 21. [https://doi.org/10.1093/annonc/mdj115 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16371411 PubMed]<br />
#Chen YM, Shih JF, Perng RP, Tsai CM, Whang-Peng J. A randomized trial of different docetaxel schedules in non-small cell lung cancer patients who failed previous platinum-based chemotherapy. Chest. 2006 Apr;129(4):1031-8. [http://journal.chestnet.org/article/S0012-3692(15)38821-8/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16608954 PubMed]<br />
#Ramlau R, Gervais R, Krzakowski M, von Pawel J, Kaukel E, Abratt RP, Dharan B, Grotzinger KM, Ross G, Dane G, Shepherd FA. Phase III study comparing oral topotecan to intravenous docetaxel in patients with pretreated advanced non-small-cell lung cancer. J Clin Oncol. 2006 Jun 20;24(18):2800-7. Epub 2006 May 8. [https://doi.org/10.1200/JCO.2005.03.6491 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16682727 PubMed]<br />
#'''V-15-32:''' Maruyama R, Nishiwaki Y, Tamura T, Yamamoto N, Tsuboi M, Nakagawa K, Shinkai T, Negoro S, Imamura F, Eguchi K, Takeda K, Inoue A, Tomii K, Harada M, Masuda N, Jiang H, Itoh Y, Ichinose Y, Saijo N, Fukuoka M. Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol. 2008 Sep 10;26(26):4244-52. [https://doi.org/10.1200/JCO.2007.15.0185 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18779611 PubMed]<br />
##'''HRQoL analysis:''' Sekine I, Ichinose Y, Nishiwaki Y, Yamamoto N, Tsuboi M, Nakagawa K, Shinkai T, Negoro S, Imamura F, Eguchi K, Takeda K, Itoh Y, Tamura T, Saijo N, Fukuoka M. Quality of life and disease-related symptoms in previously treated Japanese patients with non-small-cell lung cancer: results of a randomized phase III study (V-15-32) of gefitinib versus docetaxel. Ann Oncol. 2009 Sep;20(9):1483-8. Epub 2009 Mar 12. [https://doi.org/10.1093/annonc/mdp031 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19282468 PubMed]<br />
#'''INTEREST:''' Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008 Nov 22;372(9652):1809-18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61758-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19027483 PubMed] NCT00076388<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/151 Project Data Sphere]<br />
#Fidias PM, Dakhil SR, Lyss AP, Loesch DM, Waterhouse DM, Bromund JL, Chen R, Hristova-Kazmierski M, Treat J, Obasaju CK, Marciniak M, Gill J, Schiller JH. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Feb 1;27(4):591-8. Epub 2008 Dec 15. [https://doi.org/10.1200/JCO.2008.17.1405 link to original article]'''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19075278 PubMed]<br />
#'''ISTANA:''' Lee DH, Park K, Kim JH, Lee JS, Shin SW, Kang JH, Ahn MJ, Ahn JS, Suh C, Kim SW. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010 Feb 15;16(4):1307-14. Epub 2010 Feb 9. [http://clincancerres.aacrjournals.org/content/16/4/1307.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20145166 PubMed] NCT00478049<br />
<!-- Presented in part at the 14th World Conference on Lung Cancer, Amsterdam, the Netherlands, July 3-7, 2011. --><br />
#'''EFC10261:''' Ramlau R, Gorbunova V, Ciuleanu TE, Novello S, Ozguroglu M, Goksel T, Baldotto C, Bennouna J, Shepherd FA, Le-Guennec S, Rey A, Miller V, Thatcher N, Scagliotti G. Aflibercept and docetaxel versus docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial. J Clin Oncol. 2012 Oct 10;30(29):3640-7. Epub 2012 Sep 10. [https://doi.org/10.1200/JCO.2012.42.6932 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22965962 PubMed] NCT00532155<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/133 Project Data Sphere]<br />
#'''LUME-Lung 1:''' Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, von Pawel J, Gottfried M, Bondarenko I, Liao M, Gann CN, Barrueco J, Gaschler-Markefski B, Novello S; LUME-Lung 1 Study Group. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55. 2. Epub 2014 Jan 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70586-2/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24411639 PubMed] NCT00805194<br />
#'''KEYNOTE-010:''' Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-50. Epub 2015 Dec 19. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01281-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/26712084 PubMed] NCT01905657<br />
##'''Update:''' Herbst RS, Garon EB, Kim DW, Cho BC, Perez-Gracia JL, Han JY, Arvis CD, Majem M, Forster MD, Monnet I, Novello S, Szalai Z, Gubens MA, Su WC, Ceresoli GL, Samkari A, Jensen EH, Lubiniecki GM, Baas P. Long-Term Outcomes and Retreatment Among Patients With Previously Treated, Programmed Death-Ligand 1‒Positive, Advanced Non‒Small-Cell Lung Cancer in the KEYNOTE-010 Study. J Clin Oncol. 2020 May 10;38(14):1580-1590. Epub 2020 Feb 20. [https://doi.org/10.1200/jco.19.02446 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32078391/ PubMed]<br />
#'''POPLAR:''' Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30;387(10030):1837-46. Epub 2016 Mar 9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00587-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/26970723 PubMed] NCT01903993<br />
#'''OAK:''' Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. Epub 2016 Dec 13. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32517-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/27979383 PubMed] NCT02008227<br />
##'''Update:''' Fehrenbacher L, von Pawel J, Park K, Rittmeyer A, Gandara DR, Ponce Aix S, Han JY, Gadgeel SM, Hida T, Cortinovis DL, Cobo M, Kowalski DM, De Marinis F, Gandhi M, Danner B, Matheny C, Kowanetz M, He P, Felizzi F, Patel H, Sandler A, Ballinger M, Barlesi F. Updated Efficacy Analysis Including Secondary Population Results for OAK: A Randomized Phase III Study of Atezolizumab versus Docetaxel in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer. J Thorac Oncol. 2018 Aug;13(8):1156-1170. Epub 2018 May 17. Erratum in: J Thorac Oncol. 2018 Nov;13(11):1800. [https://www.jto.org/article/S1556-0864(18)30611-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29777823 PubMed]<br />
##'''Update:''' von Pawel J, Bordoni R, Satouchi M, Fehrenbacher L, Cobo M, Han JY, Hida T, Moro-Sibilot D, Conkling P, Gandara DR, Rittmeyer A, Gandhi M, Yu W, Matheny C, Patel H, Sandler A, Ballinger M, Kowanetz M, Park K. Long-term survival in patients with advanced non-small-cell lung cancer treated with atezolizumab versus docetaxel: Results from the randomised phase III OAK study. Eur J Cancer. 2019 Jan;107:124-132. Epub 2018 Dec 17. [https://www.ejcancer.com/article/S0959-8049(18)31518-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/30562710 PubMed]<br />
#'''D0702035:''' Yoshioka H, Katakami N, Okamoto H, Iwamoto Y, Seto T, Takahashi T, Sunaga N, Kudoh S, Chikamori K, Harada M, Tanaka H, Saito H, Saka H, Takeda K, Nogami N, Masuda N, Harada T, Kitagawa H, Horio H, Yamanaka T, Fukuoka M, Yamamoto N, Nakagawa K. A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer. Ann Oncol. 2017 Feb 1;28(2):285-291. [https://doi.org/10.1093/annonc/mdw621 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28426104 PubMed] NCT01207011<br />
#'''E7389-G000-302:''' Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. [https://doi.org/10.1093/annonc/mdx284 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28911085 PubMed] NCT01454934<br />
#'''EAST-LC:''' Nokihara H, Lu S, Mok TSK, Nakagawa K, Yamamoto N, Shi YK, Zhang L, Soo RA, Yang JC, Sugawara S, Nishio M, Takahashi T, Goto K, Chang J, Maemondo M, Ichinose Y, Cheng Y, Lim WT, Morita S, Tamura T. Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer). Ann Oncol. 2017 Nov 1;28(11):2698-2706. [https://doi.org/10.1093/annonc/mdx419 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834128/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29045553 PubMed] JapicCTI-101155<br />
#'''JAVELIN Lung 200:''' Barlesi F, Vansteenkiste J, Spigel D, Ishii H, Garassino M, de Marinis F, Özgüroğlu M, Szczesna A, Polychronis A, Uslu R, Krzakowski M, Lee JS, Calabrò L, Arén Frontera O, Ellers-Lenz B, Bajars M, Ruisi M, Park K. Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study. Lancet Oncol. 2018 Nov;19(11):1468-79. Epub 2018 Sep 21. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30673-9/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/30262187 PubMed] NCT02395172<br />
#'''CheckMate 078:''' Wu YL, Lu S, Cheng Y, Zhou C, Wang J, Mok T, Zhang L, Tu HY, Wu L, Feng J, Zhang Y, Luft AV, Zhou J, Ma Z, Lu Y, Hu C, Shi Y, Baudelet C, Cai J, Chang J. Nivolumab Versus Docetaxel in a Predominantly Chinese Patient Population With Previously Treated Advanced NSCLC: CheckMate 078 Randomized Phase III Clinical Trial. J Thorac Oncol. 2019 May;14(5):867-875. Epub 2019 Jan 17. [https://doi.org/10.1016/j.jtho.2019.01.006 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/30659987 PubMed] NCT02613507<br />
<br />
==Docetaxel & Nintedanib {{#subobject:f8yg16|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5b63mi|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70586-2/fulltext Reck et al. 2014 (LUME-Lung 1)]<br />
|2008-2011<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Nintedanib (Vargatef)]] 200 mg PO twice per day on days 2 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''LUME-Lung 1:''' Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, von Pawel J, Gottfried M, Bondarenko I, Liao M, Gann CN, Barrueco J, Gaschler-Markefski B, Novello S; LUME-Lung 1 Study Group. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55. 2. Epub 2014 Jan 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70586-2/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24411639 PubMed] NCT00805194<br />
<br />
==Gefitinib monotherapy {{#subobject:ebbf2d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1b028f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jama.jamanetwork.com/article.aspx?articleid=197532 Kris et al. 2003 (IDEAL2)]<br />
|2000-2001<br />
| style="background-color:#1a9851" |Randomized Phase II (E-RT-de-esc)<br />
|[[#Gefitinib_monotherapy_3|Gefitinib]]; 500 mg/day<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)67625-8/fulltext Thatcher et al. 2005 (ISEL)]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Placebo_5|Placebo]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61758-4/fulltext Kim et al. 2008 (INTEREST)]<br />
|2004-2006<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#eeee01" |Seems to have non-inferior OS<br />
|-<br />
|[http://clincancerres.aacrjournals.org/content/16/4/1307.long Lee et al. 2010 (ISTANA)]<br />
|2005-2006<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|[http://clincancerres.aacrjournals.org/content/17/6/1553.long Han et al. 2011 (NCCCTS-06-177)]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gefitinib & Simvastatin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70355-3/fulltext Shi et al. 2013 (ICOGEN)]<br />
|2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Icotinib_monotherapy|Icotinib]]<br />
| style="background-color:#eeee01" |Seems to have non-inferior PFS<br />
|-<br />
|}<br />
''Note: IDEAL2 was the basis of initial FDA approval in 2003.''<br />
====Targeted therapy====<br />
<br />
*[[Gefitinib (Iressa)]] 250 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''IDEAL2:''' Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003 Oct 22;290(16):2149-58. [http://jama.jamanetwork.com/article.aspx?articleid=197532 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14570950 PubMed]<br />
#'''ISEL:''' Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005 Oct 29-Nov 4;366(9496):1527-37. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)67625-8/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/16257339 PubMed]<br />
#'''INTEREST:''' Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008 Nov 22;372(9652):1809-18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61758-4/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19027483 PubMed] NCT00076388<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/151 Project Data Sphere]<br />
#'''ISTANA:''' Lee DH, Park K, Kim JH, Lee JS, Shin SW, Kang JH, Ahn MJ, Ahn JS, Suh C, Kim SW. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010 Feb 15;16(4):1307-14. Epub 2010 Feb 9. [http://clincancerres.aacrjournals.org/content/16/4/1307.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20145166 PubMed] NCT00478049<br />
#'''NCCCTS-06-177:''' Han JY, Lee SH, Yoo NJ, Hyung LS, Moon YJ, Yun T, Kim HT, Lee JS. A randomized phase II study of gefitinib plus simvastatin versus gefitinib alone in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res. 2011 Mar 15;17(6):1553-60. [http://clincancerres.aacrjournals.org/content/17/6/1553.long link to orinigal article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/21411446 PubMed] NCT00452244<br />
#'''ICOGEN:''' Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, Wang D, Li Q, Qin S, Hu C, Zhang Y, Chen J, Cheng Y, Feng J, Zhang H, Song Y, Wu YL, Xu N, Zhou J, Luo R, Bai C, Jin Y, Liu W, Wei Z, Tan F, Wang Y, Ding L, Dai H, Jiao S, Wang J, Liang L, Zhang W, Sun Y. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 2013 Sep;14(10):953-61. Epub 2013 Aug 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70355-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/23948351 PubMed] ChiCTR-TRC-09000506<br />
<br />
==Gemcitabine monotherapy {{#subobject:63e7a9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 1000 mg/m<sup>2</sup> {{#subobject:dda826|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ Katakami et al. 2017 (E7389-G000-302)]<br />
|2011-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Eribulin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|rowspan=2|[https://doi.org/10.1016/j.annonc.2020.02.006 Planchard et al. 2020 (ARCTIC)]<br />
|rowspan=2|2015-2016<br />
|rowspan=2 style="background-color:#1a9851" |Phase III (C)<br />
|1. Durvalumab & Tremelimumab<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|2. Durvalumab<br> 3. Tremelimumab<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 1250 mg/m<sup>2</sup> {{#subobject:7f2a5c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ Katakami et al. 2017 (E7389-G000-302)]<br />
|2011-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Eribulin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''E7389-G000-302:''' Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. [https://doi.org/10.1093/annonc/mdx284 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28911085 PubMed] NCT01454934<br />
#'''ARCTIC:''' Planchard D, Reinmuth N, Orlov S, Fischer JR, Sugawara S, Mandziuk S, Marquez-Medina D, Novello S, Takeda Y, Soo R, Park K, McCleod M, Geater SL, Powell M, May R, Scheuring U, Stockman P, Kowalski D. ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer. Ann Oncol. 2020 May;31(5):609-618. Epub 2020 Feb 20. [https://doi.org/10.1016/j.annonc.2020.02.006 link to original article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/32201234 PubMed] NCT02352948<br />
<br />
==Icotinib monotherapy {{#subobject:9720a1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d7253b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70355-3/fulltext Shi et al. 2013 (ICOGEN)]<br />
|2009<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Gefitinib_monotherapy_3|Gefitinib]]<br />
| style="background-color:#eeee01" |Seems to have non-inferior PFS<br />
|-<br />
|}<br />
''Note: this drug is only approved in China.''<br />
====Targeted therapy====<br />
<br />
*[[Icotinib (Conmana)]] 125 mg PO three times per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''ICOGEN:''' Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, Wang D, Li Q, Qin S, Hu C, Zhang Y, Chen J, Cheng Y, Feng J, Zhang H, Song Y, Wu YL, Xu N, Zhou J, Luo R, Bai C, Jin Y, Liu W, Wei Z, Tan F, Wang Y, Ding L, Dai H, Jiao S, Wang J, Liang L, Zhang W, Sun Y. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 2013 Sep;14(10):953-61. Epub 2013 Aug 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70355-3/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23948351 PubMed] ChiCTR-TRC-09000506<br />
<br />
==Nivolumab monotherapy {{#subobject:7e5a40|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:f73cfc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/j.jtho.2019.01.006 Wu et al. 2019 (CheckMate 078)]<br />
|2015-2016<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1<br />
**Notably, on 9/13/16 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
#'''CheckMate 078:''' Wu YL, Lu S, Cheng Y, Zhou C, Wang J, Mok T, Zhang L, Tu HY, Wu L, Feng J, Zhang Y, Luft AV, Zhou J, Ma Z, Lu Y, Hu C, Shi Y, Baudelet C, Cai J, Chang J. Nivolumab Versus Docetaxel in a Predominantly Chinese Patient Population With Previously Treated Advanced NSCLC: CheckMate 078 Randomized Phase III Clinical Trial. J Thorac Oncol. 2019 May;14(5):867-875. Epub 2019 Jan 17. [https://doi.org/10.1016/j.jtho.2019.01.006 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/30659987 PubMed] NCT02613507<br />
<br />
==Pembrolizumab monotherapy {{#subobject:068cc1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d2e0eb|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1501824 Garon et al. 2015 (KEYNOTE-001)]<br />
|2012-2014<br />
| style="background-color:#91cf61" |Phase 1, >20 pts in dosing cohort<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01281-7/fulltext Herbst et al. 2015 (KEYNOTE-010)]<br />
|2013-2015<br />
| style="background-color:#1a9851" |Phase II/III (E-RT-switch-ooc)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: patients had previously received chemotherapy.''<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 2 mg/kg or 10 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Phase 1:''' Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28. Epub 2015 Apr 19. [https://www.nejm.org/doi/full/10.1056/NEJMoa1501824 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25891174 PubMed] NCT01295827<br />
#'''KEYNOTE-010:''' Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-50. Epub 2015 Dec 19. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01281-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/26712084 PubMed] NCT01905657<br />
##'''Update:''' Herbst RS, Garon EB, Kim DW, Cho BC, Perez-Gracia JL, Han JY, Arvis CD, Majem M, Forster MD, Monnet I, Novello S, Szalai Z, Gubens MA, Su WC, Ceresoli GL, Samkari A, Jensen EH, Lubiniecki GM, Baas P. Long-Term Outcomes and Retreatment Among Patients With Previously Treated, Programmed Death-Ligand 1‒Positive, Advanced Non‒Small-Cell Lung Cancer in the KEYNOTE-010 Study. J Clin Oncol. 2020 May 10;38(14):1580-1590. Epub 2020 Feb 20. [https://doi.org/10.1200/jco.19.02446 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32078391/ PubMed]<br />
<br />
==Pemetrexed monotherapy {{#subobject:24ad9b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Pemetrexed (Alimta) in non-small cell lung cancer]]<br />
<br />
===Regimen {{#subobject:4e0d06|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2004.08.163 Hanna et al. 2004 (JMEI)]<br />
|2001-2002<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70473-X/fulltext Kim et al. 2013 (JXBC)]<br />
|2005-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Pemetrexed_.26_Cetuximab|Pemetrexed & Cetuximab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.28132 Karampeazis et al. 2013 (CT/06.05)]<br />
|2006-2010<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ Katakami et al. 2017 (E7389-G000-302)]<br />
|2011-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Eribulin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: JXBC also evaluated docetaxel versus docetaxel & cetuximab, but did not report the efficacy of this comparison; see paper for details.''<br />
====Chemotherapy====<br />
<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*(per Ardizzoni et al. 2012):<br />
*[[Dexamethasone (Decadron)]] 4 mg or [[steroid conversions|equivalent corticosteroid]] PO twice per day on the day before, the day of, and day after each dose of [[Pemetrexed (Alimta)]]<br />
*[[Folic acid (Folate)]] 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be taken throughout pemetrexed therapy<br />
**JMEI used [[Folic acid (Folate)]] 1 mg PO once per day<br />
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be given throughout pemetrexed therapy<br />
<br />
'''21-day cycles''' <br />
<br />
===References===<br />
<br />
#'''JMEI:''' Hanna N, Shepherd FA, Fossella FV, Rodrigues Pereira J, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar M, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1;22(9):1589-97. [https://doi.org/10.1200/jco.2004.08.163 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15117980 PubMed]<br />
#'''CT/06.05:''' Karampeazis A, Voutsina A, Souglakos J, Kentepozidis N, Giassas S, Christofillakis C, Kotsakis A, Papakotoulas P, Rapti A, Agelidou M, Agelaki S, Vamvakas L, Samonis G, Mavroudis D, Georgoulias V; Hellenic Oncology Research Group. Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study. Cancer. 2013 Aug 1;119(15):2754-64. Epub 2013 May 9. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.28132 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23661337 PubMed] NCT00440414<br />
#'''JXBC:''' Kim ES, Neubauer M, Cohn A, Schwartzberg L, Garbo L, Caton J, Robert F, Reynolds C, Katz T, Chittoor S, Simms L, Saxman S. Docetaxel or pemetrexed with or without cetuximab in recurrent or progressive non-small-cell lung cancer after platinum-based therapy: a phase 3, open-label, randomised trial. Lancet Oncol. 2013 Dec;14(13):1326-36. Epub 2013 Nov 12. Erratum in: Lancet Oncol. 2014 Jan;15(1):e4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70473-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24231627 PubMed] NCT00095199<br />
#'''E7389-G000-302:''' Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. [https://doi.org/10.1093/annonc/mdx284 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28911085 PubMed] NCT01454934<br />
<br />
==S-1 monotherapy {{#subobject:7702f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:48e547|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834128/ Nokihara et al. 2017 (EAST-LC)]<br />
|2010-2014<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<br />
#'''EAST-LC:''' Nokihara H, Lu S, Mok TSK, Nakagawa K, Yamamoto N, Shi YK, Zhang L, Soo RA, Yang JC, Sugawara S, Nishio M, Takahashi T, Goto K, Chang J, Maemondo M, Ichinose Y, Cheng Y, Lim WT, Morita S, Tamura T. Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer). Ann Oncol. 2017 Nov 1;28(11):2698-2706. [https://doi.org/10.1093/annonc/mdx419 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834128/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29045553 PubMed] JapicCTI-101155<br />
<br />
==Vinorelbine monotherapy {{#subobject:f604bd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0441ba|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2000.18.12.2354 Fossella et al. 2000 (TAX 320)]<br />
| rowspan="2" |1995-1998<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Docetaxel_monotherapy_4|Docetaxel 100 mg/m<sup>2</sup>]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Docetaxel_monotherapy_4|Docetaxel 75 mg/m<sup>2</sup>]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ Katakami et al. 2017 (E7389-G000-302)]<br />
|2011-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Eribulin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|rowspan=2|[https://doi.org/10.1016/j.annonc.2020.02.006 Planchard et al. 2020 (ARCTIC)]<br />
|rowspan=2|2015-2016<br />
|rowspan=2 style="background-color:#1a9851" |Phase III (C)<br />
|1. Durvalumab & Tremelimumab<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|2. Durvalumab<br> 3. Tremelimumab<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV over 5 to 10 minutes once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
<br />
*Per TAX 320:<br />
*Patients who had either grade 4 neutropenia lasting at least 5 days or both fever and grade 3 or 4 neutropenia could receive [[:Category:Granulocyte colony-stimulating factors|G-CSF]] (dose/schedule/duration not specified)<br />
*[[Metoclopramide (Reglan)]] (dose/schedule/route not specified) used first for nausea<br />
*Nausea despite metoclopramide was treated with a 5-HT3 antagonist such as [[Ondansetron (Zofran)]] or [[Granisetron]] (dose/schedule/route not specified) prn nausea<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''TAX 320:''' Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L; TAX 320 Non-Small Cell Lung Cancer Study Group. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol. 2000 Jun;18(12):2354-62. Erratum in: J Clin Oncol. 2004 Jan 1;22(1):209. [https://doi.org/10.1200/JCO.2000.18.12.2354 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10856094 PubMed]<br />
#'''E7389-G000-302:''' Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. [https://doi.org/10.1093/annonc/mdx284 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28911085 PubMed] NCT01454934<br />
#'''ARCTIC:''' Planchard D, Reinmuth N, Orlov S, Fischer JR, Sugawara S, Mandziuk S, Marquez-Medina D, Novello S, Takeda Y, Soo R, Park K, McCleod M, Geater SL, Powell M, May R, Scheuring U, Stockman P, Kowalski D. ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer. Ann Oncol. 2020 May;31(5):609-618. Epub 2020 Feb 20. [https://doi.org/10.1016/j.annonc.2020.02.006 link to original article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/32201234 PubMed] NCT02352948<br />
<br />
=CNS metastases, all lines of therapy=<br />
==Dexamethasone monotherapy {{#subobject:adb3fe|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:6a5b0e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082599/ Mulvenna et al. 2016 (QUARTZ)]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#Dexamethasone_.26_WBRT|Dexamethasone & WBRT]]<br />
|<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior QALYs<br />
|-<br />
|}<br />
====Supportive therapy====<br />
<br />
*[[Dexamethasone (Decadron)]]<br />
<br />
===References===<br />
<br />
#'''QUARTZ:''' Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, Moore B, Brisbane I, Ardron D, Holt T, Morgan S, Lee C, Waite K, Bayman N, Pugh C, Sydes B, Stephens R, Parmar MK, Langley RE. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016 Oct 22;388(10055):2004-2014. Epub 2016 Sep 4. [https://doi.org/10.1016/s0140-6736(16)30825-x link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082599/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27604504 PubMed] ISRCTN3826061<br />
<br />
==Dexamethasone & WBRT {{#subobject:04a6d4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:da6414|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082599/ Mulvenna et al. 2016 (QUARTZ)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dexamethasone_monotherapy|Dexamethasone]]<br />
|<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior QALYs<br />
|-<br />
|}<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy|WBRT]], 20 Gy in 5 fractions<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]]<br />
<br />
===References===<br />
<br />
#'''QUARTZ:''' Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, Moore B, Brisbane I, Ardron D, Holt T, Morgan S, Lee C, Waite K, Bayman N, Pugh C, Sydes B, Stephens R, Parmar MK, Langley RE. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016 Oct 22;388(10055):2004-2014. Epub 2016 Sep 4. [https://doi.org/10.1016/s0140-6736(16)30825-x link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082599/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27604504 PubMed] ISRCTN3826061<br />
<br />
==Teniposide & WBRT {{#subobject:04facd4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:19bu14|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.19.3400 Postmus et al. 2000]<br />
|1989-1995<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Teniposide<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Teniposide (Vumon)]]<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy|WBRT]], 30 Gy in 10 fractions<br />
<br />
===References===<br />
<br />
#Postmus PE, Haaxma-Reiche H, Smit EF, Groen HJ, Karnicka H, Lewinski T, van Meerbeeck J, Clerico M, Gregor A, Curran D, Sahmoud T, Kirkpatrick A, Giaccone G; European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy--a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol. 2000 Oct 1;18(19):3400-8. [https://doi.org/10.1200/JCO.2000.18.19.3400 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11013281 PubMed]<br />
<br />
=Investigational agents=<br />
''Drugs with some degree of promising activity in clinical trials.''<br />
<br />
[[Category:Non-small cell lung cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Lung cancers]]</div>Karinehttps://hemonc.org/w/index.php?title=Non-small_cell_lung_cancer&diff=49696Non-small cell lung cancer2021-05-14T16:24:10Z<p>Karine: Paz-Ares 2021 new regimen</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Amit_Kulkarni.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Akulkarni|Amit Kulkarni, MBBS]]<br>University of Minnesota<br>Minneapolis, MN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/AmitKulkarniMD AmitKulkarniMD]<br />
| style="background-color:#F0F0F0" |[[File:TravisOsterman.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Travisosterman|Travis Osterman, DO, MS, FAMIA]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/TravisOsterman TravisOsterman]<br>[https://www.linkedin.com/in/travis-osterman-1850b236/ LinkedIn]<br />
|-<br />
|}<br />
''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Non-small cell lung cancer_-_historical|historical regimens page]]. If you still can't find it, please let us know so we can add it!''.<br />
<br>There are several related dedicated pages:<br />
<br />
*'''Histology-specific:'''<br />
**'''[[Non-small_cell_lung_cancer,_Nonsquamous|NSCLC, Nonsquamous]]'''<br />
**'''[[Non-small_cell_lung_cancer,_Squamous|NSCLC, Squamous]]'''<br />
*'''Biomarker-specific:'''<br />
**'''[[Non-small_cell_lung_cancer,_ALK-positive|NSCLC, ALK-positive]]'''<br />
**'''[[Non-small_cell_lung_cancer,_BRAF-mutated|NSCLC, BRAF-mutated]]'''<br />
**'''[[Non-small_cell_lung_cancer,_EGFR-mutated|NSCLC, EGFR-mutated]]'''<br />
**'''[[Non-small_cell_lung_cancer,_KRAS-mutated|NSCLC, KRAS-mutated]]'''<br />
**'''[[Non-small cell lung cancer, MET-mutated|NSCLC, MET-mutated]]'''<br />
**'''[[Non-small cell lung cancer, RET-positive|NSCLC, RET-positive]]'''<br />
**'''[[Non-small_cell_lung_cancer,_ROS1-positive|NSCLC, ROS1-positive]]'''<br />
*'''[[CNS carcinoma]]'''<br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
<br />
*'''2020:''' Schneider et al. [https://doi.org/10.1200/jco.19.02748 Lung Cancer Surveillance After Definitive Curative-Intent Therapy: ASCO Guideline]<br />
<br />
===Older===<br />
*'''2017:''' Hanna et al. [https://doi.org/10.1200/JCO.2017.74.6065 Systemic therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update] [https://pubmed.ncbi.nlm.nih.gov/28806116 PubMed]<br />
*'''2015:''' Masters et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019421/ Systemic therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update]<br />
*'''2009:''' Azzoli et al. [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2793036/ American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non–Small-Cell Lung Cancer]<br />
<br />
==ASCO/CCO==<br />
===Current===<br />
*'''2021:''' Hanna et al. [https://doi.org/10.1200/jco.20.03570 Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update]<br />
*'''2020:''' Hanna et al. [https://doi.org/10.1200/jco.19.03022 Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update]<br />
*'''2017:''' Kris et al. [https://doi.org/10.1200/JCO.2017.72.4401 Adjuvant systemic therapy and adjuvant radiation therapy for stage I to IIIA completely resected non–small-cell lung cancers: American Society of Clinical Oncology/Cancer Care Ontario clinical practice guideline update] [https://pubmed.ncbi.nlm.nih.gov/28437162 PubMed]<br />
<br />
===Older===<br />
*'''2007:''' Pisters et al. [https://doi.org/10.1200/JCO.2007.14.1226 Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline] [https://pubmed.ncbi.nlm.nih.gov/17954710 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2018:''' Planchard et al. [https://doi.org/10.1093/annonc/mdy275 Metastatic Non-Small-Cell Lung Cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
*'''2015:''' Eberhardt et al. [https://doi.org/10.1093/annonc/mdv187 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer]<br />
<br />
===Older===<br />
*'''2016:''' Novello et al. [https://doi.org/10.1093/annonc/mdw326 Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
*'''2014:''' Vansteenkiste et al. [https://doi.org/10.1093/annonc/mdu089 2nd ESMO Consensus Conference on Lung Cancer: early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up]<br />
*'''2014:''' Besse et al. [https://doi.org/10.1093/annonc/mdu123 2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and further lines of treatment in advanced disease]<br />
*'''2014:''' Kerr et al. [https://doi.org/10.1093/annonc/mdu145 Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer]<br />
*'''2013:''' Vansteenkiste et al. [https://doi.org/10.1093/annonc/mdt241 Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
<br />
==KSMO/ESMO==<br />
*'''2020:''' Park et al. [https://doi.org/10.1016/j.annonc.2019.10.026 Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with locally-advanced unresectable non-small-cell lung cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf NCCN Guidelines - Non-Small Cell Lung Cancer]<br />
<br />
=Neoadjuvant therapy=<br />
==Cisplatin & Docetaxel (DC) {{#subobject:cab6b8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e8cc0c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60294-X/fulltext Pless et al. 2015 (SAKK 16/00)]<br />
|2001-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Docetaxel, then RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS<br />
|-<br />
|}<br />
''This trial included patients with Stage IIIA or N2 NSCLC.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]]<br />
*[[Docetaxel (Taxotere)]]<br />
<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Surgical_resection|Complete resection]]<br />
<br />
===References===<br />
<br />
#'''SAKK 16/00:''' Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S, Gerard MA, Xyrafas A, Früh M, Cathomas R, Zippelius A, Roth A, Bijelovic M, Ochsenbein A, Meier UR, Mamot C, Rauch D, Gautschi O, Betticher DC, Mirimanoff RO, Peters S; SAKK Lung Cancer Project Group. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015 Sep 12;386(9998):1049-56. Epub 2015 Aug 11. Erratum in: Lancet. 2015 Sep 12;386(9998):1040. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60294-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/26275735 PubMed] NCT00030771<br />
<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:c567c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b0097e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2010.33.7089 Scagliotti et al. 2011 (CHEST)]<br />
|2000-2004<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_neoadjuvant_therapy|Surgery alone]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''This trial included patients with Stage IB to IIIA NSCLC.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1, '''given at least 4 hours after gemcitabine'''<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Surgical_resection|Complete resection]], 2 to 6 weeks after last dose of chemotherapy<br />
<br />
===References===<br />
<br />
#'''CHEST:''' Scagliotti GV, Pastorino U, Vansteenkiste JF, Spaggiari L, Facciolo F, Orlowski TM, Maiorino L, Hetzel M, Leschinger M, Visseren-Grul C, Torri V. Randomized phase III study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to IIIA non-small-cell lung cancer. J Clin Oncol. 2012 Jan 10;30(2):172-8. Epub 2011 Nov 28. [https://doi.org/10.1200/JCO.2010.33.7089 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22124104 PubMed]<br />
<br />
=Adjuvant therapy=<br />
==Carboplatin & Paclitaxel (CP) {{#subobject:3a6ad9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:59db47|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652093/ Strauss et al. 2008 (CALGB 9633)]<br />
|1996-2003<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Lobectomy|Lobectomy]] or [[Surgery#Pneumonectomy|pneumonectomy]], within 4 to 8 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 45 to 60 minutes once on day 1<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<!-- Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA, and at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA. --><br />
<br />
#'''CALGB 9633:''' Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, Gillenwater HH, Watson DM, Sugarbaker DJ, Schilsky RL, Vokes EE, Green MR. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008 Nov 1;26(31):5043-51. Epub 2008 Sep 22. [https://doi.org/10.1200/jco.2008.16.4855 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652093/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18809614 PubMed]<br />
<br />
==Cisplatin & Docetaxel (DC) {{#subobject:211cca|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
DC: '''<u>D</u>'''ocetaxel & '''<u>C</u>'''isplatin<br />
===Regimen {{#subobject:bc45d4|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[http://icvts.oxfordjournals.org/content/20/6/783.long Barlesi et al. 2015]<br />
|2004-2007<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_2|Cisplatin & Gemcitabine]]<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of QoL<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30691-5/fulltext Wakelee et al. 2017 (ECOG-ACRIN E1505)]<br />
|2007-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Cisplatin, Docetaxel, Bevacizumab<br> 2. Cisplatin, Gemcitabine, Bevacizumab<br> 3. Cisplatin, Pemetrexed, Bevacizumab<br> 4. Cisplatin, Vinorelbine, Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Barlesi et al. 2015: Complete R0 [[Surgery#Lung_cancer_surgery|resection]], within 8 weeks<br />
*ECOG-ACRIN E1505: Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 6 to 12 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 3 cycles (Barlesi et al. 2015) or 4 cycles (ECOG-ACRIN E1505)'''<br />
<br />
===References===<br />
<br />
#Barlesi F, Chouaid C, Crequit J, Le Caer H, Pujol JL, Legodec J, Vergnenegre A, Le Treut J, Fabre-Guillevin E, Loundou A, Auquier P, Simeoni MC, Thomas PA. A randomized trial comparing adjuvant chemotherapy with gemcitabine plus cisplatin with docetaxel plus cisplatin in patients with completely resected non-small-cell lung cancer with quality of life as the primary objective. Interact Cardiovasc Thorac Surg. 2015 Jun;20(6):783-90. Epub 2015 Mar 11. [http://icvts.oxfordjournals.org/content/20/6/783.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25765952 PubMed]<br />
#'''ECOG-ACRIN E1505:''' Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30691-5/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29129443 PubMed] NCT00324805<br />
<br />
==Cisplatin & Etoposide (EP) {{#subobject:dbad67|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a211c5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa031644 Arriagada et al. 2004 (IALT)]<br />
|1995-2000<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 60 days<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#'''IALT:''' Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. [https://www.nejm.org/doi/full/10.1056/NEJMoa031644 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14736927 PubMed]<br />
##'''Update:''' Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. [https://doi.org/10.1200/JCO.2009.23.2272 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19933916 PubMed]<br />
<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:289ea6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GC: '''<u>G</u>'''emcitabine & '''<u>C</u>'''isplatin<br />
===Regimen variant #1, 75/1200 x 4 {{#subobject:4cd112|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30691-5/fulltext Wakelee et al. 2017 (ECOG-ACRIN E1505)]<br />
|2007-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Cisplatin, Docetaxel, Bevacizumab<br> 2. Cisplatin, Gemcitabine, Bevacizumab<br> 3. Cisplatin, Pemetrexed, Bevacizumab<br> 4. Cisplatin, Vinorelbine, Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 6 to 12 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1200 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #2, 75/1250 x 3 {{#subobject:22cb4c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[http://icvts.oxfordjournals.org/content/20/6/783.long Barlesi et al. 2015]<br />
|2004-2007<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Docetaxel_.28DC.29_2|Cisplatin & Docetaxel]]<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of QoL<br />
|-<br />
|}<br />
''This trial included patients with Stage IB–III NSCLC.''<br />
====Preceding treatment====<br />
<br />
*Complete R0 [[Surgery#Lung_cancer_surgery|resection]], within 8 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#Barlesi F, Chouaid C, Crequit J, Le Caer H, Pujol JL, Legodec J, Vergnenegre A, Le Treut J, Fabre-Guillevin E, Loundou A, Auquier P, Simeoni MC, Thomas PA. A randomized trial comparing adjuvant chemotherapy with gemcitabine plus cisplatin with docetaxel plus cisplatin in patients with completely resected non-small-cell lung cancer with quality of life as the primary objective. Interact Cardiovasc Thorac Surg. 2015 Jun;20(6):783-90. Epub 2015 Mar 11. [http://icvts.oxfordjournals.org/content/20/6/783.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25765952 PubMed]<br />
#'''ECOG-ACRIN E1505:''' Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30691-5/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29129443 PubMed] NCT00324805<br />
<br />
==Cisplatin & Pemetrexed {{#subobject:1caad6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CPx: '''<u>C</u>'''isplatin & '''<u>P</u>'''emetre'''<u>x</u>'''ed<br />
===Regimen {{#subobject:73f03b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mds578 Kreuter et al. 2013 (TREAT)]<br />
|2006-2009<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin_.26_Vinorelbine|Cisplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet secondary endpoint of OS<sup>1</sup><br />
| style="background-color:#1a9850" |Superior clinical feasibility rate<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30691-5/fulltext Wakelee et al. 2017 (ECOG-ACRIN E1505)]<br />
|2007-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Cisplatin, Docetaxel, Bevacizumab<br> 2. Cisplatin, Gemcitabine, Bevacizumab<br> 3. Cisplatin, Pemetrexed, Bevacizumab<br> 4. Cisplatin, Vinorelbine, Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://www.nature.com/articles/s41416-019-0533-3 Groen et al. 2019 (NVALT-8)]<br />
|2007-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CPx & Nadroparin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS<br />
|<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for TREAT is based on the 2016 update.''<br><br />
''Note: In TREAT, this treatment was intended for pathologically confirmed NSCLC stages (according to the TNM staging system version 6) IB, IIA, IIB or T3N1.''<br />
====Preceding treatment====<br />
<br />
*TREAT & NVALT-8: Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 4 to 6 weeks<br />
*ECOG-ACRIN E1505: Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 6 to 12 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#'''TREAT:''' Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt W, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Zuna I, Griesinger F, Thomas M; TREAT investigators; AIO Lung Cancer Study Group; LLCG Leuven Lung Cancer Group. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study. Ann Oncol. 2013 Apr;24(4):986-92. Epub 2012 Nov 15. [https://doi.org/10.1093/annonc/mds578 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23161898 PubMed] NCT00349089<br />
##'''Update:''' Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt WE, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Griesinger F, Thomas M; TREAT investigators. Three-year follow-up of a randomized phase II trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine (the TREAT study). J Thorac Oncol. 2016 Jan;11(1):85-93. [http://www.jto.org/article/S1556-0864(15)00023-4/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/26762743 PubMed]<br />
#'''ECOG-ACRIN E1505:''' Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30691-5/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29129443 PubMed] NCT00324805<br />
#'''NVALT-8:''' Groen HJM, van der Heijden EHFM, Klinkenberg TJ, Biesma B, Aerts J, Verhagen A, Kloosterziel C, Pieterman R, van den Borne B, Smit HJM, Hoekstra O, Schramel FMNH, van der Noort V, van Tinteren H, Smit EF, Dingemans AC; NVALT Study Group. Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study. Br J Cancer. 2019 Aug;121(5):372-377. Epub 2019 Jul 24. [https://www.nature.com/articles/s41416-019-0533-3 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/31337877 PubMed] NTR1250/1217<br />
<br />
==Cisplatin & Vinblastine {{#subobject:af5cc1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1d592|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa031644 Arriagada et al. 2004 (IALT)]<br />
|1995-2000<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: Exact days for parts of the regimen were not specified by Arriagada et al. 2004. This vinblastine schedule is extrapolated from regimen information in Table 1 in which vinblastine is said to be given "weekly from days 1 to 29" and "then every 2 weeks after day 43 until last cisplatin administration.''<br />
====Preceding treatment====<br />
<br />
*Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 60 days<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 22, 43, 64<br />
*[[Vinblastine (Velban)]] 4 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 43, 57<br />
<br />
'''12-week course'''<br />
<br />
===References===<br />
<br />
#'''IALT:''' Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. [https://www.nejm.org/doi/full/10.1056/NEJMoa031644 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14736927 PubMed]<br />
##'''Update:''' Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. [https://doi.org/10.1200/JCO.2009.23.2272 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19933916 PubMed]<br />
<br />
==Cisplatin & Vindesine {{#subobject:80fe2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:2d16cd|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa031644 Arriagada et al. 2004 (IALT)]<br />
|1995-2000<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: Exact days for parts of the regimen were not specified by Arriagada et al. 2004. This vindesine schedule is extrapolated from regimen information in Table 1 in which vindesine is said to be given "weekly from days 1 to 29" and "then every 2 weeks after day 43 until last cisplatin administration.''<br />
====Preceding treatment====<br />
<br />
*Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 60 days<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 22, 43, 64<br />
*[[Vindesine (Eldisine)]] 3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 43, 57<br />
<br />
'''12-week course'''<br />
<br />
===References===<br />
<br />
#'''IALT:''' Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. [https://www.nejm.org/doi/full/10.1056/NEJMoa031644 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14736927 PubMed]<br />
##'''Update:''' Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. [https://doi.org/10.1200/JCO.2009.23.2272 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19933916 PubMed]<br />
<br />
==Cisplatin & Vinorelbine {{#subobject:ab1b88|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CVb: '''<u>C</u>'''isplatin & '''<u>V</u>'''inorel'''<u>b</u>'''ine<br />
===Regimen variant #1, cisplatin 50 mg/m<sup>2</sup>, 2 weeks out of 4 {{#subobject:c1a368|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa043623 Winton et al. 2005 (JBR.10)]<br />
|1994-2001<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|<br />
|-<br />
|[https://doi.org/10.1093/annonc/mds578 Kreuter et al. 2013 (TREAT)]<br />
|2006-2009<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Cisplatin_.26_Pemetrexed|Cisplatin & Pemetrexed]]<br />
| style="background-color:#ffffbf" |Did not meet secondary endpoint of OS<sup>1</sup><br />
| style="background-color:#1a9850" |Superior clinical feasibility rate<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for TREAT is based on the 2016 update.''<br />
====Preceding treatment====<br />
<br />
*JBR.10: Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 6 weeks<br />
*TREAT: Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 4 to 6 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 4 cycles'''<br />
===Regimen variant #2, cisplatin 75 mg/m<sup>2</sup>, q3wk {{#subobject:04b3e6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30691-5/fulltext Wakelee et al. 2017 (ECOG-ACRIN E1505)]<br />
|2007-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Cisplatin, Docetaxel, Bevacizumab<br> 2. Cisplatin, Gemcitabine, Bevacizumab<br> 3. Cisplatin, Pemetrexed, Bevacizumab<br> 4. Cisplatin, Vinorelbine, Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 6 to 12 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #3, cisplatin 100 mg/m<sup>2</sup>, q4wk {{#subobject:6edee|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(06)70804-X/fulltext Douillard et al. 2006 (ANITA)]<br />
|1994-2000<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa031644 Arriagada et al. 2004 (IALT)]<br />
|1995-2000<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*IALT: Complete [[Surgery#Lung_cancer_surgery|surgical resection]], within 60 days<br />
*ANITA: Complete [[Surgery#Lung_cancer_surgery|surgical resection]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#'''IALT:''' Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. [https://www.nejm.org/doi/full/10.1056/NEJMoa031644 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14736927 PubMed]<br />
##'''Update:''' Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. [https://doi.org/10.1200/JCO.2009.23.2272 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19933916 PubMed]<br />
#'''JBR.10:''' Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao MS, Gandara D, Kesler K, Demmy T, Shepherd F; National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin vs observation in resected non-small-cell lung cancer. N Engl J Med. 2005 Jun 23;352(25):2589-97. [https://www.nejm.org/doi/full/10.1056/NEJMoa043623 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15972865 PubMed]<br />
##'''Update:''' Butts CA, Ding K, Seymour L, Twumasi-Ankrah P, Graham B, Gandara D, Johnson DH, Kesler KA, Green M, Vincent M, Cormier Y, Goss G, Findlay B, Johnston M, Tsao MS, Shepherd FA. Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol. 2010 Jan 1;28(1):29-34. Epub 2009 Nov 23. [https://doi.org/10.1200/JCO.2009.24.0333 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799232/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19933915 PubMed]<br />
#'''ANITA:''' Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Rodrigues Pereira J, Le Groumellec A, Lorusso V, Clary C, Torres AJ, Dahabreh J, Souquet PJ, Astudillo J, Fournel P, Artal-Cortes A, Jassem J, Koubkova L, His P, Riggi M, Hurteloup P. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006 Sep;7(9):719-27. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(06)70804-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/16945766 PubMed] ISRCTN95053737<br />
#'''TREAT:''' Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt W, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Zuna I, Griesinger F, Thomas M; TREAT investigators; AIO Lung Cancer Study Group; LLCG. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study. Ann Oncol. 2013 Apr;24(4):986-92. Epub 2012 Nov 15. [https://doi.org/10.1093/annonc/mds578 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23161898 PubMed] NCT00349089<br />
##'''Update:''' Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt WE, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Griesinger F, Thomas M; TREAT investigators. Three-year follow-up of a randomized phase II trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine (the TREAT study). J Thorac Oncol. 2016 Jan;11(1):85-93. [http://www.jto.org/article/S1556-0864(15)00023-4/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/26762743 PubMed]<br />
#'''ECOG-ACRIN E1505:''' Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30691-5/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29129443 PubMed] NCT00324805<br />
<br />
=Induction chemotherapy for locally advanced disease=<br />
==Carboplatin & Paclitaxel (CP) {{#subobject:b2de53|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PC: '''<u>P</u>'''aclitaxel & '''<u>C</u>'''arboplatin<br />
===Regimen variant #1, 6/200 {{#subobject:4d4e46|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.05.4163 Huber et al. 2006 (CTRT99/97)]<br />
|1997-2002<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.55.405 Belani et al. 2005 (LAMP)]<br />
|1998-2001<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/JCO.2006.07.3569 Vokes et al. 2007 (CALGB 39801)]<br />
|1998-2002<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 30 minutes once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''21-day cycle for 2 cycles'''<br />
<br />
====Subsequent treatment====<br />
<br />
*LAMP: [[#Radiation_therapy|RT]] x 63 Gy<br />
*CTRT99/97: Paclitaxel & RT versus [[#Radiation_therapy|RT]]<br />
*CALGB 39801: [[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_RT|Carboplatin, Paclitaxel, RT]]<br />
<br />
===Regimen variant #2, 6/225 {{#subobject:1ec13b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295560/ Hoang et al. 2012 (ECOG 3598)]<br />
|2000-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#ECOG_3598|See link]]<br />
| style="background-color:#ffffbf" |[[Complex_multipart_regimens#ECOG_3598|See link]]<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 2 cycles'''<br />
<br />
====Subsequent treatment====<br />
<br />
*[[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_RT|Carboplatin, Paclitaxel, RT]]<br />
<br />
===References===<br />
<br />
#'''LAMP:''' Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. [https://doi.org/10.1200/jco.2005.55.405 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16087941 PubMed]<br />
#'''CTRT99/97:''' Huber RM, Flentje M, Schmidt M, Pöllinger B, Gosse H, Willner J, Ulm K; Bronchial Carcinoma Therapy Group. Simultaneous chemoradiotherapy compared with radiotherapy alone after induction chemotherapy in inoperable stage IIIA or IIIB non-small-cell lung cancer: study CTRT99/97 by the Bronchial Carcinoma Therapy Group. J Clin Oncol. 2006 Sep 20;24(27):4397-404. [https://doi.org/10.1200/JCO.2005.05.4163 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16983107 PubMed]<br />
#'''CALGB 39801:''' Vokes EE, Herndon JE 2nd, Kelley MJ, Cicchetti MG, Ramnath N, Neill H, Atkins JN, Watson DM, Akerley W, Green MR; [[Study_Groups#CALGB|CALGB]]. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol. 2007 May 1;25(13):1698-704. Epub 2007 Apr 2. [https://doi.org/10.1200/JCO.2006.07.3569 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17404369 PubMed]<br />
#'''ECOG 3598:''' Hoang T, Dahlberg SE, Schiller JH, Mehta MP, Fitzgerald TJ, Belinsky SA, Johnson DH. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol. 2012 Feb 20;30(6):616-22. Epub 2012 Jan 23. [https://doi.org/10.1200/JCO.2011.36.9116 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295560/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22271472 PubMed] NCT00004859<br />
<br />
==Cisplatin & Vinblastine {{#subobject:6b4fa8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:2433e7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199010043231403 Dillman et al. 1990 (CALGB 8433)]<br />
|1984-1987<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br />
|-<br />
|[https://academic.oup.com/jnci/article-abstract/87/3/198/932006 Sause et al. 1995 (RTOG 88-08)]<br />
|1989-1992<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ Curran et al. 2011 (RTOG 9410)]<br />
|1994-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#RTOG_9410|See link]]<br />
| style="background-color:#fc8d59" |[[Complex_multipart_regimens#RTOG_9410|See link]]<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for CALGB 8433 is based on the 1996 update.''<br><br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 29<br />
*[[Vinblastine (Velban)]] 5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29<br />
<br />
'''5-week course'''<br />
<br />
====Subsequent treatment====<br />
<br />
*[[#Radiation_therapy|RT]] x 60 to 63 Gy<br />
<br />
===References===<br />
<br />
#'''CALGB 8433:''' Dillman RO, Seagren SL, Propert KJ, Guerra J, Eaton WL, Perry MC, Carey RW, Frei EF 3rd, Green MR. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med. 1990 Oct 4;323(14):940-5. [https://www.nejm.org/doi/full/10.1056/NEJM199010043231403 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/2169587 PubMed]<br />
##'''Update:''' Dillman RO, Herndon J, Seagren SL, Eaton WL Jr, Green MR. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst. 1996 Sep 4;88(17):1210-5. [https://academic.oup.com/jnci/article/88/17/1210/911128 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8780630 PubMed]<br />
#'''RTOG 88-08:''' Sause WT, Scott C, Taylor S, Johnson D, Livingston R, Komaki R, Emami B, Curran WJ, Byhardt RW, Turrisi AT, Dar AR, Cox JD. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst. 1995 Feb 1;87(3):198-205. [https://academic.oup.com/jnci/article-abstract/87/3/198/932006 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/7707407 PubMed]<br />
##'''Update:''' Sause W, Kolesar P, Taylor S IV, Johnson D, Livingston R, Komaki R, Emami B, Curran W Jr, Byhardt R, Dar AR, Turrisi A 3rd. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest. 2000 Feb;117(2):358-64. [https://journal.chestnet.org/article/S0012-3692(15)48622-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/10669675 PubMed]<br />
#'''RTOG 9410:''' Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. [http://jnci.oxfordjournals.org/content/103/19/1452.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21903745 PubMed]<br />
<br />
=Definitive therapy for locally advanced disease=<br />
==Carboplatin & Paclitaxel (CP) & RT {{#subobject:899399|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PC & RT: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''arboplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen variant #1, 2/40/60 {{#subobject:5d3a16|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.24.5050 Yamamoto et al. 2010 (WJTOG0105)]<br />
|2001-2005<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. MVP & RT<br> 2. Carboplatin, Irinotecan, RT<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Paclitaxel (Taxol)]] 40 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 60 Gy<br />
<br />
'''6-week course'''<br />
<br />
===Regimen variant #2, 2/45/60 {{#subobject:5d4d16|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902826/ Lu et al. 2010 (ID99-303)]<br />
|2000-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PC, AE-941, RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295560/ Hoang et al. 2012 (ECOG 3598)]<br />
|2000-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#ECOG_3598|See link]]<br />
| style="background-color:#ffffbf" |[[Complex_multipart_regimens#ECOG_3598|See link]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419359/ Bradley et al. 2015 (RTOG 0617)]<br />
| rowspan="2" |2007-2011<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Carboplatin, Paclitaxel, Cetuximab, concurrent RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. Carboplatin, Paclitaxel, high-dose RT<br> 3. Carboplatin, Paclitaxel, Cetuximab, high-dose RT<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdx009 Liang et al. 2017]<br />
|2007-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin.2C_Etoposide.2C_RT|EP & RT]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Preceding treatment====<br />
<br />
*ECOG 3598: [[#Carboplatin_.26_Paclitaxel_.28CP.29_2|PC]] induction x 2<br />
<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 2 IV over 30 minutes once per day on days 1, 8, 15, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 45 mg/m<sup>2</sup> IV over 1 to 3 hours once per day on days 1, 8, 15, '''given first'''<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 2 Gy fractions x 30 fractions (total of 60 Gy)<br />
<br />
'''6-week course'''<br />
====Subsequent treatment====<br />
<br />
*RTOG 0617: [[#Carboplatin_.26_Paclitaxel_.28CP.29_3|PC]] consolidation x 2<br />
<br />
===Regimen variant #3, 2/45/63 {{#subobject:59d765|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.55.405 Belani et al. 2005 (LAMP)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Carboplatin_.26_Paclitaxel_.28CP.29_2|PC induction]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 2 IV over 30 minutes once per day on days 1, 8, 15, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 45 mg/m<sup>2</sup> IV over 1 to 3 hours once per day on days 1, 8, 15, '''given first'''<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 1.8 Gy fractions x 25 fractions, then 2 Gy fractions x 9 fractions<br />
<br />
'''7-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[#Carboplatin_.26_Paclitaxel_.28CP.29_3|PC]] consolidation x 2<br />
<br />
===Regimen variant #4, 2/50/66 {{#subobject:c54de8|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2006.07.3569 Vokes et al. 2007 (CALGB 39801)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Carboplatin_.26_Paclitaxel_.28CP.29_2|PC]] x 2 versus [[#No_induction|no induction]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 2 IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36, 43, '''given first'''<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 66 Gy<br />
<br />
'''7-week course'''<br />
===References===<br />
<br />
#'''LAMP:''' Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. [https://doi.org/10.1200/jco.2005.55.405 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16087941 PubMed]<br />
#'''CALGB 39801:''' Vokes EE, Herndon JE 2nd, Kelley MJ, Cicchetti MG, Ramnath N, Neill H, Atkins JN, Watson DM, Akerley W, Green MR; [[Study_Groups#CALGB|CALGB]]. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol. 2007 May 1;25(13):1698-704. Epub 2007 Apr 2. [https://doi.org/10.1200/JCO.2006.07.3569 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17404369 PubMed]<br />
#'''ID99-303:''' Lu C, Lee JJ, Komaki R, Herbst RS, Feng L, Evans WK, Choy H, Desjardins P, Esparaz BT, Truong MT, Saxman S, Kelaghan J, Bleyer A, Fisch MJ. Chemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer: a randomized phase III trial. J Natl Cancer Inst. 2010 Jun 16;102(12):859-65. Epub 2010 May 26. [https://academic.oup.com/jnci/article/102/12/859/2568981 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902826/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20505152 PubMed] NCT00005838<br />
#'''WJTOG0105:''' Yamamoto N, Nakagawa K, Nishimura Y, Tsujino K, Satouchi M, Kudo S, Hida T, Kawahara M, Takeda K, Katakami N, Sawa T, Yokota S, Seto T, Imamura F, Saka H, Iwamoto Y, Semba H, Chiba Y, Uejima H, Fukuoka M. Phase III study comparing second- and third-generation regimens with concurrent thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer: West Japan Thoracic Oncology Group WJTOG0105. J Clin Oncol. 2010 Aug 10;28(23):3739-45. Epub 2010 Jul 12. [https://doi.org/10.1200/JCO.2009.24.5050 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20625120 PubMed]<br />
#'''ECOG 3598:''' Hoang T, Dahlberg SE, Schiller JH, Mehta MP, Fitzgerald TJ, Belinsky SA, Johnson DH. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol. 2012 Feb 20;30(6):616-22. Epub 2012 Jan 23. [https://doi.org/10.1200/JCO.2011.36.9116 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295560/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22271472 PubMed] NCT00004859<br />
#'''RTOG 0617:''' Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. Epub 2015 Jan 16. [https://doi.org/10.1016/s1470-2045(14)71207-0 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419359/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25601342 PubMed] NCT00533949<br />
##'''Update:''' Bradley JD, Hu C, Komaki RR, Masters GA, Blumenschein GR, Schild SE, Bogart JA, Forster KM, Magliocco AM, Kavadi VS, Narayan S, Iyengar P, Robinson CG, Wynn RB, Koprowski CD, Olson MR, Meng J, Paulus R, Curran WJ Jr, Choy H. Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Mar 1;38(7):706-714. Epub 2019 Dec 16. [https://doi.org/10.1200/jco.19.01162 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048161/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31841363 PubMed]<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/236 Project Data Sphere]<br />
<!-- Note: This study was previously oral presented as: 15th World Conference on Lung Cancer, Sydney, 27–30 October 2013. --><br />
#Liang J, Bi N, Wu S, Chen M, Lv C, Zhao L, Shi A, Jiang W, Xu Y, Zhou Z, Wang W, Chen D, Hui Z, Lv J, Zhang H, Feng Q, Xiao Z, Wang X, Liu L, Zhang T, Du L, Chen W, Shyr Y, Yin W, Li J, He J, Wang L. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial. Ann Oncol. 2017 Apr 1;28(4):777-783. [https://doi.org/10.1093/annonc/mdx009 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28137739 PubMed] NCT01494558<br />
<br />
==Carboplatin, Vinorelbine, RT {{#subobject:c9edfa|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a0fcb6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776981/ Strøm et al. 2013 (Conrad)]<br />
|2006-2011<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Carboplatin_.26_Vinorelbine|Carboplatin & Vinorelbine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 60 minutes once on day 1<br />
*[[Vinorelbine (Navelbine)]] 60 mg/m<sup>2</sup> PO once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 42 Gy in 15 fractions<br />
<br />
===References===<br />
<br />
#'''Conrad:''' Strøm HH, Bremnes RM, Sundstrøm SH, Helbekkmo N, Fløtten O, Aasebø U; Norwegian Lung Cancer Study Group. Concurrent palliative chemoradiation leads to survival and quality of life benefits in poor prognosis stage III non-small-cell lung cancer: a randomised trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2013 Sep 17;109(6):1467-75. Epub 2013 Aug 20. [https://www.nature.com/articles/bjc2013466 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776981/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23963145 PubMed] ISRCTN63778716<br />
<br />
==Carboplatin & RT {{#subobject:f563a8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Carboplatin & RT: Carboplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:6b0bae|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70139-0/fulltext Atagi et al. 2012 (JCOG0301)]<br />
|2003-2010<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Radiation_therapy|RT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 60 Gy, details not available in abstract<br />
<br />
===References===<br />
<br />
#'''JCOG0301:''' Atagi S, Kawahara M, Yokoyama A, Okamoto H, Yamamoto N, Ohe Y, Sawa T, Ishikura S, Shibata T, Fukuda H, Saijo N, Tamura T; [[Study_Groups#JCOG|JCOG]] Lung Cancer Study Group. Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Lancet Oncol. 2012 Jul;13(7):671-8. Epub 2012 May 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70139-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22622008 PubMed] NCT00132665<br />
<br />
==Cisplatin & RT {{#subobject:e6b41e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Cisplatin & RT: Cisplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:6b0bae|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199202203260805 Schaake-Koning et al. 1992]<br />
|rowspan=2|1984-1989<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Cisplatin_.26_RT|Cisplatin & RT]]; weekly cisplatin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Radiation_therapy|RT]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 6 mg/m<sup>2</sup> IV once per day on days of radiation<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] as follows:<br />
**Weeks 1 & 2: 3 Gy fractions, five fractions per week<br />
**Weeks 3 to 5: no radiation<br />
**Weeks 6 & 7: 2.5 Gy fractions, five fractions per week<br />
<br />
'''7-week course'''<br />
<br />
===References===<br />
<br />
#Schaake-Koning C, van den Bogaert W, Dalesio O, Festen J, Hoogenhout J, van Houtte P, Kirkpatrick A, Koolen M, Maat B, Nijs A, Renaud A, Rodrigus P, Schuster-Uitterhoeve L, Sculier JP, van Zandwijk N, Bartelink H. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med. 1992 Feb 20;326(8):524-30. [https://www.nejm.org/doi/full/10.1056/NEJM199202203260805 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/1310160 PubMed]<br />
<br />
==Cisplatin, Docetaxel, RT {{#subobject:6d901b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
DC & RT: '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
<br>DP & RT: '''<u>D</u>'''ocetaxel, '''<u>P</u>'''latinol (Cisplatin), '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen variant #1, 20/20 {{#subobject:fdef61|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2308-5 Oh et al. 2013 (KASLC 0401)]<br />
|2005-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. TP & RT<br> 2. GP & RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[https://doi.org/10.1200/JCO.2014.60.0130 Ahn et al. 2015 (KCSG-LU05-04)]<br />
|2005-2011<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''In KCSG-LU05-04, no benefit was observed to giving post-definitive consolidation.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Docetaxel (Taxotere)]] 20 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 33 fractions (total dose: 66 Gy)<br />
<br />
'''6-week course'''<br />
====Subsequent treatment====<br />
<br />
*KCSG-LU05-04: [[#Cisplatin_.26_Docetaxel_.28DC.29_3|Cisplatin & Docetaxel]] consolidation versus no further treatment<br />
<br />
===Regimen variant #2, 40/40 {{#subobject:6a7064|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.24.7577 Segawa et al. 2010 (OLCSG 0007)]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|MVP & RT<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''28-day cycle for 2 cycles'''<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]]<br />
<br />
===References===<br />
<br />
#'''OLCSG 0007:''' Segawa Y, Kiura K, Takigawa N, Kamei H, Harita S, Hiraki S, Watanabe Y, Sugimoto K, Shibayama T, Yonei T, Ueoka H, Takemoto M, Kanazawa S, Takata I, Nogami N, Hotta K, Hiraki A, Tabata M, Matsuo K, Tanimoto M. Phase III trial comparing docetaxel and cisplatin combination chemotherapy with mitomycin, vindesine, and cisplatin combination chemotherapy with concurrent thoracic radiotherapy in locally advanced non-small-cell lung cancer: OLCSG 0007. J Clin Oncol. 2010 Jul 10;28(20):3299-306. Epub 2010 Jun 7. [https://doi.org/10.1200/JCO.2009.24.7577 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20530281 PubMed] UMIN000000085<br />
#'''KASLC 0401:''' Oh IJ, Kim KS, Kim YC, Ban HJ, Kwon YS, Kim YI, Lim SC, Chung WK, Nam TK, Song JY, Yoon MS, Ahn SJ. A phase III concurrent chemoradiotherapy trial with cisplatin and paclitaxel or docetaxel or gemcitabine in unresectable non-small cell lung cancer: KASLC 0401. Cancer Chemother Pharmacol. 2013 Dec;72(6):1247-54. Epub 2013 Oct 5. [https://link.springer.com/article/10.1007%2Fs00280-013-2308-5 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24091849 PubMed]<br />
#'''KCSG-LU05-04:''' Ahn JS, Ahn YC, Kim JH, Lee CG, Cho EK, Lee KC, Chen M, Kim DW, Kim HK, Min YJ, Kang JH, Choi JH, Kim SW, Zhu G, Wu YL, Kim SR, Lee KH, Song HS, Choi YL, Sun JM, Jung SH, Ahn MJ, Park K. Multinational randomized phase III trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small-cell lung cancer: KCSG-LU05-04. J Clin Oncol. 2015 Aug 20;33(24):2660-6. Epub 2015 Jul 6. [https://doi.org/10.1200/JCO.2014.60.0130 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26150444 PubMed] NCT00326378<br />
<br />
==Cisplatin, Etoposide, RT {{#subobject:743aa8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
EP & RT: '''<u>E</u>'''toposide, '''<u>P</u>'''latinol (Cisplatin), '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen variant #1, 45 Gy with response-adapted treatment {{#subobject:dcb6c1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2002.03.055 Albain et al. 2002 (SWOG 9019)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407808/ Albain et al. 2009 (RTOG 93-09)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Etoposide (Vepesid)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''28-day cycle for 2 cycles'''<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions (total dose: 45 Gy), to start within 24 hours of cycle 1 day 1<br />
<br />
'''5-week course'''<br />
====Subsequent treatment====<br />
<br />
*SWOG 9019: Patients were re-imaged with CT scan (bone scan and head imaging were only done if patients had new symptoms), and those without progression or new metastatic disease received an additional 2 Gy per day x 8 fractions for a total of 61 Gy administered overall<br />
*RTOG 93-09: Additional radiation to 61 Gy, then [[#Cisplatin_.26_Etoposide_.28EP.29_2|cisplatin & etoposide consolidation]] versus surgery, then [[#Cisplatin_.26_Etoposide_.28EP.29_2|cisplatin & etoposide consolidation]]<br />
<br />
===Regimen variant #2, 60 to 66 Gy {{#subobject:426dfc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2007.14.4824 Kelly et al. 2008 (SWOG S0023)]<br />
|2001-2005<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/JCO.2008.17.7840 Hanna et al. 2008 (HOG Lun 01-24)]<br />
|2002-2006<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdx009 Liang et al. 2017]<br />
|2007-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_RT|PC & RT]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Etoposide (Vepesid)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 to 2 Gy fractions x 30 to 33 fractions (total dose: 60 to 66 Gy)<br />
<br />
'''6- to 6.5-week course'''<br />
<br />
====Subsequent treatment====<br />
<br />
*SWOG S0023: Docetaxel x 3, then gefitinib versus [[Non-small_cell_lung_cancer_-_null_regimens#Placebo|placebo]]<br />
*HOG Lun 01-24: Docetexal consolidation versus [[Non-small_cell_lung_cancer_-_null_regimens#Observation_2|observation]]<br />
*Liang et al. 2017: Optional consolidation chemotherapy<br />
<br />
===Regimen variant #3, 66 Gy, split cisplatin {{#subobject:f35aaa|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.03.070 Fournel et al. 2005 (NPC 95-01)]<br />
|1996-2000<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|Cisplatin & Vinorelbine, then [[#Radiation_therapy|RT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: this is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
*[[Etoposide (Vepesid)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 33 fractions (total dose: 66 Gy)<br />
<br />
'''6.5-week course'''<br />
<br />
====Subsequent treatment====<br />
<br />
*[[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine consolidation]]<br />
<br />
===Regimen variant #4, 69.6 Gy (hyperfractionated) {{#subobject:3ea5c6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ Curran et al. 2011 (RTOG 9410)]<br />
|rowspan=2|1994-1998<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Cisplatin.2C_Vinblastine.2C_RT|Cisplatin, Vinblastine, RT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Cisplatin_.26_Vinblastine_2|Cisplatin & Vinblastine]], then [[#Radiation_therapy|RT]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Etoposide (Vepesid)]] 50 mg PO twice per day on days 1 to 5, 8 to 12<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.2 Gy fractions (total dose: 69.6 Gy), given twice per day for 5 days per week, starting on cycle 1 day 1<br />
<br />
===References===<br />
<br />
#'''SWOG 9019:''' Albain KS, Crowley JJ, Turrisi AT 3rd, Gandara DR, Farrar WB, Clark JI, Beasley KR, Livingston RB. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol. 2002 Aug 15;20(16):3454-60. [https://doi.org/10.1200/jco.2002.03.055 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12177106 PubMed]<br />
#'''NPC 95-01:''' Fournel P, Robinet G, Thomas P, Souquet PJ, Léna H, Vergnenégre A, Delhoume JY, Le Treut J, Silvani JA, Dansin E, Bozonnat MC, Daurés JP, Mornex F, Pérol M; Groupe Lyon-Saint-Etienne d'Oncologie Thoracique; Groupe Français de Pneumo-Cancérologie. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol. 2005 Sep 1;23(25):5910-7. Epub 2005 Aug 8. [https://doi.org/10.1200/JCO.2005.03.070 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16087956/ PubMed]<br />
#'''SWOG S0023:''' Kelly K, Chansky K, Gaspar LE, Albain KS, Jett J, Ung YC, Lau DH, Crowley JJ, Gandara DR. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol. 2008 May 20;26(15):2450-6. Epub 2008 Mar 31. [https://doi.org/10.1200/JCO.2007.14.4824 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18378568 PubMed]<br />
#'''HOG Lun 01-24:''' Hanna N, Neubauer M, Yiannoutsos C, McGarry R, Arseneau J, Ansari R, Reynolds C, Govindan R, Melnyk A, Fisher W, Richards D, Bruetman D, Anderson T, Chowhan N, Nattam S, Mantravadi P, Johnson C, Breen T, White A, Einhorn L; Hoosier Oncology Group; US Oncology. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol. 2008 Dec 10;26(35):5755-60. Epub 2008 Nov 10. [https://doi.org/10.1200/JCO.2008.17.7840 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19001323 PubMed]<br />
#'''RTOG 93-09:''' Albain KS, Swann RS, Rusch VW, Turrisi AT 3rd, Shepherd FA, Smith C, Chen Y, Livingston RB, Feins RH, Gandara DR, Fry WA, Darling G, Johnson DH, Green MR, Miller RC, Ley J, Sause WT, Cox JD. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009 Aug 1;374(9687):379-86. Epub 2009 Jul 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60737-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407808/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19632716 PubMed]<br />
#'''RTOG 9410:''' Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. [http://jnci.oxfordjournals.org/content/103/19/1452.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21903745 PubMed]<br />
#Liang J, Bi N, Wu S, Chen M, Lv C, Zhao L, Shi A, Jiang W, Xu Y, Zhou Z, Wang W, Chen D, Hui Z, Lv J, Zhang H, Feng Q, Xiao Z, Wang X, Liu L, Zhang T, Du L, Chen W, Shyr Y, Yin W, Li J, He J, Wang L. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial. Ann Oncol. 2017 Apr 1;28(4):777-783. [https://doi.org/10.1093/annonc/mdx009 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28137739 PubMed] NCT01494558<br />
<br />
==Cisplatin, Vinblastine, RT {{#subobject:54c5c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c057fe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ Curran et al. 2011 (RTOG 9410)]<br />
|rowspan=2|1994-1998<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Cisplatin.2C_Etoposide.2C_RT|Cisplatin, Etoposide, RT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Cisplatin_.26_Vinblastine_2|Cisplatin & Vinblastine]], then [[#Radiation_therapy|RT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 29<br />
*[[Vinblastine (Velban)]] 5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]]<br />
<br />
'''5-week course'''<br />
<br />
===References===<br />
<br />
#'''RTOG 9410:''' Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. [http://jnci.oxfordjournals.org/content/103/19/1452.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21903745 PubMed]<br />
<br />
==Cisplatin, Vinorelbine, RT {{#subobject:59gcc4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c8ygfe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2015.62.6812 Eberhardt et al. 2015 (ESPATUE)]<br />
|2004-2013<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|Surgery<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Cisplatin & Paclitaxel<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]]<br />
*[[Vinorelbine (Navelbine)]]<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]]<br />
<br />
===References===<br />
<br />
#'''ESPATUE:''' Eberhardt WE, Pöttgen C, Gauler TC, Friedel G, Veit S, Heinrich V, Welter S, Budach W, Spengler W, Kimmich M, Fischer B, Schmidberger H, De Ruysscher D, Belka C, Cordes S, Hepp R, Lütke-Brintrup D, Lehmann N, Schuler M, Jöckel KH, Stamatis G, Stuschke M. Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE). J Clin Oncol. 2015 Dec 10;33(35):4194-201. Epub 2015 Nov 2. [https://doi.org/10.1200/JCO.2015.62.6812 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26527789 PubMed]<br />
<br />
==Radiation therapy {{#subobject:6a90fb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen variant #1, 20 Gy {{#subobject:1g2326|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063335/ Ball et al. 1997]<br />
|1988-1993<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & RT<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] 4 Gy in 5 fractions (20 Gy total)<br />
<br />
'''5-day course'''<br />
<br />
===Regimen variant #2, 45 Gy + 18 Gy boost (63 Gy total) {{#subobject:5d7861|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ Curran et al. 2011 (RTOG 9410)]<br />
|1994-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#RTOG_9410|See link]]<br />
|[[Complex_multipart_regimens#RTOG_9410|See link]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.55.405 Belani et al. 2005 (LAMP)]<br />
|1998-2001<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*LAMP: [[#Carboplatin_.26_Paclitaxel_.28CP.29_2|Carboplatin & Paclitaxel]] x 2<br />
*RTOG 9410: [[#Cisplatin_.26_Vinblastine_2|Cisplatin & Vinblastine]] x 5 wk<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] 45 Gy in 1.8 Gy fractions x 25 fractions, then 18 Gy boost in 2 Gy fractions x 9 fractions<br />
<br />
'''7-week course'''<br />
<br />
===Regimen variant #3, 60 Gy {{#subobject:12f326|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://annals.org/aim/article-abstract/705110/thoracic-radiation-therapy-alone-compared-combined-chemoradiotherapy-locally-unresectable-non Morton et al. 1991]<br />
|1983-1987<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MACC & RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.1999.17.1.4 Clamon et al. 1999 (CALGB 9130)]<br />
|1991-NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_RT|Carboplatin & RT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.redjournal.org/article/S0360-3016(01)02797-3/fulltext Bradley et al. 2002 (RTOG 93-04)]<br />
|1994-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Beta-interferon & RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdh100 Groen et al. 2004]<br />
|1995-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_RT|Carboplatin & RT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS24<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70139-0/fulltext Atagi et al. 2012 (JCOG0301)]<br />
|2003-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_RT|Carboplatin & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*CALGB 9130: [[#Cisplatin_.26_Vinblastine_2|Cisplatin & Vinblastine]] x 5 wk<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] 60 Gy<br />
<br />
'''One course'''<br />
===References===<br />
<br />
#Morton RF, Jett JR, McGinnis WL, Earle JD, Therneau TM, Krook JE, Elliott TE, Mailliard JA, Nelimark RA, Maksymiuk AW, Drummond RG, Laurie JA, Kugler JW, Anderson RT. Thoracic radiation therapy alone compared with combined chemoradiotherapy for locally unresectable non-small cell lung cancer: a randomized, phase III trial. Ann Intern Med. 1991 Nov 1;115(9):681-6. [https://annals.org/aim/article-abstract/705110/thoracic-radiation-therapy-alone-compared-combined-chemoradiotherapy-locally-unresectable-non link to original article] [https://pubmed.ncbi.nlm.nih.gov/1656827 PubMed]<br />
#Ball D, Smith J, Bishop J, Olver I, Davis S, O'Brien P, Bernshaw D, Ryan G, Millward M. A phase III study of radiotherapy with and without continuous-infusion fluorouracil as palliation for non-small-cell lung cancer. Br J Cancer. 1997;75(5):690-7. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063335/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/9043026 PubMed]<br />
#'''CALGB 9130:''' Clamon G, Herndon J, Cooper R, Chang AY, Rosenman J, Green MR; [[Study_Groups#CALGB|CALGB]]; [[Study_Groups#ECOG|ECOG]]. Radiosensitization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol. 1999 Jan;17(1):4-11. [https://doi.org/10.1200/JCO.1999.17.1.4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10458211 PubMed]<br />
#'''RTOG 93-04:''' Bradley JD, Scott CB, Paris KJ, Demas WF, Machtay M, Komaki R, Movsas B, Rubin P, Sause WT. A phase III comparison of radiation therapy with or without recombinant beta-interferon for poor-risk patients with locally advanced non-small-cell lung cancer (RTOG 93-04). Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1173-9. [https://www.redjournal.org/article/S0360-3016(01)02797-3/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11955727 PubMed]<br />
#Groen HJ, van der Leest AH, Fokkema E, Timmer PR, Nossent GD, Smit WJ, Nabers J, Hoekstra HJ, Hermans J, Otter R, van Putten JW, de Vries EG, Mulder NH. Continuously infused carboplatin used as radiosensitizer in locally unresectable non-small-cell lung cancer: a multicenter phase III study. Ann Oncol. 2004 Mar;15(3):427-32. [https://doi.org/10.1093/annonc/mdh100 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14998844 PubMed]<br />
#'''LAMP:''' Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. [https://doi.org/10.1200/jco.2005.55.405 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16087941 PubMed]<br />
#'''RTOG 9410:''' Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. [http://jnci.oxfordjournals.org/content/103/19/1452.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21903745 PubMed]<br />
#'''JCOG0301:''' Atagi S, Kawahara M, Yokoyama A, Okamoto H, Yamamoto N, Ohe Y, Sawa T, Ishikura S, Shibata T, Fukuda H, Saijo N, Tamura T; [[Study_Groups#JCOG|JCOG]] Lung Cancer Study Group. Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Lancet Oncol. 2012 Jul;13(7):671-8. Epub 2012 May 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70139-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22622008 PubMed] NCT00132665<br />
<br />
=Consolidation or maintenance after definitive therapy for inoperable disease=<br />
<br />
==Carboplatin & Paclitaxel (CP) {{#subobject:81d5a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d729a8|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.55.405 Belani et al. 2005 (LAMP)]<br />
|1998-2001<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419359/ Bradley et al. 2015 (RTOG 0617)]<br />
|2007-2011<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_RT|Carboplatin, Paclitaxel, RT]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 30 minutes once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''21-day cycle for 2 cycles'''<br />
<br />
===References===<br />
<br />
#'''LAMP:''' Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. [https://doi.org/10.1200/jco.2005.55.405 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16087941 PubMed]<br />
#'''RTOG 0617:''' Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. Epub 2015 Jan 16. [https://doi.org/10.1016/s1470-2045(14)71207-0 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419359/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25601342 PubMed] NCT00533949<br />
##'''Update:''' Bradley JD, Hu C, Komaki RR, Masters GA, Blumenschein GR, Schild SE, Bogart JA, Forster KM, Magliocco AM, Kavadi VS, Narayan S, Iyengar P, Robinson CG, Wynn RB, Koprowski CD, Olson MR, Meng J, Paulus R, Curran WJ Jr, Choy H. Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Mar 1;38(7):706-714. Epub 2019 Dec 16. [https://doi.org/10.1200/jco.19.01162 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048161/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31841363 PubMed]<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/272 Project Data Sphere]<br />
<br />
==Durvalumab monotherapy {{#subobject:6f72e5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:04242b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1709937 Antonia et al. 2017 (PACIFIC)]<br />
|2014-2016<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Placebo_2|Placebo]]<br />
| style="background-color:#1a9850" |Superior OS<sup>1</sup> <br>Median OS: Not reached vs 29.1 mo <br>(HR 0.69, 95% CI 0.55-0.86)<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2019 update.''<br />
====Preceding treatment====<br />
<br />
*"Two or more cycles (defined according to local practice) of platinum-based chemotherapy (containing etoposide, vinblastine, vinorelbine, a taxane [paclitaxel or docetaxel], or pemetrexed) concurrently with definitive radiation therapy (54 to 66 Gy), in which the mean dose to the lung was less than 20 Gy, the V20 (the volume of lung parenchyma that received 20 Gy or more) was less than 35%, or both."<br />
<br />
====Immunotherapy====<br />
<br />
*[[Durvalumab (Imfinzi)]] 10 mg/kg IV once on day 1<br />
<br />
'''14-day cycle for up to 26 cycles (1 year)'''<br />
<br />
===References===<br />
<br />
#'''PACIFIC:''' Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. Epub 2017 Sep 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1709937 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28885881 PubMed] NCT02125461<br />
##'''Update:''' Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Faivre-Finn C, Reck M, Vansteenkiste J, Spigel DR, Wadsworth C, Melillo G, Taboada M, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018 Dec 13;379(24):2342-2350. Epub 2018 Sep 25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1709937 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30280658 PubMed]<br />
##'''Update:''' Gray JE, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, Cho BC, Planchard D, Paz-Ares L, Faivre-Finn C, Vansteenkiste JF, Spigel DR, Wadsworth C, Taboada M, Dennis PA, Özgüroğlu M, Antonia SJ. Three-Year Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC-Update from PACIFIC. J Thorac Oncol. 2020 Feb;15(2):288-293. Epub 2019 Oct 14. [https://doi.org/10.1016/j.jtho.2019.10.002 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7244187/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31622733 PubMed]<br />
#'''KEYLYNK-012:''' NCT04380636<br />
<br />
=Advanced or metastatic disease, first-line=<br />
<br />
==Carboplatin & Docetaxel {{#subobject:bdce59|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
DCb: '''<u>D</u>'''ocetaxel & '''<u>C</u>'''ar'''<u>b</u>'''oplatin<br />
===Regimen {{#subobject:bce236|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/jco.2003.12.046 Fossella et al. 2003 (TAX 326)]<br />
| rowspan="2" |1998-2000<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Cisplatin_.26_Docetaxel_.28DC.29_3|Cisplatin & Docetaxel]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdl078 Booton et al. 2006 (BTOG1)]<br />
|2001-2002<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[Non-small_cell_lung_cancer_-_historical#MIC_3|MIC]]<br> 2. [[Non-small_cell_lung_cancer_-_historical#MVP_.28Vinblastine.29|MVP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2011.35.5214 Groen et al. 2011 (NVALT-4)]<br />
|2003-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Carboplatin, Docetaxel, Celecoxib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.21.9618 Lynch et al. 2010 (BMS099)]<br />
|2005-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Carboplatin, Docetaxel, Cetuximab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for up to 5 cycles (NVALT-4), 6 cycles (BMS099), or indefinitely'''<br />
<br />
===References===<br />
<!-- Previously presented in part at the Annual Meeting of the American Society of Clinical Oncology (ASCO), San Francisco, CA, May 12–15, 2001; the Annual Meeting of ASCO, Orlando, FL, May 18–21, 2002; and the Congress of the European Society for Medical Oncology, Nice, France, October 18–22, 2002. --><br />
<br />
#'''TAX 326:''' Fossella F, Rodrigues Pereira J, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. [https://doi.org/10.1200/jco.2003.12.046 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12837811 PubMed]<br />
#'''BTOG1:''' Booton R, Lorigan P, Anderson H, Baka S, Ashcroft L, Nicolson M, O'Brien M, Dunlop D, O'Byrne K, Laurence V, Snee M, Dark G, Thatcher N. A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer: a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1). Ann Oncol. 2006 Jul;17(7):1111-9. Epub 2006 Apr 7. [https://doi.org/10.1093/annonc/mdl078 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16603599 PubMed]<br />
#'''BMS099:''' Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, Paschold E, Iannotti NO, Dakhil S, Gorton S, Pautret V, Weber MR, Woytowitz D. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol. 2010 Feb 20;28(6):911-7. Epub 2010 Jan 25. [https://doi.org/10.1200/JCO.2009.21.9618 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20100966 PubMed] NCT00112294<br />
<!-- Presented in part at the 45th Annual Meeting of the American Society of Clinical Oncology, May 29-June 2, 2009, Orlando, FL. --><br />
#'''NVALT-4:''' Groen HJ, Sietsma H, Vincent A, Hochstenbag MM, van Putten JW, van den Berg A, Dalesio O, Biesma B, Smit HJ, Termeer A, Hiltermann TJ, van den Borne BE, Schramel FM. Randomized, placebo-controlled phase III study of docetaxel plus carboplatin with celecoxib and cyclooxygenase-2 expression as a biomarker for patients with advanced non-small-cell lung cancer: the NVALT-4 study. J Clin Oncol. 2011 Nov 10;29(32):4320-6. Epub 2011 Oct 11. [https://doi.org/10.1200/JCO.2011.35.5214 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21990410 PubMed] NTR1703<br />
<br />
==Carboplatin & Etoposide (CE) {{#subobject:4c2ff5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f920ac|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1990.8.9.1556 Klastersky et al. 1990 (EORTC 07861)]<br />
|1987-1989<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Etoposide_.28EP.29_2|Cisplatin & Etoposide]]<br />
| style="background-color:#fee08b" |Might have inferior ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] 325 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''3- to 4-week cycles'''<br />
<br />
===References===<br />
<br />
#'''EORTC 07861:''' Klastersky J, Sculier JP, Lacroix H, Dabouis G, Bureau G, Libert P, Richez M, Ravez P, Vandermoten G, Thiriaux J, Cordier R, Finet C, Berchier MC, Sergysels R, Mommen P, Paesmans M. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organisation for Research and Treatment of Cancer Protocol 07861. J Clin Oncol. 1990 Sep;8(9):1556-62. [https://doi.org/10.1200/JCO.1990.8.9.1556 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2167953 PubMed]<br />
<br />
==Carboplatin & Gemcitabine (GCb) {{#subobject:8669e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GC: '''<u>G</u>'''emcitabine & '''<u>C</u>'''arboplatin<br />
<br>GCa: '''<u>G</u>'''emcitabine & '''<u>Ca</u>'''rboplatin<br />
<br>GCb: '''<u>G</u>'''emcitabine & '''<u>C</u>'''ar'''<u>b</u>'''oplatin<br />
===Regimen variant #1, 4/1000 {{#subobject:fa3601|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360329/ Helbekkmo et al. 2007]<br />
|2003-2004<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Carboplatin_.26_Vinorelbine|VC]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: AUC was calculated using the Chatelut formula.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 4 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===Regimen variant #2, 5/1000 q3wk {{#subobject:cfb199|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2008.20.9114 Grønberg et al. 2009]<br />
|2005-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Pemetrexed|Carboplatin & Pemetrexed]]<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRQoL<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 4 cycles'''<br />
<br />
===Regimen variant #3, 5/1000 q4wk {{#subobject:82e4e7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.11535/abstract Danson et al. 2003]<br />
|1997-2001<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[Non-small_cell_lung_cancer_-_historical#MIC_3|MIC]]<br> 2. [[Non-small_cell_lung_cancer_-_historical#MVP_.28Vinblastine.29|MVP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #4, 5/1200 {{#subobject:58b47e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(03)00233-2/fulltext Zatloukal et al. 2003]<br />
|1999-2001<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of grade 3/4 toxicity<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.03.037 Rudd et al. 2005]<br />
|1999-2001<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Non-small_cell_lung_cancer_-_historical#MIC_3|MIC]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1200 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #5, 5/1250 q3wk {{#subobject:4bca29|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.01.2781 Sederholm et al. 2005]<br />
|1998-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691357/ Bepler et al. 2013 (MCC-15005)]<br />
|2007-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ERCC1 and RRM1 expression-based chemotherapy<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS6<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
| style="background-color:#d73027" |Inferior HRQoL<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 to 6 cycles'''<br />
<br />
===Regimen variant #6, 5/1250 q4wk {{#subobject:7e79d9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70254-7/fulltext Wu et al. 2013 (FASTACT-2)]<br />
|2009-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer,_EGFR-mutated#Carboplatin_.26_Gemcitabine_.28GCb.29.2FErlotinib|Carboplatin & Gemcitabine/Erlotinib]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm.'' <br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #7, 6/1000 {{#subobject:c7aefa|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdm430 Kosmidis et al. 2007]<br />
|2000-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_Paclitaxel|Gemcitabine & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #8, 6/1250 ("GCb6") {{#subobject:afcfd9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.ejcancer.com/article/S0959-8049(17)31001-8/fulltext Ferry et al. 2017 (BTOG2)]<br />
| rowspan="2" |2005-2009<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]; GC50<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|<br />
|-<br />
|2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]; GC80<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
| style="background-color:#d73027" |Inferior HRQoL<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 to 6 cycles'''<br />
<br />
===Regimen variant #9, 300/1000 {{#subobject:9c94c9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(01)00493-7/fulltext Grigorescu et al. 2002]<br />
|1997-2000<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Non-small_cell_lung_cancer_-_historical#Cisplatin_.26_Vinblastine|Cisplatin & Vinblastine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Grigorescu AC, Draghici IN, Nitipir C, Gutulescu N, Corlan E. Gemcitabine (GEM) and carboplatin (CBDCA) versus cisplatin (CDDP) and vinblastine (VLB) in advanced non-small-cell lung cancer (NSCLC) stages III and IV: a phase III randomised trial. Lung Cancer. 2002 Jul;37(1):9-14. [https://www.lungcancerjournal.info/article/S0169-5002(01)00493-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12057861 PubMed]<br />
#Danson S, Middleton MR, O'Byrne KJ, Clemons M, Ranson M, Hassan J, Anderson H, Burt PA, Fairve-Finn C, Stout R, Dowd I, Ashcroft L, Beresford C, Thatcher N. Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer. 2003 Aug 1;98(3):542-53. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.11535/abstract link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12879472 PubMed]<br />
#Zatloukal P, Petruzelka L, Zemanová M, Kolek V, Skricková J, Pesek M, Fojtů H, Grygárková I, Sixtová D, Roubec J, Horenková E, Havel L, Průsa P, Nováková L, Skácel T, Kůta M. Gemcitabine plus cisplatin vs gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial. Lung Cancer. 2003 Sep;41(3):321-31. [https://www.lungcancerjournal.info/article/S0169-5002(03)00233-2/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12928123 PubMed]<br />
#Rudd RM, Gower NH, Spiro SG, Eisen TG, Harper PG, Littler JA, Hatton M, Johnson PW, Martin WM, Rankin EM, James LE, Gregory WM, Qian W, Lee SM; London Lung Cancer Group. Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer Group. J Clin Oncol. 2005 Jan 1;23(1):142-53. [https://doi.org/10.1200/JCO.2005.03.037 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15625369 PubMed]<br />
#Sederholm C, Hillerdal G, Lamberg K, Kölbeck K, Dufmats M, Westberg R, Gawande SR; Swedish Lung Cancer Study Group. Phase III trial of gemcitabine plus carboplatin versus single-agent gemcitabine in the treatment of locally advanced or metastatic non-small-cell lung cancer: the Swedish Lung Cancer Study Group. J Clin Oncol. 2005 Nov 20;23(33):8380-8. [https://doi.org/10.1200/jco.2005.01.2781 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16293868 PubMed]<br />
#Helbekkmo N, Sundstrøm SH, Aasebø U, Brunsvig PF, von Plessen C, Hjelde HH, Garpestad OK, Bailey A, Bremnes RM; Norwegian Lung Cancer Study Group. Vinorelbine/carboplatin vs gemcitabine/carboplatin in advanced NSCLC shows similar efficacy, but different impact of toxicity. Br J Cancer. 2007 Aug 6;97(3):283-9. Epub 2007 Jun 26. [https://www.nature.com/articles/6603869 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360329/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17595658 PubMed]<br />
#Kosmidis PA, Kalofonos HP, Christodoulou C, Syrigos K, Makatsoris T, Skarlos D, Bakogiannis C, Nicolaides C, Bafaloukos D, Bamias A, Samantas E, Xiros N, Boukovinas I, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group. Ann Oncol. 2008 Jan;19(1):115-22. Epub 2007 Oct 15. [https://doi.org/10.1093/annonc/mdm430 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17938425 PubMed]<br />
<!-- Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL; and the International Association for the Study of Lung Cancer 12th World Conference on Lung Cancer, September 2-6, 2007, Seoul, Korea. --><br />
#Grønberg BH, Bremnes RM, Fløtten O, Amundsen T, Brunsvig PF, Hjelde HH, Kaasa S, von Plessen C, Stornes F, Tollåli T, Wammer F, Aasebø U, Sundstrøm S; Norwegian Lung Cancer Study Group. Phase III study by the Norwegian Lung Cancer Study Group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Jul 1;27(19):3217-24. Epub 2009 May 11. [https://doi.org/10.1200/jco.2008.20.9114 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19433683 PubMed]<br />
#'''ALPHA A1-99002L:''' Treat JA, Gonin R, Socinski MA, Edelman MJ, Catalano RB, Marinucci DM, Ansari R, Gillenwater HH, Rowland KM, Comis RL, Obasaju CK, Belani CP; Alpha Oncology Research Network. A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2010 Mar;21(3):540-7. Epub 2009 Oct 15. [https://doi.org/10.1093/annonc/mdp352 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19833819 PubMed] NCT00054392<br />
#'''MCC-15005:''' Bepler G, Williams C, Schell MJ, Chen W, Zheng Z, Simon G, Gadgeel S, Zhao X, Schreiber F, Brahmer J, Chiappori A, Tanvetyanon T, Pinder-Schenck M, Gray J, Haura E, Antonia S, Fischer JR. Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2013 Jul 1;31(19):2404-12. Epub 2013 May 20. [https://doi.org/10.1200/JCO.2012.46.9783 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691357/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23690416 PubMed] NCT00499109<br />
#'''FASTACT-2:''' Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, Srimuninnimit V, Sriuranpong V, Sandoval-Tan J, Zhu Y, Liao M, Zhou C, Pan H, Lee V, Chen YM, Sun Y, Margono B, Fuerte F, Chang GC, Seetalarom K, Wang J, Cheng A, Syahruddin E, Qian X, Ho J, Kurnianda J, Liu HE, Jin K, Truman M, Bara I, Mok T. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013 Jul;14(8):777-86. Epub 2013 Jun 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70254-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23782814 PubMed] NCT00883779<br />
#'''KEYNOTE-024:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1606774/suppl_file/nejmoa1606774_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27718847 PubMed] NCT02142738<br />
##'''HRQoL analysis:''' Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30690-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29129441 PubMed]<br />
##'''Update:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. [https://doi.org/10.1200/JCO.18.00149 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30620668 PubMed]<br />
#'''BTOG2:''' Ferry D, Billingham L, Jarrett H, Dunlop D, Woll PJ, Nicolson M, Shah R, Thompson J, Spicer J, Muthukumar D, Skailes G, Leonard P, Chetiyawardana AD, Wells P, Lewanski C, Crosse B, Hill M, Gaunt P, O'Byrne K; British Thoracic Oncology Group. Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: results from a British Thoracic Oncology Group randomised phase III trial. Eur J Cancer. 2017 Sep;83:302-312. Epub 2017 Aug 4. [https://www.ejcancer.com/article/S0959-8049(17)31001-8/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28780466 PubMed] NCT00112710<br />
<br />
==Carboplatin & Paclitaxel (CP) {{#subobject:c5fbdf|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CP: '''<u>C</u>'''arboplatin & '''<u>P</u>'''aclitaxel<br />
<br>PC: '''<u>P</u>'''aclitaxel & '''<u>C</u>'''arboplatin<br />
<br>TC: '''<u>T</u>'''axol (Paclitaxel) & '''<u>C</u>'''arboplatin<br />
===Regimen variant #1, 5/200 {{#subobject:5g4ff1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
| style="background-color:#d73027" |Inferior HRQoL<br />
|-<br />
|rowspan=2|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7146551/ Rizvi et al. 2020 (MYSTIC)]<br />
|rowspan=2|2015-2016<br />
|rowspan=2 style="background-color:#1a9851" |Phase III (C)<br />
|Durvalumab<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|<br />
|-<br />
|Durvalumab & Tremelimumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS<br />
|<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 15 to 60 minutes once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''21-day cycle for 4 to 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*KEYNOTE-024: Patients with nonsquamous histology could optionally proceed to [[#Pemetrexed_monotherapy_2|pemetrexed switch maintenance]]<br />
<br />
===Regimen variant #2, 6/175 {{#subobject:e3545d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962260/ Stathopoulos et al. 2004]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Paclitaxel & Vinorelbine<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of ORR/OS<br />
|-<br />
|[https://doi.org/10.1200/jco.2011.38.4032 Lynch et al. 2012 (CA184-041)]<br />
|2008-2009<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Ipilimumab|CP & Ipilimumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Steroids|Corticosteroids]] could be used as premedication for [[Paclitaxel (Taxol)]] infusion.<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #3, 6/200 {{#subobject:5f5ff1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2002.20.5.1335 Socinski et al. 2002]<br />
|1998-2000<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|CP]]; indefinite<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of QoL<br />
|-<br />
|[https://doi.org/10.1200/JCO.2002.12.112 Kosmidis et al. 2002]<br />
|1998-2000<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Gemcitabine_.26_Paclitaxel|Gemcitabine & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdf332 Rosell et al. 2002]<br />
|1996-1997<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/jco.2004.11.022 Johnson et al. 2004]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Bevacizumab|PacCBev]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.04.044 Leighl et al. 2005 (NCIC-CTG BR.18)]<br />
|2000-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CP & BMS-275291<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
| style="background-color:#1a9850" |Less toxic<br />
|-<br />
| rowspan="3" |[https://doi.org/10.1093/annonc/mdl377 Ohe et al. 2006 (FACS)]<br />
| rowspan="3" |2000-2002<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|<br />
|-<br />
|2. [[#Cisplatin_.26_Irinotecan_.28IC.29|Cisplatin & Irinotecan]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|<br />
|-<br />
|3. [[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.02.840 Herbst et al. 2005 (TRIBUTE)]<br />
|2001-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Erlotinib|CP & Erlotinib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://www.clinical-lung-cancer.com/article/S1525-7304(11)70705-7/pdf Schuette et al. 2006]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|CP]]; weekly<br />
| style="background-color:#ffffbf" |Seems to have non-inferior ORR<br />
| style="background-color:#ffffbf" |Mixed toxicity<br />
|-<br />
|[https://doi.org/10.1200/JCO.2007.12.2689 Blumenschein et al. 2008 (SPIRIT II)]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Bexarotene|CP & Bexarotene]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2010.32.8971 Hirsh et al. 2011 (A8501001)]<br />
|2005-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CP & Agatolimod<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.26.1321 Scagliotti et al. 2010 (ESCAPE)]<br />
|2006-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Sorafenib|CP & Sorafenib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2010.31.0326 Okamoto et al. 2010 (LETS)]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Carboplatin & S-1<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/jco.2011.39.5848 Socinski et al. 2012 (CA031)]<br />
|2007-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_nab-Paclitaxel|Carboplatin & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior ORR<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2011.35.0660 Lara et al. 2011 (ATTRACT-1)]<br />
|2008-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CP & Vadimezan<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067944/ Langer et al. 2014 (A4021016)]<br />
|2008-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CP & Figitumumab<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(13)01028-9/fulltext Laurie et al. 2013 (NCIC-CTG BR.29)]<br />
|2008-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Cediranib|CP & Cediranib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
| style="background-color:#1a9850" |Less toxic<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30694-0/fulltext Herbst et al. 2017 (SWOG S0819)]<br />
|2009-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Cetuximab|CP & Cetuximab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS<br />
|<br />
|-<br />
|[http://clincancerres.aacrjournals.org/content/23/8/1937.full Ramalingam et al. 2016 (M10-898)]<br />
|2012-2013<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Veliparib|CP & Veliparib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
| style="background-color:#d73027" |Inferior HRQoL<br />
|-<br />
|rowspan=2|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7146551/ Rizvi et al. 2020 (MYSTIC)]<br />
|rowspan=2|2015-2016<br />
|rowspan=2 style="background-color:#1a9851" |Phase III (C)<br />
|Durvalumab<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|<br />
|-<br />
|Durvalumab & Tremelimumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS<br />
|<br />
|-<br />
|}<br />
''Note: Patients in TRIBUTE received a maximum of 6 cycles. Patients in SWOG S0819 were EGFR FISH positive.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 15 to 60 minutes once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''21-day cycle for 3 or more cycles'''<br />
====Subsequent treatment====<br />
<br />
*Socinski et al. 2002, upon progression: Paclitaxel<br />
*KEYNOTE-024: Patients with nonsquamous histology could optionally proceed, after 4 to 6 cycles, to [[#Pemetrexed_monotherapy_2|pemetrexed switch maintenance]]<br />
<br />
===Regimen variant #4, 6/225 {{#subobject:847441|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2001.19.13.3210 Kelly et al. 2001 (SWOG 9509)]<br />
|1996-1998<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
| rowspan="3" |[https://www.nejm.org/doi/full/10.1056/NEJMoa011954 Schiller et al. 2002 (ECOG E1594)]<br />
| rowspan="3" |1996-1999<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Cisplatin_.26_Docetaxel_.28DC.29_3|Cisplatin & Docetaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|3. [[#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.07.172 Lilenbaum et al. 2005 (CALGB 9730)]<br />
|1997-2000<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Paclitaxel<br />
| style="background-color:#1a9850" |Superior FFS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2004.07.215 Herbst et al. 2004 (INTACT 2)]<br />
|2000-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CP & Gefitinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.01.3771 Williamson et al. 2005 (SWOG S0003)]<br />
|2000-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CP & Tirapazamine<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2007.13.1912 Belani et al. 2008]<br />
|2000-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|CP]]; weekly paclitaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdp352 Treat et al. 2009 (ALPHA A1-99002L)]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|Carboplatin & Gemcitabine]]<br> 2. Gemcitabine & Paclitaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(08)70261-4/fulltext Kubota et al. 2008 (JMTO LC00-03)]<br />
|2001-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Vinorelbine, then Docetaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.jto.org/article/S1556-0864(15)31941-9/fulltext Weissman et al. 2011]<br />
|2004-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GEMOX<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.21.9618 Lynch et al. 2010 (BMS099)]<br />
|2005-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CP & Cetuximab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''21-day cycle for up to 4 cycles (Belani et al. 2008), 6 cycles (Weissman et al. 2011), 10 cycles (SWOG 9509), or indefinitely (ECOG E1594)'''<br />
====Subsequent treatment====<br />
<br />
*Belani et al. 2008: Paclitaxel maintenance<br />
<br />
===References===<br />
<br />
#'''SWOG 9509:''' Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, Ramsey SD, Wozniak AJ, Weiss GR, Moore DF, Israel VK, Livingston RB, Gandara DR. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol. 2001 Jul 1;19(13):3210-8. [https://doi.org/10.1200/JCO.2001.19.13.3210 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11432888 PubMed]<br />
#'''ECOG E1594:''' Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; [[Study_Groups#ECOG|ECOG]]. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. [https://www.nejm.org/doi/full/10.1056/NEJMoa011954 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11784875 PubMed]<br />
#Socinski MA, Schell MJ, Peterman A, Bakri K, Yates S, Gitten R, Unger P, Lee J, Lee JH, Tynan M, Moore M, Kies MS. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol. 2002 Mar 1;20(5):1335-43. [https://doi.org/10.1200/JCO.2002.20.5.1335 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11870177 PubMed]<br />
#Kosmidis P, Mylonakis N, Nicolaides C, Kalophonos C, Samantas E, Boukovinas J, Fountzilas G, Skarlos D, Economopoulos T, Tsavdaridis D, Papakostas P, Bacoyiannis C, Dimopoulos M. Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol. 2002 Sep 1;20(17):3578-85. [https://doi.org/10.1200/JCO.2002.12.112 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12202657 PubMed]<br />
#Rosell R, Gatzemeier U, Betticher DC, Keppler U, Macha HN, Pirker R, Berthet P, Breau JL, Lianes P, Nicholson M, Ardizzoni A, Chemaissani A, Bogaerts J, Gallant G. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol. 2002 Oct;13(10):1539-49. [https://doi.org/10.1093/annonc/mdf332 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12377641 PubMed]<br />
#'''INTACT 2:''' Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, Wolf MK, Krebs AD, Averbuch SD, Ochs JS, Grous J, Fandi A, Johnson DH. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. J Clin Oncol. 2004 Mar 1;22(5):785-94. [https://doi.org/10.1200/JCO.2004.07.215 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/14990633 PubMed]<br />
#Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004 Jun 1;22(11):2184-91. [https://doi.org/10.1200/jco.2004.11.022 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15169807 PubMed]<br />
#Stathopoulos GP, Veslemes M, Georgatou N, Antoniou D, Giamboudakis P, Katis K, Tsavdaridis D, Rigatos SK, Dimitroulis I, Bastani S, Loukides S, Vergos K, Marossis K, Grigoratou T, Kalatzi E, Charalambatou M, Paspalli A, Michalopoulou P, Stoka M, Gerogianni A. Front-line paclitaxel-vinorelbine versus paclitaxel-carboplatin in patients with advanced non-small-cell lung cancer: a randomized phase III trial. Ann Oncol. 2004 Jul;15(7):1048-55. [https://doi.org/10.1093/annonc/mdq234 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962260/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15205198 PubMed]<br />
#'''CALGB 9730:''' Lilenbaum RC, Herndon JE 2nd, List MA, Desch C, Watson DM, Miller AA, Graziano SL, Perry MC, Saville W, Chahinian P, Weeks JC, Holland JC, Green MR. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the Cancer and Leukemia Group B (study 9730). J Clin Oncol. 2005 Jan 1;23(1):190-6. [https://doi.org/10.1200/JCO.2005.07.172 link to original article]'''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15625373 PubMed]<br />
#'''NCIC-CTG BR.18:''' Leighl NB, Paz-Ares L, Douillard JY, Peschel C, Arnold A, Depierre A, Santoro A, Betticher DC, Gatzemeier U, Jassem J, Crawford J, Tu D, Bezjak A, Humphrey JS, Voi M, Galbraith S, Hann K, Seymour L, Shepherd FA. Randomized phase III study of matrix metalloproteinase inhibitor BMS-275291 in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR18. J Clin Oncol. 2005 Apr 20;23(12):2831-9. [https://doi.org/10.1200/JCO.2005.04.044 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15837997 PubMed]<br />
#'''TRIBUTE:''' Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, Tran HT, Klein P, Li X, Ramies D, Johnson DH, Miller VA; TRIBUTE Investigator Group. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005 Sep 1;23(25):5892-9. Epub 2005 Jul 25. [https://doi.org/10.1200/JCO.2005.02.840 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16043829 PubMed]<br />
#'''SWOG S0003:''' Williamson SK, Crowley JJ, Lara PN Jr, McCoy J, Lau DH, Tucker RW, Mills GM, Gandara DR; [[Study_Groups#SWOG|SWOG]]. Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003. J Clin Oncol. 2005 Dec 20;23(36):9097-104. [https://doi.org/10.1200/JCO.2005.01.3771 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16361616 PubMed]<br />
#Schuette W, Blankenburg T, Guschall W, Dittrich I, Schroeder M, Schweisfurth H, Chemaissani A, Schumann C, Dickgreber N, Appel T, Ukena D. Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin. Clin Lung Cancer. 2006 Mar;7(5):338-43. [https://www.clinical-lung-cancer.com/article/S1525-7304(11)70705-7/pdf link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16640806 PubMed]<br />
#'''FACS:''' Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. [https://doi.org/10.1093/annonc/mdl377 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17079694 PubMed]<br />
#Belani CP, Ramalingam S, Perry MC, LaRocca RV, Rinaldi D, Gable PS, Tester WJ. Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol. 2008 Jan 20;26(3):468-73. [https://doi.org/10.1200/JCO.2007.13.1912 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18202422 PubMed]<br />
#'''SPIRIT II:''' Blumenschein GR Jr, Khuri FR, von Pawel J, Gatzemeier U, Miller WH Jr, Jotte RM, Le Treut J, Sun SL, Zhang JK, Dziewanowska ZE, Negro-Vilar A. Phase III trial comparing carboplatin, paclitaxel, and bexarotene with carboplatin and paclitaxel in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT II. J Clin Oncol. 2008 Apr 10;26(11):1879-85. [https://doi.org/10.1200/JCO.2007.12.2689 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18398153 PubMed]<br />
#'''JMTO LC00-03:''' Kubota K, Kawahara M, Ogawara M, Nishiwaki Y, Komuta K, Minato K, Fujita Y, Teramukai S, Fukushima M, Furuse K; Japan Multi-National Trial Organisation. Vinorelbine plus gemcitabine followed by docetaxel versus carboplatin plus paclitaxel in patients with advanced non-small-cell lung cancer: a randomised, open-label, phase III study. Lancet Oncol. 2008 Dec;9(12):1135-42. Epub 2008 Nov 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(08)70261-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19013107 PubMed] NCT00079287<br />
#'''ALPHA A1-99002L:''' Treat JA, Gonin R, Socinski MA, Edelman MJ, Catalano RB, Marinucci DM, Ansari R, Gillenwater HH, Rowland KM, Comis RL, Obasaju CK, Belani CP; Alpha Oncology Research Network. A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2010 Mar;21(3):540-7. Epub 2009 Oct 15. [https://doi.org/10.1093/annonc/mdp352 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19833819 PubMed] NCT00054392<br />
#'''BMS099:''' Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, Paschold E, Iannotti NO, Dakhil S, Gorton S, Pautret V, Weber MR, Woytowitz D. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol. 2010 Feb 20;28(6):911-7. Epub 2010 Jan 25. [https://doi.org/10.1200/JCO.2009.21.9618 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20100966 PubMed] NCT00112294<br />
#'''ESCAPE:''' Scagliotti G, Novello S, von Pawel J, Reck M, Rodrigues Pereira J, Thomas M, Abrão Miziara JE, Balint B, De Marinis F, Keller A, Arén O, Csollak M, Albert I, Barrios CH, Grossi F, Krzakowski M, Cupit L, Cihon F, Dimatteo S, Hanna N. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol. 2010 Apr 10;28(11):1835-42. Epub 2010 Mar 8. [https://doi.org/10.1200/JCO.2009.26.1321 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20212250 PubMed] NCT00300885<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/274 Project Data Sphere]<br />
#'''LETS:''' Okamoto I, Yoshioka H, Morita S, Ando M, Takeda K, Seto T, Yamamoto N, Saka H, Asami K, Hirashima T, Kudoh S, Satouchi M, Ikeda N, Iwamoto Y, Sawa T, Miyazaki M, Tamura K, Kurata T, Fukuoka M, Nakagawa K; West Japan Oncology Group. Phase III trial comparing oral S-1 plus carboplatin with paclitaxel plus carboplatin in chemotherapy-naïve patients with advanced non-small-cell lung cancer: results of a West Japan Oncology Group study. J Clin Oncol. 2010 Dec 20;28(36):5240-6. Epub 2010 Nov 15. [https://doi.org/10.1200/JCO.2010.31.0326 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21079147 PubMed] UMIN000000503<br />
#Weissman CH, Reynolds CH, Neubauer MA, Pritchard S, Kobina S, Asmar L. A phase III randomized trial of gemcitabine-oxaliplatin versus carboplatin-paclitaxel as first-line therapy in patients with advanced non-small cell lung cancer. J Thorac Oncol. 2011 Feb;6(2):358-64. [https://www.jto.org/article/S1556-0864(15)31941-9/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/21206386 PubMed]<br />
<!-- Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL. --><br />
#'''A8501001:''' Hirsh V, Paz-Ares L, Boyer M, Rosell R, Middleton G, Eberhardt WE, Szczesna A, Reiterer P, Saleh M, Arrieta O, Bajetta E, Webb RT, Raats J, Benner RJ, Fowst C, Meech SJ, Readett D, Schiller JH. Randomized phase III trial of paclitaxel/carboplatin with or without PF-3512676 (Toll-like receptor 9 agonist) as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2011 Jul 1;29(19):2667-74. Epub 2011 May 31. [https://doi.org/10.1200/JCO.2010.32.8971 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21632509 PubMed] NCT00254891<br />
#'''ATTRACT-1:''' Lara PN Jr, Douillard JY, Nakagawa K, von Pawel J, McKeage MJ, Albert I, Losonczy G, Reck M, Heo DS, Fan X, Fandi A, Scagliotti G. Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. J Clin Oncol. 2011 Aug 1;29(22):2965-71. Epub 2011 Jun 27. [https://doi.org/10.1200/JCO.2011.35.0660 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21709202 PubMed] NCT00662597<br />
<!-- Presented in part at The Chicago Multidisciplinary Symposium in Thoracic Oncology, Chicago, IL, December 9-11, 2010, and the 14th World Congress on Lung Cancer, Amsterdam, the Netherlands, July 3-7, 2011. --><br />
#'''CA184-041:''' Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. [https://doi.org/10.1200/jco.2011.38.4032 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22547592 PubMed] NCT00527735<br />
<!-- Presented at the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago, IL, June 4-8, 2010; the 47th Annual Meeting of ASCO, Chicago, IL, June 2-7, 2011, and 14th World Conference on Lung Cancer, Amsterdam Rai, the Netherlands, July 3-7, 2011. --><br />
#'''CA031:''' Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, Hon JK, Hirsh V, Bhar P, Zhang H, Iglesias JL, Renschler MF. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2055-62. Epub 2012 Apr 30. [https://doi.org/10.1200/jco.2011.39.5848 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22547591 PubMed] NCT00540514<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/108 Project Data Sphere]<br />
#'''NCIC-CTG BR.29:''' Laurie SA, Solomon BJ, Seymour L, Ellis PM, Goss GD, Shepherd FA, Boyer MJ, Arnold AM, Clingan P, Laberge F, Fenton D, Hirsh V, Zukin M, Stockler MR, Lee CW, Chen EX, Montenegro A, Ding K, Bradbury PA. Randomised, double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC Clinical Trials Group study BR29. Eur J Cancer. 2014 Mar;50(4):706-12. Epub 2013 Dec 17. [https://www.ejcancer.com/article/S0959-8049(13)01028-9/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24360368 PubMed] NCT00795340<br />
<!-- Presented in part at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. --><br />
#'''A4021016:''' Langer CJ, Novello S, Park K, Krzakowski M, Karp DD, Mok T, Benner RJ, Scranton JR, Olszanski AJ, Jassem J. Randomized, phase III trial of first-line figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2014 Jul 1;32(19):2059-66. Epub 2014 Jun 2. [https://doi.org/10.1200/jco.2013.54.4932 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067944/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24888810 PubMed] NCT00596830<br />
#'''KEYNOTE-024:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1606774/suppl_file/nejmoa1606774_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27718847 PubMed] NCT02142738<br />
##'''HRQoL analysis:''' Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30690-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29129441 PubMed]<br />
##'''Update:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. [https://doi.org/10.1200/JCO.18.00149 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30620668 PubMed]<br />
#'''M10-898:''' Ramalingam SS, Blais N, Mazieres J, Reck M, Jones CM, Juhasz E, Urban L, Orlov S, Barlesi F, Kio E, Keiholz U, Qin Q, Qian J, Nickner C, Dziubinski J, Xiong H, Ansell P, McKee M, Giranda V, Gorbunova V. Randomized, placebo-controlled, phase II study of veliparib in combination with carboplatin and paclitaxel for advanced/metastatic non-small cell lung cancer. Clin Cancer Res. 2017 Apr 15;23(8):1937-1944. Epub 2016 Oct 10. [http://clincancerres.aacrjournals.org/content/23/8/1937.full link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/27803064 PubMed] NCT01560104<br />
#'''SWOG S0819:''' Herbst RS, Redman MW, Kim ES, Semrad TJ, Bazhenova L, Masters G, Oettel K, Guaglianone P, Reynolds C, Karnad A, Arnold SM, Varella-Garcia M, Moon J, Mack PC, Blanke CD, Hirsch FR, Kelly K, Gandara DR. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol. 2018 Jan;19(1):101-114. Epub 2017 Nov 20. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30694-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29169877 PubMed] NCT00946712<br />
#'''MYSTIC:''' Rizvi NA, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn MJ, van den Heuvel MM, Cobo M, Vicente D, Smolin A, Moiseyenko V, Antonia SJ, Le Moulec S, Robinet G, Natale R, Schneider J, Shepherd FA, Geater SL, Garon EB, Kim ES, Goldberg SB, Nakagawa K, Raja R, Higgs BW, Boothman AM, Zhao L, Scheuring U, Stockman PK, Chand VK, Peters S; MYSTIC Investigators. Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 May 1;6(5):661-674. [https://doi.org/10.1001/jamaoncol.2020.0237 link to original article] '''contains verified protocol in supplement''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7146551/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32271377 PubMed] NCT02453282<br />
<br />
==Carboplatin & nab-Paclitaxel {{#subobject:413b7d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:bcb4af|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2011.39.5848 Socinski et al. 2012 (CA031)]<br />
|2007-2009<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#1a9850" |Superior ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 mg/mL/min (per Calvert formula) IV once on day 1, '''given second'''<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, '''given first'''<br />
<br />
'''21-day cycle for 6 cycles'''; treatment could continue at physician's discretion if there was no progressive disease or unacceptable toxicity<br />
<br />
===References===<br />
<br />
#'''CA031:''' Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, Hon JK, Hirsh V, Bhar P, Zhang H, Iglesias JL, Renschler MF. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2055-62. Epub 2012 Apr 30. [https://doi.org/10.1200/jco.2011.39.5848 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22547591 PubMed] NCT00540514<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/108 Project Data Sphere]<br />
<br />
==Carboplatin & Paclitaxel (CP) & Bevacizumab {{#subobject:1c2c25|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PacCBev: '''<u>Pac</u>'''litaxel, '''<u>C</u>'''arboplatin, '''<u>Bev</u>'''acizumab <br />
<br>B+CP: '''<u>B</u>'''evacizumab, '''<u>C</u>'''arboplatin, '''<u>Pac</u>'''litaxel<br />
<br>BCP: '''<u>B</u>'''evacizumab, '''<u>C</u>'''arboplatin, '''<u>Pac</u>'''litaxel<br />
===Regimen {{#subobject:7df5c3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2004.11.022 Johnson et al. 2004]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30694-0/fulltext Herbst et al. 2017 (SWOG S0819)]<br />
|2009-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Carboplatin, Paclitaxel, Bevacizumab, Cetuximab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS<br />
|-<br />
|}<br />
====Biomarker eligibility criteria====<br />
*SWOG S0819: EGFR FISH positive<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 15 to 30 minutes once on day 1, '''given second, starting 60 minutes after the completion of paclitaxel'''<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
====Targeted therapy====<br />
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1, '''given third, starting 60 minutes after the completion of carboplatin'''<br />
**Infusion time per Johnson, et al. 2004 was over 90 minutes for cycle 1; if tolerated, given over 30 to 60 minutes for cycles 2 and later<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004 Jun 1;22(11):2184-91. [https://doi.org/10.1200/jco.2004.11.022 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15169807 PubMed]<br />
#'''SWOG S0819:''' Herbst RS, Redman MW, Kim ES, Semrad TJ, Bazhenova L, Masters G, Oettel K, Guaglianone P, Reynolds C, Karnad A, Arnold SM, Varella-Garcia M, Moon J, Mack PC, Blanke CD, Hirsch FR, Kelly K, Gandara DR. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol. 2018 Jan;19(1):101-114. Epub 2017 Nov 20. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30694-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29169877 PubMed] NCT00946712<br />
<br />
==Carboplatin & Paclitaxel (CP) & Ipilimumab {{#subobject:e8ba81|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f70cfc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2011.38.4032 Lynch et al. 2012 (CA184-041)]<br />
|2008-2009<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
''Note: this is the "phased" approach to this regimen.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Immunotherapy====<br />
<br />
*[[Ipilimumab (Yervoy)]] as follows:<br />
**Cycles 3 to 6: 10 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Steroids|Corticosteroids]] could be used as premedication for [[Paclitaxel (Taxol)]] infusion or for toxicity management.<br />
<br />
'''21-day cycle for up to 6 cycles''' <br />
====Subsequent treatment====<br />
<br />
*[[#Ipilimumab_monotherapy|Maintenance ipilimumab]]<br />
<br />
===References===<br />
<!-- Presented in part at The Chicago Multidisciplinary Symposium in Thoracic Oncology, Chicago, IL, December 9-11, 2010, and the 14th World Congress on Lung Cancer, Amsterdam, the Netherlands, July 3-7, 2011. --><br />
<br />
#'''CA184-041:''' Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. [https://doi.org/10.1200/jco.2011.38.4032 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22547592 PubMed] NCT00527735<br />
<br />
==Carboplatin & Pemetrexed {{#subobject:920f46|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CP: '''<u>C</u>'''arboplatin & '''<u>P</u>'''emetrexed<br />
<br>Carbo-Pem: '''<u>Carbo</u>'''platin & '''<u>Pem</u>'''etrexed<br />
===Example orders===<br />
<br />
*[[Example orders for Carboplatin (Paraplatin) and Pemetrexed (Alimta) in non-small cell lung cancer]]<br />
<br />
===Regimen variant #1, 5/500 x 6 {{#subobject:f0cdea|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
| style="background-color:#d73027" |Inferior HRQoL<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 15 to 60 minutes once on day 1, '''given second'''<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*(Ardizzoni et al. 2012 contained more details):<br />
*[[Dexamethasone (Decadron)]] 4 mg or [[steroid conversions|equivalent corticosteroid]] PO twice per day on the day before, the day of, and day after each dose of [[Pemetrexed (Alimta)]]<br />
*[[Folic acid (Folate)]] 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be taken throughout pemetrexed therapy<br />
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be given throughout pemetrexed therapy<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*Optional [[#Pemetrexed_monotherapy_2|pemetrexed maintenance]]<br />
<br />
===Regimen variant #2, 6/500 x 4 {{#subobject:ecc998|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2008.20.9114 Grønberg et al. 2009]<br />
|2005-2006<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Carboplatin_.26_Gemcitabine_.28GCb.29|Carboplatin & Gemcitabine]]<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRQoL<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 15 to 60 minutes once on day 1, '''given second'''<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*(Ardizzoni et al. 2012 contained more details):<br />
*[[Dexamethasone (Decadron)]] 4 mg or [[steroid conversions|equivalent corticosteroid]] PO twice per day on the day before, the day of, and day after each dose of [[Pemetrexed (Alimta)]]<br />
*[[Folic acid (Folate)]] 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be taken throughout pemetrexed therapy<br />
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be given throughout pemetrexed therapy<br />
<br />
'''21-day cycle for up to 4 cycles'''<br />
<br />
===Regimen variant #3, 6/500 x 6 {{#subobject:8aad39|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
| style="background-color:#d73027" |Inferior HRQoL<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM once every 9 weeks, first dose prior to [[Pemetrexed (Alimta)]]<br />
*[[Folic acid (Folate)]] 1 mg PO once per day<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*Optional [[#Pemetrexed_monotherapy_2|pemetrexed maintenance]]<br />
<br />
===References===<br />
<!-- Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL; and the International Association for the Study of Lung Cancer 12th World Conference on Lung Cancer, September 2-6, 2007, Seoul, Korea. --><br />
<br />
#Grønberg BH, Bremnes RM, Fløtten O, Amundsen T, Brunsvig PF, Hjelde HH, Kaasa S, von Plessen C, Stornes F, Tollåli T, Wammer F, Aasebø U, Sundstrøm S; Norwegian Lung Cancer Study Group. Phase III study by the Norwegian Lung Cancer Study Group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Jul 1;27(19):3217-24. Epub 2009 May 11. [https://doi.org/10.1200/jco.2008.20.9114 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19433683 PubMed]<br />
#'''KEYNOTE-024:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1606774/suppl_file/nejmoa1606774_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27718847 PubMed] NCT02142738<br />
##'''HRQoL analysis:''' Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30690-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29129441 PubMed]<br />
##'''Update:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. [https://doi.org/10.1200/JCO.18.00149 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30620668 PubMed]<br />
<br />
==Carboplatin & Vinorelbine {{#subobject:e7a434|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VC: '''<u>V</u>'''inorelbine & '''<u>C</u>'''arboplatin<br />
===Regimen variant #1, IV vinorelbine {{#subobject:a9c41c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.lungcancerjournal.info/article/S0169-5002(05)00119-4/fulltext Tan et al. 2005 (GLOB 2)]<br />
|2000-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_Vinorelbine|Gemcitabine & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #2, PO vinorelbine {{#subobject:bd4ba1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405221/ Fløtten et al. 2012]<br />
|2007-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_Vinorelbine|Gemcitabine & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 60 mg/m<sup>2</sup> PO once per day on days 1 & 8<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''GLOB 2:''' Tan EH, Szczesna A, Krzakowski M, Macha HN, Gatzemeier U, Mattson K, Wernli M, Reiterer P, Hui R, Pawel JV, Bertetto O, Pouget JC, Burillon JP, Parlier Y, Abratt R; GLOB 2 group. Randomized study of vinorelbine--gemcitabine versus vinorelbine--carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer. 2005 Aug;49(2):233-40. [http://www.lungcancerjournal.info/article/S0169-5002(05)00119-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16022917 PubMed]<br />
#Fløtten Ø, Grønberg BH, Bremnes R, Amundsen T, Sundstrøm S, Rolke H, Hornslien K, Wentzel-Larsen T, Aasebø U, von Plessen C; Norwegian Lung Cancer Study Group. Vinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC: a phase III randomised controlled trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2012 Jul 24;107(3):442-7. Epub 2012 Jul 3. [https://www.nature.com/articles/bjc2012284 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405221/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22759880 PubMed]<br />
<br />
==Cemiplimab monotherapy {{#subobject:179ig6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:igjaze|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/s0140-6736(21)00228-2 Sezer et al. 2021 (EMPOWER-Lung 1)]<br />
|2017-2020<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|1. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|Carboplatin & Gemcitabine]]<br> 2. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br> 3. [[#Carboplatin_.26_Pemetrexed|Carboplatin & Pemetrexed]]<br> 4. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br> 5. [[#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]]<br> 6. Cisplatin & Pemetrexed<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: some of the comparator platinum doublets appear to be histology-specific, but this is not specified in the manuscript or protocol. We have reached out to the authors for clarification. Per Sanofi, "it was strongly recommended that patients with squamous NSCLC do not receive pemetrexed-containing regimens"; otherwise, no histology-specific guidance was provided to the investigator.''<br />
====Biomarker eligibility criteria====<br />
*PD-L1 expressed in at least 50% of tumor cells<br />
====Immunotherapy====<br />
*[[Cemiplimab (Libtayo)]] 350 mg IV over 30 minutes once on day 1<br />
<br />
'''21-day cycle for up to 36 cycles (2 years)'''<br />
===References===<br />
#'''EMPOWER-Lung 1:''' Sezer A, Kilickap S, Gümüş M, Bondarenko I, Özgüroğlu M, Gogishvili M, Turk HM, Cicin I, Bentsion D, Gladkov O, Clingan P, Sriuranpong V, Rizvi N, Gao B, Li S, Lee S, McGuire K, Chen CI, Makharadze T, Paydas S, Nechaeva M, Seebach F, Weinreich DM, Yancopoulos GD, Gullo G, Lowy I, Rietschel P. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet. 2021 Feb 13;397(10274):592-604. [https://doi.org/10.1016/s0140-6736(21)00228-2 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33581821/ PubMed] NCT03088540<br />
<br />
==Cisplatin & Docetaxel (DC) {{#subobject:179d86|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
DC: '''<u>D</u>'''ocetaxel & '''<u>C</u>'''isplatin<br />
<br>DP: '''<u>D</u>'''ocetaxel & '''<u>P</u>'''latinol (Cisplatin)<br />
<br>Doc-Cis: '''<u>Doc</u>'''etaxel & '''<u>Cis</u>'''platin<br />
===Regimen variant #1, 50/75 {{#subobject:c60a4e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://ar.iiarjournals.org/content/33/12/5477.long Berghmans et al. 2013 (ELCWP-01041)]<br />
|2003-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[Non-small_cell_lung_cancer_-_historical#GIP|GIP]]<br> 2. [[Non-small_cell_lung_cancer_-_historical#Ifosfamide_.26_Gemcitabine|IG]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 75/75 {{#subobject:154c29|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="3" |[https://www.nejm.org/doi/full/10.1056/NEJMoa011954 Schiller et al. 2002 (ECOG E1594)]<br />
| rowspan="3" |1996-1999<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|3. [[#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/jco.2003.12.046 Fossella et al. 2003 (TAX 326)]<br />
| rowspan="2" |1998-2000<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Docetaxel]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2006.09.7915 Cobo et al. 2007]<br />
|2001-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ERCC1 mRNA-guided therapy<br />
| style="background-color:#fc8d59" |Seems to have inferior ORR<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdn774 Tan et al. 2009 (GLOB3)]<br />
|2004-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTF<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles (GLOB3) or indefinitely (E1594, TAX326)'''<br />
<br />
===Regimen variant #3, 80/60 {{#subobject:5a7d3b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2004.06.114 Kubota et al. 2004]<br />
|1998-2000<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Non-small_cell_lung_cancer_-_historical#Cisplatin_.26_Vindesine|Cisplatin & Vindesine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.23.3445 Takeda et al. 2009 (WJTOG0203)]<br />
|2003-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Regimen_classes#Platinum_doublet|Platinum doublet]] x 3, then Gefitinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478975/ Kubota et al. 2015 (TCOG0701 CATS)]<br />
|2007-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & S-1<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given second'''<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''<br />
<br />
'''21-day cycle for 3 to 6 cycles'''<br />
<br />
===Regimen variant #4, 80/100 {{#subobject:b1a602|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)04644-4/fulltext Georgoulias et al. 2001]<br />
|1997-1999<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Docetaxel_.26_Gemcitabine|Docetaxel & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of ORR/TTP<br />
|-<br />
|[https://doi.org/10.3816/clc.2003.n.008 Georgoulias et al. 2003]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 2<br />
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#Georgoulias V, Papadakis E, Alexopoulos A, Tsiafaki X, Rapti A, Veslemes M, Palamidas P, Vlachonikolis I; Greek Oncology Cooperative Group (GOCG) for Lung Cancer. Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet. 2001 May 12;357(9267):1478-84. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)04644-4/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/11377599 PubMed]<br />
#'''ECOG E1594:''' Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; [[Study_Groups#ECOG|ECOG]]. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. [https://www.nejm.org/doi/full/10.1056/NEJMoa011954 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11784875 PubMed]<br />
#Georgoulias V, Pallis AG, Kourousis C, Alexopoulos A, Ardavanis A, Agelidou A, Agelidou M, Toumbis M, Tzannes S, Pavlakou G, Ziotopoulos P, Tzelepatiotis E, Samaras N; Hellenic Oncology Research Group. Docetaxel versus docetaxel/cisplatin in patients with advanced non-small-cell lung cancer: preliminary analysis of a multicenter, randomized phase III study. Clin Lung Cancer. 2003 Mar;4(5):288-93. [https://doi.org/10.3816/clc.2003.n.008 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14609446 PubMed]<br />
##'''Update:''' Georgoulias V, Ardavanis A, Agelidou A, Agelidou M, Chandrinos V, Tsaroucha E, Toumbis M, Kouroussis C, Syrigos K, Polyzos A, Samaras N, Papakotoulas P, Christofilakis C, Ziras N, Alegakis A. Docetaxel versus docetaxel plus cisplatin as front-line treatment of patients with advanced non-small-cell lung cancer: a randomized, multicenter phase III trial. J Clin Oncol. 2004 Jul 1;22(13):2602-9. [https://doi.org/10.1200/JCO.2004.11.004 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15226327 PubMed]<br />
<!-- Previously presented in part at the Annual Meeting of the American Society of Clinical Oncology (ASCO), San Francisco, CA, May 12–15, 2001; the Annual Meeting of ASCO, Orlando, FL, May 18–21, 2002; and the Congress of the European Society for Medical Oncology, Nice, France, October 18–22, 2002. --><br />
#'''TAX 326:''' Fossella F, Rodrigues Pereira J, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. [https://doi.org/10.1200/jco.2003.12.046 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12837811 PubMed]<br />
#Kubota K, Watanabe K, Kunitoh H, Noda K, Ichinose Y, Katakami N, Sugiura T, Kawahara M, Yokoyama A, Yokota S, Yoneda S, Matsui K, Kudo S, Shibuya M, Isobe T, Segawa Y, Nishiwaki Y, Ohashi Y, Niitani H; Japanese Taxotere Lung Cancer Study Group. Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group. J Clin Oncol. 2004 Jan 15;22(2):254-61. [https://doi.org/10.1200/JCO.2004.06.114 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/14722033 PubMed]<br />
#Cobo M, Isla D, Massuti B, Montes A, Sanchez JM, Provencio M, Viñolas N, Paz-Ares L, Lopez-Vivanco G, Muñoz MA, Felip E, Alberola V, Camps C, Domine M, Sanchez JJ, Sanchez-Ronco M, Danenberg K, Taron M, Gandara D, Rosell R. Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in non-small-cell lung cancer. J Clin Oncol. 2007 Jul 1;25(19):2747-54. [https://doi.org/10.1200/JCO.2006.09.7915 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17602080 PubMed]<br />
#Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, Yang SH, Choi JH, Heo DS, Park SY, Shin SW, Ahn MJ, Lee JS, Yun YH, Lee JW, Park K. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007 Nov 20;25(33):5233-9. [https://doi.org/10.1200/JCO.2007.10.8134 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18024869 PubMed]<br />
#'''GLOB3:''' Tan EH, Rolski J, Grodzki T, Schneider CP, Gatzemeier U, Zatloukal P, Aitini E, Carteni G, Riska H, Tsai YH, Abratt R. Global Lung Oncology Branch trial 3 (GLOB3): final results of a randomised multinational phase III study alternating oral and iv vinorelbine plus cisplatin versus docetaxel plus cisplatin as first-line treatment of advanced non-small-cell lung cancer. Ann Oncol. 2009 Jul;20(7):1249-56. Epub 2009 Mar 10. [https://doi.org/10.1093/annonc/mdn774 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19276396 PubMed]<br />
#'''WJTOG0203:''' Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. [https://doi.org/10.1200/JCO.2009.23.3445 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20038730 PubMed]<br />
#'''ELCWP-01041:''' Berghmans T, Lafitte JJ, Scherpereel A, Paesmans M, Lecomte J, Marco VG, Meert AP, Leclercq N, Sculier JP; European Lung Cancer Working Party. An ELCWP phase III trial comparing ifosfamide and cisplatin regimens in advanced NSCLC. Anticancer Res. 2013 Dec;33(12):5477-82. [http://ar.iiarjournals.org/content/33/12/5477.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24324084 PubMed] NCT00622349<br />
#'''TCOG0701 CATS:''' Kubota K, Sakai H, Katakami N, Nishio M, Inoue A, Okamoto H, Isobe H, Kunitoh H, Takiguchi Y, Kobayashi K, Nakamura Y, Ohmatsu H, Sugawara S, Minato K, Fukuda M, Yokoyama A, Takeuchi M, Michimae H, Gemma A, Kudoh S; Tokyo Cooperative Oncology Group. A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial. Ann Oncol. 2015 Jul;26(7):1401-8. Epub 2015 Apr 23. [https://doi.org/10.1093/annonc/mdv190 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478975/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/25908605 PubMed] UMIN000000608<br />
<br />
==Cisplatin & Etoposide (EP) {{#subobject:0d191d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PE: '''<u>P</u>'''latinol (Cisplatin) & '''<u>E</u>'''toposide<br />
<br>EC: '''<u>E</u>'''toposide & '''<u>C</u>'''isplatin<br />
===Regimen variant #1, 60/360 {{#subobject:2888e6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1986.4.1.14 Ruckdeschel et al. 1986 (ECOG E1581)]<br />
|1981-1983<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[Non-small_cell_lung_cancer_-_historical#CAMP|CAMP]]<br> 2. [[Non-small_cell_lung_cancer_-_historical#Cisplatin_.26_Vindesine|Cisplatin & Vindesine]]<br> 3. [[Non-small_cell_lung_cancer_-_historical#MVP_.28Vinblastine.29|MVP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint<br />
|-<br />
|}<br />
''Note: this is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Etoposide (Vepesid)]] 120 mg/m<sup>2</sup> IV once per day on days 4, 6, 8<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 75/300 {{#subobject:5151cf|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.3.623 Bonomi et al. 2000 (ECOG E5592)]<br />
|1993-1994<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdi216 Belani et al. 2005]<br />
|1995-1996<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 45 minutes once per day on days 1 to 3<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #3, 100/300 {{#subobject:5281cf|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1999.17.1.12 Cardenal et al. 1999]<br />
|1995-1996<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior TTP<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #4, 105/600 {{#subobject:5a56cf|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819990215%2985%3A4%3C855%3A%3AAID-CNCR12%3E3.0.CO%3B2-R Font et al. 1999]<br />
|1993-1995<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Etoposide_.28EP.29_2|PE]]; dose-dense<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Etoposide (Vepesid)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #5, 120/300 {{#subobject:d94e47|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1990.8.9.1556 Klastersky et al. 1990 (EORTC 07861)]<br />
|1987-1989<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Etoposide_.28CE.29|Carboplatin & Etoposide]]<br />
| style="background-color:#d9ef8b" |Might have superior ORR<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2077209/ Comella et al. 1996]<br />
|1993-1995<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Carboplatin, Cisplatin, Etoposide, Vinorelbine<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 120 mg/m<sup>2</sup> IV once on day 1<br />
**Comella et al. 1996 gave 40 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''3- to 4-week cycles'''<br />
<br />
===References===<br />
<br />
#'''ECOG E1581:''' Ruckdeschel JC, Finkelstein DM, Ettinger DS, Creech RH, Mason BA, Joss RA, Vogl S. A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer. J Clin Oncol. 1986 Jan;4(1):14-22. [https://doi.org/10.1200/JCO.1986.4.1.14 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/3510278 PubMed]<br />
#'''EORTC 07861:''' Klastersky J, Sculier JP, Lacroix H, Dabouis G, Bureau G, Libert P, Richez M, Ravez P, Vandermoten G, Thiriaux J, Cordier R, Finet C, Berchier MC, Sergysels R, Mommen P, Paesmans M. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organisation for Research and Treatment of Cancer Protocol 07861. J Clin Oncol. 1990 Sep;8(9):1556-62. [https://doi.org/10.1200/JCO.1990.8.9.1556 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2167953 PubMed]<br />
#Comella P, Frasci G, De Cataldis G, Panza N, Cioffi R, Curcio C, Belli M, Bianco A, Ianniello G, Maiorino L, Della Vittoria M, Perchard J, Comella G; Gruppo Oncologico Campano. Cisplatin/carboplatin + etoposide + vinorelbine in advanced non-small-cell lung cancer: a multicentre randomised trial. Br J Cancer. 1996 Dec;74(11):1805-11. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2077209/ link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/8956797 PubMed]<br />
#Cardenal F, López-Cabrerizo MP, Antón A, Alberola V, Massuti B, Carrato A, Barneto I, Lomas M, García M, Lianes P, Montalar J, Vadell C, González-Larriba JL, Nguyen B, Artal A, Rosell R. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 1999 Jan;17(1):12-8. [https://doi.org/10.1200/JCO.1999.17.1.12 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10458212 PubMed]<br />
#Font A, Moyano AJ, Puerto JM, Tres A, Garcia-Giron C, Barneto I, Anton A, Sanchez JJ, Salvador A, Rosell R; Spanish Lung Cancer Group. Increasing dose intensity of cisplatin-etoposide in advanced nonsmall cell lung carcinoma: a phase III randomized trial of the Spanish Lung Cancer Group. Cancer. 1999 Feb 15;85(4):855-63. [https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819990215%2985%3A4%3C855%3A%3AAID-CNCR12%3E3.0.CO%3B2-R link to original article] [https://pubmed.ncbi.nlm.nih.gov/10091762 PubMed]<br />
#'''ECOG E5592:''' Bonomi P, Kim K, Fairclough D, Cella D, Kugler J, Rowinsky E, Jiroutek M, Johnson D. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000 Feb;18(3):623-31. [https://doi.org/10.1200/JCO.2000.18.3.623 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10653877 PubMed]<br />
#Belani CP, Lee JS, Socinski MA, Robert F, Waterhouse D, Rowland K, Ansari R, Lilenbaum R, Natale RB. Randomized phase III trial comparing cisplatin-etoposide to carboplatin-paclitaxel in advanced or metastatic non-small cell lung cancer. Ann Oncol. 2005 Jul;16(7):1069-75. Epub 2005 Apr 28. [https://doi.org/10.1093/annonc/mdi216 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15860487 PubMed]<br />
<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:fb3ee0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GC: '''<u>G</u>'''emcitabine & '''<u>C</u>'''isplatin<br />
<br>GP: '''<u>G</u>'''emcitabine & '''<u>P</u>'''latinol (Cisplatin)<br />
===Regimen variant #1, 70/1000 {{#subobject:b0126d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2007.10.8134 Park et al. 2007]<br />
|2002-2004<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]; 6 cycles<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #2, 75/1250 q3wk {{#subobject:0e126e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.03.170 Bissett et al. 2005]<br />
|1999-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GC & Prinomastat<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdm061 Novello et al. 2007]<br />
|2001-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]] x 2, then gemcitabine x 3<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdr030 Manegold et al. 2011]<br />
|2005-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GC & PF-3512676<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
| style="background-color:#d73027" |Inferior HRQoL<br />
|-<br />
|}<br />
''Note: Patients in Novello et al. 2007 received 5 cycles. Patients in KEYNOTE-024 received 4 to 6 cycles.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 30 minutes once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles (see note)'''<br />
<br />
===Regimen variant #3, 75/1250 q4wk {{#subobject:64837d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70254-7/fulltext Wu et al. 2013 (FASTACT-2)]<br />
|2009-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer,_EGFR-mutated#Cisplatin_.26_Gemcitabine.2FErlotinib|GC/Erlotinib]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm.'' <br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #4, 80/1000 {{#subobject:816a83|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="3" |[https://doi.org/10.1093/annonc/mdl377 Ohe et al. 2006 (FACS)]<br />
| rowspan="3" |2000-2002<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|2. [[#Cisplatin_.26_Irinotecan_.28IC.29|Cisplatin & Irinotecan]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|3. [[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.23.3445 Takeda et al. 2009 (WJTOG0203)]<br />
|2003-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Regimen_classes#Platinum_doublet|Platinum doublet]] x 3, then Gefitinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 6 cycles (WJTOG0203) or indefinitely (FACS)'''<br />
<br />
===Regimen variant #5, 80/1125 {{#subobject:10bc56|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394313/ Wachters et al. 2003]<br />
|1998-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Epirubicin & Gemcitabine<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 2<br />
*[[Gemcitabine (Gemzar)]] 1125 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 5 cycles'''<br />
<br />
===Regimen variant #6, 80/1200 x 6 {{#subobject:744a8d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2003.06.099 Gridelli et al. 2003]<br />
|1998-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_Vinorelbine|Gemcitabine & Vinorelbine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70146-8/fulltext Gridelli et al. 2007 (GECO)]<br />
|2003-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. GC & Rofecoxib<br> 2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]; PCI<br> 3. Cisplatin, PCI Gemcitabine, Rofecoxib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2011.41.2056 Gridelli et al. 2012 (TORCH)]<br />
|2006-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Erlotinib<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1200 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*TORCH, at progression: [[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
<br />
===Regimen variant #7, 80/1250 x 4 {{#subobject:f2149d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ejcancer.com/article/S0959-8049(17)31001-8/fulltext Ferry et al. 2017 (BTOG2)]<br />
|rowspan=2|2005-2009<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]; GC50<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|2. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb6]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2011.39.9782 Pérol et al. 2012 (IFCT-GFPC 0502)]<br />
|2006-2009<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
<br />
*IFCT-GFPC 0502: [[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy|Erlotinib switch maintenance]] versus [[#Gemcitabine_monotherapy_2|gemcitabine maintenance]] versus [[Non-small_cell_lung_cancer_-_null_regimens#Observation_3|observation]]<br />
<br />
===Regimen variant #8, 80/1250 x 6 {{#subobject:646326|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2004.08.001 Giaccone et al. 2004 (INTACT 1)]<br />
|2000-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GC & Gefitinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.05.1474 Gatzemeier et al. 2007 (TALENT)]<br />
|2001-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GC & Erlotinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322957/ Boni et al. 2012 (FAST)]<br />
|rowspan=2|2001-2006<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. GIN<br> 2. GN<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|3. [[Non-small_cell_lung_cancer_-_historical#GIP|GIP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.04.3299 Paz-Ares et al. 2006]<br />
|2002-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GC & Aprinocarsen<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #9, 100/1000 q3wk {{#subobject:ec88d3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.spandidos-publications.com/ijo/39/4/1011 Ridolfi et al. 2011]<br />
|2000-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GC & LD IL-2<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #10, 100/1000 q4wk {{#subobject:a352e8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1999.17.11.3522 Crinò et al. 1999]<br />
|1995-1997<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Non-small_cell_lung_cancer_-_historical#MIC_2|MIC]]<br />
| style="background-color:#91cf60" |Seems to have superior ORR<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.1.122 Sandler et al. 2000]<br />
|1995-1997<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Non-small_cell_lung_cancer_-_historical#Cisplatin_monotherapy|Cisplatin]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
| rowspan="3" |[https://www.nejm.org/doi/full/10.1056/NEJMoa011954 Schiller et al. 2002 (ECOG E1594)]<br />
| rowspan="3" |1996-1999<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Cisplatin_.26_Docetaxel_.28DC.29_3|Cisplatin & Docetaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|3. [[#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://doi.org/10.1200/jco.2007.15.0375 Scagliotti et al. 2008 (JMDB)]<br />
|2004-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Cisplatin_.26_Pemetrexed|Cisplatin & Pemetrexed]]<br />
| style="background-color:#eeee01" |Seems to have non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #11, 100/1250 {{#subobject:8bb0be|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1999.17.1.12 Cardenal et al. 1999]<br />
|1995-1996<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Cisplatin_.26_Etoposide_.28EP.29_2|Cisplatin & Etoposide]]<br />
| style="background-color:#1a9850" |Superior TTP<br />
|-<br />
|[https://doi.org/10.1200/JCO.2003.12.038 Alberola et al. 2003]<br />
|1998-2000<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[Stub#PGV|CGV]]<br> 2. GV-VI<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 6 cycles (Alberola et al. 2003) or indefinitely (Cardenal et al. 1999)'''<br />
<br />
===Regimen variant #12, 100/1400 {{#subobject:b9409e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(02)00444-0/fulltext Gebbia et al. 2003]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1400 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''28-day cycles'''<br />
===References===<br />
<br />
#Cardenal F, López-Cabrerizo MP, Antón A, Alberola V, Massuti B, Carrato A, Barneto I, Lomas M, García M, Lianes P, Montalar J, Vadell C, González-Larriba JL, Nguyen B, Artal A, Rosell R. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 1999 Jan;17(1):12-8. [https://doi.org/10.1200/JCO.1999.17.1.12 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10458212 PubMed]<br />
#Crinò L, Scagliotti GV, Ricci S, De Marinis F, Rinaldi M, Gridelli C, Ceribelli A, Bianco R, Marangolo M, Di Costanzo F, Sassi M, Barni S, Ravaioli A, Adamo V, Portalone L, Cruciani G, Masotti A, Ferrara G, Gozzelino F, Tonato M. Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol. 1999 Nov;17(11):3522-30. [https://doi.org/10.1200/JCO.1999.17.11.3522 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10550150 PubMed]<br />
#Sandler AB, Nemunaitis J, Denham C, von Pawel J, Cormier Y, Gatzemeier U, Mattson K, Manegold C, Palmer MC, Gregor A, Nguyen B, Niyikiza C, Einhorn LH. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2000 Jan;18(1):122-30. [https://doi.org/10.1200/JCO.2000.18.1.122 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10623702 PubMed]<br />
#'''ECOG E1594:''' Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; [[Study_Groups#ECOG|ECOG]]. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. [https://www.nejm.org/doi/full/10.1056/NEJMoa011954 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11784875 PubMed]<br />
#Gebbia V, Galetta D, Caruso M, Verderame F, Pezzella G, Valdesi M, Borsellino N, Pandolfo G, Durini E, Rinaldi M, Loizzi M, Gebbia N, Valenza R, Tirrito ML, Varvara F, Colucci G; Gruppo Ocologico Italia Meridionale. Gemcitabine and cisplatin versus vinorelbine and cisplatin versus ifosfamide+gemcitabine followed by vinorelbine and cisplatin versus vinorelbine and cisplatin followed by ifosfamide and gemcitabine in stage IIIB-IV non small cell lung carcinoma: a prospective randomized phase III trial of the Gruppo Oncologico Italia Meridionale. Lung Cancer. 2003 Feb;39(2):179-89. [https://www.lungcancerjournal.info/article/S0169-5002(02)00444-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12581571 PubMed]<br />
#Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B, Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava S, Hirsh V, Bezjak A, Seymour L, Perrone F; Italian GEMVIN Investigators; NCIC-CTG. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Aug 15;21(16):3025-34. Epub 2003 Jul 1. [https://doi.org/10.1200/JCO.2003.06.099 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12837810 PubMed]<br />
#Alberola V, Camps C, Provencio M, Isla D, Rosell R, Vadell C, Bover I, Ruiz-Casado A, Azagra P, Jiménez U, González-Larriba JL, Diz P, Cardenal F, Artal A, Carrato A, Morales S, Sanchez JJ, de las Peñas R, Felip E, López-Vivanco G; Spanish Lung Cancer Group. Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial. J Clin Oncol. 2003 Sep 1;21(17):3207-13. [https://doi.org/10.1200/JCO.2003.12.038 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12947054 PubMed]<br />
#Zatloukal P, Petruzelka L, Zemanová M, Kolek V, Skricková J, Pesek M, Fojtů H, Grygárková I, Sixtová D, Roubec J, Horenková E, Havel L, Průsa P, Nováková L, Skácel T, Kůta M. Gemcitabine plus cisplatin vs gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial. Lung Cancer. 2003 Sep;41(3):321-31. [https://www.lungcancerjournal.info/article/S0169-5002(03)00233-2/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12928123 PubMed]<br />
#Wachters FM, Van Putten JW, Kramer H, Erjavec Z, Eppinga P, Strijbos JH, de Leede GP, Boezen HM, de Vries EG, Groen HJ. First-line gemcitabine with cisplatin or epirubicin in advanced non-small-cell lung cancer: a phase III trial. Br J Cancer. 2003 Oct 6;89(7):1192-9. [https://www.nature.com/articles/6601283 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394313/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/14520444 PubMed]<br />
#'''INTACT 1:''' Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A, Johnson DH. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol. 2004 Mar 1;22(5):777-84. [https://doi.org/10.1200/JCO.2004.08.001 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/14990632 PubMed]<br />
#Bissett D, O'Byrne KJ, von Pawel J, Gatzemeier U, Price A, Nicolson M, Mercier R, Mazabel E, Penning C, Zhang MH, Collier MA, Shepherd FA. Phase III study of matrix metalloproteinase inhibitor prinomastat in non-small-cell lung cancer. J Clin Oncol. 2005 Feb 1;23(4):842-9. [https://doi.org/10.1200/JCO.2005.03.170 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15681529 PubMed]<br />
#Paz-Ares L, Douillard JY, Koralewski P, Manegold C, Smit EF, Reyes JM, Chang GC, John WJ, Peterson PM, Obasaju CK, Lahn M, Gandara DR. Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase C-alpha antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2006 Mar 20;24(9):1428-34. [https://doi.org/10.1200/JCO.2005.04.3299 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16549837 PubMed]<br />
#'''FACS:''' Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. [https://doi.org/10.1093/annonc/mdl377 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17079694 PubMed]<br />
#Novello S, Bruzzi P, Barone C, Buosi R, Masotti A, Michetti G, Fioretti M, Barbera S, Spatafora M, Garetto L, Mazzanti P, Dongiovanni V, Selvaggi G, Crinò L, Scagliotti GV. Phase III study in stage IV non-small-cell lung cancer patients treated with two courses of cisplatin/gemcitabine followed by a randomization to three additional courses of the same combination or gemcitabine alone. Ann Oncol. 2007 May;18(5):903-8. Epub 2007 Mar 9. [https://doi.org/10.1093/annonc/mdm061 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17351253 PubMed]<br />
#'''TALENT:''' Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, Milanowski J, Karnicka-Mlodkowski H, Pesek M, Serwatowski P, Ramlau R, Janaskova T, Vansteenkiste J, Strausz J, Manikhas GM, Von Pawel J. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol. 2007 Apr 20;25(12):1545-52. [https://doi.org/10.1200/JCO.2005.05.1474 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17442998 PubMed]<br />
#'''GECO:''' Gridelli C, Gallo C, Ceribelli A, Gebbia V, Gamucci T, Ciardiello F, Carozza F, Favaretto A, Daniele B, Galetta D, Barbera S, Rosetti F, Rossi A, Maione P, Cognetti F, Testa A, Di Maio M, Morabito A, Perrone F; GECO investigators. Factorial phase III randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study. Lancet Oncol. 2007 Jun;8(6):500-12. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70146-8/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17513173 PubMed] NCT00385606<br />
#Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, Yang SH, Choi JH, Heo DS, Park SY, Shin SW, Ahn MJ, Lee JS, Yun YH, Lee JW, Park K. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007 Nov 20;25(33):5233-9. [https://doi.org/10.1200/JCO.2007.10.8134 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18024869 PubMed]<br />
#'''JMDB:''' Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. Epub 2008 May 27. [https://doi.org/10.1200/jco.2007.15.0375 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18506025 PubMed]<br />
#'''WJTOG0203:''' Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. [https://doi.org/10.1200/JCO.2009.23.3445 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20038730 PubMed]<br />
#Manegold C, van Zandwijk N, Szczesna A, Zatloukal P, Au JS, Blasinska-Morawiec M, Serwatowski P, Krzakowski M, Jassem J, Tan EH, Benner RJ, Ingrosso A, Meech SJ, Readett D, Thatcher N. A phase III randomized study of gemcitabine and cisplatin with or without PF-3512676 (TLR9 agonist) as first-line treatment of advanced non-small-cell lung cancer. Ann Oncol. 2012 Jan;23(1):72-7. Epub 2011 Apr 4. [https://doi.org/10.1093/annonc/mdr030 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/21464154 PubMed]<br />
#Ridolfi L, Bertetto O, Santo A, Naglieri E, Lopez M, Recchia F, Lissoni P, Galliano M, Testore F, Porta C, Maglie M, Dall'agata M, Fumagalli L, Ridolfi R. Chemotherapy with or without low-dose interleukin-2 in advanced non-small cell lung cancer: results from a phase III randomized multicentric trial. Int J Oncol. 2011 Oct;39(4):1011-7. Epub 2011 Jun 24. [https://www.spandidos-publications.com/ijo/39/4/1011 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/21720704 PubMed]<br />
#'''FAST:''' Boni C, Tiseo M, Boni L, Baldini E, Recchia F, Barone C, Grossi F, Germano D, Matano E, Marini G, Labianca R, Di Costanzo F, Bagnulo A, Pennucci C, Caroti C, Mencoboni M, Zanelli F, Prochilo T, Cafferata MA, Ardizzoni A; Gruppo Oncologico Italiano di Ricerca Clinica. Triplets versus doublets, with or without cisplatin, in the first-line treatment of stage IIIB-IV non-small cell lung cancer (NSCLC) patients: a multicenter randomised factorial trial (FAST). Br J Cancer. 2012 Feb 14;106(4):658-65. Epub 2012 Jan 12. [https://www.nature.com/articles/bjc2011606 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322957/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22240782 PubMed]<br />
#'''TORCH:''' Gridelli C, Ciardiello F, Gallo C, Feld R, Butts C, Gebbia V, Maione P, Morgillo F, Genestreti G, Favaretto A, Leighl N, Wierzbicki R, Cinieri S, Alam Y, Siena S, Tortora G, Felletti R, Riccardi F, Mancuso G, Rossi A, Cantile F, Tsao MS, Saieg M, da Cunha Santos G, Piccirillo MC, Di Maio M, Morabito A, Perrone F. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: the TORCH randomized trial. J Clin Oncol. 2012 Aug 20;30(24):3002-11. Epub 2012 Jul 9. [https://doi.org/10.1200/JCO.2011.41.2056 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22778317 PubMed] NCT00349219<br />
##'''HRQoL analysis:''' Di Maio M, Leighl NB, Gallo C, Feld R, Ciardiello F, Butts C, Maione P, Gebbia V, Morgillo F, Wierzbicki R, Favaretto A, Alam Y, Cinieri S, Siena S, Bianco R, Riccardi F, Spatafora M, Ravaioli A, Felletti R, Fregoni V, Genestreti G, Rossi A, Mancuso G, Fasano M, Morabito A, Tsao MS, Signoriello S, Perrone F, Gridelli C. Quality of life analysis of TORCH, a randomized trial testing first-line erlotinib followed by second-line cisplatin/gemcitabine chemotherapy in advancednon-small-cell lung cancer. J Thorac Oncol. 2012 Dec;7(12):1830-1844. [https://www.jto.org/article/S1556-0864(15)33167-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/23154555 PubMed]<br />
#'''IFCT-GFPC 0502:''' Pérol M, Chouaid C, Pérol D, Barlési F, Gervais R, Westeel V, Crequit J, Léna H, Vergnenègre A, Zalcman G, Monnet I, Le Caer H, Fournel P, Falchero L, Poudenx M, Vaylet F, Ségura-Ferlay C, Devouassoux-Shisheboran M, Taron M, Milleron B. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2012 Oct 1;30(28):3516-24. Epub 2012 Sep 4. [https://doi.org/10.1200/JCO.2011.39.9782 link to original article]'''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22949150 PubMed] NCT00300586<br />
#'''FASTACT-2:''' Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, Srimuninnimit V, Sriuranpong V, Sandoval-Tan J, Zhu Y, Liao M, Zhou C, Pan H, Lee V, Chen YM, Sun Y, Margono B, Fuerte F, Chang GC, Seetalarom K, Wang J, Cheng A, Syahruddin E, Qian X, Ho J, Kurnianda J, Liu HE, Jin K, Truman M, Bara I, Mok T. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013 Jul;14(8):777-86. Epub 2013 Jun 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70254-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23782814 PubMed] NCT00883779<br />
#'''KEYNOTE-024:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1606774/suppl_file/nejmoa1606774_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27718847 PubMed] NCT02142738<br />
##'''HRQoL analysis:''' Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30690-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29129441 PubMed]<br />
##'''Update:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. [https://doi.org/10.1200/JCO.18.00149 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30620668 PubMed]<br />
#'''BTOG2:''' Ferry D, Billingham L, Jarrett H, Dunlop D, Woll PJ, Nicolson M, Shah R, Thompson J, Spicer J, Muthukumar D, Skailes G, Leonard P, Chetiyawardana AD, Wells P, Lewanski C, Crosse B, Hill M, Gaunt P, O'Byrne K. Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: results from a British Thoracic Oncology Group randomised phase III trial. Eur J Cancer. 2017 Sep;83:302-312. Epub 2017 Aug 4. [https://www.ejcancer.com/article/S0959-8049(17)31001-8/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28780466 PubMed] NCT00112710<br />
<br />
==Cisplatin & Gemcitabine (GC) & Cetuximab {{#subobject:fb3990|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b02hcd|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2007.13.0856 Butts et al. 2008]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|-<br />
|}<br />
''Note: this was a non-comparative study.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
====Targeted therapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**Cycle 1: 400 mg/m<sup>2</sup> IV once on day 1, then 250 mg/m<sup>2</sup> IV once per day on days 8 & 15<br />
**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Butts CA, Bodkin D, Middleman EL, Englund CW, Ellison D, Alam Y, Kreisman H, Graze P, Maher J, Ross HJ, Ellis PM, McNulty W, Kaplan E, Pautret V, Weber MR, Shepherd FA. Randomized phase II study of gemcitabine plus cisplatin or carboplatin [corrected], with or without cetuximab, as first-line therapy for patients with advanced or metastatic non small-cell lung cancer. J Clin Oncol. 2007 Dec 20;25(36):5777-84. Erratum in: J Clin Oncol. 2008 Jul 1;26(19): 3295. [https://doi.org/10.1200/jco.2007.13.0856 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18089875 PubMed]<br />
<br />
==Cisplatin & Irinotecan (IC) {{#subobject:c1250d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
IP: '''<u>I</u>'''rinotecan & '''<u>P</u>'''latinol (Cisplatin)<br />
===Regimen {{#subobject:4cf321|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747545/ Negoro et al. 2003]<br />
| rowspan="2" |1995-1998<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Non-small_cell_lung_cancer_-_historical#Cisplatin_.26_Vindesine|Cisplatin & Vindesine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|Irinotecan<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
| rowspan="3" |[https://doi.org/10.1093/annonc/mdl377 Ohe et al. 2006 (FACS)]<br />
| rowspan="3" |2000-2002<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|3. [[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.23.3445 Takeda et al. 2009 (WJTOG0203)]<br />
|2003-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Regimen_classes#Platinum_doublet|Platinum doublet]] x 3, then Gefitinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Irinotecan (Camptosar)]] 60 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles (WJTOG0203) or indefinitely (FACS)'''<br />
<br />
===References===<br />
<br />
#Negoro S, Masuda N, Takada Y, Sugiura T, Kudoh S, Katakami N, Ariyoshi Y, Ohashi Y, Niitani H, Fukuoka M; CPT-11 Lung Cancer Study Group West. Randomised phase III trial of irinotecan combined with cisplatin for advanced non-small-cell lung cancer. Br J Cancer. 2003 Feb 10;88(3):335-41. [https://www.nature.com/articles/6600725 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747545/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12569373 PubMed]<br />
#'''FACS:''' Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. [https://doi.org/10.1093/annonc/mdl377 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17079694 PubMed]<br />
#'''WJTOG0203:''' Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. [https://doi.org/10.1200/JCO.2009.23.3445 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20038730 PubMed]<br />
<br />
==Cisplatin & Paclitaxel {{#subobject:7f19fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PC: '''<u>P</u>'''aclitaxel & '''<u>C</u>'''isplatin<br />
===Regimen variant #1, 70/175 x 4 {{#subobject:a142cf|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2007.10.8134 Park et al. 2007]<br />
|2002-2004<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]] x 6<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #2, 70/175 x 6 {{#subobject:a16yqf|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2007.10.8134 Park et al. 2007]<br />
|2002-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]] x 4<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|[https://doi.org/10.1016/j.annonc.2020.10.479 Shi et al. 2020 (PM-03-2015)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Paclitaxel micellar<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #3, 75/135, q2wk {{#subobject:df98d7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962260/ Stathopoulos et al. 2010a]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Liposomal Cisplatin & Paclitaxel<br />
| style="background-color:#ffffbf" |Did not meet secondary endpoints<br />
| style="background-color:#d73027" |More toxic<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 135 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycle for up to 9 cycles'''<br />
<br />
===Regimen variant #4, 75/135, q3wk {{#subobject:5f385|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.3.623 Bonomi et al. 2000 (ECOG E5592)]<br />
|1993-1994<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Cisplatin_.26_Etoposide_.28EP.29_2|Cisplatin & Etoposide]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
| rowspan="3" |[https://www.nejm.org/doi/full/10.1056/NEJMoa011954 Schiller et al. 2002 (ECOG E1594)]<br />
| rowspan="3" |1996-1999<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Cisplatin_.26_Docetaxel_.28DC.29_3|Cisplatin & Docetaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 2, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 135 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1, '''given first'''<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #5, 80/175 {{#subobject:2730a0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.19.3390 Gatzemeier et al. 2000]<br />
|1995-1996<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_historical#Cisplatin_monotherapy|Cisplatin]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://doi.org/10.1200/JCO.2003.03.195 Smit et al. 2003 (EORTC 08975)]<br />
|1998-2000<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br> 2. Gemcitabine & Paclitaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #6, 80/200 {{#subobject:96cd6e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdf332 Rosell et al. 2002]<br />
|1996-1997<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#'''ECOG E5592:''' Bonomi P, Kim K, Fairclough D, Cella D, Kugler J, Rowinsky E, Jiroutek M, Johnson D. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000 Feb;18(3):623-31. [https://doi.org/10.1200/JCO.2000.18.3.623 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10653877 PubMed]<br />
#Gatzemeier U, von Pawel J, Gottfried M, ten Velde GP, Mattson K, de Marinis F, Harper P, Salvati F, Robinet G, Lucenti A, Bogaerts J, Gallant G. Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000 Oct 1;18(19):3390-9. [https://doi.org/10.1200/JCO.2000.18.19.3390 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11013280 PubMed]<br />
#'''ECOG E1594:''' Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; [[Study_Groups#ECOG|ECOG]]. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. [https://www.nejm.org/doi/full/10.1056/NEJMoa011954 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11784875 PubMed]<br />
#Rosell R, Gatzemeier U, Betticher DC, Keppler U, Macha HN, Pirker R, Berthet P, Breau JL, Lianes P, Nicholson M, Ardizzoni A, Chemaissani A, Bogaerts J, Gallant G. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol. 2002 Oct;13(10):1539-49. [https://doi.org/10.1093/annonc/mdf332 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12377641 PubMed]<br />
#'''EORTC 08975:''' Smit EF, van Meerbeeck JP, Lianes P, Debruyne C, Legrand C, Schramel F, Smit H, Gaafar R, Biesma B, Manegold C, Neymark N, Giaccone G; [[Study_Groups#EORTC|EORTC]] Lung Cancer Group. Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organisation for Research and Treatment of Cancer Lung Cancer Group--EORTC 08975. J Clin Oncol. 2003 Nov 1;21(21):3909-17. [https://doi.org/10.1200/JCO.2003.03.195 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/14581415 PubMed]<br />
#Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, Yang SH, Choi JH, Heo DS, Park SY, Shin SW, Ahn MJ, Lee JS, Yun YH, Lee JW, Park K. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007 Nov 20;25(33):5233-9. [https://doi.org/10.1200/JCO.2007.10.8134 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18024869 PubMed]<br />
#Stathopoulos GP, Antoniou D, Dimitroulis J, Michalopoulou P, Bastas A, Marosis K, Stathopoulos J, Provata A, Yiamboudakis P, Veldekis D, Lolis N, Georgatou N, Toubis M, Pappas Ch, Tsoukalas G. Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial. Ann Oncol. 2010 Nov;21(11):2227-32. Epub 2010 May 3. [https://doi.org/10.1093/annonc/mdq234 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962260/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20439345 PubMed]<br />
#'''PM-03-2015:''' Shi M, Gu A, Tu H, Huang C, Wang H, Yu Z, Wang X, Cao L, Shu Y, Wang H, Yang R, Li X, Chang J, Hu Y, Shen P, Hu Y, Guo Z, Tao M, Zhang Y, Liu X, Sun Q, Zhang X, Jiang Z, Zhao J, Chen F, Yu H, Zhang W, Sun J, Li D, Zhou J, Han B, Wu YL. Comparing nanoparticle polymeric micellar paclitaxel and solvent-based paclitaxel as first-line treatment of advanced non-small-cell lung cancer: an open-label, randomized, multicenter, phase III trial. Ann Oncol. 2021 Jan;32(1):85-96. Epub 2020 Oct 29. [https://doi.org/10.1016/j.annonc.2020.10.479 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/33130217 PubMed] NCT02667743<br />
<br />
==Cisplatin & Vinorelbine {{#subobject:bdd6b2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CV: '''<u>C</u>'''isplatin & '''<u>V</u>'''inorelbine<br />
<br>NP: '''<u>N</u>'''avelbine (Vinorelbine) & '''<u>P</u>'''latinol (Cisplatin)<br />
<br>PV: '''<u>P</u>'''latinol (Cisplatin) & '''<u>V</u>'''inorelbine<br />
<br>VC: '''<u>V</u>'''inorelbine & '''<u>C</u>'''isplatin<br />
===Regimen variant #1, 75/25 {{#subobject:21f9be|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(04)00772-5/fulltext Martoni et al. 2005]<br />
|1998-2003<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*Vinorelbine maintenance<br />
<br />
===Regimen variant #2, 80/25 {{#subobject:daeaf6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="3" |[https://doi.org/10.1093/annonc/mdl377 Ohe et al. 2006 (FACS)]<br />
| rowspan="3" |2000-2002<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|3. [[#Cisplatin_.26_Irinotecan_.28IC.29|Cisplatin & Irinotecan]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.23.3445 Takeda et al. 2009 (WJTOG0203)]<br />
|2003-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Regimen_classes#Platinum_doublet|Platinum doublet]] x 3, then Gefitinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60569-9/fulltext Pirker et al. 2009 (FLEX)]<br />
|2004-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin.2C_Vinorelbine.2C_Cetuximab|Cisplatin, Vinorelbine, Cetuximab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles (FLEX; WJTOG0203) or indefinitely (FACS)'''<br />
<br />
===Regimen variant #3, 80/30, 2 out of 3 weeks vinorelbine {{#subobject:6c3243|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2003.06.099 Gridelli et al. 2003]<br />
|1998-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_Vinorelbine|Gemcitabine & Vinorelbine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.04.016 Georgoulias et al. 2005]<br />
|1999-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Docetaxel_.26_Gemcitabine|Docetaxel & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(08)00009-3/fulltext Gebbia et al. 2008]<br />
|2003-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]; 3 out of 4 weeks<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
| style="background-color:#1a9850" |Less toxic<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 8<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 6 cycles (Gridelli et al. 2003) or up to 9 cycles (Georgoulias et al. 2005)'''<br />
<br />
===Regimen variant #4, 80/30, weekly vinorelbine {{#subobject:6c3243|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/oxfordjournals.annonc.a058687 Depierre et al. 1994]<br />
|1989-1991<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Vinorelbine<br />
| style="background-color:#1a9850" |Superior TTP<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdf316 Souquet et al. 2002 (GLOB-1)]<br />
|1998-1999<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#NIP|NIP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS1<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #5, 100/25 {{#subobject:45998f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1998.16.7.2459 Wozniak et al. 1998]<br />
|1993-1995<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Non-small_cell_lung_cancer_-_historical#Cisplatin_monotherapy|Cisplatin]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2001.19.13.3210 Kelly et al. 2001 (SWOG 9509)]<br />
|1996-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2002.02.068 Scagliotti et al. 2002]<br />
|1998-2000<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br> 2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/jco.2003.12.046 Fossella et al. 2003 (TAX 326)]<br />
| rowspan="2" |1998-2000<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Carboplatin_.26_Docetaxel|Carboplatin & Docetaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Cisplatin_.26_Docetaxel_.28DC.29_3|Cisplatin & Docetaxel]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2007.12.2614 Ramlau et al. 2008 (SPIRIT I)]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CV & Bexarotene<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 10 cycles (SWOG 9509) or indefinitely (TAX 326, SPIRIT I)'''<br />
<br />
===Regimen variant #6, 100/30 {{#subobject:cda93a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1023/a:1008338312647 Robinet et al. 2001 (GFPC 95-1)]<br />
|1995-1997<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CV & concurrent WBRT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdi126 Pujol et al. 2005]<br />
|1999-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Docetaxel_.26_Gemcitabine|Docetaxel & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: patients in GFPC 95-1 had intracranial metastases.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 60 to 120 minutes once on day 1<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV over 10 to 20 minutes once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*GFPC 95-1: [[External_beam_radiotherapy|WBRT]]<br />
<br />
===Regimen variant #7, 120/30 {{#subobject:2bf191|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.1994.12.2.360 Le Chevalier et al. 1994]<br />
| rowspan="2" |1989-1991<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|1. Cisplatin & Vindesine<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|2. Vinorelbine<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2000.18.7.1451 Comella et al. 2000]<br />
| rowspan="2" |1997-1999<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[Stub#PGV|PGV]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Note: in Comella et al. 2000, vinorelbine was given for a total of 10 weeks.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 120 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] as follows:<br />
**Cycle 1: 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Cycle 2 onwards: 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
'''28-day cycle for 1 cycle, then 42-day cycles (see note)'''<br />
<br />
===References===<br />
<br />
#Depierre A, Chastang C, Quoix E, Lebeau B, Blanchon F, Paillot N, Lemarie E, Milleron B, Moro D, Clavier J, Herman D, Tuchais E, Jacoulet P, Brechot JM, Cordier JF, Solal-Celigny P, Badri N, Besenval M. Vinorelbine versus vinorelbine plus cisplatin in advanced non-small cell lung cancer: a randomized trial. Ann Oncol. 1994 Jan;5(1):37-42. [https://doi.org/10.1093/oxfordjournals.annonc.a058687 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/8172790 PubMed]<br />
#Le Chevalier T, Brisgand D, Douillard JY, Pujol JL, Alberola V, Monnier A, Riviere A, Lianes P, Chomy P, Cigolari S, Gottfried M, Ruffle P, Panizo A, Gaspard MH, Ravaioli A, Besenval M, Besson F, Martinez A, Berthaud P, Tursz T. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol. 1994 Feb;12(2):360-7. [https://doi.org/10.1200/JCO.1994.12.2.360 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/8113844 PubMed]<br />
#Wozniak AJ, Crowley JJ, Balcerzak SP, Weiss GR, Spiridonidis CH, Baker LH, Albain KS, Kelly K, Taylor SA, Gandara DR, Livingston RB; [[Study_Groups#SWOG|SWOG]]. Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol. 1998 Jul;16(7):2459-65. [https://doi.org/10.1200/JCO.1998.16.7.2459 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9667264 PubMed]<br />
#Comella P, Frasci G, Panza N, Manzione L, De Cataldis G, Cioffi R, Maiorino L, Micillo E, Lorusso V, Di Rienzo G, Filippelli G, Lamberti A, Natale M, Bilancia D, Nicolella G, Di Nota A, Comella G; Southern Italy Cooperative Oncology Group. Randomized trial comparing cisplatin, gemcitabine, and vinorelbine with either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non-small-cell lung cancer: interim analysis of a phase III trial of the Southern Italy Cooperative Oncology Group. J Clin Oncol. 2000 Apr;18(7):1451-7. [https://doi.org/10.1200/JCO.2000.18.7.1451 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10735892 PubMed]<br />
#'''GFPC 95-1:''' Robinet G, Thomas P, Breton JL, Léna H, Gouva S, Dabouis G, Bennouna J, Souquet PJ, Balmes P, Thiberville L, Fournel P, Quoix E, Riou R, Rebattu P, Pérol M, Paillotin D, Mornex F. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Français de Pneumo-Cancérologie (GFPC) Protocol 95-1. Ann Oncol. 2001 Jan;12(1):59-67. [https://doi.org/10.1023/a:1008338312647 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11249050 PubMed]<br />
#'''SWOG 9509:''' Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, Ramsey SD, Wozniak AJ, Weiss GR, Moore DF, Israel VK, Livingston RB, Gandara DR. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol. 2001 Jul 1;19(13):3210-8. [https://doi.org/10.1200/JCO.2001.19.13.3210 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11432888 PubMed]<br />
#Scagliotti GV, De Marinis F, Rinaldi M, Crinò L, Gridelli C, Ricci S, Matano E, Boni C, Marangolo M, Failla G, Altavilla G, Adamo V, Ceribelli A, Clerici M, Di Costanzo F, Frontini L, Tonato M; Italian Lung Cancer Project. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol. 2002 Nov 1;20(21):4285-91. [https://doi.org/10.1200/JCO.2002.02.068 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12409326 PubMed]<br />
#'''GLOB-1:''' Souquet PJ, Tan EH, Rodrigues Pereira J, Van Klaveren R, Price A, Gatzemeier U, Jaworski M, Burillon JP, Aubert D. GLOB-1: a prospective randomised clinical phase III trial comparing vinorelbine-cisplatin with vinorelbine-ifosfamide-cisplatin in metastatic non-small-cell lung cancer patients. Ann Oncol. 2002 Dec;13(12):1853-61. Erratum in: Ann Oncol. 2003 Feb;14(2):347. [https://doi.org/10.1093/annonc/mdf316 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12453852 PubMed]<br />
<!-- Previously presented in part at the Annual Meeting of the American Society of Clinical Oncology (ASCO), San Francisco, CA, May 12–15, 2001; the Annual Meeting of ASCO, Orlando, FL, May 18–21, 2002; and the Congress of the European Society for Medical Oncology, Nice, France, October 18–22, 2002. --><br />
#'''TAX 326:''' Fossella F, Rodrigues Pereira J, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. [https://doi.org/10.1200/jco.2003.12.046 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12837811 PubMed]<br />
#Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B, Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava S, Hirsh V, Bezjak A, Seymour L, Perrone F; Italian GEMVIN Investigators; NCIC-CTG. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Aug 15;21(16):3025-34. Epub 2003 Jul 1. [https://doi.org/10.1200/JCO.2003.06.099 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12837810 PubMed]<br />
#Martoni A, Marino A, Sperandi F, Giaquinta S, Di Fabio F, Melotti B, Guaraldi M, Palomba G, Preti P, Petralia A, Artioli F, Picece V, Farris A, Mantovani L. Multicentre randomised phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer. Eur J Cancer. 2005 Jan;41(1):81-92. [https://www.ejcancer.com/article/S0959-8049(04)00772-5/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15617993 PubMed]<br />
#Georgoulias V, Ardavanis A, Tsiafaki X, Agelidou A, Mixalopoulou P, Anagnostopoulou O, Ziotopoulos P, Toubis M, Syrigos K, Samaras N, Polyzos A, Christou A, Kakolyris S, Kouroussis C, Androulakis N, Samonis G, Chatzidaki D. Vinorelbine plus cisplatin versus docetaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol. 2005 May 1;23(13):2937-45. Epub 2005 Feb 22. [https://doi.org/10.1200/JCO.2005.04.016 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15728228 PubMed]<br />
#Pujol JL, Breton JL, Gervais R, Rebattu P, Depierre A, Morère JF, Milleron B, Debieuvre D, Castéra D, Souquet PJ, Moro-Sibilot D, Lemarié E, Kessler R, Janicot H, Braun D, Spaeth D, Quantin X, Clary C. Gemcitabine-docetaxel versus cisplatin-vinorelbine in advanced or metastatic non-small-cell lung cancer: a phase III study addressing the case for cisplatin. Ann Oncol. 2005 Apr;16(4):602-10. Epub 2005 Mar 1. [https://doi.org/10.1093/annonc/mdi126 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15741225 PubMed]<br />
#'''FACS:''' Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. [https://doi.org/10.1093/annonc/mdl377 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17079694 PubMed]<br />
#Gebbia V, Galetta D, Lorusso V, Caruso M, Verderame F, Pezzella G, Borsellino N, Durini E, Valenza R, Agostara B, Colucci G; Gruppo Oncologico Italia Meridionale. Cisplatin plus weekly vinorelbine versus cisplatin plus vinorelbine on days 1 and 8 in advanced non-small cell lung cancer: a prospective randomized phase III trial of the GOIM (Gruppo Oncologico Italia Meridionale). Lung Cancer. 2008 Sep;61(3):369-77. Epub 2008 Mar 4. [https://www.lungcancerjournal.info/article/S0169-5002(08)00009-3/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18308419 PubMed]<br />
#'''SPIRIT I:''' Ramlau R, Zatloukal P, Jassem J, Schwarzenberger P, Orlov SV, Gottfried M, Rodrigues Pereira J, Temperley G, Negro-Vilar R, Rahal S, Zhang JK, Negro-Vilar A, Dziewanowska ZE. Randomized phase III trial comparing bexarotene (L1069-49)/cisplatin/vinorelbine with cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT I. J Clin Oncol. 2008 Apr 10;26(11):1886-92. [https://doi.org/10.1200/JCO.2007.12.2614 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18398154 PubMed]<br />
#'''FLEX:''' Pirker R, Rodrigues Pereira J, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009 May 2;373(9674):1525-31. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60569-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19410716 PubMed] NCT00148798<br />
#'''WJTOG0203:''' Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. [https://doi.org/10.1200/JCO.2009.23.3445 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20038730 PubMed]<br />
<br />
==Cisplatin, Vinorelbine, Cetuximab {{#subobject:9c28e0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b4c5e3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60569-9/fulltext Pirker et al. 2009 (FLEX)]<br />
|2004-2006<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_.26_Vinorelbine_2|Cisplatin & Vinorelbine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
====Targeted therapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**Cycle 1: 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, then 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 8 & 15<br />
**Cycles 2 to 6: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
====Subsequent treatment====<br />
<br />
*Cetuximab maintenance<br />
<br />
===References===<br />
<br />
#'''FLEX:''' Pirker R, Rodrigues Pereira J, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009 May 2;373(9674):1525-31. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60569-9/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19410716 PubMed] NCT00148798<br />
<br />
==Docetaxel & Vinorelbine {{#subobject:18h94c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:abi4b2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.6.1346 Miller et al. 2000]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]]<br />
*[[Vinorelbine (Navelbine)]]<br />
<br />
===References===<br />
<br />
#Miller VA, Krug LM, Ng KK, Pizzo B, Perez W, Heelan RT, Kris MG. Phase II trial of docetaxel and vinorelbine in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000 Mar;18(6):1346-50. [https://doi.org/10.1200/JCO.2000.18.6.1346 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10715307 PubMed]<br />
<br />
==Gemcitabine & Paclitaxel {{#subobject:29305d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GT: '''<u>G</u>'''emcitabine & '''<u>T</u>'''axol (Paclitaxel)<br />
<br />
===Regimen variant #1, 1000/125 {{#subobject:b3708b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2002.12.112 Kosmidis et al. 2002]<br />
|1998-2000<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdm430 Kosmidis et al. 2007]<br />
|2000-2004<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Carboplatin_.26_Gemcitabine_.28GCb.29|Carboplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdl396 Comella et al. 2006 (SICOG 0101)]<br />
|2001-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Gemcitabine_.26_Vinorelbine|GV]]<br> 2. [[Stub#PGT|PGT]]<br> 3. [[Stub#PGV|PGV]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Paclitaxel (Taxol)]] 125 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #2, 1000/200 {{#subobject:b9275b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdq445 Kosmidis et al. 2010]<br />
|2004-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Paclitaxel & Vinorelbine<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#Kosmidis PA, Kalofonos HP, Christodoulou C, Syrigos K, Makatsoris T, Skarlos D, Bakogiannis C, Nicolaides C, Bafaloukos D, Bamias A, Samantas E, Xiros N, Boukovinas I, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group. Ann Oncol. 2008 Jan;19(1):115-22. Epub 2007 Oct 15. [https://doi.org/10.1093/annonc/mdm430 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17938425 PubMed]<br />
#'''SICOG 0101:''' Comella P, Filippelli G, De Cataldis G, Massidda B, Frasci G, Maiorino L, Putzu C, Mancarella S, Palmeri S, Cioffi R, Roselli M, Buzzi F, Milia V, Gambardella A, Natale D, Bianco M, Ghiani M, Masullo P; Southern Italy Cooperative Oncology Group. Efficacy of the combination of cisplatin with either gemcitabine and vinorelbine or gemcitabine and paclitaxel in the treatment of locally advanced or metastatic non-small-cell lung cancer: a phase III randomised trial of the Southern Italy Cooperative Oncology Group (SICOG 0101). Ann Oncol. 2007 Feb;18(2):324-30. Epub 2006 Oct 27. [https://doi.org/10.1093/annonc/mdl396 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17071935 PubMed]<br />
#Kosmidis PA, Fountzilas G, Eleftheraki AG, Kalofonos HP, Pentheroudakis G, Skarlos D, Dimopoulos MA, Bafaloukos D, Pectasides D, Samantas E, Boukovinas J, Lambaki S, Katirtzoglou N, Bakogiannis C, Syrigos KN; Hellenic Cooperative Oncology Group. Paclitaxel and gemcitabine versus paclitaxel and vinorelbine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol. 2011 Apr;22(4):827-34. Epub 2010 Sep 29. [https://doi.org/10.1093/annonc/mdq445 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20880999 PubMed] ACTRN12609000946213<br />
<br />
==Gemcitabine & Vinorelbine {{#subobject:3c6eb0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VG: '''<u>V</u>'''inorelbine & '''<u>G</u>'''emcitabine<br />
<br>GV: '''<u>G</u>'''emcitabine & '''<u>V</u>'''inorelbine<br />
<br>G+V: '''<u>G</u>'''emcitabine & '''<u>V</u>'''inorelbine<br />
===Regimen variant #1, 1000/25, 2 weeks out of 3 (IV vinorelbine) {{#subobject:a01f58|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2004.10.576 Laack et al. 2004]<br />
|1999-2001<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[Stub#GVP|GVP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[http://www.lungcancerjournal.info/article/S0169-5002(05)00119-4/fulltext Tan et al. 2005 (GLOB 2)]<br />
|2000-2002<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Carboplatin_.26_Vinorelbine|Carboplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*"[[:Category:Emesis_prevention|Antiemetic]] agents and other supportive treatments were provided at the discretion of the treating physician."<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 1000/25, 3 weeks out of 4 (IV vinorelbine) {{#subobject:2c7f61|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.clinical-lung-cancer.com/article/S1525-7304(11)70825-7/pdf Greco et al. 2007]<br />
|1998-2005<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|PCG<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
| style="background-color:#1a9850" |Less toxic<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3, 1000/60 (PO vinorelbine) {{#subobject:c8251a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405221/ Fløtten et al. 2012]<br />
|2007-2009<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Carboplatin_.26_Vinorelbine|Carboplatin & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Vinorelbine (Navelbine)]] 60 mg/m<sup>2</sup> PO once per day on days 1 & 8<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===Regimen variant #4, 1200/30 {{#subobject:c8uv1a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(01)00392-0/fulltext Frasci et al. 2001]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Vinorelbine_monotherapy|Vinorelbine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1200 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#Frasci G, Lorusso V, Panza N, Comella P, Nicolella G, Bianco A, DeCataldis G, Belli M, Iannelli N, Massidda B, Mascia V, Comella G, De Lena M; Southern Italy Cooperative Oncology Group. Gemcitabine plus vinorelbine yields better survival outcome than vinorelbine alone in elderly patients with advanced non-small cell lung cancer: a Southern Italy Cooperative Oncology Group (SICOG) phase III trial. Lung Cancer. 2001 Dec;34 Suppl 4:S65-9. [https://www.lungcancerjournal.info/article/S0169-5002(01)00392-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11742706 PubMed]<br />
#Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B, Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava S, Hirsh V, Bezjak A, Seymour L, Perrone F; Italian GEMVIN Investigators; NCIC-CTG. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Aug 15;21(16):3025-34. Epub 2003 Jul 1. [https://doi.org/10.1200/JCO.2003.06.099 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12837810 PubMed]<br />
#Laack E, Dickgreber N, Müller T, Knuth A, Benk J, Lorenz C, Gieseler F, Dürk H, Engel-Riedel W, Dalhoff K, Kortsik C, Graeven U, Burk M, Dierlamm T, Welte T, Burkholder I, Edler L, Hossfeld DK; German and Swiss Lung Cancer Study Group. Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung cancer: from the German and Swiss Lung Cancer Study Group. J Clin Oncol. 2004 Jun 15;22(12):2348-56. [https://doi.org/10.1200/JCO.2004.10.576 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15197195 PubMed]<br />
#'''GLOB 2:''' Tan EH, Szczesna A, Krzakowski M, Macha HN, Gatzemeier U, Mattson K, Wernli M, Reiterer P, Hui R, Pawel JV, Bertetto O, Pouget JC, Burillon JP, Parlier Y, Abratt R; GLOB 2 group. Randomized study of vinorelbine--gemcitabine versus vinorelbine--carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer. 2005 Aug;49(2):233-40. [http://www.lungcancerjournal.info/article/S0169-5002(05)00119-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16022917 PubMed]<br />
#Greco FA, Spigel DR, Kuzur ME, Shipley D, Gray JR, Thompson DS, Burris HA, Yardley DA, Pati A, Webb CD, Gandhi JG, Hainsworth JD. Paclitaxel/Carboplatin/gemcitabine versus gemcitabine/vinorelbine in advanced non-small-cell lung cancer: a phase II/III study of the Minnie Pearl Cancer Research Network. Clin Lung Cancer. 2007 Sep;8(8):483-7. [https://www.clinical-lung-cancer.com/article/S1525-7304(11)70825-7/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/17922972 PubMed]<br />
#Fløtten Ø, Grønberg BH, Bremnes R, Amundsen T, Sundstrøm S, Rolke H, Hornslien K, Wentzel-Larsen T, Aasebø U, von Plessen C; Norwegian Lung Cancer Study Group. Vinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC: a phase III randomised controlled trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2012 Jul 24;107(3):442-7. Epub 2012 Jul 3. [https://www.nature.com/articles/bjc2012284 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405221/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22759880 PubMed]<br />
<br />
==Ipilimumab & Nivolumab {{#subobject:517ff0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3a481c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1801946 Hellmann et al. 2018 (CheckMate 227)]<br />
|rowspan=2|2015-2016<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|1. [[#Nivolumab_monotherapy|Nivolumab]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[Regimen_classes#Platinum_doublet|Platinum doublet]]<br />
| style="background-color:#1a9850" |Superior OS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2019 update.''<br />
====Immunotherapy====<br />
<br />
*[[Ipilimumab (Yervoy)]] 1 mg/kg IV once on day 1<br />
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once per day on days 1, 15, 29<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<br />
#'''CheckMate 227:''' Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018 May 31;378(22):2093-2104. Epub 2018 Apr 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1801946 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29658845 PubMed] NCT02477826<br />
##'''Update:''' Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, Park K, Alexandru A, Lupinacci L, de la Mora Jimenez E, Sakai H, Albert I, Vergnenegre A, Peters S, Syrigos K, Barlesi F, Reck M, Borghaei H, Brahmer JR, O'Byrne KJ, Geese WJ, Bhagavatheeswaran P, Rabindran SK, Kasinathan RS, Nathan FE, Ramalingam SS. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019 Nov 21;381(21):2020-2031. Epub 2019 Sep 28. [https://www.nejm.org/doi/full/10.1056/NEJMoa1910231 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31562796 PubMed]<br />
<br />
==Ipilimumab & Nivolumab & Platinum doublet {{#subobject:#08c783|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:#c626c7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30641-0/fulltext Paz-Ares et al. 2021 (CheckMate 9LA)]<br />
|rowspan=2|2017-2019<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[Regimen_classes#Platinum_doublet|Platinum doublet]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Platinum doublet histology-based.''<br />
====Immunotherapy====<br />
<br />
*[[Ipilimumab (Yervoy)]] 1 mg/kg intravenously every 6 weeks<br />
*[[Nivolumab (Opdivo)]] 360 mg intravenously every 3 weeks<br />
<br />
continued until progression <br />
<br />
====Chemotherapy====<br />
<br />
===References===<br />
<br />
#'''CheckMate 9LA''' Paz-Ares L, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Salman P, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, John T, Carbone DP, Meadows-Shropshire S, Agrawal S, Oukessou A, Yan J, Reck M. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):198-211. Epub 2021 Jan 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30641-0/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/33476593 PubMed] NCT02477826<br />
<br />
==Nivolumab monotherapy {{#subobject:PYR1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:PYV1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613493 Carbone et al. 2017 (CheckMate 026)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[Regimen_classes#Platinum_doublet|Platinum doublet]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''Note: control arm patients in CheckMate 026 received investigator's choice of platinum doublet; the most commonly used regimen was [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|carboplatin & paclitaxel]].''<br />
====Immunotherapy====<br />
<br />
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1<br />
**Notably, on 9/13/16 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''CheckMate 026:''' Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van den Heuvel MM, Ciuleanu TE, Badin F, Ready N, Hiltermann TJN, Nair S, Juergens R, Peters S, Minenza E, Wrangle JM, Rodriguez-Abreu D, Borghaei H, Blumenschein GR Jr, Villaruz LC, Havel L, Krejci J, Corral Jaime J, Chang H, Geese WJ, Bhagavatheeswaran P, Chen AC, Socinski MA; CheckMate 026 Investigators. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017 Jun 22;376(25):2415-2426. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613493 link to original article]'''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28636851 PubMed] NCT02041533<br />
#'''CheckMate 227:''' Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018 May 31;378(22):2093-2104. Epub 2018 Apr 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1801946 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29658845 PubMed] NCT02477826<br />
<br />
==Pembrolizumab monotherapy {{#subobject:430dc7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d2e0ab|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1501824 Garon et al. 2015 (KEYNOTE-001)]<br />
|2012-2014<br />
| style="background-color:#91cf61" |Phase 1, >20 pts in dosing cohort<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|1. [[#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]]<br> 2. [[#Carboplatin_.26_Paclitaxel_4 | Carboplatin & Paclitaxel]]<br> 3. [[#Carboplatin_.26_Pemetrexed | Carboplatin & Pemetrexed]]<br> 4. [[#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]]<br> 5. [[#Cisplatin_.26_Pemetrexed_2 | Cisplatin & Pemetrexed]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior HRQoL<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32409-7/fulltext Mok et al. 2019 (KEYNOTE-042)]<br />
|2014-2017<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|1. [[#Carboplatin_.26_Paclitaxel_6 | Carboplatin & Paclitaxel]]<br> 2. [[#Carboplatin_.26_Pemetrexed_2 | Carboplatin & Pemetrexed]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|<br />
|-<br />
|}<br />
''KEYNOTE-024 required PD-L1 to be expressed on at least '''50% of tumor cells''', no EGFR/ALK mutations. Treatment choice for patients in the comparator arm was up to the investigators; most with nonsquamous histology received carboplatin & pemetrexed, whereas most with squamous histology received carboplatin & gemcitabine. Patients could receive a maximum of 35 cycles. ORR was 45% (95% CI: 37-53).''<br />
<br>''KEYNOTE-042 required PD-L1 to be expressed on at least '''1% of tumor cells'''. Treatment choice for patients in the comparator arm was carboplatin & paclitaxel for patients with squamous histology, and carboplatin & pemetrexed for patients with nonsquamous histology.''<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Phase 1:''' Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28. Epub 2015 Apr 19. [https://www.nejm.org/doi/full/10.1056/NEJMoa1501824 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25891174 PubMed] NCT01295827<br />
#'''KEYNOTE-024:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1606774/suppl_file/nejmoa1606774_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27718847 PubMed] NCT02142738<br />
##'''HRQoL analysis:''' Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30690-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29129441 PubMed]<br />
##'''Update:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. [https://doi.org/10.1200/JCO.18.00149 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30620668 PubMed]<br />
<!-- # '''Abstract:''' Tony Mok, Yi-Long Wu, Patricia A, Watson, Jin Zhang, Reshma A. Rangwala, and Gilberto Lopes. Phase 3 KEYNOTE-042 trial of pembrolizumab (MK-3475) versus platinum doublet chemotherapy in treatment-naive patients (pts) with PD-L1–positive advanced non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2015 33:15_suppl, TPS8105-TPS8105 [https://doi.org/10.1200/jco.2015.33.15_suppl.tps8105 link to abstract] --><br />
#'''KEYNOTE-042:''' Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. Epub 2019 Apr 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32409-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/30955977 PubMed] NCT02220894<br />
<br />
=Advanced or metastatic disease, first-line, elderly or poor performance status=<br />
<br />
==Carboplatin & Gemcitabine (GCb) {{#subobject:2f045e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CG: '''<u>C</u>'''arboplatin & '''<u>G</u>'''emcitabine<br />
===Regimen {{#subobject:c4b462|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdq637 Biesma et al. 2011 (NVALT-3)]<br />
|2003-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_7|CP]]<br />
|<br />
| style="background-color:#ffffbf" |Similar QoL<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 4 cycles'''<br />
===References===<br />
<br />
#'''NVALT-3:''' Biesma B, Wymenga AN, Vincent A, Dalesio O, Smit HJ, Stigt JA, Smit EF, van Felius CL, van Putten JW, Slaets JP, Groen HJ; Dutch Chest Physician Study Group. Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study. Ann Oncol. 2011 Jul;22(7):1520-7. Epub 2011 Jan 20. [https://doi.org/10.1093/annonc/mdq637 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21252061 PubMed] NTR925<br />
<br />
==Carboplatin & Paclitaxel (CP) {{#subobject:050d96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TC: '''<u>T</u>'''axol (Paclitaxel) & '''<u>C</u>'''arboplatin<br />
<br>CP: '''<u>C</u>'''arboplatin & '''<u>P</u>'''aclitaxel<br />
===Regimen variant #1, 5/175 {{#subobject:5dd7ea|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdq637 Biesma et al. 2011 (NVALT-3)]<br />
|2003-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Gemcitabine_.28GCb.29_4|CG]]<br />
|<br />
| style="background-color:#ffffbf" |Similar QoL<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for up to 4 cycles'''<br />
<br />
===Regimen variant #2, 6/90 {{#subobject:bd42df|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960780-0/fulltext Quoix et al. 2011 (IFCT-0501)]<br />
|rowspan=2|2006-2009<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. [[#Vinorelbine_monotherapy|Vinorelbine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Study involved only patients 70 to 89 years old''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 90 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
<br />
*Growth factor support was not recommended as primary prophylaxis during cycle 1, but could be used if the patient develops grade 3-4 neutropenia<br />
<br />
'''28-day cycle for up to 4 cycles'''<br />
<br />
===Regimen variant #3, 6/200 {{#subobject:7ba15a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2007.13.2720 Lilenbaum et al. 2008]<br />
|2002-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Erlotinib<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 15 to 60 minutes once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''21-day cycle for up to 4 cycles'''<br />
<br />
===Regimen variant #4, 6/225 {{#subobject:e1af15|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.jto.org/article/S1556-0864(15)31485-4/fulltext Langer et al. 2008]<br />
|2002-2003<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Carboplatin & PPX<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Lilenbaum R, Axelrod R, Thomas S, Dowlati A, Seigel L, Albert D, Witt K, Botkin D. Randomized phase II trial of erlotinib or standard chemotherapy in patients with advanced non-small-cell lung cancer and a performance status of 2. J Clin Oncol. 2008 Feb 20;26(6):863-9. [https://doi.org/10.1200/jco.2007.13.2720 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18281658 PubMed]<br />
#Langer CJ, O'Byrne KJ, Socinski MA, Mikhailov SM, Leśniewski-Kmak K, Smakal M, Ciuleanu TE, Orlov SV, Dediu M, Heigener D, Eisenfeld AJ, Sandalic L, Oldham FB, Singer JW, Ross HJ. Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. J Thorac Oncol. 2008 Jun;3(6):623-30. [https://www.jto.org/article/S1556-0864(15)31485-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18520802 PubMed]<br />
#'''NVALT-3:''' Biesma B, Wymenga AN, Vincent A, Dalesio O, Smit HJ, Stigt JA, Smit EF, van Felius CL, van Putten JW, Slaets JP, Groen HJ; Dutch Chest Physician Study Group. Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study. Ann Oncol. 2011 Jul;22(7):1520-7. Epub 2011 Jan 20. [https://doi.org/10.1093/annonc/mdq637 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21252061 PubMed] NTR925<br />
#'''IFCT-0501:''' Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960780-0/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21831418 PubMed] NCT00298415<br />
<br />
==Carboplatin & Pemetrexed {{#subobject:fc1ec6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Carboplatin (Paraplatin) and Pemetrexed (Alimta) in non-small cell lung cancer]]<br />
<br />
===Regimen {{#subobject:b1cc1a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2012.48.1911 Zukin et al. 2013 (INCA-Lung001)]<br />
|2008-2011<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Pemetrexed_monotherapy|Pemetrexed]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 15 to 60 minutes once on day 1, '''given second'''<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*(Ardizzoni et al. 2012 contained more details):<br />
*[[Dexamethasone (Decadron)]] 4 mg or [[steroid conversions|equivalent corticosteroid]] PO twice per day on the day before, the day of, and day after each dose of [[Pemetrexed (Alimta)]]<br />
*[[Folic acid (Folate)]] 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be taken throughout pemetrexed therapy<br />
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be given throughout pemetrexed therapy<br />
<br />
'''21-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
<!-- Presented at the 48th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2012. --><br />
<br />
#'''INCA-Lung001:''' Zukin M, Barrios CH, Rodrigues Pereira J, De Albuquerque Ribeiro R, de Mendonça Beato CA, do Nascimento YN, Murad A, Franke FA, Precivale M, de Lima Araujo LH, Da Rocha Baldotto CS, Vieira FM, Small IA, Ferreira CG, Lilenbaum RC. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. 2013 Aug 10;31(23):2849-53. Epub 2013 Jun 17. [https://doi.org/10.1200/jco.2012.48.1911 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23775961 PubMed] NCT01836575<br />
<br />
==Carboplatin, Pemetrexed, Bevacizumab {{#subobject:03239b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8a4c4f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1002/cncr.30986 Spigel et al. 2018 (ToPPS)]<br />
|2009-2013<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|1. [[#Pemetrexed_monotherapy|Pemetrexed]]<br> 2. [[#Pemetrexed_.26_Bevacizumab|Pemetrexed & Bevacizumab]]<br />
|PFS: 4.8 mo<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] as follows:<br />
**Cycles 1 to 4: AUC 5 IV once on day 1<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*Premedications, [[Folic acid (Folate)]], and vitamin supplementation per standard guidelines<br />
*Antiemetics per standard guidelines<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ToPPS:''' Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. [https://doi.org/10.1002/cncr.30986 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29451696 PubMed] NCT00892710<br />
<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:21a22f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b72a5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(13)00155-4/fulltext Morabito et al. 2013 (CAPPA-2)]<br />
|2008-2012<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2017.76.8390 Gridelli et al. 2018 (MILES-3)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2017.76.8390 Gridelli et al. 2018 (MILES-4)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''MILES studies involved only patients at least 70 years old. CAPPA-2 allowed patients aged 18-70 with ECOG PS = 2.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]]<br />
*[[Gemcitabine (Gemzar)]]<br />
<br />
===References===<br />
<br />
#'''CAPPA-2:''' Morabito A, Gebbia V, Di Maio M, Cinieri S, Viganò MG, Bianco R, Barbera S, Cavanna L, De Marinis F, Montesarchio V, Costanzo R, Sandomenico C, Montanino A, Mancuso G, Russo P, Nacci A, Giordano P, Daniele G, Piccirillo MC, Rocco G, Gridelli C, Gallo C, Perrone F. Randomized phase III trial of gemcitabine and cisplatin vs gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study. Lung Cancer. 2013 Jul;81(1):77-83. Epub 2013 May 1. [https://www.lungcancerjournal.info/article/S0169-5002(13)00155-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23643177 PubMed] NCT00526643<br />
#'''MILES-3/MILES-4:''' Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. [https://doi.org/10.1200/JCO.2017.76.8390 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30028656 PubMed] NCT01405586; NCT01656551<br />
<br />
==Docetaxel monotherapy {{#subobject:17ba7f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Docetaxel (Taxotere) in non-small cell lung cancer]]<br />
<br />
===Regimen variant #1, 25 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:22a876|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/jjco/article/45/1/88/889067 Tsukada et al. 2014 (JCOG0207)]<br />
|2003-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Docetaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 36 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:110876|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1002/cncr.23019 Hainsworth et al. 2007]<br />
|2001-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Docetaxel_.26_Gemcitabine|Docetaxel & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 36 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3, 38 mg/m<sup>2</sup>, 2 out of 3 weeks {{#subobject:75b593|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.clinical-lung-cancer.com/article/S1525-7304(11)00016-7/fulltext Karampeazis et al. 2011]<br />
|2003-2008<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Vinorelbine_monotherapy|Vinorelbine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 38 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #4, 60 mg/m<sup>2</sup> q3wk {{#subobject:afca35|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2006.06.1044 Kudoh et al. 2006 (WJTOG 9904)]<br />
|2000-2003<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Vinorelbine_monotherapy|Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2014.55.8627 Abe et al. 2015 (JCOG0803/WJOG4307L)]<br />
|2008-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Docetaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''This is the PMDA-approved dose.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
'''21-day cycle for up to 4 cycles (WJTOG 9904) or indefinitely'''<br />
===References===<br />
<br />
#'''WJTOG 9904:''' Kudoh S, Takeda K, Nakagawa K, Takada M, Katakami N, Matsui K, Shinkai T, Sawa T, Goto I, Semba H, Seto T, Ando M, Satoh T, Yoshimura N, Negoro S, Fukuoka M. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol. 2006 Aug 1;24(22):3657-63. [https://doi.org/10.1200/JCO.2006.06.1044 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16877734 PubMed]<br />
#Hainsworth JD, Spigel DR, Farley C, Shipley DL, Bearden JD, Gandhi J, Houston GA, Greco FA. Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network. Cancer. 2007 Nov 1;110(9):2027-34. [https://onlinelibrary.wiley.com/doi/abs/10.1002/cncr.23019 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17823908 PubMed]<br />
#Karampeazis A, Vamvakas L, Agelidou A, Kentepozidis N, Chainis K, Chandrinos V, Vardakis N, Pallis AG, Christophyllakis C, Georgoulias V; Hellenic Oncology Research Group. Docetaxel vs vinorelbine in elderly patients with advanced non--small-cell lung cancer: a Hellenic Oncology Research Group randomized phase III study. Clin Lung Cancer. 2011 May;12(3):155-60. Epub 2011 Apr 27. [https://www.clinical-lung-cancer.com/article/S1525-7304(11)00016-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21663857 PubMed]<br />
#'''JCOG0207:''' Tsukada H, Yokoyama A, Goto K, Shinkai T, Harada M, Ando M, Shibata T, Ohe Y, Tamura T, Saijo N; Lung Cancer Study Group of the Japan Clinical Oncology Group (JCOG). Randomized controlled trial comparing docetaxel-cisplatin combination with weekly docetaxel alone in elderly patients with advanced non-small-cell lung cancer: Japan Clinical Oncology Group (JCOG) 0207. Jpn J Clin Oncol. 2015 Jan;45(1):88-95. Epub 2014 Nov 6. [https://academic.oup.com/jjco/article/45/1/88/889067 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/25378648 PubMed] UMIN C000000146<br />
#'''JCOG0803/WJOG4307L:''' Abe T, Takeda K, Ohe Y, Kudoh S, Ichinose Y, Okamoto H, Yamamoto N, Yoshioka H, Minato K, Sawa T, Iwamoto Y, Saka H, Mizusawa J, Shibata T, Nakamura S, Ando M, Yokoyama A, Nakagawa K, Saijo N, Tamura T. Randomized phase III trial comparing weekly docetaxel plus cisplatin versus docetaxel monotherapy every 3 weeks in elderly patients with advanced non-small-cell lung cancer: the intergroup trial JCOG0803/WJOG4307L. J Clin Oncol. 2015 Feb 20;33(6):575-81. Epub 2015 Jan 12. [https://doi.org/10.1200/JCO.2014.55.8627 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25584004 PubMed] UMIN000001424<br />
<br />
==Gemcitabine monotherapy {{#subobject:21a88f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 1000 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:137c9f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.jto.org/article/S1556-0864(15)33345-1/fulltext O'Brien et al. 2008]<br />
|2002-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Paclitaxel poliglumex<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #2, 1150 mg/m<sup>2</sup>, 2 out of 3 weeks {{#subobject:340c10|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960780-0/fulltext Quoix et al. 2011 (IFCT-0501)]<br />
|2006-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_7|Carboplatin & Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Study involved only patients 70 to 89 years old''<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1150 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*Growth factor support was not recommended as primary prophylaxis during cycle 1, but could be used if the patient develops grade 3 to 4 neutropenia<br />
<br />
'''21-day cycle for up to 5 cycles'''<br />
<br />
===Regimen variant #3, 1200 mg/m<sup>2</sup>, 2 out of 3 weeks {{#subobject:b8de5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[http://jnci.oxfordjournals.org/content/95/5/362.long Gridelli et al. 2003 (MILES)]<br />
|rowspan=2|1997-2000<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Gemcitabine_.26_Vinorelbine_2|Gemcitabine & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Vinorelbine_monotherapy|Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793001/ Reynolds et al. 2009 (USO-03012)]<br />
|2004-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Gemcitabine_.28GCb.29_2|Carboplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(13)00155-4/fulltext Morabito et al. 2013 (CAPPA-2)]<br />
|2008-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_6|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2017.76.8390 Gridelli et al. 2018 (MILES-3)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_6|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2017.76.8390 Gridelli et al. 2018 (MILES-4)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_6|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''MILES studies involved only patients at least 70 years old. CAPPA-2 allowed patients aged 18-70 with ECOG PS = 2.''<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1200 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*"[[:Category:Emesis_prevention|Antiemetic]] agents and other supportive treatments were provided at the discretion of the treating physician."<br />
<br />
'''21-day cycle for 4 to 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''MILES:''' Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. [http://jnci.oxfordjournals.org/content/95/5/362.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12618501 PubMed]<br />
#'''SICOG 9909:''' Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, Maiorino L, Guida M, Panza N, Mancarella S, Cioffi R. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004 Aug 2;91(3):489-97. [https://www.nature.com/articles/6602011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409832/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15266334 PubMed]<br />
#O'Brien ME, Socinski MA, Popovich AY, Bondarenko IN, Tomova A, Bilynsky BT, Hotko YS, Ganul VL, Kostinsky IY, Eisenfeld AJ, Sandalic L, Oldham FB, Bandstra B, Sandler AB, Singer JW. Randomized phase III trial comparing single-agent paclitaxel Poliglumex (CT-2103, PPX) with single-agent gemcitabine or vinorelbine for the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. J Thorac Oncol. 2008 Jul;3(7):728-34. [https://www.jto.org/article/S1556-0864(15)33345-1/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18594318 PubMed]<br />
#'''USO-03012:''' Reynolds C, Obasaju C, Schell MJ, Li X, Zheng Z, Boulware D, Caton JR, Demarco LC, O'Rourke MA, Shaw Wright G, Boehm KA, Asmar L, Bromund J, Peng G, Monberg MJ, Bepler G. Randomized phase III trial of gemcitabine-based chemotherapy with in situ RRM1 and ERCC1 protein levels for response prediction in non-small-cell lung cancer. J Clin Oncol. 2009 Dec 1;27(34):5808-15. Epub 2009 Nov 2. [https://doi.org/10.1200/JCO.2009.21.9766 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793001/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19884554 PubMed] NCT00190710<br />
#'''IFCT-0501:''' Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960780-0/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21831418 PubMed] NCT00298415<br />
#'''CAPPA-2:''' Morabito A, Gebbia V, Di Maio M, Cinieri S, Viganò MG, Bianco R, Barbera S, Cavanna L, De Marinis F, Montesarchio V, Costanzo R, Sandomenico C, Montanino A, Mancuso G, Russo P, Nacci A, Giordano P, Daniele G, Piccirillo MC, Rocco G, Gridelli C, Gallo C, Perrone F. Randomized phase III trial of gemcitabine and cisplatin vs gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study. Lung Cancer. 2013 Jul;81(1):77-83. Epub 2013 May 1. [https://www.lungcancerjournal.info/article/S0169-5002(13)00155-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23643177 PubMed] NCT00526643<br />
#'''MILES-3/MILES-4:''' Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. [https://doi.org/10.1200/JCO.2017.76.8390 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30028656 PubMed] NCT01405586; NCT01656551<br />
<br />
==Gemcitabine & Paclitaxel {{#subobject:fa1732|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GT: '''<u>G</u>'''emcitabine & '''<u>T</u>'''axol (Paclitaxel)<br />
===Regimen {{#subobject:a80095|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409832/ Comella et al. 2004 (SICOG 9909)]<br />
|rowspan=2|1999-2003<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Gemcitabine_monotherapy|Gemcitabine]]<br> 2. [[Non-small_cell_lung_cancer_-_historical#Paclitaxel_monotherapy|Paclitaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|3. [[#Gemcitabine_.26_Vinorelbine_2|GV]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''SICOG 9909:''' Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, Maiorino L, Guida M, Panza N, Mancarella S, Cioffi R. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004 Aug 2;91(3):489-97. [https://www.nature.com/articles/6602011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409832/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15266334 PubMed]<br />
<br />
==Gemcitabine & Vinorelbine {{#subobject:0e1f07|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GV: '''<u>G</u>'''emcitabine & '''<u>V</u>'''inorelbine<br />
<br>VG: '''<u>V</u>'''inorelbine & '''<u>G</u>'''emcitabine<br />
===Regimen variant #1, 1000/25 {{#subobject:4d6b82|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[http://jnci.oxfordjournals.org/content/95/5/362.long Gridelli et al. 2003 (MILES)]<br />
|rowspan=2|1997-2000<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Vinorelbine_monotherapy|Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''This study involved only patients at least 70 years old''<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*"[[:Category:Emesis_prevention|Antiemetic]] agents and other supportive treatments were provided at the discretion of the treating physician."<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #2, 1200/30 {{#subobject:07e5b2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.13.2529 Frasci et al. 2000]<br />
|1997-1999<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Vinorelbine_monotherapy|Vinorelbine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''This study involved only patients at least 70 years old''<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1200 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Frasci G, Lorusso V, Panza N, Comella P, Nicolella G, Bianco A, De Cataldis G, Iannelli A, Bilancia D, Belli M, Massidda B, Piantedosi F, Comella G, De Lena M. Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000 Jul;18(13):2529-36. [https://doi.org/10.1200/JCO.2000.18.13.2529 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10893283 PubMed]<br />
#'''MILES:''' Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. [http://jnci.oxfordjournals.org/content/95/5/362.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12618501 PubMed]<br />
#'''SICOG 9909:''' Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, Maiorino L, Guida M, Panza N, Mancarella S, Cioffi R. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004 Aug 2;91(3):489-97. [https://www.nature.com/articles/6602011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409832/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15266334 PubMed]<br />
<br />
==Pemetrexed monotherapy {{#subobject:615e55|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Pemetrexed (Alimta) in non-small cell lung cancer]]<br />
<br />
===Regimen {{#subobject:7f11b0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2012.48.1911 Zukin et al. 2013 (INCA-Lung001)]<br />
|2008-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Pemetrexed_3|Carboplatin & Pemetrexed]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2017.76.8390 Gridelli et al. 2018 (MILES-4)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Cisplatin & Gemcitabine<br> 2. Cisplatin & Pemetrexed<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1<br />
<br />
'''21-day cycle for up to 4 cycles (INCA-Lung001) or 6 cycles (MILES-4)'''<br />
<br />
===References===<br />
<!-- Presented at the 48th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2012. --><br />
<br />
#'''INCA-Lung001:''' Zukin M, Barrios CH, Rodrigues Pereira J, De Albuquerque Ribeiro R, de Mendonça Beato CA, do Nascimento YN, Murad A, Franke FA, Precivale M, de Lima Araujo LH, Da Rocha Baldotto CS, Vieira FM, Small IA, Ferreira CG, Lilenbaum RC. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. 2013 Aug 10;31(23):2849-53. Epub 2013 Jun 17. [https://doi.org/10.1200/jco.2012.48.1911 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23775961 PubMed] NCT01836575<br />
#'''ToPPS:''' Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. [https://doi.org/10.1002/cncr.30986 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29451696 PubMed] NCT00892710<br />
#'''MILES-4:''' Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. [https://doi.org/10.1200/JCO.2017.76.8390 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30028656 PubMed] NCT01405586; NCT01656551<br />
<br />
==Pemetrexed & Bevacizumab {{#subobject:3c119a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e31aed|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1002/cncr.30986 Spigel et al. 2018 (ToPPS)]<br />
|2009-2013<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|1. [[#Pemetrexed_monotherapy|Pemetrexed]]<br> 2. [[#Carboplatin.2C_Pemetrexed.2C_Bevacizumab_2|Carboplatin, Pemetrexed, Bevacizumab]]<br />
|PFS: 4.0 mo<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*Premedications, [[Folic acid (Folate)]], and vitamin supplementation per standard guidelines<br />
*Antiemetics per standard guidelines<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ToPPS:''' Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. [https://doi.org/10.1002/cncr.30986 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29451696 PubMed] NCT00892710<br />
<br />
==Vinorelbine monotherapy {{#subobject:aa0ce0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 25 mg/m<sup>2</sup> {{#subobject:5beb7a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2006.06.1044 Kudoh et al. 2006 (WJTOG 9904)]<br />
|2000-2003<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.clinical-lung-cancer.com/article/S1525-7304(11)00016-7/fulltext Karampeazis et al. 2011]<br />
|2003-2008<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960780-0/fulltext Quoix et al. 2011 (IFCT-0501)]<br />
|2006-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_7|Carboplatin & Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''IFCT-0501 involved only patients 70 to 89 years old''<br />
====Chemotherapy====<br />
<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*Growth factor support was not recommended as primary prophylaxis during cycle 1, but could be used if the patient develops grade 3 to 4 neutropenia<br />
<br />
'''21-day cycle for up to 4 cycles (WJTOG 9904), 5 cycles (IFCT-0501), or 6 cycles (Karampeazis et al. 2011)'''<br />
<br />
===Regimen variant #2, 30 mg/m<sup>2</sup> {{#subobject:408bee|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jnci.oxfordjournals.org/content/91/1/66.long Gridelli et al. 1999 (ELVIS)]<br />
|1996-1997<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
| rowspan="2" |[http://jnci.oxfordjournals.org/content/95/5/362.long Gridelli et al. 2003 (MILES)]<br />
|rowspan=2|1997-2000<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Gemcitabine_.26_Vinorelbine|Gemcitabine & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Study involved only patients at least 70 years old''<br />
====Chemotherapy====<br />
<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*(varies depending on reference):<br />
*ELVIS: [[Metoclopramide (Reglan)]] 20 mg IV bolus once per day on days 1 & 8, prior to [[Vinorelbine (Navelbine)]]<br />
*MILES: "[[:Category:Emesis_prevention|Antiemetic]] agents and other supportive treatments were provided at the discretion of the treating physician."<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''ELVIS:''' Gridelli C, Perrone F, Gallo C; Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 1999 Jan 6;91(1):66-72. [http://jnci.oxfordjournals.org/content/91/1/66.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9890172 PubMed]<br />
#'''MILES:''' Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. [http://jnci.oxfordjournals.org/content/95/5/362.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12618501 PubMed]<br />
#'''WJTOG 9904:''' Kudoh S, Takeda K, Nakagawa K, Takada M, Katakami N, Matsui K, Shinkai T, Sawa T, Goto I, Semba H, Seto T, Ando M, Satoh T, Yoshimura N, Negoro S, Fukuoka M. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol. 2006 Aug 1;24(22):3657-63. [https://doi.org/10.1200/JCO.2006.06.1044 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16877734 PubMed]<br />
#Karampeazis A, Vamvakas L, Agelidou A, Kentepozidis N, Chainis K, Chandrinos V, Vardakis N, Pallis AG, Christophyllakis C, Georgoulias V; Hellenic Oncology Research Group. Docetaxel vs vinorelbine in elderly patients with advanced non--small-cell lung cancer: a Hellenic Oncology Research Group randomized phase III study. Clin Lung Cancer. 2011 May;12(3):155-60. Epub 2011 Apr 27. [https://www.clinical-lung-cancer.com/article/S1525-7304(11)00016-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21663857 PubMed]<br />
#'''IFCT-0501:''' Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960780-0/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21831418 PubMed] NCT00298415<br />
<br />
=Maintenance after first-line therapy=<br />
<br />
==Bevacizumab monotherapy {{#subobject:75f589|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e01dd1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2012.47.3983 Johnson et al. 2013 (ATLAS-NSCLC)]<br />
|2006-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Erlotinib & Bevacizumab maintenance<br />
| style="background-color:#d73027" |Inferior PFS<sup>1</sup><br />
| style="background-color:#1a9850" |Less toxic<br />
|-<br />
|}<br />
''<sup>1</sup>While this arm was inferior in ATLAS, the authors note that, due to toxicity, the "two-drug maintenance regimen will not lead to a new postchemotherapy standard of care."''<br><br />
''Note: This trial should not be confused with the ones with the same name in breast cancer and in renal cell carcinoma.''<br />
====Preceding treatment====<br />
<br />
*Carboplatin, Docetaxel, Bevacizumab x 4 or Carboplatin, Gemcitabine, Bevacizumab x 4 or [[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Bevacizumab|PacCBev]] x 4 or Cisplatin, Docetaxel, Bevacizumab x 4 or [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Bevacizumab|Cisplatin, Gemcitabine, Bevacizumab]] x 4 or Cisplatin, Vinorelbine, Bevacizumab x 4<br />
<br />
====Targeted therapy====<br />
<br />
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ATLAS:''' Johnson BE, Kabbinavar F, Fehrenbacher L, Hainsworth J, Kasubhai S, Kressel B, Lin CY, Marsland T, Patel T, Polikoff J, Rubin M, White L, Yang JC, Bowden C, Miller V. ATLAS: randomized, double-blind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2013 Nov 1;31(31):3926-34. Epub 2013 Oct 7. [https://doi.org/10.1200/JCO.2012.47.3983 link to original article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/24101054 PubMed] NCT00257608<br />
<br />
==Gemcitabine monotherapy {{#subobject:5d1f99|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ce1f77|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(06)00060-2/fulltext Brodowicz et al. 2006]<br />
|1999-2002<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Observation_3|Observation]]<br />
| style="background-color:#1a9850" |Superior TTP<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2011.39.9782 Pérol et al. 2012 (IFCT-GFPC 0502)]<br />
|rowspan=2|2006-2009<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy|Erlotinib]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[Non-small_cell_lung_cancer_-_null_regimens#Observation_3|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]] x 4<br />
<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Brodowicz T, Krzakowski M, Zwitter M, Tzekova V, Ramlau R, Ghilezan N, Ciuleanu T, Cucevic B, Gyurkovits K, Ulsperger E, Jassem J, Grgic M, Saip P, Szilasi M, Wiltschke C, Wagnerova M, Oskina N, Soldatenkova V, Zielinski C, Wenczl M; Central European Cooperative Oncology Group. Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer. 2006 May;52(2):155-63. Epub 2006 Mar 29. [https://www.lungcancerjournal.info/article/S0169-5002(06)00060-2/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16569462 PubMed]<br />
#'''IFCT-GFPC 0502:''' Pérol M, Chouaid C, Pérol D, Barlési F, Gervais R, Westeel V, Crequit J, Léna H, Vergnenègre A, Zalcman G, Monnet I, Le Caer H, Fournel P, Falchero L, Poudenx M, Vaylet F, Ségura-Ferlay C, Devouassoux-Shisheboran M, Taron M, Milleron B. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2012 Oct 1;30(28):3516-24. Epub 2012 Sep 4. [https://doi.org/10.1200/JCO.2011.39.9782 link to original article]'''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22949150 PubMed] NCT00300586<br />
<br />
==Ipilimumab monotherapy {{#subobject:b19c3f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b4472a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2011.38.4032 Lynch et al. 2012 (CA184-041)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Ipilimumab|Carboplatin, Paclitaxel, Ipilimumab]] x 6<br />
<br />
====Immunotherapy====<br />
<br />
*[[Ipilimumab (Yervoy)]] 10 mg/kg IV once on day 1<br />
<br />
'''12-week cycles'''<br />
<br />
===References===<br />
<!-- Presented in part at The Chicago Multidisciplinary Symposium in Thoracic Oncology, Chicago, IL, December 9-11, 2010, and the 14th World Congress on Lung Cancer, Amsterdam, the Netherlands, July 3-7, 2011. --><br />
<br />
#'''CA184-041:''' Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. [https://doi.org/10.1200/jco.2011.38.4032 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22547592 PubMed] NCT00527735<br />
<br />
==Pembrolizumab monotherapy {{#subobject:0hg651|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d2e0eb|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|(ZEAL-1L)<br />
|2020-ongoing<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Niraparib & Pembrolizumab<br />
| style="background-color:#d3d3d3" |In progress<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Platinum-based induction therapy<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
#'''ZEAL-1L:''' NCT04475939<br />
<br />
==Pemetrexed monotherapy {{#subobject:ed7aa9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Pemetrexed (Alimta) in non-small cell lung cancer]]<br />
<br />
===Regimen {{#subobject:2b465b|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61497-5/fulltext Ciuleanu et al. 2009 (JMEN)]<br />
|2005-2007<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Placebo_5|Placebo]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 Reck et al. 2016 (KEYNOTE-024)]<br />
|2014-2015<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32409-7/fulltext Mok et al. 2019 (KEYNOTE-042)]<br />
|2014-2017<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1801005 Gandhi et al. 2018 (KEYNOTE-189)]<br />
|2016-2017<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*JMEN: Platinum-based chemotherapy x 4<br />
*KEYNOTE-024: [[#Carboplatin_.26_Paclitaxel_.28CP.29_4|Carboplatin & Paclitaxel]] or [[#Carboplatin_.26_Pemetrexed|Carboplatin & Pemetrexed]] or [[#Cisplatin_.26_Pemetrexed_2 |Cisplatin & Pemetrexed]]<br />
*KEYNOTE-189 (control arm): [[#Carboplatin_.26_Pemetrexed_2|Carboplatin & Pemetrexed]] x 4 or [[#Cisplatin_.26_Pemetrexed_2 |Cisplatin & Pemetrexed]] x 4<br />
*KEYNOTE-189 (experimental arm): [[#Pemetrexed_.26_Pembrolizumab|Pemetrexed & Pembrolizumab maintenance]] x 2 y<br />
*KEYNOTE-042: [[#Carboplatin_.26_Pemetrexed_2|Carboplatin & Pemetrexed]] x 6<br />
<br />
====Chemotherapy====<br />
<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[Folic acid (Folate)]]<br />
*[[Cyanocobalamin (Vitamin B12)]]<br />
*[[Dexamethasone (Decadron)]]<br />
*"Investigators followed current American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) guidelines for use of colony-stimulating factors and erythropoiesis-stimulating agents."<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''JMEN:''' Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Rodrigues Pereira J, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009 Oct 24;374(9699):1432-40. Epub 2009 Sep 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61497-5/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19767093 PubMed]<br />
#'''KEYNOTE-024:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. [https://www.nejm.org/doi/full/10.1056/NEJMoa1606774 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1606774/suppl_file/nejmoa1606774_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27718847 PubMed] NCT02142738<br />
##'''HRQoL analysis:''' Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30690-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29129441 PubMed]<br />
##'''Update:''' Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. [https://doi.org/10.1200/JCO.18.00149 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30620668 PubMed]<br />
#'''KEYNOTE-189:''' Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1801005 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1801005/suppl_file/nejmoa1801005_protocol.pdf link to protocol] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29658856 PubMed] NCT02578680<br />
<!-- # '''Abstract:''' Tony Mok, Yi-Long Wu, Patricia A, Watson, Jin Zhang, Reshma A. Rangwala, and Gilberto Lopes. Phase 3 KEYNOTE-042 trial of pembrolizumab (MK-3475) versus platinum doublet chemotherapy in treatment-naive patients (pts) with PD-L1–positive advanced non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2015 33:15_suppl, TPS8105-TPS8105 [https://doi.org/10.1200/jco.2015.33.15_suppl.tps8105 link to abstract] --><br />
#'''KEYNOTE-042:''' Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. Epub 2019 Apr 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32409-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/30955977 PubMed] NCT02220894<br />
<br />
==Pemetrexed & Pembrolizumab {{#subobject:4f9073|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0365c3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1801005 Gandhi et al. 2018 (KEYNOTE-189)]<br />
|2016-2017<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Complex_multipart_regimens#KEYNOTE-189|See link]]<br />
|style="background-color:#1a9850"|[[Complex_multipart_regimens#KEYNOTE-189|See link]]<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Non-small_cell_lung_cancer#Carboplatin.2C_Pemetrexed.2C_Pembrolizumab|Carboplatin, Pemetrexed, Pembrolizumab]] x 4 or [[Non-small_cell_lung_cancer#Cisplatin.2C_Pemetrexed.2C_Pembrolizumab|Cisplatin, Pemetrexed, Pembrolizumab]] x 4<br />
====Immunotherapy====<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV over 30 minutes once on day 1, '''given first, at least 30 minutes prior to pemetrexed'''<br />
====Chemotherapy====<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1, '''given second'''<br />
<br />
====Supportive medications====<br />
*[[Folic acid (Folate)]] according to local guidelines<br />
*[[Cyanocobalamin (Vitamin B12)]] according to local guidelines<br />
*[[:Category:Steroids|Corticosteroids]] according to local guidelines<br />
<br />
'''21-day cycle for up to 2 years (35 cycles total, including induction)'''<br />
====Subsequent treatment====<br />
*[[Non-small_cell_lung_cancer#Pemetrexed_monotherapy_2|Pemetrexed maintenance]]<br />
<br />
===References===<br />
# '''KEYNOTE-189:''' Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1801005 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1801005/suppl_file/nejmoa1801005_protocol.pdf link to protocol] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29658856 PubMed] NCT02578680<br />
<br />
=Advanced or metastatic disease, second-line=<br />
<br />
==Cabozantinib monotherapy {{#subobject:47f237|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1276ee|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30561-7/fulltext Neal et al. 2016 (ECOG-ACRIN 1512)]<br />
|rowspan=2|2013-2014<br />
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|1. [[#Cabozantinib_.26_Erlotinib|Cabozantinib & Erlotinib]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
<br />
*[[Cabozantinib (Cometriq)]] 60 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''ECOG-ACRIN 1512:''' Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30561-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27825638 PubMed] NCT01708954<br />
<br />
==Cabozantinib & Erlotinib {{#subobject:d9d1c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:238161|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30561-7/fulltext Neal et al. 2016 (ECOG-ACRIN 1512)]<br />
|rowspan=2|2013-2014<br />
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|1. [[#Cabozantinib_monotherapy|Cabozantinib]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
<br />
*[[Cabozantinib (Cometriq)]] 40 mg PO once per day<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''ECOG-ACRIN 1512:''' Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30561-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27825638 PubMed] NCT01708954<br />
<br />
==Carboplatin & Pemetrexed {{#subobject:60fd1d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Carboplatin (Paraplatin) and Pemetrexed (Alimta) in non-small cell lung cancer]]<br />
<br />
===Regimen {{#subobject:95c37d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2012.43.6758 Ardizzoni et al. 2012 (GOIRC 02-2006)]<br />
|2007-2009<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Pemetrexed_monotherapy_3|Pemetrexed]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 15 to 60 minutes once on day 1, '''given second'''<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*(Ardizzoni et al. 2012 contained more details):<br />
*[[Dexamethasone (Decadron)]] 4 mg or [[steroid conversions|equivalent corticosteroid]] PO twice per day on the day before, the day of, and day after each dose of [[Pemetrexed (Alimta)]]<br />
*[[Folic acid (Folate)]] 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be taken throughout pemetrexed therapy<br />
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be given throughout pemetrexed therapy<br />
<br />
'''21-day cycle for 4 to 6 cycles'''<br />
<br />
===References===<br />
<!-- Presented at the 47th Annual Meeting of the American Society of Clinical Oncology, Chicago, June 3-7, 2011; 14th World Conference on Lung Cancer, Amsterdam, the Netherlands, July 3-7, 2011; and 13th National Congress of Medical Oncology, Bologna, Italy, November 5-7, 2011. --><br />
<br />
#'''GOIRC 02-2006:''' Ardizzoni A, Tiseo M, Boni L, Vincent AD, Passalacqua R, Buti S, Amoroso D, Camerini A, Labianca R, Genestreti G, Boni C, Ciuffreda L, Di Costanzo F, de Marinis F, Crinò L, Santo A, Pazzola A, Barbieri F, Zilembo N, Colantonio I, Tibaldi C, Mattioli R, Cafferata MA, Camisa R, Smit EF. Pemetrexed versus pemetrexed and carboplatin as second-line chemotherapy in advanced non-small-cell lung cancer: results of the GOIRC 02-2006 randomized phase II study and pooled analysis with the NVALT7 trial. J Clin Oncol. 2012 Dec 20;30(36):4501-7. Epub 2012 Oct 29. [https://doi.org/10.1200/jco.2012.43.6758 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23109689 PubMed] NCT00786331<br />
<br />
==Docetaxel monotherapy {{#subobject:ffa516|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Docetaxel (Taxotere) in non-small cell lung cancer]]<br />
<br />
===Regimen variant #1, 33.3 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:5b378|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(08)00307-3/fulltext Gebbia et al. 2008 (DISTAL-2)]<br />
|2005-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Capecitabine_.26_Docetaxel_.28TX.29|Capecitabine & Docetaxel]]<br> 2. Docetaxel & Gemcitabine<br> 3. [[#Docetaxel_.26_Vinorelbine|Docetaxel & Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 33.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 35 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:5b296|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.02.3739 Schuette et al. 2005]<br />
|2000-2003<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Docetaxel_monotherapy_2|Docetaxel]]; 75 mg/m<sup>2</sup>, every 3 wks<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70310-3/fulltext Garassino et al. 2013 (TAILOR<sub>NSCLC</sub>)]<br />
|2007-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note that there is another trial named TAILOR in colorectal cancer.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**8 mg PO once per day on days 1, 8, 15; 12 hours prior to [[Docetaxel (Taxotere)]]<br />
**10 mg IV once per day on days 1, 8, 15; 30 minutes prior to [[Docetaxel (Taxotere)]]<br />
**8 mg PO once per day on days 1, 8, 15; 12 hours after [[Docetaxel (Taxotere)]]<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3, 50 mg/m<sup>2</sup> q2wk, limited duration {{#subobject:4cf20a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2994826/ Pallis et al. 2010 (HORG CT/04.14)]<br />
|2004-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Carboplatin & Docetaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''These patients had previously been treated with a platinum-free regimen.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #4, 60 mg/m<sup>2</sup> q3wk, limited duration {{#subobject:b90b5e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225192/ Herbst et al. 2010 (ZODIAC)]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Vandetanib|Docetaxel & Vandetanib]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|}<br />
''This is the PMDA-approved dose. While statistically inferior, the median PFS difference was only 0.8 months.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #5, 60 mg/m<sup>2</sup> q3wk, indefinite {{#subobject:3afa13|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdn705 Takeda et al. 2009 (JCOG 0104)]<br />
|2002-2003<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel & Gemcitabine<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2013.52.4694 Kawaguchi et al. 2014 (DELTA<sub>NSCLC</sub>)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2960845-X/fulltext Garon et al. 2014 (REVEL)]<br />
|2010-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440713 Gridelli et al. 2018 (AvaALL)]<br />
|2011-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Investigator's choice of:<br> 1. Docetaxel & Bevacizumab<br> 2. Erlotinib & Bevacizumab<br> 3. Pemetrexed & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''This is the PMDA-approved dose, the dose used for East Asian patients in REVEL, and the dose used in Japanese patients in EAST-LC. Note that there is another trial named DELTA in indolent lymphoma.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV over at least 60 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #6, 75 mg/m<sup>2</sup> q3wk, limited duration {{#subobject:500ace|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225192/ Herbst et al. 2010 (ZODIAC)]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Vandetanib|Docetaxel & Vandetanib]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|}<br />
''Note: while statistically inferior, the median PFS difference in ZODIAC was only 0.8 months.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #7, 75 mg/m<sup>2</sup> q3wk, indefinite {{#subobject:b495b6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409790/ Gridelli et al. 2004 (DISTAL 01)]<br />
|2000-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_monotherapy_2|Docetaxel]]; 33.3 mg/m<sup>2</sup>, 6 out of 8 wks<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of QoL<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.02.3739 Schuette et al. 2005]<br />
|2000-2003<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_monotherapy_2|Docetaxel]]; 35 mg/m<sup>2</sup>, 3 out of 4 wks<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2391114/ Paz-Ares et al. 2008 (STELLAR 2)]<br />
|2002-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Paclitaxel poliglumex<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2009.23.4146 Krzakowski et al. 2010]<br />
|2003-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Vinflunine<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(12)00616-2/fulltext Sun et al. 2012 (JMID)]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pemetrexed_monotherapy_3|Pemetrexed]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70385-0/fulltext Ciuleanu et al. 2012 (TITAN)]<br />
|2006-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70310-3/fulltext Garassino et al. 2013 (TAILOR<sub>NSCLC</sub>)]<br />
|2007-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2960845-X/fulltext Garon et al. 2014 (REVEL)]<br />
|2010-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440713 Gridelli et al. 2018 (AvaALL)]<br />
|2011-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Investigator's choice of:<br> 1. Docetaxel & Bevacizumab<br> 2. Erlotinib & Bevacizumab<br> 3. Pemetrexed & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.00816 Pillai et al. 2019 (GALAXY-2)]<br />
|2013-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel & Ganetespib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*Per JMEI: [[Dexamethasone (Decadron)]] 8 mg PO twice per day on days -1 to 2 (3 days)<br />
*Per Chem et al. 2006: [[Dexamethasone (Decadron)]] as follows:<br />
**8 mg PO once per day on days 1, 8, 15; 12 hours prior to [[Docetaxel (Taxotere)]]<br />
**10 mg IV once per day on days 1, 8, 15; 30 minutes prior to [[Docetaxel (Taxotere)]]<br />
**8 mg PO once per day on days 1, 8, 15; 12 hours after [[Docetaxel (Taxotere)]]<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''DISTAL 01:''' Gridelli C, Gallo C, Di Maio M, Barletta E, Illiano A, Maione P, Salvagni S, Piantedosi FV, Palazzolo G, Caffo O, Ceribelli A, Falcone A, Mazzanti P, Brancaccio L, Capuano MA, Isa L, Barbera S, Perrone F. A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer: the DISTAL 01 study. Br J Cancer. 2004 Dec 13;91(12):1996-2004. [https://www.nature.com/articles/6602241 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409790/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15558071 PubMed]<br />
#Schuette W, Nagel S, Blankenburg T, Lautenschlaeger C, Hans K, Schmidt EW, Dittrich I, Schweisfurth H, von Weikersthal LF, Raghavachar A, Reissig A, Serke M. Phase III study of second-line chemotherapy for advanced non-small-cell lung cancer with weekly compared with 3-weekly docetaxel. J Clin Oncol. 2005 Nov 20;23(33):8389-95. [https://doi.org/10.1200/JCO.2005.02.3739 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16293869 PubMed]<br />
#'''STELLAR 2:''' Paz-Ares L, Ross H, O'Brien M, Riviere A, Gatzemeier U, Von Pawel J, Kaukel E, Freitag L, Digel W, Bischoff H, García-Campelo R, Iannotti N, Reiterer P, Bover I, Prendiville J, Eisenfeld AJ, Oldham FB, Bandstra B, Singer JW, Bonomi P. Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer. Br J Cancer. 2008 May 20;98(10):1608-13. Epub 2008 May 13. [https://www.nature.com/articles/6604372 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2391114/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18475293 PubMed]<br />
#'''DISTAL-2:''' Gebbia V, Gridelli C, Verusio C, Frontini L, Aitini E, Daniele B, Gamucci T, Mancuso G, Di Maio M, Gallo C, Perrone F, Morabito A. Weekly docetaxel vs docetaxel-based combination chemotherapy as second-line treatment of advanced non-small-cell lung cancer patients: the DISTAL-2 randomized trial. Lung Cancer. 2009 Feb;63(2):251-8. Epub 2008 Jul 15. [https://www.lungcancerjournal.info/article/S0169-5002(08)00307-3/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18632181 PubMed] NCT00345059<br />
#'''JCOG 0104:''' Takeda K, Negoro S, Tamura T, Nishiwaki Y, Kudoh S, Yokota S, Matsui K, Semba H, Nakagawa K, Takada Y, Ando M, Shibata T, Saijo N. Phase III trial of docetaxel plus gemcitabine versus docetaxel in second-line treatment for non-small-cell lung cancer: results of a Japan Clinical Oncology Group trial (JCOG0104). Ann Oncol. 2009 May;20(5):835-41. Epub 2009 Jan 22. [https://doi.org/10.1093/annonc/mdn705 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19164456 PubMed]<br />
#Krzakowski M, Ramlau R, Jassem J, Szczesna A, Zatloukal P, Von Pawel J, Sun X, Bennouna J, Santoro A, Biesma B, Delgado FM, Salhi Y, Vaissiere N, Hansen O, Tan EH, Quoix E, Garrido P, Douillard JY. Phase III trial comparing vinflunine with docetaxel in second-line advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy. J Clin Oncol. 2010 May 1;28(13):2167-73. Epub 2010 Mar 29. [https://doi.org/10.1200/JCO.2009.23.4146 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20351334 PubMed]<br />
#'''ZODIAC:''' Herbst RS, Sun Y, Eberhardt WE, Germonpré P, Saijo N, Zhou C, Wang J, Li L, Kabbinavar F, Ichinose Y, Qin S, Zhang L, Biesma B, Heymach JV, Langmuir P, Kennedy SJ, Tada H, Johnson BE. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2010 Jul;11(7):619-26. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70132-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225192/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20570559 PubMed] NCT00312377<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/163 Project Data Sphere]<br />
#'''HORG CT/04.14:''' Pallis AG, Agelaki S, Agelidou A, Varthalitis I, Syrigos K, Kentepozidis N, Pavlakou G, Kotsakis A, Kontopodis E, Georgoulias V. A randomized phase III study of the docetaxel/carboplatin combination versus docetaxel single-agent as second line treatment for patients with advanced/metastatic non-small cell lung cancer. BMC Cancer. 2010 Nov 19;10:633. [https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-10-633 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2994826/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21092076 PubMed] NCT00430651<br />
#'''TITAN:''' Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, Johannsdottir HK, Klughammer B, Gonzalez EE. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. 2012 Mar;13(3):300-8. Epub 2012 Jan 24. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70385-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22277837 PubMed] NCT00556322<br />
#'''JMID:''' Sun Y, Wu YL, Zhou CC, Zhang L, Zhang L, Liu XY, Yu SY, Jiang GL, Li K, Qin SK, Ma SL, Han L, Quinlivan M, Orlando M, Zhang XQ. Second-line pemetrexed versus docetaxel in Chinese patients with locally advanced or metastatic non-small cell lung cancer: a randomized, open-label study. Lung Cancer. 2013 Feb;79(2):143-50. Epub 2012 Nov 20. [https://www.lungcancerjournal.info/article/S0169-5002(12)00616-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/23182660 PubMed] NCT00391274<br />
#'''TAILOR:''' Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, Bianchi F, Bettini A, Longo F, Moscetti L, Tomirotti M, Marabese M, Ganzinelli M, Lauricella C, Labianca R, Floriani I, Giaccone G, Torri V, Scanni A, Marsoni S; TAILOR trialists. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013 Sep;14(10):981-8. Epub 2013 Jul 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70310-3/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23883922 PubMed] NCT00637910<br />
#'''DELTA:''' Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol. 2014 Jun 20;32(18):1902-8. Epub 2014 May 19. [https://doi.org/10.1200/JCO.2013.52.4694 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24841974 PubMed]<br />
#'''REVEL:''' Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Pérol M. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23;384(9944):665-73. Epub 2014 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2960845-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24933332 PubMed] NCT01168973<br />
#'''AvaALL:''' Gridelli C, de Castro Carpeno J, Dingemans AC, Griesinger F, Grossi F, Langer C, Ohe Y, Syrigos K, Thatcher N, Das-Gupta A, Truman M, Donica M, Smoljanovic V, Bennouna J. Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):e183486. Epub 2018 Dec 13. Erratum in: JAMA Oncol. 2018 Dec 1;4(12):1792. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2698039 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440713 link to PMC article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/30177994 PubMed] NCT01351415<br />
#'''GALAXY-2:''' Pillai RN, Fennell DA, Kovcin V, Ciuleanu TE, Ramlau R, Kowalski D, Schenker M, Yalcin I, Teofilovici F, Vukovic VM, Ramalingam SS. Randomized Phase III Study of Ganetespib, a Heat Shock Protein 90 Inhibitor, With Docetaxel Versus Docetaxel in Advanced Non-Small-Cell Lung Cancer (GALAXY-2). J Clin Oncol. 2020 Feb 20;38(6):613-622. Epub 2019 Dec 12. [https://doi.org/10.1200/JCO.19.00816 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/31829907 PubMed]<br />
#'''DUBLIN-3:''' NCT02504489<br />
<br />
==Docetaxel & Ramucirumab {{#subobject:7b9570|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 60 mg/m<sup>2</sup> docetaxel {{#subobject:07d626|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2960845-X/fulltext Garon et al. 2014 (REVEL)]<br />
|2010-2013<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Docetaxel_monotherapy_2|Docetaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior OS <br>Median OS: 10.5 mo vs 9.1 mo <br>(HR 0.86, 95% CI 0.75-0.98)<br />
|-<br />
|}<br />
''Note: This is the PMDA-approved dose and the dose recommended for East Asians. The FDA only provides recommendations for ramucirumab dosing.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Ramucirumab (Cyramza)]] 10 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*Colony-stimulating factors and erythroid-stimulating factor use per investigator discretion.<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 75 mg/m<sup>2</sup> docetaxel {{#subobject:b3ec19|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2960845-X/fulltext Garon et al. 2014 (REVEL)]<br />
|2010-2013<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Docetaxel_monotherapy_2|Docetaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior OS <br>Median OS: 10.5 mo vs 9.1 mo <br>(HR 0.86, 95% CI 0.75-0.98)<br />
|-<br />
|}<br />
''Note: The FDA only provides recommendations for ramucirumab dosing.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Ramucirumab (Cyramza)]] 10 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*Colony-stimulating factors and erythroid-stimulating factor use per investigator discretion.<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''REVEL:''' Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Pérol M. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23;384(9944):665-73. Epub 2014 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2960845-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24933332 PubMed] NCT01168973<br />
<br />
==Docetaxel & Vandetanib {{#subobject:827eac|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 60 mg/m<sup>2</sup> docetaxel {{#subobject:c0b4c2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225192/ Herbst et al. 2010 (ZODIAC)]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Docetaxel_monotherapy_2|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
''This is the PMDA-approved dose of docetaxel. While statistically superior, the median PFS difference was only 0.8 months. Vandetanib is continued until disease progression, unacceptable toxicity, or withdrawal of consent.''<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] as follows:<br />
**Cycles 1 up to 6: 60 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Vandetanib (Caprelsa)]] 100 mg PO once per day<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 75 mg/m<sup>2</sup> docetaxel {{#subobject:10fe1c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225192/ Herbst et al. 2010 (ZODIAC)]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Docetaxel_monotherapy_2|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
''While statistically superior, the median PFS difference was only 0.8 months. Vandetanib is continued until disease progression, unacceptable toxicity, or withdrawal of consent.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Vandetanib (Caprelsa)]] 100 mg PO once per day<br />
<br />
'''21-day cycle for up to 6 cycles (see note)'''<br />
<br />
===References===<br />
<br />
#'''ZODIAC:''' Herbst RS, Sun Y, Eberhardt WE, Germonpré P, Saijo N, Zhou C, Wang J, Li L, Kabbinavar F, Ichinose Y, Qin S, Zhang L, Biesma B, Heymach JV, Langmuir P, Kennedy SJ, Tada H, Johnson BE. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2010 Jul;11(7):619-26. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70132-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225192/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20570559 PubMed] NCT00312377<br />
<br />
==Gefitinib monotherapy {{#subobject:ebfac2d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1b01c8f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.27630 Sun et al. 2012 (KCSG-LU08-01)]<br />
|2008-2010<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[#Pemetrexed_monotherapy_3|Pemetrexed]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
<br />
*[[Gefitinib (Iressa)]] 250 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''KCSG-LU08-01:''' Sun JM, Lee KH, Kim SW, Lee DH, Min YJ, Yun HJ, Kim HK, Song HS, Kim YH, Kim BS, Hwang IG, Lee K, Jo SJ, Lee JW, Ahn JS, Park K, Ahn MJ; Korean Cancer Study Group. Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial. Cancer. 2012 Dec 15;118(24):6234-42. Epub 2012 Jun 6. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.27630 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22674612 PubMed] NCT01066195<br />
<br />
==Gemcitabine monotherapy {{#subobject:b327a9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dac826|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1999.17.7.2081 Crinò et al. 1999a]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Crinò L, Mosconi AM, Scagliotti G, Selvaggi G, Novello S, Rinaldi M, Della Giulia M, Gridelli C, Rossi A, Calandri C, De Marinis F, Noseda M, Tonato M. Gemcitabine as second-line treatment for advanced non-small-cell lung cancer: a phase II trial. J Clin Oncol. 1999 Jul;17(7):2081-5. [https://doi.org/10.1200/JCO.1999.17.7.2081 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10561261 PubMed]<br />
<br />
==Pemetrexed monotherapy {{#subobject:24fa23b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Pemetrexed (Alimta) in non-small cell lung cancer]]<br />
<br />
===Regimen {{#subobject:4e0b1b|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdm592 Cullen et al. 2008]<br />
|2004-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pemetrexed_monotherapy_3|Pemetrexed]]; high-dose<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.lungcancerjournal.info/article/S0169-5002(12)00616-2/fulltext Sun et al. 2012 (JMID)]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70385-0/fulltext Ciuleanu et al. 2012 (TITAN)]<br />
|2006-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2010.29.5717 de Boer et al. 2011 (ZEAL)]<br />
|2007-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Pemetrexed_.26_Vandetanib|Pemetrexed & Vandetanib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://doi.org/10.1200/jco.2012.43.6758 Ardizzoni et al. 2012 (GOIRC 02-2006)]<br />
|2007-2009<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Carboplatin_.26_Pemetrexed_4|Carboplatin & Pemetrexed]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.27630 Sun et al. 2012 (KCSG-LU08-01)]<br />
|2008-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gefitinib_monotherapy_3|Gefitinib]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440713 Gridelli et al. 2018 (AvaALL)]<br />
|2011-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Investigator's choice of:<br> 1. Docetaxel & Bevacizumab<br> 2. Erlotinib & Bevacizumab<br> 3. Pemetrexed & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*(per Ardizzoni et al. 2012):<br />
*[[Dexamethasone (Decadron)]] 4 mg or [[steroid conversions|equivalent corticosteroid]] PO twice per day on the day before, the day of, and day after each dose of [[Pemetrexed (Alimta)]]<br />
*[[Folic acid (Folate)]] 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be taken throughout pemetrexed therapy<br />
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be given throughout pemetrexed therapy<br />
<br />
'''21-day cycles''' <br />
<br />
''GOIRC 02-2006 treated patients for up to 4 cycles or until progressive disease, unacceptable toxicity, or patient refusal.''<br />
<br />
===References===<br />
<br />
#Cullen MH, Zatloukal P, Sörenson S, Novello S, Fischer JR, Joy AA, Zereu M, Peterson P, Visseren-Grul CM, Iscoe N. A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2008 May;19(5):939-45. Epub 2008 Feb 17. [https://doi.org/10.1093/annonc/mdm592 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18283036 PubMed]<br />
<!-- Presented as a poster discussion at the 45th Annual Meeting of the American Society of Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and as an oral presentation at the 13th World Congress on Lung Cancer, July 31-August 4, 2009, San Francisco, CA, and at the European Cancer Organisation 15/34th European Society for Medical Oncology Congress, September 20-24, 2009, Berlin, Germany. --><br />
#'''ZEAL:''' de Boer RH, Arrieta Ó, Yang CH, Gottfried M, Chan V, Raats J, de Marinis F, Abratt RP, Wolf J, Blackhall FH, Langmuir P, Milenkova T, Read J, Vansteenkiste JF. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2011 Mar 10;29(8):1067-74. Epub 2011 Jan 31. [https://doi.org/10.1200/JCO.2010.29.5717 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/21282537 PubMed] NCT00418886<br />
#'''TITAN:''' Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, Johannsdottir HK, Klughammer B, Gonzalez EE. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. 2012 Mar;13(3):300-8. Epub 2012 Jan 24. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70385-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22277837 PubMed] NCT00556322<br />
#'''KCSG-LU08-01:''' Sun JM, Lee KH, Kim SW, Lee DH, Min YJ, Yun HJ, Kim HK, Song HS, Kim YH, Kim BS, Hwang IG, Lee K, Jo SJ, Lee JW, Ahn JS, Park K, Ahn MJ; Korean Cancer Study Group. Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial. Cancer. 2012 Dec 15;118(24):6234-42. Epub 2012 Jun 6. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.27630 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22674612 PubMed] NCT01066195<br />
<!-- Presented at the 47th Annual Meeting of the American Society of Clinical Oncology, Chicago, June 3-7, 2011; 14th World Conference on Lung Cancer, Amsterdam, the Netherlands, July 3-7, 2011; and 13th National Congress of Medical Oncology, Bologna, Italy, November 5-7, 2011. --><br />
#'''GOIRC 02-2006:''' Ardizzoni A, Tiseo M, Boni L, Vincent AD, Passalacqua R, Buti S, Amoroso D, Camerini A, Labianca R, Genestreti G, Boni C, Ciuffreda L, Di Costanzo F, de Marinis F, Crinò L, Santo A, Pazzola A, Barbieri F, Zilembo N, Colantonio I, Tibaldi C, Mattioli R, Cafferata MA, Camisa R, Smit EF. Pemetrexed versus pemetrexed and carboplatin as second-line chemotherapy in advanced non-small-cell lung cancer: results of the GOIRC 02-2006 randomized phase II study and pooled analysis with the NVALT7 trial. J Clin Oncol. 2012 Dec 20;30(36):4501-7. Epub 2012 Oct 29. [https://doi.org/10.1200/jco.2012.43.6758 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23109689 PubMed] NCT00786331<br />
#'''JMID:''' Sun Y, Wu YL, Zhou CC, Zhang L, Zhang L, Liu XY, Yu SY, Jiang GL, Li K, Qin SK, Ma SL, Han L, Quinlivan M, Orlando M, Zhang XQ. Second-line pemetrexed versus docetaxel in Chinese patients with locally advanced or metastatic non-small cell lung cancer: a randomized, open-label study. Lung Cancer. 2013 Feb;79(2):143-50. Epub 2012 Nov 20. [https://www.lungcancerjournal.info/article/S0169-5002(12)00616-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/23182660 PubMed] NCT00391274<br />
#'''AvaALL:''' Gridelli C, de Castro Carpeno J, Dingemans AC, Griesinger F, Grossi F, Langer C, Ohe Y, Syrigos K, Thatcher N, Das-Gupta A, Truman M, Donica M, Smoljanovic V, Bennouna J. Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):e183486. Epub 2018 Dec 13. Erratum in: JAMA Oncol. 2018 Dec 1;4(12):1792. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2698039 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440713 link to PMC article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/30177994 PubMed] NCT01351415<br />
<br />
=Advanced or metastatic disease, third-line=<br />
==Cabozantinib monotherapy {{#subobject:47f237|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1276ee|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30561-7/fulltext Neal et al. 2016 (ECOG-ACRIN 1512)]<br />
|rowspan=2|2013-2014<br />
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|1. [[#Cabozantinib_.26_Erlotinib|Cabozantinib & Erlotinib]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
<br />
*[[Cabozantinib (Cometriq)]] 60 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''ECOG-ACRIN 1512:''' Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30561-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27825638 PubMed] NCT01708954<br />
<br />
==Cabozantinib & Erlotinib {{#subobject:d9d1c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:238161|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30561-7/fulltext Neal et al. 2016 (ECOG-ACRIN 1512)]<br />
|rowspan=2|2013-2014<br />
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|1. [[#Cabozantinib_monotherapy|Cabozantinib]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
<br />
*[[Cabozantinib (Cometriq)]] 40 mg PO once per day<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''ECOG-ACRIN 1512:''' Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30561-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27825638 PubMed] NCT01708954<br />
<br />
==Docetaxel monotherapy {{#subobject:ff8fa6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Docetaxel (Taxotere) in non-small cell lung cancer]]<br />
<br />
===Regimen {{#subobject:3a685a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2013.52.4694 Kawaguchi et al. 2014 (DELTA<sub>NSCLC</sub>)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|}<br />
''This is the PMDA-approved dose. Note that there is another trial named DELTA in indolent lymphoma.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV over at least 60 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''DELTA:''' Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol. 2014 Jun 20;32(18):1902-8. Epub 2014 May 19. [https://doi.org/10.1200/JCO.2013.52.4694 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24841974 PubMed]<br />
<br />
=Advanced or metastatic disease, subsequent lines of therapy=<br />
''Note: this section includes regimens that were tested in second-line and beyond; those tested specifically in the [[#Advanced_or_metastatic_disease.2C_second-line|second-line]] or [[#Advanced_or_metastatic_disease.2C_third-line|third-line]] are to be found above.''<br />
==Afatinib monotherapy {{#subobject:1bf6db|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 30 mg/day {{#subobject:f69d3b|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
''This is the FDA-recommended dose for patients with "severe renal impairment".''<br />
====Targeted therapy====<br />
<br />
*[[Afatinib (Gilotrif)]] 30 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen variant #2, 50 mg/day {{#subobject:f109f9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70087-6/fulltext Miller et al. 2012 (LUX-Lung 1)]<br />
|2008-2009<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Placebo_5|Placebo]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://doi.org/10.1200/jco.2012.45.0981 Katakami et al. 2013 (LUX-Lung 4)]<br />
|2009-2011<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#6e016b; color:white " |ORR: 8% (95% CI: 3-18)<br />
|-<br />
|}<br />
''In LUX-Lung 4, 72.6% of patients were EGFR mutation positive. This was third or fourth line therapy for participants, who had progressed while receiving erlotinib and/or gefitinib and had received one or two previous lines of chemotherapy, including at least one platinum-based regimen.'' <br />
====Targeted therapy====<br />
<br />
*[[Afatinib (Gilotrif)]] 50 mg PO once per day, given 1 hour before eating food<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''LUX-Lung 1:''' Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang JC. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012 May;13(5):528-38. Epub 2012 Mar 26. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70087-6/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22452896 PubMed] NCT00656136<br />
##'''HRQoL analysis:''' Hirsh V, Cadranel J, Cong XJ, Fairclough D, Finnern HW, Lorence RM, Miller VA, Palmer M, Yang JC. Symptom and quality of life benefit of afatinib in advanced non-small-cell lung cancer patients previously treated with erlotinib or gefitinib: results of a randomized phase IIb/III trial (LUX-Lung 1). J Thorac Oncol. 2013 Feb;8(2):229-37. [https://www.jto.org/article/S1556-0864(15)32746-5/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/23328549 PubMed]<br />
#'''LUX-Lung 4:''' Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, Ichinose Y, Koboyashi K, Takeda K, Kiura K, Nishio K, Seki Y, Ebisawa R, Shahidi M, Yamamoto N. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013 Sep 20;31(27):3335-41. Epub 2013 Jul 1. [https://doi.org/10.1200/jco.2012.45.0981 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23816963 PubMed] NCT00711594<br />
<br />
==Afatinib & Paclitaxel {{#subobject:3d0a87|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0cb697|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769992/ Schuler et al. 2015 (LUX-Lung 5)]<br />
|2010-2011<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Single-agent chemotherapy<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Afatinib (Gilotrif)]] 40 mg PO once per day<br />
<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''LUX-Lung 5:''' Schuler M, Yang JC, Park K, Kim JH, Bennouna J, Chen YM, Chouaid C, De Marinis F, Feng JF, Grossi F, Kim DW, Liu X, Lu S, Strausz J, Vinnyk Y, Wiewrodt R, Zhou C, Wang B, Chand VK, Planchard D; LUX-Lung 5 Investigators. Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial. Ann Oncol. 2016 Mar;27(3):417-23. Epub 2015 Dec 8. [https://doi.org/10.1093/annonc/mdv597 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769992/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26646759 PubMed] NCT01085136<br />
<br />
==Amrubicin monotherapy {{#subobject:d1a9ba|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f264a4|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdw621 Yoshioka et al. 2017 (D0702035)]<br />
|2010-2012<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Amrubicin (Calsed)]] 35 mg/m<sup>2</sup> IV over 5 minutes once per day on days 1 to 3<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''D0702035:''' Yoshioka H, Katakami N, Okamoto H, Iwamoto Y, Seto T, Takahashi T, Sunaga N, Kudoh S, Chikamori K, Harada M, Tanaka H, Saito H, Saka H, Takeda K, Nogami N, Masuda N, Harada T, Kitagawa H, Horio H, Yamanaka T, Fukuoka M, Yamamoto N, Nakagawa K. A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer. Ann Oncol. 2017 Feb 1;28(2):285-291. [https://doi.org/10.1093/annonc/mdw621 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28426104 PubMed] NCT01207011<br />
<br />
==Atezolizumab monotherapy {{#subobject:412fc4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:9f357f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00587-0/fulltext Fehrenbacher et al. 2016 (POPLAR)]<br />
|2013-2014<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ooc)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32517-X/fulltext Rittmeyer et al. 2016 (OAK)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''POPLAR:''' Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30;387(10030):1837-46. Epub 2016 Mar 9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00587-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/26970723 PubMed] NCT01903993<br />
#'''OAK:''' Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32517-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/27979383 PubMed] NCT02008227<br />
##'''Update:''' Fehrenbacher L, von Pawel J, Park K, Rittmeyer A, Gandara DR, Ponce Aix S, Han JY, Gadgeel SM, Hida T, Cortinovis DL, Cobo M, Kowalski DM, De Marinis F, Gandhi M, Danner B, Matheny C, Kowanetz M, He P, Felizzi F, Patel H, Sandler A, Ballinger M, Barlesi F. Updated Efficacy Analysis Including Secondary Population Results for OAK: A Randomized Phase III Study of Atezolizumab versus Docetaxel in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer. J Thorac Oncol. 2018 Aug;13(8):1156-1170. Epub 2018 May 17. Erratum in: J Thorac Oncol. 2018 Nov;13(11):1800. [https://www.jto.org/article/S1556-0864(18)30611-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29777823 PubMed]<br />
##'''Update:''' von Pawel J, Bordoni R, Satouchi M, Fehrenbacher L, Cobo M, Han JY, Hida T, Moro-Sibilot D, Conkling P, Gandara DR, Rittmeyer A, Gandhi M, Yu W, Matheny C, Patel H, Sandler A, Ballinger M, Kowanetz M, Park K. Long-term survival in patients with advanced non-small-cell lung cancer treated with atezolizumab versus docetaxel: Results from the randomised phase III OAK study. Eur J Cancer. 2019 Jan;107:124-132. Epub 2018 Dec 17. [https://www.ejcancer.com/article/S0959-8049(18)31518-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/30562710 PubMed]<br />
<br />
==Docetaxel monotherapy {{#subobject:fd1716|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Docetaxel (Taxotere) in non-small cell lung cancer]]<br />
<br />
===Regimen variant #1, 35 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:5b296|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[http://journal.chestnet.org/article/S0012-3692(15)38821-8/fulltext Chen et al. 2006]<br />
| rowspan="2" |2002-2004<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Docetaxel_monotherapy_4|Docetaxel]]; 40 mg/m<sup>2</sup>, 2 out of 3 wks<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoint<br />
|-<br />
|2. [[#Docetaxel_monotherapy_4|Docetaxel]]; 75 mg/m<sup>2</sup>, every 3 wks<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoint<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**8 mg PO once per day on days 1, 8, 15; 12 hours prior to [[Docetaxel (Taxotere)]]<br />
**10 mg IV once per day on days 1, 8, 15; 30 minutes prior to [[Docetaxel (Taxotere)]]<br />
**8 mg PO once per day on days 1, 8, 15; 12 hours after [[Docetaxel (Taxotere)]]<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 60 mg/m<sup>2</sup> q3wk, indefinite {{#subobject:3a67f3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2007.15.0185 Maruyama et al. 2008 (V-15-32)]<br />
|2003-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gefitinib<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2013.52.4694 Kawaguchi et al. 2014 (DELTA<sub>NSCLC</sub>)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdw621 Yoshioka et al. 2017 (D0702035)]<br />
|2010-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Amrubicin_monotherapy|Amrubicin]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834128/ Nokihara et al. 2017 (EAST-LC)]<br />
|2010-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
''This is the PMDA-approved dose, the dose used for East Asian patients in REVEL, and the dose used in Japanese patients in EAST-LC.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV over at least 60 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #3, 75 mg/m<sup>2</sup> q3wk, indefinite {{#subobject:b495b6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.10.2095 Shepherd et al. 2000 (TAX 317)]<br />
|1994-1998<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Non-small_cell_lung_cancer_-_historical#Best_supportive_care_2|Best supportive care]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2000.18.12.2354 Fossella et al. 2000 (TAX 320)]<br />
| rowspan="2" |1995-1998<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Docetaxel_monotherapy_4|Docetaxel]]; 100 mg/m<sup>2</sup><br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. Ifosfamide<br> 3. [[#Vinorelbine_monotherapy_2|Vinorelbine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdj115 Camps et al. 2005]<br />
|2000-2003<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]; 36 mg/m<sup>2</sup>, 6 out of 8 wks<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[https://doi.org/10.1200/jco.2004.08.163 Hanna et al. 2004 (JMEI)]<br />
|2001-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pemetrexed_monotherapy_3|Pemetrexed]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.03.6491 Ramlau et al. 2006]<br />
|2001-2003<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Topotecan<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
| rowspan="2" |[http://journal.chestnet.org/article/S0012-3692(15)38821-8/fulltext Chen et al. 2006]<br />
| rowspan="2" |2002-2004<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Docetaxel_monotherapy_4|Docetaxel]]; 35 mg/m<sup>2</sup>, 3 out of 4 wks<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoint<br />
|-<br />
|2. [[#Docetaxel_monotherapy_4|Docetaxel]]; 40 mg/m<sup>2</sup>, 2 out of 3 wks<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoint<br />
|-<br />
|[https://doi.org/10.1200/JCO.2008.17.1405 Fidias et al. 2008]<br />
|2002-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel consolidation<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61758-4/fulltext Kim et al. 2008 (INTEREST)]<br />
|2004-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gefitinib_monotherapy_3|Gefitinib]]<br />
| style="background-color:#eeee01" |Seems to have non-inferior OS<br />
|-<br />
|[http://clincancerres.aacrjournals.org/content/16/4/1307.long Lee et al. 2010 (ISTANA)]<br />
|2005-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gefitinib_monotherapy_3|Gefitinib]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2012.42.6932 Ramlau et al. 2012 (EFC10261)]<br />
|2007-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel & ziv-Aflibercept<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70586-2/fulltext Reck et al. 2014 (LUME-Lung 1)]<br />
|2008-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Nintedanib|Docetaxel & Nintedanib]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834128/ Nokihara et al. 2017 (EAST-LC)]<br />
|2010-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ Katakami et al. 2017 (E7389-G000-302)]<br />
|2011-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Eribulin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00587-0/fulltext Fehrenbacher et al. 2016 (POPLAR)]<br />
|2013-2014<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01281-7/fulltext Herbst et al. 2015 (KEYNOTE-010)]<br />
|2013-2015<br />
| style="background-color:#1a9851" |Phase II/III (C)<br />
|[[#Pembrolizumab_monotherapy_3|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32517-X/fulltext Rittmeyer et al. 2016 (OAK)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://doi.org/10.1016/j.jtho.2019.01.006 Wu et al. 2019 (CheckMate 078)]<br />
|2015-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Nivolumab_monotherapy_2|Nivolumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30673-9/fulltext Barlesi et al. 2018 (JAVELIN Lung 200)]<br />
|2015-2017<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Avelumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*Per JMEI: [[Dexamethasone (Decadron)]] 8 mg PO twice per day on days -1 to 2 (3 days)<br />
*Per Chem et al. 2006: [[Dexamethasone (Decadron)]] as follows:<br />
**8 mg PO once per day on days 1, 8, 15; 12 hours prior to [[Docetaxel (Taxotere)]]<br />
**10 mg IV once per day on days 1, 8, 15; 30 minutes prior to [[Docetaxel (Taxotere)]]<br />
**8 mg PO once per day on days 1, 8, 15; 12 hours after [[Docetaxel (Taxotere)]]<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #4, 100 mg/m<sup>2</sup> q3wk {{#subobject:465aa0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1995.13.3.645 Fossella et al. 1995]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#Fossella FV, Lee JS, Shin DM, Calayag M, Huber M, Perez-Soler R, Murphy WK, Lippman S, Benner S, Glisson B, Chasen M, Hong WK, Raber M. Phase II study of docetaxel for advanced or metastatic platinum-refractory non-small-cell lung cancer. J Clin Oncol. 1995 Mar;13(3):645-51. [https://doi.org/10.1200/JCO.1995.13.3.645 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/7884425 PubMed]<br />
#'''TAX 317:''' Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, Levitan N, Gressot L, Vincent M, Burkes R, Coughlin S, Kim Y, Berille J. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000 May;18(10):2095-103. [https://doi.org/10.1200/JCO.2000.18.10.2095 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10811675 PubMed]<br />
#'''TAX 320:''' Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L; TAX 320 Non-Small Cell Lung Cancer Study Group. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol. 2000 Jun;18(12):2354-62. Erratum in: J Clin Oncol. 2004 Jan 1;22(1):209. [https://doi.org/10.1200/JCO.2000.18.12.2354 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10856094 PubMed]<br />
#'''JMEI:''' Hanna N, Shepherd FA, Fossella FV, Rodrigues Pereira J, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar M, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1;22(9):1589-97. [https://doi.org/10.1200/jco.2004.08.163 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15117980 PubMed]<br />
#Camps C, Massuti B, Jiménez A, Maestu I, Gómez RG, Isla D, González JL, Almenar D, Blasco A, Rosell R, Carrato A, Viñolas N, Batista N, Girón CG, Galán A, López M, Blanco R, Provencio M, Diz P, Felip E; Spanish Lung Cancer Group. Randomized phase III study of 3-weekly versus weekly docetaxel in pretreated advanced non-small-cell lung cancer: a Spanish Lung Cancer Group trial. Ann Oncol. 2006 Mar;17(3):467-72. Epub 2005 Dec 21. [https://doi.org/10.1093/annonc/mdj115 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16371411 PubMed]<br />
#Chen YM, Shih JF, Perng RP, Tsai CM, Whang-Peng J. A randomized trial of different docetaxel schedules in non-small cell lung cancer patients who failed previous platinum-based chemotherapy. Chest. 2006 Apr;129(4):1031-8. [http://journal.chestnet.org/article/S0012-3692(15)38821-8/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16608954 PubMed]<br />
#Ramlau R, Gervais R, Krzakowski M, von Pawel J, Kaukel E, Abratt RP, Dharan B, Grotzinger KM, Ross G, Dane G, Shepherd FA. Phase III study comparing oral topotecan to intravenous docetaxel in patients with pretreated advanced non-small-cell lung cancer. J Clin Oncol. 2006 Jun 20;24(18):2800-7. Epub 2006 May 8. [https://doi.org/10.1200/JCO.2005.03.6491 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16682727 PubMed]<br />
#'''V-15-32:''' Maruyama R, Nishiwaki Y, Tamura T, Yamamoto N, Tsuboi M, Nakagawa K, Shinkai T, Negoro S, Imamura F, Eguchi K, Takeda K, Inoue A, Tomii K, Harada M, Masuda N, Jiang H, Itoh Y, Ichinose Y, Saijo N, Fukuoka M. Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol. 2008 Sep 10;26(26):4244-52. [https://doi.org/10.1200/JCO.2007.15.0185 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18779611 PubMed]<br />
##'''HRQoL analysis:''' Sekine I, Ichinose Y, Nishiwaki Y, Yamamoto N, Tsuboi M, Nakagawa K, Shinkai T, Negoro S, Imamura F, Eguchi K, Takeda K, Itoh Y, Tamura T, Saijo N, Fukuoka M. Quality of life and disease-related symptoms in previously treated Japanese patients with non-small-cell lung cancer: results of a randomized phase III study (V-15-32) of gefitinib versus docetaxel. Ann Oncol. 2009 Sep;20(9):1483-8. Epub 2009 Mar 12. [https://doi.org/10.1093/annonc/mdp031 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19282468 PubMed]<br />
#'''INTEREST:''' Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008 Nov 22;372(9652):1809-18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61758-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19027483 PubMed] NCT00076388<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/151 Project Data Sphere]<br />
#Fidias PM, Dakhil SR, Lyss AP, Loesch DM, Waterhouse DM, Bromund JL, Chen R, Hristova-Kazmierski M, Treat J, Obasaju CK, Marciniak M, Gill J, Schiller JH. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Feb 1;27(4):591-8. Epub 2008 Dec 15. [https://doi.org/10.1200/JCO.2008.17.1405 link to original article]'''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19075278 PubMed]<br />
#'''ISTANA:''' Lee DH, Park K, Kim JH, Lee JS, Shin SW, Kang JH, Ahn MJ, Ahn JS, Suh C, Kim SW. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010 Feb 15;16(4):1307-14. Epub 2010 Feb 9. [http://clincancerres.aacrjournals.org/content/16/4/1307.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20145166 PubMed] NCT00478049<br />
<!-- Presented in part at the 14th World Conference on Lung Cancer, Amsterdam, the Netherlands, July 3-7, 2011. --><br />
#'''EFC10261:''' Ramlau R, Gorbunova V, Ciuleanu TE, Novello S, Ozguroglu M, Goksel T, Baldotto C, Bennouna J, Shepherd FA, Le-Guennec S, Rey A, Miller V, Thatcher N, Scagliotti G. Aflibercept and docetaxel versus docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial. J Clin Oncol. 2012 Oct 10;30(29):3640-7. Epub 2012 Sep 10. [https://doi.org/10.1200/JCO.2012.42.6932 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22965962 PubMed] NCT00532155<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/133 Project Data Sphere]<br />
#'''LUME-Lung 1:''' Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, von Pawel J, Gottfried M, Bondarenko I, Liao M, Gann CN, Barrueco J, Gaschler-Markefski B, Novello S; LUME-Lung 1 Study Group. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55. 2. Epub 2014 Jan 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70586-2/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24411639 PubMed] NCT00805194<br />
#'''KEYNOTE-010:''' Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-50. Epub 2015 Dec 19. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01281-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/26712084 PubMed] NCT01905657<br />
##'''Update:''' Herbst RS, Garon EB, Kim DW, Cho BC, Perez-Gracia JL, Han JY, Arvis CD, Majem M, Forster MD, Monnet I, Novello S, Szalai Z, Gubens MA, Su WC, Ceresoli GL, Samkari A, Jensen EH, Lubiniecki GM, Baas P. Long-Term Outcomes and Retreatment Among Patients With Previously Treated, Programmed Death-Ligand 1‒Positive, Advanced Non‒Small-Cell Lung Cancer in the KEYNOTE-010 Study. J Clin Oncol. 2020 May 10;38(14):1580-1590. Epub 2020 Feb 20. [https://doi.org/10.1200/jco.19.02446 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32078391/ PubMed]<br />
#'''POPLAR:''' Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30;387(10030):1837-46. Epub 2016 Mar 9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00587-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/26970723 PubMed] NCT01903993<br />
#'''OAK:''' Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. Epub 2016 Dec 13. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32517-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/27979383 PubMed] NCT02008227<br />
##'''Update:''' Fehrenbacher L, von Pawel J, Park K, Rittmeyer A, Gandara DR, Ponce Aix S, Han JY, Gadgeel SM, Hida T, Cortinovis DL, Cobo M, Kowalski DM, De Marinis F, Gandhi M, Danner B, Matheny C, Kowanetz M, He P, Felizzi F, Patel H, Sandler A, Ballinger M, Barlesi F. Updated Efficacy Analysis Including Secondary Population Results for OAK: A Randomized Phase III Study of Atezolizumab versus Docetaxel in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer. J Thorac Oncol. 2018 Aug;13(8):1156-1170. Epub 2018 May 17. Erratum in: J Thorac Oncol. 2018 Nov;13(11):1800. [https://www.jto.org/article/S1556-0864(18)30611-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29777823 PubMed]<br />
##'''Update:''' von Pawel J, Bordoni R, Satouchi M, Fehrenbacher L, Cobo M, Han JY, Hida T, Moro-Sibilot D, Conkling P, Gandara DR, Rittmeyer A, Gandhi M, Yu W, Matheny C, Patel H, Sandler A, Ballinger M, Kowanetz M, Park K. Long-term survival in patients with advanced non-small-cell lung cancer treated with atezolizumab versus docetaxel: Results from the randomised phase III OAK study. Eur J Cancer. 2019 Jan;107:124-132. Epub 2018 Dec 17. [https://www.ejcancer.com/article/S0959-8049(18)31518-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/30562710 PubMed]<br />
#'''D0702035:''' Yoshioka H, Katakami N, Okamoto H, Iwamoto Y, Seto T, Takahashi T, Sunaga N, Kudoh S, Chikamori K, Harada M, Tanaka H, Saito H, Saka H, Takeda K, Nogami N, Masuda N, Harada T, Kitagawa H, Horio H, Yamanaka T, Fukuoka M, Yamamoto N, Nakagawa K. A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer. Ann Oncol. 2017 Feb 1;28(2):285-291. [https://doi.org/10.1093/annonc/mdw621 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28426104 PubMed] NCT01207011<br />
#'''E7389-G000-302:''' Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. [https://doi.org/10.1093/annonc/mdx284 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28911085 PubMed] NCT01454934<br />
#'''EAST-LC:''' Nokihara H, Lu S, Mok TSK, Nakagawa K, Yamamoto N, Shi YK, Zhang L, Soo RA, Yang JC, Sugawara S, Nishio M, Takahashi T, Goto K, Chang J, Maemondo M, Ichinose Y, Cheng Y, Lim WT, Morita S, Tamura T. Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer). Ann Oncol. 2017 Nov 1;28(11):2698-2706. [https://doi.org/10.1093/annonc/mdx419 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834128/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29045553 PubMed] JapicCTI-101155<br />
#'''JAVELIN Lung 200:''' Barlesi F, Vansteenkiste J, Spigel D, Ishii H, Garassino M, de Marinis F, Özgüroğlu M, Szczesna A, Polychronis A, Uslu R, Krzakowski M, Lee JS, Calabrò L, Arén Frontera O, Ellers-Lenz B, Bajars M, Ruisi M, Park K. Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study. Lancet Oncol. 2018 Nov;19(11):1468-79. Epub 2018 Sep 21. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30673-9/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/30262187 PubMed] NCT02395172<br />
#'''CheckMate 078:''' Wu YL, Lu S, Cheng Y, Zhou C, Wang J, Mok T, Zhang L, Tu HY, Wu L, Feng J, Zhang Y, Luft AV, Zhou J, Ma Z, Lu Y, Hu C, Shi Y, Baudelet C, Cai J, Chang J. Nivolumab Versus Docetaxel in a Predominantly Chinese Patient Population With Previously Treated Advanced NSCLC: CheckMate 078 Randomized Phase III Clinical Trial. J Thorac Oncol. 2019 May;14(5):867-875. Epub 2019 Jan 17. [https://doi.org/10.1016/j.jtho.2019.01.006 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/30659987 PubMed] NCT02613507<br />
<br />
==Docetaxel & Nintedanib {{#subobject:f8yg16|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5b63mi|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70586-2/fulltext Reck et al. 2014 (LUME-Lung 1)]<br />
|2008-2011<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Nintedanib (Vargatef)]] 200 mg PO twice per day on days 2 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''LUME-Lung 1:''' Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, von Pawel J, Gottfried M, Bondarenko I, Liao M, Gann CN, Barrueco J, Gaschler-Markefski B, Novello S; LUME-Lung 1 Study Group. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55. 2. Epub 2014 Jan 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70586-2/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24411639 PubMed] NCT00805194<br />
<br />
==Gefitinib monotherapy {{#subobject:ebbf2d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1b028f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jama.jamanetwork.com/article.aspx?articleid=197532 Kris et al. 2003 (IDEAL2)]<br />
|2000-2001<br />
| style="background-color:#1a9851" |Randomized Phase II (E-RT-de-esc)<br />
|[[#Gefitinib_monotherapy_3|Gefitinib]]; 500 mg/day<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)67625-8/fulltext Thatcher et al. 2005 (ISEL)]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Non-small_cell_lung_cancer_-_null_regimens#Placebo_5|Placebo]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61758-4/fulltext Kim et al. 2008 (INTEREST)]<br />
|2004-2006<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#eeee01" |Seems to have non-inferior OS<br />
|-<br />
|[http://clincancerres.aacrjournals.org/content/16/4/1307.long Lee et al. 2010 (ISTANA)]<br />
|2005-2006<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|[http://clincancerres.aacrjournals.org/content/17/6/1553.long Han et al. 2011 (NCCCTS-06-177)]<br />
|2006-2008<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gefitinib & Simvastatin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70355-3/fulltext Shi et al. 2013 (ICOGEN)]<br />
|2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Icotinib_monotherapy|Icotinib]]<br />
| style="background-color:#eeee01" |Seems to have non-inferior PFS<br />
|-<br />
|}<br />
''Note: IDEAL2 was the basis of initial FDA approval in 2003.''<br />
====Targeted therapy====<br />
<br />
*[[Gefitinib (Iressa)]] 250 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''IDEAL2:''' Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003 Oct 22;290(16):2149-58. [http://jama.jamanetwork.com/article.aspx?articleid=197532 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14570950 PubMed]<br />
#'''ISEL:''' Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005 Oct 29-Nov 4;366(9496):1527-37. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)67625-8/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/16257339 PubMed]<br />
#'''INTEREST:''' Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008 Nov 22;372(9652):1809-18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61758-4/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19027483 PubMed] NCT00076388<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/151 Project Data Sphere]<br />
#'''ISTANA:''' Lee DH, Park K, Kim JH, Lee JS, Shin SW, Kang JH, Ahn MJ, Ahn JS, Suh C, Kim SW. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010 Feb 15;16(4):1307-14. Epub 2010 Feb 9. [http://clincancerres.aacrjournals.org/content/16/4/1307.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20145166 PubMed] NCT00478049<br />
#'''NCCCTS-06-177:''' Han JY, Lee SH, Yoo NJ, Hyung LS, Moon YJ, Yun T, Kim HT, Lee JS. A randomized phase II study of gefitinib plus simvastatin versus gefitinib alone in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res. 2011 Mar 15;17(6):1553-60. [http://clincancerres.aacrjournals.org/content/17/6/1553.long link to orinigal article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/21411446 PubMed] NCT00452244<br />
#'''ICOGEN:''' Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, Wang D, Li Q, Qin S, Hu C, Zhang Y, Chen J, Cheng Y, Feng J, Zhang H, Song Y, Wu YL, Xu N, Zhou J, Luo R, Bai C, Jin Y, Liu W, Wei Z, Tan F, Wang Y, Ding L, Dai H, Jiao S, Wang J, Liang L, Zhang W, Sun Y. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 2013 Sep;14(10):953-61. Epub 2013 Aug 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70355-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/23948351 PubMed] ChiCTR-TRC-09000506<br />
<br />
==Gemcitabine monotherapy {{#subobject:63e7a9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 1000 mg/m<sup>2</sup> {{#subobject:dda826|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ Katakami et al. 2017 (E7389-G000-302)]<br />
|2011-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Eribulin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|rowspan=2|[https://doi.org/10.1016/j.annonc.2020.02.006 Planchard et al. 2020 (ARCTIC)]<br />
|rowspan=2|2015-2016<br />
|rowspan=2 style="background-color:#1a9851" |Phase III (C)<br />
|1. Durvalumab & Tremelimumab<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|2. Durvalumab<br> 3. Tremelimumab<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 1250 mg/m<sup>2</sup> {{#subobject:7f2a5c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ Katakami et al. 2017 (E7389-G000-302)]<br />
|2011-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Eribulin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''E7389-G000-302:''' Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. [https://doi.org/10.1093/annonc/mdx284 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28911085 PubMed] NCT01454934<br />
#'''ARCTIC:''' Planchard D, Reinmuth N, Orlov S, Fischer JR, Sugawara S, Mandziuk S, Marquez-Medina D, Novello S, Takeda Y, Soo R, Park K, McCleod M, Geater SL, Powell M, May R, Scheuring U, Stockman P, Kowalski D. ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer. Ann Oncol. 2020 May;31(5):609-618. Epub 2020 Feb 20. [https://doi.org/10.1016/j.annonc.2020.02.006 link to original article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/32201234 PubMed] NCT02352948<br />
<br />
==Icotinib monotherapy {{#subobject:9720a1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d7253b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70355-3/fulltext Shi et al. 2013 (ICOGEN)]<br />
|2009<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Gefitinib_monotherapy_3|Gefitinib]]<br />
| style="background-color:#eeee01" |Seems to have non-inferior PFS<br />
|-<br />
|}<br />
''Note: this drug is only approved in China.''<br />
====Targeted therapy====<br />
<br />
*[[Icotinib (Conmana)]] 125 mg PO three times per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''ICOGEN:''' Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, Wang D, Li Q, Qin S, Hu C, Zhang Y, Chen J, Cheng Y, Feng J, Zhang H, Song Y, Wu YL, Xu N, Zhou J, Luo R, Bai C, Jin Y, Liu W, Wei Z, Tan F, Wang Y, Ding L, Dai H, Jiao S, Wang J, Liang L, Zhang W, Sun Y. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 2013 Sep;14(10):953-61. Epub 2013 Aug 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70355-3/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23948351 PubMed] ChiCTR-TRC-09000506<br />
<br />
==Nivolumab monotherapy {{#subobject:7e5a40|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:f73cfc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/j.jtho.2019.01.006 Wu et al. 2019 (CheckMate 078)]<br />
|2015-2016<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1<br />
**Notably, on 9/13/16 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
#'''CheckMate 078:''' Wu YL, Lu S, Cheng Y, Zhou C, Wang J, Mok T, Zhang L, Tu HY, Wu L, Feng J, Zhang Y, Luft AV, Zhou J, Ma Z, Lu Y, Hu C, Shi Y, Baudelet C, Cai J, Chang J. Nivolumab Versus Docetaxel in a Predominantly Chinese Patient Population With Previously Treated Advanced NSCLC: CheckMate 078 Randomized Phase III Clinical Trial. J Thorac Oncol. 2019 May;14(5):867-875. Epub 2019 Jan 17. [https://doi.org/10.1016/j.jtho.2019.01.006 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/30659987 PubMed] NCT02613507<br />
<br />
==Pembrolizumab monotherapy {{#subobject:068cc1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d2e0eb|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1501824 Garon et al. 2015 (KEYNOTE-001)]<br />
|2012-2014<br />
| style="background-color:#91cf61" |Phase 1, >20 pts in dosing cohort<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01281-7/fulltext Herbst et al. 2015 (KEYNOTE-010)]<br />
|2013-2015<br />
| style="background-color:#1a9851" |Phase II/III (E-RT-switch-ooc)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: patients had previously received chemotherapy.''<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 2 mg/kg or 10 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Phase 1:''' Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28. Epub 2015 Apr 19. [https://www.nejm.org/doi/full/10.1056/NEJMoa1501824 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25891174 PubMed] NCT01295827<br />
#'''KEYNOTE-010:''' Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-50. Epub 2015 Dec 19. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01281-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/26712084 PubMed] NCT01905657<br />
##'''Update:''' Herbst RS, Garon EB, Kim DW, Cho BC, Perez-Gracia JL, Han JY, Arvis CD, Majem M, Forster MD, Monnet I, Novello S, Szalai Z, Gubens MA, Su WC, Ceresoli GL, Samkari A, Jensen EH, Lubiniecki GM, Baas P. Long-Term Outcomes and Retreatment Among Patients With Previously Treated, Programmed Death-Ligand 1‒Positive, Advanced Non‒Small-Cell Lung Cancer in the KEYNOTE-010 Study. J Clin Oncol. 2020 May 10;38(14):1580-1590. Epub 2020 Feb 20. [https://doi.org/10.1200/jco.19.02446 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32078391/ PubMed]<br />
<br />
==Pemetrexed monotherapy {{#subobject:24ad9b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Pemetrexed (Alimta) in non-small cell lung cancer]]<br />
<br />
===Regimen {{#subobject:4e0d06|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2004.08.163 Hanna et al. 2004 (JMEI)]<br />
|2001-2002<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70473-X/fulltext Kim et al. 2013 (JXBC)]<br />
|2005-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Pemetrexed_.26_Cetuximab|Pemetrexed & Cetuximab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.28132 Karampeazis et al. 2013 (CT/06.05)]<br />
|2006-2010<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[Non-small_cell_lung_cancer_-_historical#Erlotinib_monotherapy_2|Erlotinib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ Katakami et al. 2017 (E7389-G000-302)]<br />
|2011-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Eribulin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: JXBC also evaluated docetaxel versus docetaxel & cetuximab, but did not report the efficacy of this comparison; see paper for details.''<br />
====Chemotherapy====<br />
<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*(per Ardizzoni et al. 2012):<br />
*[[Dexamethasone (Decadron)]] 4 mg or [[steroid conversions|equivalent corticosteroid]] PO twice per day on the day before, the day of, and day after each dose of [[Pemetrexed (Alimta)]]<br />
*[[Folic acid (Folate)]] 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be taken throughout pemetrexed therapy<br />
**JMEI used [[Folic acid (Folate)]] 1 mg PO once per day<br />
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of [[Pemetrexed (Alimta)]], to be given throughout pemetrexed therapy<br />
<br />
'''21-day cycles''' <br />
<br />
===References===<br />
<br />
#'''JMEI:''' Hanna N, Shepherd FA, Fossella FV, Rodrigues Pereira J, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar M, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1;22(9):1589-97. [https://doi.org/10.1200/jco.2004.08.163 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15117980 PubMed]<br />
#'''CT/06.05:''' Karampeazis A, Voutsina A, Souglakos J, Kentepozidis N, Giassas S, Christofillakis C, Kotsakis A, Papakotoulas P, Rapti A, Agelidou M, Agelaki S, Vamvakas L, Samonis G, Mavroudis D, Georgoulias V; Hellenic Oncology Research Group. Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study. Cancer. 2013 Aug 1;119(15):2754-64. Epub 2013 May 9. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.28132 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23661337 PubMed] NCT00440414<br />
#'''JXBC:''' Kim ES, Neubauer M, Cohn A, Schwartzberg L, Garbo L, Caton J, Robert F, Reynolds C, Katz T, Chittoor S, Simms L, Saxman S. Docetaxel or pemetrexed with or without cetuximab in recurrent or progressive non-small-cell lung cancer after platinum-based therapy: a phase 3, open-label, randomised trial. Lancet Oncol. 2013 Dec;14(13):1326-36. Epub 2013 Nov 12. Erratum in: Lancet Oncol. 2014 Jan;15(1):e4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70473-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24231627 PubMed] NCT00095199<br />
#'''E7389-G000-302:''' Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. [https://doi.org/10.1093/annonc/mdx284 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28911085 PubMed] NCT01454934<br />
<br />
==S-1 monotherapy {{#subobject:7702f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:48e547|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834128/ Nokihara et al. 2017 (EAST-LC)]<br />
|2010-2014<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Docetaxel_monotherapy_4|Docetaxel]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<br />
#'''EAST-LC:''' Nokihara H, Lu S, Mok TSK, Nakagawa K, Yamamoto N, Shi YK, Zhang L, Soo RA, Yang JC, Sugawara S, Nishio M, Takahashi T, Goto K, Chang J, Maemondo M, Ichinose Y, Cheng Y, Lim WT, Morita S, Tamura T. Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer). Ann Oncol. 2017 Nov 1;28(11):2698-2706. [https://doi.org/10.1093/annonc/mdx419 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834128/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29045553 PubMed] JapicCTI-101155<br />
<br />
==Vinorelbine monotherapy {{#subobject:f604bd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0441ba|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2000.18.12.2354 Fossella et al. 2000 (TAX 320)]<br />
| rowspan="2" |1995-1998<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Docetaxel_monotherapy_4|Docetaxel 100 mg/m<sup>2</sup>]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Docetaxel_monotherapy_4|Docetaxel 75 mg/m<sup>2</sup>]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ Katakami et al. 2017 (E7389-G000-302)]<br />
|2011-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Eribulin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|rowspan=2|[https://doi.org/10.1016/j.annonc.2020.02.006 Planchard et al. 2020 (ARCTIC)]<br />
|rowspan=2|2015-2016<br />
|rowspan=2 style="background-color:#1a9851" |Phase III (C)<br />
|1. Durvalumab & Tremelimumab<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|2. Durvalumab<br> 3. Tremelimumab<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV over 5 to 10 minutes once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
<br />
*Per TAX 320:<br />
*Patients who had either grade 4 neutropenia lasting at least 5 days or both fever and grade 3 or 4 neutropenia could receive [[:Category:Granulocyte colony-stimulating factors|G-CSF]] (dose/schedule/duration not specified)<br />
*[[Metoclopramide (Reglan)]] (dose/schedule/route not specified) used first for nausea<br />
*Nausea despite metoclopramide was treated with a 5-HT3 antagonist such as [[Ondansetron (Zofran)]] or [[Granisetron]] (dose/schedule/route not specified) prn nausea<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''TAX 320:''' Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L; TAX 320 Non-Small Cell Lung Cancer Study Group. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol. 2000 Jun;18(12):2354-62. Erratum in: J Clin Oncol. 2004 Jan 1;22(1):209. [https://doi.org/10.1200/JCO.2000.18.12.2354 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10856094 PubMed]<br />
#'''E7389-G000-302:''' Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. [https://doi.org/10.1093/annonc/mdx284 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834051/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28911085 PubMed] NCT01454934<br />
#'''ARCTIC:''' Planchard D, Reinmuth N, Orlov S, Fischer JR, Sugawara S, Mandziuk S, Marquez-Medina D, Novello S, Takeda Y, Soo R, Park K, McCleod M, Geater SL, Powell M, May R, Scheuring U, Stockman P, Kowalski D. ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer. Ann Oncol. 2020 May;31(5):609-618. Epub 2020 Feb 20. [https://doi.org/10.1016/j.annonc.2020.02.006 link to original article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/32201234 PubMed] NCT02352948<br />
<br />
=CNS metastases, all lines of therapy=<br />
==Dexamethasone monotherapy {{#subobject:adb3fe|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:6a5b0e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082599/ Mulvenna et al. 2016 (QUARTZ)]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#Dexamethasone_.26_WBRT|Dexamethasone & WBRT]]<br />
|<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior QALYs<br />
|-<br />
|}<br />
====Supportive therapy====<br />
<br />
*[[Dexamethasone (Decadron)]]<br />
<br />
===References===<br />
<br />
#'''QUARTZ:''' Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, Moore B, Brisbane I, Ardron D, Holt T, Morgan S, Lee C, Waite K, Bayman N, Pugh C, Sydes B, Stephens R, Parmar MK, Langley RE. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016 Oct 22;388(10055):2004-2014. Epub 2016 Sep 4. [https://doi.org/10.1016/s0140-6736(16)30825-x link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082599/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27604504 PubMed] ISRCTN3826061<br />
<br />
==Dexamethasone & WBRT {{#subobject:04a6d4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:da6414|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082599/ Mulvenna et al. 2016 (QUARTZ)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Dexamethasone_monotherapy|Dexamethasone]]<br />
|<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior QALYs<br />
|-<br />
|}<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy|WBRT]], 20 Gy in 5 fractions<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]]<br />
<br />
===References===<br />
<br />
#'''QUARTZ:''' Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, Moore B, Brisbane I, Ardron D, Holt T, Morgan S, Lee C, Waite K, Bayman N, Pugh C, Sydes B, Stephens R, Parmar MK, Langley RE. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016 Oct 22;388(10055):2004-2014. Epub 2016 Sep 4. [https://doi.org/10.1016/s0140-6736(16)30825-x link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082599/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27604504 PubMed] ISRCTN3826061<br />
<br />
==Teniposide & WBRT {{#subobject:04facd4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:19bu14|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.19.3400 Postmus et al. 2000]<br />
|1989-1995<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Teniposide<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Teniposide (Vumon)]]<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy|WBRT]], 30 Gy in 10 fractions<br />
<br />
===References===<br />
<br />
#Postmus PE, Haaxma-Reiche H, Smit EF, Groen HJ, Karnicka H, Lewinski T, van Meerbeeck J, Clerico M, Gregor A, Curran D, Sahmoud T, Kirkpatrick A, Giaccone G; European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy--a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol. 2000 Oct 1;18(19):3400-8. [https://doi.org/10.1200/JCO.2000.18.19.3400 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11013281 PubMed]<br />
<br />
=Investigational agents=<br />
''Drugs with some degree of promising activity in clinical trials.''<br />
<br />
[[Category:Non-small cell lung cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Lung cancers]]</div>Karinehttps://hemonc.org/w/index.php?title=Prostate_cancer&diff=49690Prostate cancer2021-05-14T14:52:57Z<p>Karine: formating</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" style="color:white; font-size:125%; background-color:#08519c" align="center" |'''Page editor'''<br />
! colspan="2" style="color:white; font-size:125%; background-color:#08519c" align="center" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:LauraGraham.jpg|frameless|upright=0.3|center]]<br />
|<big>Laura S. Graham, MD<br>University of Washington<br>Fred Hutchinson Cancer Research Center<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/LauraGrahamMD LauraGrahamMD]<br />
| style="background-color:#F0F0F0" |[[File:Alikhaki.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Alikhaki|Ali Raza Khaki, MD]]<br>Stanford University<br>Palo Alto, CA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/arkhaki arkhaki]<br />
|-<br />
|}<br />
''Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the [[Prostate_cancer_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Prostate cancer - null regimens|this page]]. If you still can't find it, please let us know so we can add it!'' <br><br />
'''Note: this page contains regimens for prostate cancer which were not tested in biomarker-specific populations. The following links will take you to biomarker-specific subpages:'''<br />
*Regimens for [[Prostate_cancer,_BRCA-mutated|'''BRCA-mutated prostate cancer are here''']].<br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/genitourinary-cancer ASCO]==<br />
<br />
*'''2018:''' Morris et al. [https://doi.org/10.1200/JCO.2018.78.0619 Optimizing Anticancer Therapy in Metastatic Non-Castrate Prostate Cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2017:''' Virgo et al. [https://doi.org/10.1200/JCO.2017.72.8030 Second-Line Hormonal Therapy for Men With Chemotherapy-Naïve, Castration-Resistant Prostate Cancer: American Society of Clinical Oncology Provisional Clinical Opinion] [https://www.ncbi.nlm.nih.gov/pubmed/28441112 PubMed]<br />
*'''2016:''' [https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/genitourinary-cancer#/9336 Active Surveillance for the Management of Localized Prostate Cancer Endorsement]<br />
*'''2015:''' [https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/genitourinary-cancer#/9426 Prostate Cancer Survivorship Care Guideline Endorsement]<br />
<br />
===Older===<br />
<br />
*'''2014:''' [https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/genitourinary-cancer#/9486 Adjuvant and Salvage Radiotherapy After Prostatectomy Endorsement]<br />
*'''2012:''' [https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/genitourinary-cancer#/9501 Screening for Prostate Cancer with Prostate-Specific Antigen (PSA) Testing PCO]<br />
*'''2009:''' [https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/genitourinary-cancer#/9511 Use of 5-alpha Reductase Inhibitors for Prostate Cancer Chemoprevention]<br />
*'''2007:''' [https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/genitourinary-cancer#/9516 Non-Hormonal Therapy for Men With Metastatic Hormone-Refractory (castration-resistant) Prostate Cancer Endorsement]<br />
<br />
==ASCO & CCO==<br />
<br />
*'''2014:''' Basch et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876355/ Systemic Therapy in Men With Metastatic Castration-Resistant Prostate Cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline]<br />
<br />
==AUA==<br />
<br />
*[https://www.auanet.org/education/guidelines/castration-resistant-prostate-cancer.cfm Castration-Resistant Prostate Cancer: AUA Guideline @ AUAnet] <br />
**[https://www.auanet.org/common/pdf/education/clinical-guidance/Castration-Resistant-Prostate-Cancer.pdf PDF (2015) @ AUAnet]<br />
*[https://www.auajournals.org/doi/full/10.1016/j.juro.2015.10.086 Castration-Resistant Prostate Cancer: AUA Guideline Amendment 2015] [https://www.ncbi.nlm.nih.gov/pubmed/26498056 PubMed]<br />
<br />
==EAU/ESTRO/SIOG==<br />
<br />
*'''2017:''' [http://www.europeanurology.com/article/S0302-2838(16)30469-9/fulltext EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer] [https://www.ncbi.nlm.nih.gov/pubmed/27591931 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2020:''' Parker et al. [https://doi.org/10.1016/j.annonc.2020.06.011 Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
===Older===<br />
*'''2015:''' Parker et al. [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Cancer-of-the-Prostate ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
*'''2013:''' Horwich et al. [https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mdt208 ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/23813930 PubMed]<br />
*'''2012:''' Horwich et al. [https://annonc.oxfordjournals.org/content/24/5/1141.full.pdf+html ESMO Consensus Conference Guidelines] [https://www.ncbi.nlm.nih.gov/pubmed/23303340 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf NCCN Guidelines - Prostate Cancer]<br />
<br />
==St Gallen==<br />
<br />
*'''2015:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511225/ Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC)]<br />
<br />
=Induction ADT=<br />
==ADT {{#subobject:8ab01b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:25b39f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2003.05.004 Roach et al. 2003 (RTOG 94-13)]<br />
|1995-1999<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#ADT|ADT]]; adjuvant<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2014.58.0662 Pisansky et al. 2014 (RTOG 9910)]<br />
|2000-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT|ADT]] x 28 weeks<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of disease-specific mortality<br />
|-<br />
|}<br />
''Note: these are clinical trials that did not specify a particular drug to be used for androgen deprivation. See papers for details.''<br />
====Endocrine therapy====<br />
<br />
*[[:Category:GnRH agonists|LHRH agonist]]<br />
*[[Bicalutamide (Casodex)]] or [[Flutamide (Eulexin)]]<br />
<br />
'''8-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[#ADT_.26_RT|ADT & RT]]<br />
<br />
===References===<br />
<br />
#'''RTOG 94-13:''' Roach M 3rd, DeSilvio M, Lawton C, Uhl V, Machtay M, Seider MJ, Rotman M, Jones C, Asbell SO, Valicenti RK, Han S, Thomas CR Jr, Shipley WS; Radiation Therapy Oncology Group. Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol. 2003 May 15;21(10):1904-11. [https://doi.org/10.1200/JCO.2003.05.004 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12743142 PubMed]<br />
##'''Update:''' Lawton CA, DeSilvio M, Roach M 3rd, Uhl V, Kirsch R, Seider M, Rotman M, Jones C, Asbell S, Valicenti R, Hahn S, Thomas CR Jr. An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions. Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):646-55. Epub 2007 May 24. [https://www.redjournal.org/article/S0360-3016(07)00641-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917177/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/17531401 PubMed]<br />
#'''RTOG 9910:''' Pisansky TM, Hunt D, Gomella LG, Amin MB, Balogh AG, Chinn DM, Seider MJ, Duclos M, Rosenthal SA, Bauman GS, Gore EM, Rotman MZ, Lukka HR, Shipley WU, Dignam JJ, Sandler HM. Duration of androgen suppression before radiotherapy for localized prostate cancer: Radiation Therapy Oncology Group randomized clinical trial 9910. J Clin Oncol. 2015 Feb 1;33(4):332-9. Epub 2014 Dec 22. [https://doi.org/10.1200/JCO.2014.58.0662 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302214/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25534388 PubMed] NCT00005044<br />
<br />
==Flutamide & Goserelin {{#subobject:b10d66 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:afbb9c |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.redjournal.org/article/S0360-3016(04)00264-0/fulltext Crook et al. 2004]<br />
|1995-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Flutamide_.26_Goserelin|Flutamide & Goserelin]] x 8 mo<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PSA-PFS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]]<br />
*[[Goserelin (Zoladex)]]<br />
<br />
'''3-month course'''<br />
====Subsequent treatment====<br />
<br />
*[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
<br />
===References===<br />
<br />
#Crook J, Ludgate C, Malone S, Lim J, Perry G, Eapen L, Bowen J, Robertson S, Lockwood G. Report of a multicenter Canadian phase III randomized trial of 3 months vs 8 months neoadjuvant androgen deprivation before standard-dose radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys. 2004 Sep 1;60(1):15-23. [https://www.redjournal.org/article/S0360-3016(04)00264-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15337535 PubMed]<br />
<br />
==Leuprolide monotherapy {{#subobject:1a6bc7 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:53abfc |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70328-6/fulltext Denham et al. 2014 (RADAR)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this trial had 4 arms including a randomization to zoledronic acid; see paper for details.''<br />
====Endocrine therapy====<br />
<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 3-month depot]] 22.5 mg IM once on day 1<br />
<br />
'''3-month cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Prostate_cancer_-_historical#Radiation_therapy|RT]], then [[#Leuprolide_monotherapy|Leuprolide]] x 12 mo versus [[Prostate_cancer_-_null_regimens#Observation|Observation]]<br />
<br />
===References===<br />
<br />
#'''RADAR:''' Denham JW, Joseph D, Lamb DS, Spry NA, Duchesne G, Matthews J, Atkinson C, Tai KH, Christie D, Kenny L, Turner S, Gogna NK, Diamond T, Delahunt B, Oldmeadow C, Attia J, Steigler A. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): an open-label, randomised, phase 3 factorial trial. Lancet Oncol. 2014 Sep;15(10):1076-89. Epub 2014 Aug 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70328-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25130995 PubMed] NCT00193856<br />
##'''Update:''' Denham JW, Joseph D, Lamb DS, Spry NA, Duchesne G, Matthews J, Atkinson C, Tai KH, Christie D, Kenny L, Turner S, Gogna NK, Diamond T, Delahunt B, Oldmeadow C, Attia J, Steigler A. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomised, phase 3, factorial trial. Lancet Oncol. 2019 Feb;20(2):267-281. Epub 2018 Dec 19. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30757-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30579763 PubMed]<br />
<br />
=Definitive therapy, including active surveillance=<br />
==Active surveillance==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa012794 Holmberg et al. 2002 (SPCG-4)]<br />
|1989-1999<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Surgery#Radical_prostatectomy|Radical prostatectomy]]<br />
| style="background-color:#d73027" |Inferior OS<sup>1</sup><br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429335/ Wilt et al. 2012 (PIVOT)]<br />
|1994-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Surgery#Radical_prostatectomy|Radical prostatectomy]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61619-X/fulltext Fleshner et al. 2012 (REDEEM)]<br />
|2006-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Dutasteride<br />
| style="background-color:#d73027" |Inferior TTP<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30661-1/fulltext Azzouzi et al. 2016 (CLIN1001 PCM301)]<br />
|2011-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Padeliporfin<br />
| style="background-color:#d73027" |Inferior TTP<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for SPCG-4 is based on the 2014 update.''<br><br />
''No antineoplastic therapy; consists of various strategies of close monitoring and re-biopsy.''<br />
===References===<br />
<br />
#'''SPCG-4:''' Holmberg L, Bill-Axelson A, Helgesen F, Salo JO, Folmerz P, Häggman M, Andersson SO, Spångberg A, Busch C, Nordling S, Palmgren J, Adami HO, Johansson JE, Norlén BJ; Scandinavian Prostatic Cancer Group. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med. 2002 Sep 12;347(11):781-9. [https://www.nejm.org/doi/10.1056/NEJMoa012794 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12226148 PubMed]<br />
##'''Update:''' Bill-Axelson A, Holmberg L, Ruutu M, Häggman M, Andersson SO, Bratell S, Spångberg A, Busch C, Nordling S, Garmo H, Palmgren J, Adami HO, Norlén BJ, Johansson JE; Scandinavian Prostate Cancer Group. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2005 May 12;352(19):1977-84. [https://www.nejm.org/doi/full/10.1056/NEJMoa043739 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15888698 PubMed]<br />
##'''Update:''' Bill-Axelson A, Holmberg L, Filén F, Ruutu M, Garmo H, Busch C, Nordling S, Häggman M, Andersson SO, Bratell S, Spångberg A, Palmgren J, Adami HO, Johansson JE; Scandinavian Prostate Cancer Group. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial. J Natl Cancer Inst. 2008 Aug 20;100(16):1144-54. Epub 2008 Aug 11. [https://academic.oup.com/jnci/article/100/16/1144/916419 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518167/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18695132 PubMed]<br />
##'''Update:''' Bill-Axelson A, Holmberg L, Ruutu M, Garmo H, Stark JR, Busch C, Nordling S, Häggman M, Andersson SO, Bratell S, Spångberg A, Palmgren J, Steineck G, Adami HO, Johansson JE; SPCG-4 Investigators. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2011 May 5;364(18):1708-17. [https://www.nejm.org/doi/10.1056/NEJMoa1011967 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21542742 PubMed]<br />
##'''Update:''' Bill-Axelson A, Holmberg L, Garmo H, Rider JR, Taari K, Busch C, Nordling S, Häggman M, Andersson SO, Spångberg A, Andrén O, Palmgren J, Steineck G, Adami HO, Johansson JE. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med. 2014 Mar 6;370(10):932-42. [https://www.nejm.org/doi/10.1056/NEJMoa1311593 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118145/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24597866 PubMed]<br />
##'''Update:''' Bill-Axelson A, Holmberg L, Garmo H, Taari K, Busch C, Nordling S, Häggman M, Andersson SO, Andrén O, Steineck G, Adami HO, Johansson JE. Radical Prostatectomy or Watchful Waiting in Prostate Cancer - 29-Year Follow-up. N Engl J Med. 2018 Dec 13;379(24):2319-2329. [https://www.nejm.org/doi/full/10.1056/NEJMoa1807801 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30575473 PubMed]<br />
#'''REDEEM:''' Fleshner NE, Lucia MS, Egerdie B, Aaron L, Eure G, Nandy I, Black L, Rittmaster RS. Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial. Lancet. 2012 Mar 24;379(9821):1103-11. Epub 2012 Jan 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61619-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22277570 PubMed] NCT00363311<br />
#'''PIVOT:''' Wilt TJ, Brawer MK, Jones KM, Barry MJ, Aronson WJ, Fox S, Gingrich JR, Wei JT, Gilhooly P, Grob BM, Nsouli I, Iyer P, Cartagena R, Snider G, Roehrborn C, Sharifi R, Blank W, Pandya P, Andriole GL, Culkin D, Wheeler T; Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012 Jul 19;367(3):203-13. Erratum in: N Engl J Med. 2012 Aug 9;367(6):582. [https://www.nejm.org/doi/10.1056/NEJMoa1113162 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429335/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22808955 PubMed] NCT00007644<br />
##'''Update:''' Wilt TJ, Jones KM, Barry MJ, Andriole GL, Culkin D, Wheeler T, Aronson WJ, Brawer MK. Follow-up of prostatectomy versus observation for early prostate cancer. N Engl J Med. 2017 Jul 13;377(2):132-142. [https://www.nejm.org/doi/10.1056/NEJMoa1615869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28700844 PubMed]<br />
#'''CLIN1001 PCM301:''' Azzouzi AR, Vincendeau S, Barret E, Cicco A, Kleinclauss F, van der Poel HG, Stief CG, Rassweiler J, Salomon G, Solsona E, Alcaraz A, Tammela TT, Rosario DJ, Gomez-Veiga F, Ahlgren G, Benzaghou F, Gaillac B, Amzal B, Debruyne FM, Fromont G, Gratzke C, Emberton M; PCM301 Study Group. Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial. Lancet Oncol. 2017 Feb;18(2):181-191. Epub 2016 Dec 20. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30661-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28007457 PubMed] NCT01310894<br />
<br />
==ADT {{#subobject:c3c2cb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c615a3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243932/ Warde et al. 2011 (NCIC-CTG PR.3/UK MRC PR07)]<br />
|1995-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_RT|ADT & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: these are clinical trials that did not specify a particular therapy to be used for androgen deprivation. See papers for details; the below are examples.''<br />
====Endocrine therapy====<br />
<br />
*ADT with ONE of the following:<br />
**[[:Category:GnRH agonists|LHRH agonist/analogue]]<br />
**[[:Category:GnRH antagonists|LHRH antagonist]]<br />
**[[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]]<br />
<br />
===References===<br />
<br />
#'''NCIC-CTG PR.3/UK MRC PR07:''' Warde P, Mason M, Ding K, Kirkbride P, Brundage M, Cowan R, Gospodarowicz M, Sanders K, Kostashuk E, Swanson G, Barber J, Hiltz A, Parmar MK, Sathya J, Anderson J, Hayter C, Hetherington J, Sydes MR, Parulekar W; NCIC-CTG; MRC. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011 Dec 17;378(9809):2104-11. Epub 2011 Nov 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61095-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243932/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22056152 PubMed] NCT00002633<br />
<br />
==ADT & RT {{#subobject:514ac2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT & RT: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:4aac55|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/199273 d'Amico et al. 2004]<br />
|1995-2001<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243932/ Warde et al. 2011 (NCIC-CTG PR.3/UK MRC PR07)]<br />
|1995-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#ADT_2|ADT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810095 Bolla et al. 2009 (EORTC 22961)]<br />
|1997-2001<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1016/j.ijrobp.2008.05.020 Rosenthal et al. 2008 (RTOG 9902)]<br />
|2000-2004<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/JCO.2014.58.0662 Pisansky et al. 2014 (RTOG 9910)]<br />
|2000-2004<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(18)30443-3/fulltext Nabid et al. 2018 (PCS IV)]<br />
|2000-2008<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|rowspan=2|[https://doi.org/10.1016/j.ejca.2020.10.023 Nabid et al. 2020 (PCS III)]<br />
|rowspan=2|2000-2010<br />
|rowspan=2 style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#1a9850" |Superior biochemical failure<br />
|-<br />
|2. [[#ADT_.26_RT|ADT & RT]]; dose-escalated RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of biochemical failure<br />
|-<br />
|[https://doi.org/10.1200/JCO.2015.64.8055 Bolla et al. 2016 (EORTC 22991)]<br />
|2001-2008<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7186584/ Malone et al. 2019]<br />
|2002-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70045-8/fulltext Zapatero et al. 2015 (DART01/05 GICOR)]<br />
|2005-2010<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: these are clinical trials that did not specify a particular drug to be used for androgen deprivation. See papers for details.''<br />
====Preceding treatment====<br />
<br />
*RTOG 9902 & DART01/05 GICOR: [[#ADT|ADT]] x 8 weeks<br />
*RTOG 9910: [[#ADT|ADT]] x 8 weeks versus [[#ADT|ADT]] x 28 weeks<br />
<br />
====Endocrine therapy====<br />
<br />
*ADT with ONE of the following:<br />
**[[:Category:GnRH agonists|LHRH agonist]]<br />
**Some protocols: [[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]]<br />
**Some protocols: [[Bicalutamide (Casodex)]] or [[Flutamide (Eulexin)]]<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]]<br />
<br />
'''8-week course'''<br />
====Subsequent treatment====<br />
<br />
*RTOG 9902: ADT x 2 y versus TEE x 4, then ADT x 2 y<br />
*EORTC 22961: ADT for 6 months versus ADT for 36 months<br />
*DART01/05 GICOR: ADT for 24 months versus no further treatment<br />
*PCS IV: ADT for 18 months versus ADT for 36 months<br />
<br />
===References===<br />
<br />
#D'Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA. 2004 Aug 18;292(7):821-7. [https://jamanetwork.com/journals/jama/fullarticle/199273 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15315996 PubMed]<br />
#'''RTOG 9902:''' Rosenthal SA, Bae K, Pienta KJ, Sobczak ML, Asbell SO, Rajan R, Kerlin KJ, Michalski JM, Sandler HM; Radiation Therapy Oncology Group. Phase III multi-institutional trial of adjuvant chemotherapy with paclitaxel, estramustine, and oral etoposide combined with long-term androgen suppression therapy and radiotherapy versus long-term androgen suppression plus radiotherapy alone for high-risk prostate cancer: preliminary toxicity analysis of RTOG 99-02. Int J Radiat Oncol Biol Phys. 2009 Mar 1;73(3):672-8. Epub 2008 Nov 5. [https://doi.org/10.1016/j.ijrobp.2008.05.020 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18990504 PubMed]<br />
##'''Update:''' Rosenthal SA, Hunt D, Sartor AO, Pienta KJ, Gomella L, Grignon D, Rajan R, Kerlin KJ, Jones CU, Dobelbower M, Shipley WU, Zeitzer K, Hamstra DA, Donavanik V, Rotman M, Hartford AC, Michalski J, Seider M, Kim H, Kuban DA, Moughan J, Sandler H. A phase 3 trial of 2 years of androgen suppression and radiation therapy with or without adjuvant chemotherapy for high-risk prostate cancer: final results of radiation therapy oncology group phase 3 randomized trial NRG Oncology RTOG 9902. Int J Radiat Oncol Biol Phys. 2015 Oct 1;93(2):294-302. Epub 2015 Jul 21. [https://www.redjournal.org/article/S0360-3016(15)00552-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719152/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26209502 PubMed]<br />
#'''EORTC 22961:''' Bolla M, de Reijke TM, Van Tienhoven G, Van den Bergh AC, Oddens J, Poortmans PM, Gez E, Kil P, Akdas A, Soete G, Kariakine O, van der Steen-Banasik EM, Musat E, Piérart M, Mauer ME, Collette L; [[Study_Groups#EORTC|EORTC]] Radiation Oncology Group; [[Study_Groups#EORTC|EORTC]] Genito-Urinary Tract Cancer Group. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med. 2009 Jun 11;360(24):2516-27. [https://www.nejm.org/doi/10.1056/NEJMoa0810095 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19516032 PubMed] NCT00003026<br />
#'''NCIC-CTG PR.3/UK MRC PR07:''' Warde P, Mason M, Ding K, Kirkbride P, Brundage M, Cowan R, Gospodarowicz M, Sanders K, Kostashuk E, Swanson G, Barber J, Hiltz A, Parmar MK, Sathya J, Anderson J, Hayter C, Hetherington J, Sydes MR, Parulekar W; NCIC; MRC. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011 Dec 17;378(9809):2104-11. Epub 2011 Nov 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61095-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243932/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22056152 PubMed] NCT00002633<br />
#'''RTOG 9910:''' Pisansky TM, Hunt D, Gomella LG, Amin MB, Balogh AG, Chinn DM, Seider MJ, Duclos M, Rosenthal SA, Bauman GS, Gore EM, Rotman MZ, Lukka HR, Shipley WU, Dignam JJ, Sandler HM. Duration of androgen suppression before radiotherapy for localized prostate cancer: Radiation Therapy Oncology Group randomized clinical trial 9910. J Clin Oncol. 2015 Feb 1;33(4):332-9. Epub 2014 Dec 22. [https://doi.org/10.1200/JCO.2014.58.0662 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302214/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25534388 PubMed] NCT00005044<br />
#'''DART01/05 GICOR:''' Zapatero A, Guerrero A, Maldonado X, Alvarez A, Gonzalez San Segundo C, Cabeza Rodríguez MA, Macias V, Pedro Olive A, Casas F, Boladeras A, de Vidales CM, Vazquez de la Torre ML, Villà S, Perez de la Haza A, Calvo FA. High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Mar;16(3):320-7. Epub 2015 Feb 19. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70045-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25702876 PubMed] NCT02175212<br />
#'''EORTC 22991:''' Bolla M, Maingon P, Carrie C, Villa S, Kitsios P, Poortmans PM, Sundar S, van der Steen-Banasik EM, Armstrong J, Bosset JF, Herrera FG, Pieters B, Slot A, Bahl A, Ben-Yosef R, Boehmer D, Scrase C, Renard L, Shash E, Coens C, van den Bergh AC, Collette L. Short androgen suppression and radiation dose escalation for intermediate- and high-risk localized prostate cancer: results of EORTC trial 22991. J Clin Oncol. 2016 May 20;34(15):1748-56. Epub 2016 Mar 14. [https://doi.org/10.1200/JCO.2015.64.8055 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26976418 PubMed] NCT00021450<br />
#'''PCS IV:''' Nabid A, Carrier N, Martin AG, Bahary JP, Lemaire C, Vass S, Bahoric B, Archambault R, Vincent F, Bettahar R, Duclos M, Garant MP, Souhami L. Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial. Eur Urol. 2018 Oct;74(4):432-441. Epub 2018 Jul 3. [https://www.europeanurology.com/article/S0302-2838(18)30443-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29980331 PubMed] NCT00223171<br />
#Malone S, Roy S, Eapen L, E C, MacRae R, Perry G, Bowen J, Samant R, Morgan S, Craig J, Malone K, Grimes S. Sequencing of Androgen-Deprivation Therapy With External-Beam Radiotherapy in Localized Prostate Cancer: A Phase III Randomized Controlled Trial. J Clin Oncol. 2020 Feb 20;38(6):593-601. Epub 2019 Dec 12. Erratum in: J Clin Oncol. 2020 Jun 10;38(17):2005. [https://doi.org/10.1200/jco.19.01904 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7186584/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31829912/ PubMed]<br />
#'''PCS III:''' Nabid A, Carrier N, Vigneault E, Van Nguyen T, Vavassis P, Brassard MA, Bahoric B, Archambault R, Vincent F, Bettahar R, Wilke D, Souhami L. Androgen deprivation therapy and radiotherapy in intermediate-risk prostate cancer: A randomised phase III trial. Eur J Cancer. 2021 Jan;143:64-74. Epub 2020 Dec 3. [https://doi.org/10.1016/j.ejca.2020.10.023 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33279855/ PubMed] NCT00223145<br />
<br />
==Flutamide, Goserelin, RT {{#subobject:2 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Flutamide, Goserelin, RT: Flutamide, Goserelin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:2 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.goldjournal.net/article/S0090-4295(99)80053-3/pdf Pilepich et al. 1995]<br />
|1987-1991<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|[http://www.redjournal.org/article/S0360-3016(01)01579-6/fulltext Pilepich et al. 2001 (RTOG 86-10)]<br />
|1987-1991<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#91cf60" |Seems to have superior cause-specific mortality<br />
|-<br />
|[https://doi.org/10.1200/jco.2003.11.023 Hanks et al. 2003 (RTOG 92-02)]<br />
|1992-1995<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1012348 Jones et al. 2011 (RTOG 94-08)]<br />
|1994-2001<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/299/3/289.long D'Amico et al. 2008 (DFCI 95-096)]<br />
|1995-2001<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70348-X/abstract Denham et al. 2005 (TTROG 96.01)]<br />
| rowspan="2" |1996-2000<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. Flutamide & Goserelin x 6 mo, RT<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#1a9850" |Superior EFS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]] 250 mg PO three times per day<br />
*[[Goserelin (Zoladex)]] 3.6 mg SC once on day 1<br />
<br />
'''28-day cycles, starting 2 months prior to radiation therapy and continuing at least through the end of radiation therapy'''<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] is started 2 months after start of androgen deprivation therapy (ADT), 1.8 to 2 Gy per fraction, with an initial 44 to 46 Gy to the pelvis, then an additional conedown to the prostate that resulted in a total dose of 65 to 70 Gy<br />
<br />
'''7-week course'''<br />
<br />
====Subsequent treatment====<br />
<br />
*RTOG 92-02: [[#Goserelin_monotherapy|adjuvant goserelin]] x 2 y versus [[Prostate_cancer_-_null_regimens#Observation|no further treatment]]<br />
<br />
===References===<br />
<br />
#Pilepich MV, Krall JM, al-Sarraf M, John MJ, Doggett RL, Sause WT, Lawton CA, Abrams RA, Rotman M, Rubin P, Soloway MS; Radiation Therapy Oncology Group. Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology. 1995 Apr;45(4):616-23. [https://www.goldjournal.net/article/S0090-4295(99)80053-3/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7716842 PubMed]<br />
#'''RTOG 86-10:''' Pilepich MV, Winter K, John MJ, Mesic JB, Sause W, Rubin P, Lawton C, Machtay M, Grignon D. Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 2001 Aug 1;50(5):1243-52. [http://www.redjournal.org/article/S0360-3016(01)01579-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11483335 PubMed]<br />
##'''Update:''' Roach M 3rd, Bae K, Speight J, Wolkov HB, Rubin P, Lee RJ, Lawton C, Valicenti R, Grignon D, Pilepich MV. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J Clin Oncol. 2008 Feb 1;26(4):585-91. Epub 2008 Jan 2. [https://doi.org/10.1200/jco.2007.13.9881 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18172188 PubMed]<br />
#'''RTOG 92-02:''' Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, Horwitz EM, Lawton C, Rosenthal SA, Sandler HM, Shipley WU; Radiation Therapy Oncology Group. Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol. 2003 Nov 1;21(21):3972-8. Erratum in: J Clin Oncol. 2004 Jan 15;22(2):386. [https://doi.org/10.1200/jco.2003.11.023 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14581419 PubMed]<br />
##'''Update:''' Horwitz EM, Bae K, Hanks GE, Porter A, Grignon DJ, Brereton HD, Venkatesan V, Lawton CA, Rosenthal SA, Sandler HM, Shipley WU. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol. 2008 May 20;26(15):2497-504. Epub 2008 Apr 14. [https://doi.org/10.1200/jco.2007.14.9021 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18413638 PubMed]<br />
##'''Update:''' Lawton CAF, Lin X, Hanks GE, Lepor H, Grignon DJ, Brereton HD, Bedi M, Rosenthal SA, Zeitzer KL, Venkatesan VM, Horwitz EM, Pisansky TM, Kim H, Parliament MB, Rabinovitch R, Roach M 3rd, Kwok Y, Dignam JJ, Sandler HM. Duration of androgen deprivation in locally advanced prostate cancer: long-term update of NRG Oncology RTOG 9202. Int J Radiat Oncol Biol Phys. 2017 Jun 1;98(2):296-303. Epub 2017 Feb 12. [https://doi.org/10.1016/j.ijrobp.2017.02.004 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5603177/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28463149 PubMed]<br />
#'''TTROG 96.01:''' Denham JW, Steigler A, Lamb DS, Joseph D, Mameghan H, Turner S, Matthews J, Franklin I, Atkinson C, North J, Poulsen M, Christie D, Spry NA, Tai KH, Wynne C, Duchesne G, Kovacev O, D'Este C; Trans-Tasman Radiation Oncology Group. Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial. Lancet Oncol. 2005 Nov;6(11):841-50. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70348-X/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16257791 PubMed]<br />
##'''Update:''' Denham JW, Steigler A, Lamb DS, Joseph D, Turner S, Matthews J, Atkinson C, North J, Christie D, Spry NA, Tai KH, Wynne C, D'Este C. Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial. Lancet Oncol. 2011 May;12(5):451-9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70063-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21440505 PubMed]<br />
#'''DFCI 95-096:''' D'Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA. 2008 Jan 23;299(3):289-95. [http://jama.ama-assn.org/content/299/3/289.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18212313 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
##'''Update:''' D'Amico AV, Chen MH, Renshaw A, Loffredo M, Kantoff PW. Long-term Follow-up of a Randomized Trial of Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer. JAMA. 2015 Sep 22-29;314(12):1291-3. [https://jamanetwork.com/journals/jama/fullarticle/2442924 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26393854 PubMed]<br />
#'''RTOG 94-08:''' Jones CU, Hunt D, McGowan DG, Amin MB, Chetner MP, Bruner DW, Leibenhaut MH, Husain SM, Rotman M, Souhami L, Sandler HM, Shipley WU. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med. 2011 Jul 14;365(2):107-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1012348 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21751904 PubMed] NCT00002597<br />
<br />
==Flutamide, Leuprolide, RT {{#subobject:3 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Flutamide, Leuprolide, RT: Flutamide, Leuprolide, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen variant #1, 4 months of ADT {{#subobject:3 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1012348 Jones et al. 2011 (RTOG 94-08)]<br />
|1994-2001<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]] 250 mg PO three times per day, to start 2 months prior to radiation therapy<br />
*[[Leuprolide (Lupron)]] 7.5 mg SC once on day 1, to start 2 months prior to radiation therapy<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] is started 2 months after start of androgen deprivation therapy (ADT), 1.8 to 2 Gy per fraction, with an initial 44 to 46 Gy to the pelvis, then an additional conedown to the prostate that resulted in a total dose of 65 to 70 Gy<br />
<br />
===Regimen variant #2, 3 years of ADT {{#subobject:38huac |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/j.eururo.2012.03.053 Mottet et al. 2012 (TAP 32)]<br />
|2000-2003<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Flutamide_.26_Leuprolide|Flutamide & Leuprolide]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]] 750 mg/day PO for one month<br />
*[[Leuprolide (Lupron)]] 11.25 mg SC once on day 1<br />
<br />
'''3-month cycle for 12 cycles (3 years)'''<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] started within 90 days of initiation of ADT, as follows:<br />
**Pelvis: 44 to 48 Gy given in 25 fractions over 5 weeks<br />
**Prostate: 20 to 28 Gy boost given in 10 to 12 fractions over 15 to 20 days<br />
<br />
'''One course'''<br />
<br />
===Regimen variant #3, indefinite ADT {{#subobject:5bddaf |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61815-2/fulltext Widmark et al. 2008 (SPCG-7/SFUO-3)]<br />
|1996-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Flutamide & Leuprolide<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]] 250 mg PO three times per day, to start 3 months prior to radiation therapy<br />
*[[Leuprolide (Lupron)]] by one of the following, to start 3 months prior to radiation therapy:<br />
**3.75 mg SC once per month for 3 months<br />
**11.25 mg SC once<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] 50 Gy + 20 Gy boost (total dose minimum of 70 Gy)<br />
<br />
===References===<br />
<br />
#'''SPCG-7/SFUO-3:''' Widmark A, Klepp O, Solberg A, Damber JE, Angelsen A, Fransson P, Lund JA, Tasdemir I, Hoyer M, Wiklund F, Fosså SD; Scandinavian Prostate Cancer Group; Swedish Association for Urological Oncology. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet. 2009 Jan 24;373(9660):301-8. Epub 2008 Dec 16. Erratum in: Lancet. 2009 Apr 4;373(9670):1174. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61815-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19091394 PubMed] ISRCTN01534787<br />
#'''RTOG 94-08:''' Jones CU, Hunt D, McGowan DG, Amin MB, Chetner MP, Bruner DW, Leibenhaut MH, Husain SM, Rotman M, Souhami L, Sandler HM, Shipley WU. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med. 2011 Jul 14;365(2):107-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1012348 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21751904 PubMed] NCT00002597<br />
#'''TAP 32:''' Mottet N, Peneau M, Mazeron JJ, Molinie V, Richaud P. Addition of radiotherapy to long-term androgen deprivation in locally advanced prostate cancer: an open randomised phase 3 trial. Eur Urol. 2012 Aug;62(2):213-9. Epub 2012 Apr 3. [https://doi.org/10.1016/j.eururo.2012.03.053 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22502942 PubMed] NCT01122121<br />
##'''Update:''' Sargos P, Mottet N, Bellera C, Richaud P. Long-term androgen deprivation, with or without radiotherapy, in locally advanced prostate cancer: updated results from a phase III randomised trial. BJU Int. 2020 Jun;125(6):810-816. Epub 2020 Mar 2. [https://doi.org/10.1111/bju.14768 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30946523 PubMed]<br />
<br />
==Goserelin & RT {{#subobject:1 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
Goserelin & RT: Goserelin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
<br />
===Regimen {{#subobject:1 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.1997.15.3.1013 Pilepich et al. 2005 (RTOG 85-31)]<br />
|1987-1992<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199707313370502 Bolla et al. 1997 (EORTC 22863)]<br />
|1987-1995<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Goserelin (Zoladex)]] 3.6 mg SC once on day 1, started during the last week of radiation therapy<br />
<br />
'''28-day cycles'''<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]], 1.8 to 2 Gy per fraction, with an initial 44 to 46 Gy to the pelvis, then an additional boost to the prostate that resulted in a total dose of 65 to 70 Gy in definitive radiation patients; 60 to 65 Gy total dose for post-prostatectomy patients<br />
<br />
'''One course'''<br />
<br />
===References===<br />
<br />
#'''RTOG 85-31:''' Pilepich MV, Caplan R, Byhardt RW, Lawton CA, Gallagher MJ, Mesic JB, Hanks GE, Coughlin CT, Porter A, Shipley WU, Grignon D. Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group protocol 85-31. J Clin Oncol. 1997 Mar;15(3):1013-21. [https://doi.org/10.1200/jco.1997.15.3.1013 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9060541 PubMed]<br />
##'''Update:''' Lawton CA, Winter K, Murray K, Machtay M, Mesic JB, Hanks GE, Coughlin CT, Pilepich MV. Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 2001 Mar 15;49(4):937-46. [http://www.redjournal.org/article/S0360-3016%2800%2901516-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11240234 PubMed]<br />
##'''Update:''' Pilepich MV, Winter K, Lawton CA, Krisch RE, Wolkov HB, Movsas B, Hug EB, Asbell SO, Grignon D. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1285-90. [http://www.redjournal.org/article/S0360-3016(04)02468-X/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15817329 PubMed]<br />
#'''EORTC 22863:''' Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Gil T, Collette L, Pierart M. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med. 1997 Jul 31;337(5):295-300. [https://www.nejm.org/doi/full/10.1056/NEJM199707313370502 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9233866 PubMed]<br />
##'''Update:''' Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Mattelaer J, Lopez Torecilla J, Pfeffer JR, Lino Cutajar C, Zurlo A, Pierart M. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet. 2002 Jul 13;360(9327):103-6. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)09408-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12126818 PubMed]<br />
##'''Update:''' Bolla M, Van Tienhoven G, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Billiet I, Torecilla JL, Pfeffer R, Cutajar CL, Van der Kwast T, Collette L. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol. 2010 Nov;11(11):1066-73. Epub 2010 Oct 7. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70223-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20933466 PubMed]<br />
<br />
=Adjuvant therapy=<br />
==Bicalutamide & Goserelin {{#subobject:611758|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:bdfd60|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107759/ Dorff et al. 2011 (SWOG S9921)]<br />
|2000-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ADT & Mitoxantrone<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Dosing details are not available in the manuscript; this is the common dosing used.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Radical_prostatectomy|Radical prostatectomy]]<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Bicalutamide (Casodex)]] 50 mg PO once per day<br />
*[[Goserelin (Zoladex)]] 10.8 mg SC once on day 1<br />
<br />
'''12-week cycle for 9 cycles (2 years)'''<br />
<br />
===References===<br />
<br />
#'''SWOG S9921:''' Dorff TB, Flaig TW, Tangen CM, Hussain MH, Swanson GP, Wood DP Jr, Sakr WA, Dawson NA, Haas NB, Crawford ED, Vogelzang NJ, Thompson IM, Glode LM. Adjuvant androgen deprivation for high-risk prostate cancer after radical prostatectomy: SWOG S9921 study. J Clin Oncol. 2011 May 20;29(15):2040-5. Epub 2011 Apr 18. [https://doi.org/10.1200/JCO.2010.32.2776 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107759/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21502546 PubMed] NCT00004124<br />
<br />
==Goserelin monotherapy {{#subobject:267ff5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:53d064|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199912093412401 Messing et al. 1999 (ECOG E3886)]<br />
|1988-1993<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_null_regimens#Observation|No further treatment]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://doi.org/10.1200/jco.2003.11.023 Hanks et al. 2003 (RTOG 92-02)]<br />
|1992-1995<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_null_regimens#Observation|No further treatment]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy of RTOG 92-02 based on the 2017 update.''<br />
====Preceding treatment====<br />
<br />
*ECOG E3886: [[Surgery#Radical_prostatectomy|Radical prostatectomy]]<br />
*RTOG 92-02: [[#Flutamide.2C_Goserelin.2C_RT|Flutamide, Goserelin, RT]]<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Goserelin (Zoladex)]] 3.6 mg SC once per month<br />
<br />
'''2-year course (RTOG 92-02) or until rising PSA detected (ECOG E3886)'''<br />
<br />
===References===<br />
<br />
#'''ECOG E3886:''' Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D; [[Study_Groups#ECOG|ECOG]]. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 1999 Dec 9;341(24):1781-8. [https://www.nejm.org/doi/full/10.1056/NEJM199912093412401 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10588962 PubMed]<br />
##'''Update:''' Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, di'SantAgnese PA, Trump D; [[Study_Groups#ECOG|ECOG]]. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol. 2006 Jun;7(6):472-9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(06)70700-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16750497 PubMed]<br />
#'''RTOG 92-02:''' Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, Horwitz EM, Lawton C, Rosenthal SA, Sandler HM, Shipley WU; Radiation Therapy Oncology Group. Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol. 2003 Nov 1;21(21):3972-8. Erratum in: J Clin Oncol. 2004 Jan 15;22(2):386. [https://doi.org/10.1200/jco.2003.11.023 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14581419 PubMed]<br />
##'''Update:''' Horwitz EM, Bae K, Hanks GE, Porter A, Grignon DJ, Brereton HD, Venkatesan V, Lawton CA, Rosenthal SA, Sandler HM, Shipley WU. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol. 2008 May 20;26(15):2497-504. Epub 2008 Apr 14. [https://doi.org/10.1200/jco.2007.14.9021 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18413638 PubMed]<br />
##'''Update:''' Lawton CAF, Lin X, Hanks GE, Lepor H, Grignon DJ, Brereton HD, Bedi M, Rosenthal SA, Zeitzer KL, Venkatesan VM, Horwitz EM, Pisansky TM, Kim H, Parliament MB, Rabinovitch R, Roach M 3rd, Kwok Y, Dignam JJ, Sandler HM. Duration of androgen deprivation in locally advanced prostate cancer: long-term update of NRG Oncology RTOG 9202. Int J Radiat Oncol Biol Phys. 2017 Jun 1;98(2):296-303. Epub 2017 Feb 12. [https://doi.org/10.1016/j.ijrobp.2017.02.004 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5603177/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28463149 PubMed]<br />
<br />
==Triptorelin & RT {{#subobject:611758|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:bdfd60|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30454-X/fulltext/ Sargos et al. 2020 (GETUG-AFU 17)]<br />
|2008-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Triptorelin & RT; salvage<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS<br />
|-<br />
|}<br />
''Statistical power was compromised due to unexpectedly low event rate. GETUG-AFU 17 was published concurrently along with two other Phase III trials looking at timing of radiotherapy following radical prostatectomy: [https://pubmed.ncbi.nlm.nih.gov/33002429/ RADICALS-RT] and [https://pubmed.ncbi.nlm.nih.gov/33002437/ ANZUP RAVES]. All three trials were also analyzed as part of a pre-planned meta-analysis [https://pubmed.ncbi.nlm.nih.gov/33002431/ ARTISTIC] which failed to show an EFS benefit with adjuvant radiotherapy vs. salvage radiotherapy.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Radical_prostatectomy|Radical prostatectomy]]<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Triptorelin (Trelstar LA)]] 11.25 mg IM once on day 1<br />
<br />
'''12-week cycle for 2 cycles (6 months)'''<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]]<br />
<br />
===References===<br />
<br />
#'''GETUG-AFU 17:''' Sargos P, Chabaud S, Latorzeff I, Magne N, Benyoucef A, Supiot S, Pasquier D, Abdiche MS, Gilliot O, Graff-Cailleaud P, Silva M, Bergerot P, Baumann P, Belkacemi Y, Azria D, Brihoum M, Soulie M, Richaud P. Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localized prostate cancer after radical prostatectomy (GETUG-AFU 17): a randomised, phase 3 trial. Lancet Oncol. 2020 Oct; 21(10):1341-1352. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30454-X/fulltext link to original article] '''does not contain protocol''' [https://pubmed.ncbi.nlm.nih.gov/33002438/ PubMed] NCT00667069<br />
<br />
=Salvage ADT & radiotherapy=<br />
==Bicalutamide & RT {{#subobject:2c64f0 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Bicalutamide & RT: Bicalutamide & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:4f2e28 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444881/ Shipley et al. 2017 (RTOG 9601)]<br />
|1998-2003<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|RT<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Prostatectomy|Prostatectomy]] with [[Surgery#Lymphadenectomy|lymphadenectomy]], with a postoperative detectable PSA level of 0.2 to 4.0 ng/mL<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Bicalutamide (Casodex)]] 150 mg PO once per day<br />
<br />
'''2-year course'''<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]], 64.8 Gy in 36 daily fractions of 1.8 Gy<br />
<br />
'''7-week course'''<br />
<br />
===References===<br />
<br />
#'''RTOG 9601:''' Shipley WU, Seiferheld W, Lukka HR, Major PP, Heney NM, Grignon DJ, Sartor O, Patel MP, Bahary JP, Zietman AL, Pisansky TM, Zeitzer KL, Lawton CA, Feng FY, Lovett RD, Balogh AG, Souhami L, Rosenthal SA, Kerlin KJ, Dignam JJ, Pugh SL, Sandler HM; NRG Oncology RTOG. Radiation with or without antiandrogen therapy in recurrent prostate cancer. N Engl J Med. 2017 Feb 2;376(5):417-428. [https://www.nejm.org/doi/full/10.1056/NEJMoa1607529 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444881/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28146658 PubMed] NCT00002874<br />
<br />
==Goserelin & RT {{#subobject:88575c |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Goserelin & RT: Goserelin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:fac0bd |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00111-X/fulltext Carrie et al. 2016 (GETUG-AFU 16)]<br />
|2006-2010<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Salvage RT<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Prostatectomy|Prostatectomy]], with rising PSA<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Goserelin (Zoladex)]] 0.8 mg SC once on day 1<br />
<br />
'''3-month cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]], 66 Gy in 33 daily fractions of 2 Gy<br />
<br />
'''7-week course'''<br />
<br />
===References===<br />
<br />
#'''GETUG-AFU 16:''' Carrie C, Hasbini A, de Laroche G, Richaud P, Guerif S, Latorzeff I, Supiot S, Bosset M, Lagrange JL, Beckendorf V, Lesaunier F, Dubray B, Wagner JP, N'Guyen TD, Suchaud JP, Créhange G, Barbier N, Habibian M, Ferlay C, Fourneret P, Ruffion A, Dussart S. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2016 Jun;17(6):747-756. Epub 2016 May 6. Erratum in: Lancet Oncol. 2016 Jun;17 (6):e223. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00111-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27160475 PubMed] NCT00423475<br />
##'''Update:''' Carrie C, Magné N, Burban-Provost P, Sargos P, Latorzeff I, Lagrange JL, Supiot S, Belkacemi Y, Peiffert D, Allouache N, Dubray BM, Servagi-Vernat S, Suchaud JP, Crehange G, Guerif S, Brihoum M, Barbier N, Graff-Cailleaud P, Ruffion A, Dussart S, Ferlay C, Chabaud S. Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial. Lancet Oncol. 2019 Dec;20(12):1740-1749. Epub 2019 Oct 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30486-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31629656 PubMed]<br />
<br />
<br /><br />
=Hormonal therapy for non-metastatic castrate sensitive disease=<br />
==ADT {{#subobject:6e0da9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:0415d3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jamaoncology/article-abstract/2723273 Oudard et al. 2019 (RisingPSA)]<br />
|2003-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ADT & Docetaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PSA-PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00107-8/fulltext Duchesne et al. 2016 (TOAD)]<br />
|2004-2012<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|Delayed ADT<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(15)00977-X/fulltext Schulman et al. 2015 (ICELAND)]<br />
|2006-NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Intermittent ADT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP<br />
|-<br />
|}<br />
''Note: these are clinical trials that did not specify a particular drug to be used for androgen deprivation. See papers for details.''<br />
====Endocrine therapy====<br />
<br />
*[[:Category:GnRH agonists|LHRH agonist]]<br />
*[[Bicalutamide (Casodex)]] or [[Flutamide (Eulexin)]]<br />
<br />
'''12-month course (RisingPSA) or continued indefinitely'''<br />
===References===<br />
<br />
#'''ICELAND:''' Schulman C, Cornel E, Matveev V, Tammela TL, Schraml J, Bensadoun H, Warnack W, Persad R, Salagierski M, Gómez Veiga F, Baskin-Bey E, López B, Tombal B. Intermittent versus continuous androgen deprivation therapy in patients with relapsing or locally advanced prostate cancer: a phase 3b randomised study (ICELAND). Eur Urol. 2016 Apr;69(4):720-727. Epub 2015 Oct 29. [https://www.europeanurology.com/article/S0302-2838(15)00977-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26520703 PubMed] NCT00378690<br />
#'''TOAD:''' Duchesne GM, Woo HH, Bassett JK, Bowe SJ, D'Este C, Frydenberg M, King M, Ledwich L, Loblaw A, Malone S, Millar J, Milne R, Smith RG, Spry N, Stockler M, Syme RA, Tai KH, Turner S. Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Lancet Oncol. 2016 Jun;17(6):727-737. Epub 2016 May 4. Erratum in: Lancet Oncol. 2016 Jun;17 (6):e223. Lancet Oncol. 2017 Sep;18(9):e510. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00107-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27155740 PubMed] NCT00110162<br />
#'''RisingPSA:''' Oudard S, Latorzeff I, Caty A, Miglianico L, Sevin E, Hardy-Bessard AC, Delva R, Rolland F, Mouret L, Priou F, Beuzeboc P, Gravis G, Linassier C, Gomez P, Voog E, Muracciole X, Abraham C, Banu E, Ferrero JM, Ravaud A, Krakowski I, Lagrange JL, Deplanque G, Zylberait D, Bozec L, Houede N, Culine S, Elaidi R. Effect of adding docetaxel to androgen-deprivation therapy in patients with high-risk prostate cancer with rising prostate-specific antigen levels after primary local therapy: a randomized clinical trial. JAMA Oncol. 2019 May 1;5(5):623-632. Epub 2019 Jan 31. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2723273 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512307/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30703190 PubMed] NCT00764166<br />
<br />
=Hormonal therapy for non-metastatic castrate resistant disease=<br />
==ADT {{#subobject:68ajcbz|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:0a9b7x3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1715546 Smith et al. 2017 (SPARTAN)]<br />
|2013-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_Apalutamide|ADT & Apalutamide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup><br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1800536 Hussain et al. 2018 (PROSPER)]<br />
|2013-2017<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_Enzalutamide|ADT & Enzalutamide]]<br />
| style="background-color:#d73027" |Inferior MFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1815671 Fizazi et al. 2019 (ARAMIS)]<br />
|2014-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_Darolutamide|ADT & Darolutamide]]<br />
| style="background-color:#d73027" |Inferior OS<sup>2</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for SPARTAN is based on the 2019 update.''<br><br />
''<sup>2</sup>Reported efficacy for ARAMIS is based on the 2020 update.''<br><br />
''Note: these are clinical trials that did not specify a particular drug to be used for androgen deprivation. See papers for details.''<br />
====Endocrine therapy====<br />
<br />
*[[:Category:GnRH_agonists|GnRH agonist]] or [[:Category:GnRH antagonists|GnRH antagonist]] or a history of [[Endocrine_ablation_surgery#Bilateral_orchiectomy|bilateral orchiectomy]]<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
<br />
#'''SPARTAN:''' Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, Lopez-Gitlitz A, Trudel GC, Espina BM, Shu Y, Park YC, Rackoff WR, Yu MK, Small EJ; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018 Apr 12;378(15):1408-1418. [https://www.nejm.org/doi/10.1056/NEJMoa1715546 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1715546/suppl_file/nejmoa1715546_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29420164 PubMed] NCT01946204<br />
##'''Update:''' Small EJ, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, De Porre P, Smith AA, Zhang K, Lopez-Gitlitz A, Smith MR. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. Ann Oncol. 2019 Nov 1;30(11):1813-1820. [https://doi.org/10.1093/annonc/mdz397 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927320/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/31560066 PubMed]<br />
#'''PROSPER:''' Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, Ivashchenko P, Demirhan E, Modelska K, Phung D, Krivoshik A, Sternberg CN. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018 Jun 28;378(26):2465-2474. [https://www.nejm.org/doi/full/10.1056/NEJMoa1800536 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29949494 PubMed]<br />
#'''ARAMIS:''' Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Kappeler C, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019 Mar 28;380(13):1235-1246. Epub 2019 Feb 14. [https://www.nejm.org/doi/full/10.1056/NEJMoa1815671 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30763142 PubMed] NCT02200614<br />
##'''Update:''' Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Le Berre MA, Petrenciuc O, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. N Engl J Med. 2020 Sep 10;383(11):1040-1049. [https://doi.org/10.1056/nejmoa2001342 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32905676 PubMed]<br />
<br />
==ADT & Apalutamide {{#subobject:a70eae |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT & Apalutamide: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy & Apalutamide<br />
===Regimen {{#subobject:#e085c7 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1715546 Smith et al. 2017 (SPARTAN)]<br />
|2013-2016<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup> <br>(HR 0.75, 95% CI 0.59-0.96)<br />
|-<br />
|}<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Metastasis-free survival<br />
! style="width: 33%" |Comparator metastasis-free survival<br />
! style="width: 33%" |Pt Population<br />
|-<br />
|40.5 months<br />
|16.2 months<br />
|Castrate-resistant, non-metastatic, PSA doubling time <10 months<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2019 update.''<br />
====Endocrine therapy====<br />
<br />
*[[Apalutamide (Erleada)]] 240 mg PO once per day<br />
*Patients should concurrently be receiving [[:Category:GnRH_agonists|GnRH analog]] or have had [[Endocrine_ablation_surgery#Bilateral_orchiectomy|bilateral orchiectomy]]<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''SPARTAN:''' Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, Lopez-Gitlitz A, Trudel GC, Espina BM, Shu Y, Park YC, Rackoff WR, Yu MK, Small EJ; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018 Apr 12;378(15):1408-1418. [https://www.nejm.org/doi/10.1056/NEJMoa1715546 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1715546/suppl_file/nejmoa1715546_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29420164 PubMed] NCT01946204<br />
##'''Update:''' Small EJ, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, De Porre P, Smith AA, Zhang K, Lopez-Gitlitz A, Smith MR. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. Ann Oncol. 2019 Nov 1;30(11):1813-1820. [https://doi.org/10.1093/annonc/mdz397 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927320/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/31560066 PubMed]<br />
<br />
==ADT & Darolutamide {{#subobject:d39ncb |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:#9276df |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1815671 Fizazi et al. 2019 (ARAMIS)]<br />
|2014-2018<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#1a9850" |Superior OS<sup>1</sup> <br>(HR 0.69, 95% CI 0.53-0.88)<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2020 update.''<br />
====Endocrine therapy====<br />
<br />
*[[:Category:GnRH_agonists|GnRH agonist]] or [[:Category:GnRH antagonists|GnRH antagonist]]<br />
*[[Darolutamide (Nubeqa)]] 600 mg PO twice per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''ARAMIS:''' Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Kappeler C, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019 Mar 28;380(13):1235-1246. Epub 2019 Feb 14. [https://www.nejm.org/doi/full/10.1056/NEJMoa1815671 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30763142 PubMed] NCT02200614<br />
##'''Update:''' Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Le Berre MA, Petrenciuc O, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. N Engl J Med. 2020 Sep 10;383(11):1040-1049. [https://doi.org/10.1056/nejmoa2001342 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32905676 PubMed]<br />
<br />
==ADT & Enzalutamide {{#subobject:d34e0b |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT & Enzalutamide: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy & Enzalutamide<br />
===Regimen {{#subobject:#80614f |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1800536 Hussain et al. 2018 (PROSPER)]<br />
|2013-2017<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#1a9850" |Superior MFS<br />
|-<br />
|}<br />
''Patients had castrate-resistant, non-metastatic, prostate cancer with PSA doubling time less than 10 months.''<br />
====Endocrine therapy====<br />
<br />
*[[Enzalutamide (Xtandi)]] 160 mg PO once per day<br />
*Patients should concurrently be receiving [[:Category:GnRH_agonists|GnRH agonist]] or [[:Category:GnRH antagonists|GnRH antagonist]] or have had [[Endocrine_ablation_surgery#Bilateral_orchiectomy|bilateral orchiectomy]]<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''PROSPER:''' Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, Ivashchenko P, Demirhan E, Modelska K, Phung D, Krivoshik A, Sternberg CN. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018 Jun 28;378(26):2465-2474. [https://www.nejm.org/doi/full/10.1056/NEJMoa1800536 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29949494 PubMed]<br />
<br />
=Hormonal therapy for metastatic or locally advanced disease=<br />
==ADT {{#subobject:45fc98|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:bd66bd|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.auajournals.org/doi/full/10.1097/01.ju.0000135742.13171.d2 Schröder et al. 2004 (EORTC 30846)]<br />
|1986-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Delayed ADT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00011-X/fulltext Fizazi et al. 2015 (GETUG 12)]<br />
|2002-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT.2C_Docetaxel.2C_Estramustine|ADT, Docetaxel, Estramustine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior RFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70560-0/fulltext Gravis et al. 2013 (GETUG-AFU 15)]<br />
|2004-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_Docetaxel|ADT & Docetaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398767/ James et al. 2012 (STAMPEDE)]<br />
|2005-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ADT & Celecoxib<br />
| style="background-color:#ffffbf" |Did not meet intermediate primary endpoint of FFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800035/ James et al. 2015 (STAMPEDE)]<br />
|2005-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_Docetaxel|ADT & Docetaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533216 James et al. 2017 (STAMPEDE)]<br />
|2005-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_Abiraterone|ADT & Abiraterone]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4562797/ Sweeney et al. 2015 (CHAARTED)]<br />
|2006-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_Docetaxel|ADT & Docetaxel]]<br />
| style="background-color:#d73027" |Inferior OS<sup>1</sup><br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs10147-016-1037-2 Kamba et al. 2016 (ZAPCA)]<br />
|2008-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ADT & Zoledronic acid<br />
| style="background-color:#fee08b" |Might have inferior TTTF<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1704174 Fizazi et al. 2017 (LATITUDE)]<br />
|2013-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_Abiraterone|ADT & Abiraterone]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''<sup>1</sup>In the 2018 update of CHAARTED, only patients with high-volume disease had inferior survival in the control arm.''<br><br />
''Note: these are clinical trials that did not specify a particular therapy to be used for androgen deprivation. See papers for details; the below are examples.''<br />
====Endocrine therapy====<br />
<br />
*ADT with ONE of the following:<br />
**[[:Category:GnRH agonists|LHRH agonist/analogue]]<br />
**[[:Category:GnRH antagonists|LHRH antagonist]]<br />
**[[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]]<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''EORTC 30846:''' Schröder FH, Kurth KH, Fosså SD, Hoekstra W, Karthaus PP, Debois M, Collette L; European Organisation for the Research and Treatment of Cancer Genito-urinary Group. Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local treatment of the primary tumor: results of European Organisation for the Research and Treatment of Cancer 30846--a phase III study. J Urol. 2004 Sep;172(3):923-7. [https://www.auajournals.org/doi/full/10.1097/01.ju.0000135742.13171.d2 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15310999 PubMed]<br />
#'''STAMPEDE:''' James ND, Sydes MR, Mason MD, Clarke NW, Anderson J, Dearnaley DP, Dwyer J, Jovic G, Ritchie AW, Russell JM, Sanders K, Thalmann GN, Bertelli G, Birtle AJ, O'Sullivan JM, Protheroe A, Sheehan D, Srihari N, Parmar MK; STAMPEDE Investigators. Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial. Lancet Oncol. 2012 May;13(5):549-58. Epub 2012 Mar 26. Erratum in: Lancet Oncol. 2013 Jan;14(1):e5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70088-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398767/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22452894 PubMed] NCT00268476<br />
#'''GETUG-AFU 15:''' Gravis G, Fizazi K, Joly F, Oudard S, Priou F, Esterni B, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Théodore C, Deplanque G, Ferrero JM, Pouessel D, Mourey L, Beuzeboc P, Zanetta S, Habibian M, Berdah JF, Dauba J, Baciuchka M, Platini C, Linassier C, Labourey JL, Machiels JP, El Kouri C, Ravaud A, Suc E, Eymard JC, Hasbini A, Bousquet G, Soulie M. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Feb;14(2):149-58. Epub 2013 Jan 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70560-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23306100 PubMed] NCT00104715<br />
##'''Update:''' Gravis G, Boher JM, Joly F, Soulié M, Albiges L, Priou F, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Théodore C, Deplanque G, Ferrero JM, Culine S, Mourey L, Beuzeboc P, Habibian M, Oudard S, Fizazi K; GETUG. Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: Impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial. Eur Urol. 2016 Aug;70(2):256-62. Epub 2015 Nov 21. [http://www.europeanurology.com/article/S0302-2838(15)01103-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26610858 PubMed]<br />
#'''GETUG 12:''' Fizazi K, Faivre L, Lesaunier F, Delva R, Gravis G, Rolland F, Priou F, Ferrero JM, Houede N, Mourey L, Theodore C, Krakowski I, Berdah JF, Baciuchka M, Laguerre B, Fléchon A, Ravaud A, Cojean-Zelek I, Oudard S, Labourey JL, Chinet-Charrot P, Legouffe E, Lagrange JL, Linassier C, Deplanque G, Beuzeboc P, Davin JL, Martin AL, Habibian M, Laplanche A, Culine S. Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial. Lancet Oncol. 2015 Jul;16(7):787-94. Epub 2015 May 28. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00011-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26028518 PubMed] NCT00055731<br />
#'''CHAARTED:''' Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015 Aug 20;373(8):737-46. Epub 2015 Aug 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1503747 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4562797/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26244877 Pubmed] NCT00309985<br />
##'''Update:''' Kyriakopoulos CE, Chen YH, Carducci MA, Liu G, Jarrard DF, Hahn NM, Shevrin DH, Dreicer R, Hussain M, Eisenberger M, Kohli M, Plimack ER, Vogelzang NJ, Picus J, Cooney MM, Garcia JA, DiPaola RS, Sweeney CJ. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018 Apr 10;36(11):1080-1087. Epub 2018 Jan 31. [https://doi.org/10.1200/JCO.2017.75.3657 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891129/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29384722 PubMed]<br />
##'''QoL analysis:''' Morgans AK, Chen YH, Sweeney CJ, Jarrard DF, Plimack ER, Gartrell BA, Carducci MA, Hussain M, Garcia JA, Cella D, DiPaola RS, Patrick-Miller LJ. Quality of life during treatment with chemohormonal therapy: analysis of E3805 chemohormonal androgen ablation randomized trial in prostate cancer. J Clin Oncol. 2018 Apr 10;36(11):1088-1095. Epub 2018 Mar 9. [https://doi.org/10.1200/JCO.2017.75.3335 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891128/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29522362 PubMed]<br />
#'''STAMPEDE:''' James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, Ritchie AW, Parker CC, Russell JM, Attard G, de Bono J, Cross W, Jones RJ, Thalmann G, Amos C, Matheson D, Millman R, Alzouebi M, Beesley S, Birtle AJ, Brock S, Cathomas R, Chakraborti P, Chowdhury S, Cook A, Elliott T, Gale J, Gibbs S, Graham JD, Hetherington J, Hughes R, Laing R, McKinna F, McLaren DB, O'Sullivan JM, Parikh O, Peedell C, Protheroe A, Robinson AJ, Srihari N, Srinivasan R, Staffurth J, Sundar S, Tolan S, Tsang D, Wagstaff J, Parmar MK; STAMPEDE Investigators. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016 Mar 19;387(10024):1163-77. Epub 2015 Dec 21. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01037-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800035/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26719232 PubMed] NCT00268476<br />
##'''Update:''' Clarke NW, Ali A, Ingleby FC, Hoyle A, Amos CL, Attard G, Brawley CD, Calvert J, Chowdhury S, Cook A, Cross W, Dearnaley DP, Douis H, Gilbert D, Gillessen S, Jones RJ, Langley RE, MacNair A, Malik Z, Mason MD, Matheson D, Millman R, Parker CC, Ritchie AWS, Rush H, Russell JM, Brown J, Beesley S, Birtle A, Capaldi L, Gale J, Gibbs S, Lydon A, Nikapota A, Omlin A, O'Sullivan JM, Parikh O, Protheroe A, Rudman S, Srihari NN, Simms M, Tanguay JS, Tolan S, Wagstaff J, Wallace J, Wylie J, Zarkar A, Sydes MR, Parmar MKB, James ND. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol. 2019 Dec 1;30(12):1992-2003. [https://doi.org/10.1093/annonc/mdz396 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938598/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/31560068 PubMed]<br />
#'''ZAPCA:''' Kamba T, Kamoto T, Maruo S, Kikuchi T, Shimizu Y, Namiki S, Fujimoto K, Kawanishi H, Sato F, Narita S, Satoh T, Saito H, Sugimoto M, Teishima J, Masumori N, Egawa S, Sakai H, Okada Y, Terachi T, Ogawa O; ZAPCA Study Group. A phase III multicenter, randomized, controlled study of combined androgen blockade with versus without zoledronic acid in prostate cancer patients with metastatic bone disease: results of the ZAPCA trial. Int J Clin Oncol. 2017 Feb;22(1):166-173. Epub 2016 Sep 10. [https://link.springer.com/article/10.1007%2Fs10147-016-1037-2 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27614621 PubMed] NCT00685646<br />
#'''STAMPEDE:''' James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, Ritchie AWS, Amos CL, Gilson C, Jones RJ, Matheson D, Millman R, Attard G, Chowdhury S, Cross WR, Gillessen S, Parker CC, Russell JM, Berthold DR, Brawley C, Adab F, Aung S, Birtle AJ, Bowen J, Brock S, Chakraborti P, Ferguson C, Gale J, Gray E, Hingorani M, Hoskin PJ, Lester JF, Malik ZI, McKinna F, McPhail N, Money-Kyrle J, O'Sullivan J, Parikh O, Protheroe A, Robinson A, Srihari NN, Thomas C, Wagstaff J, Wylie J, Zarkar A, Parmar MKB, Sydes MR; STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017 Jul 27;377(4):338-351. Epub 2017 Jun 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1702900 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533216 link to PMC article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1702900/suppl_file/nejmoa1702900_protocol.pdf supplementary protocol] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/28578639 PubMed] NCT00268476<br />
#'''LATITUDE:''' Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, De Porre P, Kheoh T, Park YC, Todd MB, Chi KN; LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017 Jul 27;377(4):352-360. Epub 2017 Jun 4. [https://www.nejm.org/doi/full/10.1056/NEJMoa1704174 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1704174/suppl_file/nejmoa1704174_protocol.pdf supplementary protocol] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/28578607 PubMed]<br />
##'''HRQoL analysis:''' Chi KN, Protheroe A, Rodríguez-Antolín A, Facchini G, Suttman H, Matsubara N, Ye Z, Keam B, Damião R, Li T, McQuarrie K, Jia B, De Porre P, Martin J, Todd MB, Fizazi K. Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial. Lancet Oncol. 2018 Feb;19(2):194-206. Epub 2018 Jan 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30911-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29326030 PubMed]<br />
##'''Update:''' Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, Sulur G, Luna Y, Li S, Mundle S, Chi KN. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019 May;20(5):686-700. Epub 2019 Apr 12. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30082-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30987939 PubMed]<br />
<br />
==ADT & Abiraterone {{#subobject:02afb7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT & Abiraterone: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy & Abiraterone<br />
===Regimen {{#subobject:31ffca|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533216 James et al. 2017 (STAMPEDE)]<br />
|2005-2011<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1704174 Fizazi et al. 2017 (LATITUDE)]<br />
|2013-2014<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: while LATITUDE allowed for a dose increase in prednisone, the FDA recommended dose is 5 mg PO once per day.''<br />
====Endocrine therapy====<br />
<br />
*[[Abiraterone (Zytiga)]] 1000 mg PO once per day<br />
*ADT with ONE of the following:<br />
**[[:Category:GnRH agonists|LHRH agonist/analogue]]<br />
**'''STAMPEDE only:''' [[:Category:GnRH antagonists|LHRH antagonist]]<br />
**[[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]]<br />
<br />
====Supportive medications====<br />
<br />
*Prevention of mineralocorticoid excess with ONE of the following:<br />
**'''STAMPEDE except Switzerland:''' [[Prednisolone (Millipred)]] 5 mg PO once per day<br />
**'''LATITUDE and STAMPEDE in Switzerland:''' [[Prednisone (Sterapred)]] 5 mg PO once per day<br />
***'''LATITUDE:''' "dose increase of up to 10 mg/day is permitted to manage refractory mineralocorticoid related toxicities"<br />
<br />
'''Continued indefinitely unless radiotherapy planned, in which case continued for up to 2 years'''<br />
<br />
===References===<br />
<br />
#'''STAMPEDE:''' James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, Ritchie AWS, Amos CL, Gilson C, Jones RJ, Matheson D, Millman R, Attard G, Chowdhury S, Cross WR, Gillessen S, Parker CC, Russell JM, Berthold DR, Brawley C, Adab F, Aung S, Birtle AJ, Bowen J, Brock S, Chakraborti P, Ferguson C, Gale J, Gray E, Hingorani M, Hoskin PJ, Lester JF, Malik ZI, McKinna F, McPhail N, Money-Kyrle J, O'Sullivan J, Parikh O, Protheroe A, Robinson A, Srihari NN, Thomas C, Wagstaff J, Wylie J, Zarkar A, Parmar MKB, Sydes MR; STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017 Jul 27;377(4):338-351. Epub 2017 Jun 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1702900 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533216 link to PMC article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1702900/suppl_file/nejmoa1702900_protocol.pdf supplementary protocol] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/28578639 PubMed] NCT00268476<br />
#'''LATITUDE:''' Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, De Porre P, Kheoh T, Park YC, Todd MB, Chi KN; LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017 Jul 27;377(4):352-360. Epub 2017 Jun 4. [https://www.nejm.org/doi/full/10.1056/NEJMoa1704174 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1704174/suppl_file/nejmoa1704174_protocol.pdf supplementary protocol] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/28578607 PubMed]<br />
##'''HRQoL analysis:''' Chi KN, Protheroe A, Rodríguez-Antolín A, Facchini G, Suttman H, Matsubara N, Ye Z, Keam B, Damião R, Li T, McQuarrie K, Jia B, De Porre P, Martin J, Todd MB, Fizazi K. Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial. Lancet Oncol. 2018 Feb;19(2):194-206. Epub 2018 Jan 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30911-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29326030 PubMed]<br />
##'''Update:''' Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, Sulur G, Luna Y, Li S, Mundle S, Chi KN. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019 May;20(5):686-700. Epub 2019 Apr 12. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30082-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30987939 PubMed]<br />
<br />
==ADT & Apalutamide {{#subobject:02eac3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT & Apalutamide: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy & Apalutamide<br />
===Regimen {{#subobject:31baz9|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1903307 Chi et al. 2019 (TITAN<sub>prostate</sub>)]<br />
|2015-2017<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: there are several other trials in other cancer subtypes named TITAN.''<br />
====Endocrine therapy====<br />
<br />
*[[Apalutamide (Erleada)]] 240 mg PO once per day<br />
*[[:Category:GnRH agonists|LHRH agonist/analogue]]<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''TITAN:''' Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, Juárez Soto Á, Merseburger AS, Özgüroğlu M, Uemura H, Ye D, Deprince K, Naini V, Li J, Cheng S, Yu MK, Zhang K, Larsen JS, McCarthy S, Chowdhury S; TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019 Jul 4;381(1):13-24. Epub 2019 May 31. [https://www.nejm.org/doi/full/10.1056/NEJMoa1903307 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31150574 PubMed] NCT02489318<br />
##'''Update:''' Chi KN, Chowdhury S, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, Juárez A, Merseburger AS, Özgüroğlu M, Uemura H, Ye D, Brookman-May S, Mundle SD, McCarthy SA, Larsen JS, Sun W, Bevans KB, Zhang K, Bandyopadhyay N, Agarwal N. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J Clin Oncol. 2021 Apr 29.[https://ascopubs.org/doi/full/10.1200/JCO.20.03488 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33914595/ PubMed] NCT02489318<br />
<br />
==ADT & Docetaxel {{#subobject:EJCADTdoceR|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT & Docetaxel: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy & Docetaxel<br />
===Regimen variant #1, 6 cycles {{#subobject:EJCADTdoceV|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800035/ James et al. 2015 (STAMPEDE)]<br />
|2005-2011<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4562797/ Sweeney et al. 2015 (CHAARTED)]<br />
|2006-2012<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#1a9850" |Superior OS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>In the 2018 update of CHAARTED, only patients with high-volume disease had superior survival in the experimental arm.''<br><br />
''Patients already on androgen deprivation therapy were eligible to participate in CHAARTED if there was no evidence of disease progression and if they had started ADT no more than 120 days before randomization.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*ADT with ONE of the following:<br />
**[[:Category:GnRH agonists|LHRH agonist/analogue]]<br />
**[[:Category:GnRH antagonists|LHRH antagonist]]<br />
**[[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]]<br />
**Intermittent hormonal therapy was not allowed. Antiandrogens e.g. [[Bicalutamide (Casodex)|bicalutamide]] were allowed at the start of therapy "at the discretion of the investigator."<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 8 mg PO given three times; 12 hours, 3 hours, and 1 hour before [[Docetaxel (Taxotere)]]<br />
*Daily prednisone was not required<br />
*At least calcium 500 mg and vitamin D 400 IU PO once per day<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #2, 9 cycles {{#subobject:257951|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70560-0/fulltext Gravis et al. 2013 (GETUG-AFU 15)]<br />
|2004-2008<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*ADT with one of the following:<br />
**[[:Category:GnRH agonists|LHRH agonist/analogue]] with or without [[:Category:Nonsteroidal_androgen_receptor_inhibitors|nonsteroidal androgen receptor inhibitors]]<br />
**[[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]] with or without [[:Category:Nonsteroidal_androgen_receptor_inhibitors|nonsteroidal androgen receptor inhibitors]]<br />
<br />
'''21-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<br />
#'''GETUG-AFU 15:''' Gravis G, Fizazi K, Joly F, Oudard S, Priou F, Esterni B, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Théodore C, Deplanque G, Ferrero JM, Pouessel D, Mourey L, Beuzeboc P, Zanetta S, Habibian M, Berdah JF, Dauba J, Baciuchka M, Platini C, Linassier C, Labourey JL, Machiels JP, El Kouri C, Ravaud A, Suc E, Eymard JC, Hasbini A, Bousquet G, Soulie M. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Feb;14(2):149-58. Epub 2013 Jan 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70560-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23306100 PubMed] NCT00104715<br />
##'''Update:''' Gravis G, Boher JM, Joly F, Soulié M, Albiges L, Priou F, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Théodore C, Deplanque G, Ferrero JM, Culine S, Mourey L, Beuzeboc P, Habibian M, Oudard S, Fizazi K; GETUG. Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: Impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial. Eur Urol. 2016 Aug;70(2):256-62. Epub 2015 Nov 21. [http://www.europeanurology.com/article/S0302-2838(15)01103-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26610858 PubMed]<br />
#'''CHAARTED:''' Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015 Aug 20;373(8):737-46. Epub 2015 Aug 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1503747 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4562797/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26244877 Pubmed] NCT00309985<br />
##'''Update:''' Kyriakopoulos CE, Chen YH, Carducci MA, Liu G, Jarrard DF, Hahn NM, Shevrin DH, Dreicer R, Hussain M, Eisenberger M, Kohli M, Plimack ER, Vogelzang NJ, Picus J, Cooney MM, Garcia JA, DiPaola RS, Sweeney CJ. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018 Apr 10;36(11):1080-1087. Epub 2018 Jan 31. [https://doi.org/10.1200/JCO.2017.75.3657 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891129/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29384722 PubMed]<br />
##'''QoL analysis:''' Morgans AK, Chen YH, Sweeney CJ, Jarrard DF, Plimack ER, Gartrell BA, Carducci MA, Hussain M, Garcia JA, Cella D, DiPaola RS, Patrick-Miller LJ. Quality of life during treatment with chemohormonal therapy: analysis of E3805 chemohormonal androgen ablation randomized trial in prostate cancer. J Clin Oncol. 2018 Apr 10;36(11):1088-1095. Epub 2018 Mar 9. [https://doi.org/10.1200/JCO.2017.75.3335 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891128/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29522362 PubMed]<br />
#'''STAMPEDE:''' James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, Ritchie AW, Parker CC, Russell JM, Attard G, de Bono J, Cross W, Jones RJ, Thalmann G, Amos C, Matheson D, Millman R, Alzouebi M, Beesley S, Birtle AJ, Brock S, Cathomas R, Chakraborti P, Chowdhury S, Cook A, Elliott T, Gale J, Gibbs S, Graham JD, Hetherington J, Hughes R, Laing R, McKinna F, McLaren DB, O'Sullivan JM, Parikh O, Peedell C, Protheroe A, Robinson AJ, Srihari N, Srinivasan R, Staffurth J, Sundar S, Tolan S, Tsang D, Wagstaff J, Parmar MK; STAMPEDE Investigators. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016 Mar 19;387(10024):1163-77. Epub 2015 Dec 21. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01037-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800035/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26719232 PubMed] NCT00268476<br />
##'''Update:''' Clarke NW, Ali A, Ingleby FC, Hoyle A, Amos CL, Attard G, Brawley CD, Calvert J, Chowdhury S, Cook A, Cross W, Dearnaley DP, Douis H, Gilbert D, Gillessen S, Jones RJ, Langley RE, MacNair A, Malik Z, Mason MD, Matheson D, Millman R, Parker CC, Ritchie AWS, Rush H, Russell JM, Brown J, Beesley S, Birtle A, Capaldi L, Gale J, Gibbs S, Lydon A, Nikapota A, Omlin A, O'Sullivan JM, Parikh O, Protheroe A, Rudman S, Srihari NN, Simms M, Tanguay JS, Tolan S, Wagstaff J, Wallace J, Wylie J, Zarkar A, Sydes MR, Parmar MKB, James ND. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol. 2019 Dec 1;30(12):1992-2003. [https://doi.org/10.1093/annonc/mdz396 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938598/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/31560068 PubMed]<br />
<br />
==ADT, Docetaxel, Estramustine {{#subobject:7nc12c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT, Docetaxel, Estramustine: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy, Docetaxel, Estramustine<br />
===Regimen {{#subobject:3ac6bc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00011-X/fulltext Fizazi et al. 2015 (GETUG 12)]<br />
|2002-2006<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#91cf60" |Seems to have superior RFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]]<br />
*[[Estramustine (Emcyt)]]<br />
<br />
====Endocrine therapy====<br />
<br />
*ADT with one of the following:<br />
**[[:Category:GnRH agonists|LHRH agonist/analogue]] with or without [[:Category:Nonsteroidal_androgen_receptor_inhibitors|nonsteroidal androgen receptor inhibitors]]<br />
**[[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]] with or without [[:Category:Nonsteroidal_androgen_receptor_inhibitors|nonsteroidal androgen receptor inhibitors]]<br />
<br />
===References===<br />
<br />
#'''GETUG 12:''' Fizazi K, Faivre L, Lesaunier F, Delva R, Gravis G, Rolland F, Priou F, Ferrero JM, Houede N, Mourey L, Theodore C, Krakowski I, Berdah JF, Baciuchka M, Laguerre B, Fléchon A, Ravaud A, Cojean-Zelek I, Oudard S, Labourey JL, Chinet-Charrot P, Legouffe E, Lagrange JL, Linassier C, Deplanque G, Beuzeboc P, Davin JL, Martin AL, Habibian M, Laplanche A, Culine S. Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial. Lancet Oncol. 2015 Jul;16(7):787-94. Epub 2015 May 28. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00011-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26028518 PubMed] NCT00055731<br />
<br />
==ADT & Enzalutamide {{#subobject:79lq3c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT & Enzalutamide: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy & Enzalutamide<br />
===Regimen {{#subobject:29ncbc|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1903835 Davis et al. 2019 (ENZAMET)]<br />
|2014-2017<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. ADT & Bicalutamide<br> 2. ADT & Flutamide<br> 3. ADT & Niluatmide<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.00799 Armstrong et al. 2019 (ARCHES)]<br />
|2016-2018<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#ADT_5|ADT]]<br />
| style="background-color:#1a9850" |Superior rPFS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Enzalutamide (Xtandi)]] 160 mg PO once per day<br />
*ADT with one of the following:<br />
**[[:Category:GnRH agonists|LHRH agonist/analogue]]<br />
**[[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]]<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''ENZAMET:''' Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, Coskinas X, Frydenberg M, Hague WE, Horvath LG, Joshua AM, Lawrence NJ, Marx G, McCaffrey J, McDermott R, McJannett M, North SA, Parnis F, Parulekar W, Pook DW, Reaume MN, Sandhu SK, Tan A, Tan TH, Thomson A, Tu E, Vera-Badillo F, Williams SG, Yip S, Zhang AY, Zielinski RR, Sweeney CJ; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019 Jul 11;381(2):121-131. Epub 2019 Jun 2. [https://www.nejm.org/doi/full/10.1056/NEJMoa1903835 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31157964 PubMed] NCT02446405<br />
#'''ARCHES:''' Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, Alcaraz A, Alekseev B, Iguchi T, Shore ND, Rosbrook B, Sugg J, Baron B, Chen L, Stenzl A. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019 Nov 10;37(32):2974-2986. Epub 2019 Jul 22. [https://doi.org/10.1200/JCO.19.00799 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31329516 PubMed]<br />
<br />
==Bicalutamide monotherapy {{#subobject:5 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.karger.com/Article/Abstract/19634 Tyrrell et al. 1998]<br />
|NR in abstract<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Prostate_cancer_-_historical#Castration|Castration]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS<sup>1</sup><br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(02)00311-1/fulltext Iversen et al. 2002 (SPCG-6)]<br />
|1995-1998<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior OS<sup>2</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for Tyrrell et al. 1998 is based on the 2000 update.''<br><br />
''<sup>2</sup>Reported efficacy for SPCG-6 is based on the 2006 update and is only for the locally advanced subgroup.''<br><br />
''Not approved for monotherapy in the United States. See combination regimens with goserelin & leuprolide.''<br />
====Endocrine therapy====<br />
<br />
*[[Bicalutamide (Casodex)]] 150 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
<br />
#Tyrrell CJ, Kaisary AV, Iversen P, Anderson JB, Baert L, Tammela T, Chamberlain M, Webster A, Blackledge G. A randomised comparison of 'Casodex' (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol. 1998;33(5):447-56. [https://www.karger.com/Article/Abstract/19634 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9643663 PubMed]<br />
##'''Update:''' Iversen P, Tyrrell CJ, Kaisary AV, Anderson JB, Van Poppel H, Tammela TL, Chamberlain M, Carroll K, Melezinek I. Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup. J Urol. 2000 Nov;164(5):1579-82. [https://www.auajournals.org/article/S0022-5347(05)67032-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11025708 PubMed]<br />
#'''SPCG-6:''' Iversen P, Tammela TL, Vaage S, Lukkarinen O, Lodding P, Bull-Njaa T, Viitanen J, Hoisaeter P, Lundmo P, Rasmussen F, Johansson JE, Persson BE, Carroll K; Scandinavian Prostatic Cancer Group. A randomised comparison of bicalutamide ('Casodex') 150 mg versus placebo as immediate therapy either alone or as adjuvant to standard care for early non-metastatic prostate cancer: first report from the Scandinavian Prostatic Cancer Group Study No 6. Eur Urol. 2002 Sep;42(3):204-11. [https://www.europeanurology.com/article/S0302-2838(02)00311-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12234503 PubMed]<br />
##'''Update:''' Iversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Carroll K; Scandinavian Prostatic Cancer Group. Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6. J Urol. 2004 Nov;172(5 Pt 1):1871-6. [https://www.auajournals.org/article/S0022-5347(05)60880-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15540741 PubMed]<br />
##'''Update:''' Iversen P, Johansson JE, Lodding P, Kylmälä T, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Armstrong J; Scandinavian Prostate Cancer Group. Bicalutamide 150 mg in addition to standard care for patients with early non-metastatic prostate cancer: updated results from the Scandinavian Prostate Cancer Period Group-6 Study after a median follow-up period of 7.1 years. Scand J Urol Nephrol. 2006;40(6):441-52. [https://www.tandfonline.com/doi/abs/10.1080/00365590601017329 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17130095 PubMed]<br />
<br />
==Bicalutamide & Goserelin {{#subobject:10 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 50/3.6 {{#subobject:10 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.goldjournal.net/article/S0090-4295(99)80077-6/abstract Schellhammer et al. 1995]<br />
| rowspan="2" |1992-1993<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Bicalutamide_.26_Leuprolide|Bicalutamide & Leuprolide]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Flutamide_.26_Goserelin_2|Flutamide & Goserelin]]<br> 3. [[#Flutamide_.26_Leuprolide|Flutamide & Leuprolide]]<br />
| style="background-color:#eeee01" |Equivalent TTP<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for Schellhammer et al. 1995 is based on the 1997 final update.''<br />
====Endocrine therapy====<br />
<br />
*[[Bicalutamide (Casodex)]] 50 mg PO once per day<br />
*[[Goserelin (Zoladex)]] 3.6 mg SC once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 80/3.6 {{#subobject:a8fe78|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jjco.oxfordjournals.org/content/34/1/20.full Akaza et al. 2004]<br />
|2000-2001<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Goserelin_monotherapy_2|Goserelin]]<br> 2. [[#Leuprolide_monotherapy_2|Leuprolide]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2009 update.''<br />
====Endocrine therapy====<br />
<br />
*[[Bicalutamide (Casodex)]] 80 mg PO once per day<br />
*[[Goserelin (Zoladex)]] 3.6 mg SC once on day 1<br />
<br />
'''28-day cycles'''<br />
===References===<br />
<br />
#Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer; Casodex Combination Study Group. Urology. 1995 May;45(5):745-52. [http://www.goldjournal.net/article/S0090-4295(99)80077-6/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7538237 PubMed]<br />
##'''Update:''' Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Chen Y, Kolvenbag GJ. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: analysis of time to progression; CASODEX Combination Study Group. Cancer. 1996 Nov 15;78(10):2164-9. [https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0142(19961115)78:10%3C2164::AID-CNCR18%3E3.0.CO;2-X/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8918410 PubMed]<br />
##'''Update:''' Soloway MS, Schellhammer P, Sharifi R, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of Casodex (bicalutamide) vs flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Eur Urol. 1996;29 Suppl 2:105-9. [https://doi.org/10.1159/000473848 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8717471 PubMed]<br />
##'''Update:''' Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ; Casodex Combination Study Group. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology. 1997 Sep;50(3):330-6. [https://www.goldjournal.net/article/S0090-4295(97)00279-3/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9301693 PubMed]<br />
#Akaza H, Yamaguchi A, Matsuda T, Igawa M, Kumon H, Soeda A, Arai Y, Usami M, Naito S, Kanetake H, Ohashi Y. Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: interim results of a randomized study in Japanese patients. Jpn J Clin Oncol. 2004 Jan;34(1):20-8. [http://jjco.oxfordjournals.org/content/34/1/20.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15020659 PubMed]<br />
##'''Update:''' Akaza H, Hinotsu S, Usami M, Arai Y, Kanetake H, Naito S, Hirao Y; Study Group for the Combined Androgen Blockade Therapy of Prostate Cancer. Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival. Cancer. 2009 Aug 1;115(15):3437-45. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.24395 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19536889 PubMed]<br />
<br />
==Bicalutamide & Leuprolide {{#subobject:13 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 50/7.5 {{#subobject:13 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.goldjournal.net/article/S0090-4295(99)80077-6/abstract Schellhammer et al. 1995]<br />
| rowspan="2" |1992-1993<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Bicalutamide_.26_Goserelin_2|Bicalutamide & Goserelin]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Flutamide_.26_Goserelin_2|Flutamide & Goserelin]]<br> 3. [[#Flutamide_.26_Leuprolide|Flutamide & Leuprolide]]<br />
| style="background-color:#eeee01" |Equivalent TTP<sup>1</sup><br />
|-<br />
|[https://www.auajournals.org/doi/full/10.1016/S0022-5347%2805%2965175-0 Trachtenberg et al. 2002]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Abarelix<br />
| style="background-color:#d73027" |Inferior primary endpoint<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for Schellhammer et al. 1995 is based on the 1997 final update.''<br />
====Endocrine therapy====<br />
<br />
*[[Bicalutamide (Casodex)]] 50 mg PO once per day<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 1-month depot]] 7.5 mg IM once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 80/3.75 {{#subobject:28699c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jjco.oxfordjournals.org/content/34/1/20.full Akaza et al. 2004]<br />
|2000-2001<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Goserelin_monotherapy|Goserelin]]<br> 2. [[#Leuprolide_monotherapy_2|Leuprolide]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2009 update.''<br />
====Endocrine therapy====<br />
<br />
*[[Bicalutamide (Casodex)]] 80 mg PO once per day<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 1-month depot]] 3.75 mg SC once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer; Casodex Combination Study Group. Urology. 1995 May;45(5):745-52. [http://www.goldjournal.net/article/S0090-4295(99)80077-6/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7538237 PubMed]<br />
##'''Update:''' Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Chen Y, Kolvenbag GJ. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: analysis of time to progression; CASODEX Combination Study Group. Cancer. 1996 Nov 15;78(10):2164-9. [https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0142(19961115)78:10%3C2164::AID-CNCR18%3E3.0.CO;2-X/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8918410 PubMed]<br />
##'''Update:''' Soloway MS, Schellhammer P, Sharifi R, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of Casodex (bicalutamide) vs flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Eur Urol. 1996;29 Suppl 2:105-9. [https://doi.org/10.1159/000473848 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8717471 PubMed]<br />
##'''Update:''' Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ; Casodex Combination Study Group. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology. 1997 Sep;50(3):330-6. [https://www.goldjournal.net/article/S0090-4295(97)00279-3/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9301693 PubMed]<br />
#Trachtenberg J, Gittleman M, Steidle C, Barzell W, Friedel W, Pessis D, Fotheringham N, Campion M, Garnick MB; Abarelix Study Group. A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. J Urol. 2002 Apr;167(4):1670-4. [https://www.auajournals.org/doi/full/10.1016/S0022-5347%2805%2965175-0 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11912385 PubMed]<br />
#Akaza H, Yamaguchi A, Matsuda T, Igawa M, Kumon H, Soeda A, Arai Y, Usami M, Naito S, Kanetake H, Ohashi Y. Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: interim results of a randomized study in Japanese patients. Jpn J Clin Oncol. 2004 Jan;34(1):20-8. [http://jjco.oxfordjournals.org/content/34/1/20.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15020659 PubMed]<br />
##'''Update:''' Akaza H, Hinotsu S, Usami M, Arai Y, Kanetake H, Naito S, Hirao Y; Study Group for the Combined Androgen Blockade Therapy of Prostate Cancer. Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival. Cancer. 2009 Aug 1;115(15):3437-45. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.24395 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19536889 PubMed]<br />
<br />
==Degarelix monotherapy {{#subobject:7 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Degarelix (Firmagon) in prostate cancer]]<br />
<br />
===Regimen variant #1, 240/80 {{#subobject:7 |Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2008.08183.x/full Klotz et al. 2008 (CS21)]<br />
| rowspan="2" |2006-2007<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Degarelix_monotherapy|Degarelix]]; 240/160<br />
| style="background-color:#eeee01" |Non-inferior testosterone suppression<br />
|-<br />
|2. [[#Leuprolide_monotherapy_2|Leuprolide]]<br />
| style="background-color:#eeee01" |Non-inferior testosterone suppression<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Degarelix (Firmagon)]] as follows:<br />
**Cycle 1: 240 mg SC once on day 1<br />
**Cycle 2 onwards: 80 mg SC once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 240/160 {{#subobject:7b |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2008.08183.x/full Klotz et al. 2008 (CS21)]<br />
| rowspan="2" |2006-2007<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Degarelix_monotherapy|Degarelix]]; 240/80<br />
| style="background-color:#eeee01" |Non-inferior testosterone suppression<br />
|-<br />
|2. [[#Leuprolide_monotherapy_2|Leuprolide]]<br />
| style="background-color:#eeee01" |Non-inferior testosterone suppression<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Degarelix (Firmagon)]] as follows:<br />
**Cycle 1: 240 mg SC once on day 1<br />
**Cycle 2 onwards: 160 mg SC once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3, 240/480 {{#subobject:01864f |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989846/ Ozono et al. 2018 (3550-CL-0010)]<br />
|2013-NR<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Goserelin_monotherapy_2|Goserelin]]<br />
| style="background-color:#eeee01" |Non-inferior testosterone suppression<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Degarelix (Firmagon)]] as follows:<br />
**Cycle 1: 240 mg SC once on day 1<br />
**Cycle 2 onwards: 480 mg SC once on day 1<br />
<br />
'''28-day cycle for 1 cycle, then 12-week cycles'''<br />
<br />
===References===<br />
<br />
#'''CS21:''' Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, Jensen JK, Olesen TK, Schröder FH. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008 Dec;102(11):1531-8. [https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2008.08183.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19035858 PubMed]<br />
##'''Update:''' Tombal B, Miller K, Boccon-Gibod L, Schröder F, Shore N, Crawford ED, Moul J, Jensen JK, Kold Olesen T, Persson BE. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. 2010 May;57(5):836-42. Epub 2009 Nov 20. [http://www.europeanurology.com/article/S0302-2838%2809%2901171-3 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19962227 PubMed]<br />
#'''3550-CL-0010:''' Ozono S, Tsukamoto T, Naito S, Horie S, Ohashi Y, Uemura H, Yokomizo Y, Fukasawa S, Kusuoka H, Akazawa R, Saito M, Akaza H. Efficacy and safety of 3-month dosing regimen of degarelix in Japanese subjects with prostate cancer: a phase III study. Cancer Sci. 2018 Jun;109(6):1920-1929. Epub 2018 May 23. [https://onlinelibrary.wiley.com/doi/abs/10.1111/cas.13600 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989846/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29624800 PubMed] NCT01964170<br />
<br />
==Flutamide monotherapy {{#subobject:8 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.karger.com/Article/Abstract/480795 Boccon-Gibod et al. 1997]<br />
|1989-1991<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Prostate_cancer_-_historical#Castration|Bilateral orchiectomy]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2001.19.1.62 Fosså et al. 2001 (EORTC 30903)]<br />
|1992-1998<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of TTP/OS<br />
|-<br />
|}<br />
''Not approved for monotherapy in the United States. See combination regimens with Goserelin & Leuprolide.''<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]] 250 mg PO three times per day<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
<br />
#Boccon-Gibod L, Fournier G, Bottet P, Marechal JM, Guiter J, Rischman P, Hubert J, Soret JY, Mangin P, Mallo C, Fraysse CE. Flutamide versus orchidectomy in the treatment of metastatic prostate carcinoma. Eur Urol. 1997;32(4):391-5. [https://www.karger.com/Article/Abstract/480795 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9412794 PubMed]<br />
#'''EORTC 30903:''' Fosså SD, Slee PH, Brausi M, Horenblas S, Hall RR, Hetherington JW, Aaronson N, de Prijck L, Collette L. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol. 2001 Jan 1;19(1):62-71. [https://doi.org/10.1200/JCO.2001.19.1.62 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11134196 PubMed]<br />
<br />
==Flutamide & Goserelin {{#subobject:11 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:11 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1002/cncr.1990.66.s5.1058 Iversen et al. 1990]<br />
|1986-1987<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Prostate_cancer_-_historical#Castration|Bilateral orchiectomy]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of OS/PFS/TTP<br />
|-<br />
|[https://doi.org/10.1002/cncr.1990.66.s5.1045 Keuppens et al. 1990 (EORTC 30853)]<br />
|1986-1988<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Prostate_cancer_-_historical#Castration|Bilateral orchiectomy]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br />
|-<br />
| rowspan="2" |[http://www.goldjournal.net/article/S0090-4295(99)80077-6/abstract Schellhammer et al. 1995]<br />
| rowspan="2" |1992-1993<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Bicalutamide_.26_Goserelin_2|Bicalutamide & Goserelin]]<br> 2. [[#Bicalutamide_.26_Leuprolide|Bicalutamide & Leuprolide]]<br />
| style="background-color:#eeee01" |Equivalent TTP<sup>2</sup><br />
|-<br />
|3. [[#Flutamide_.26_Leuprolide|Flutamide & Leuprolide]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682658/ Hussain et al. 2013 (SWOG-9346)]<br />
|1995-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Intermittent_ADT|Intermittent ADT]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for EORTC 30853 is based on the 1998 final update.''<br><br />
''<sup>2</sup>Reported efficacy for Schellhammer et al. 1995 is based on the 1997 final update.''<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]] 250 mg PO three times per day<br />
*[[Goserelin (Zoladex)]] 3.6 mg SC once on day 1<br />
<br />
'''28-day cycles'''<br />
===References===<br />
#'''EORTC 30853:''' Keuppens F, Denis L, Smith P, Carvalho AP, Newling D, Bond A, Sylvester R, De Pauw M, Vermeylen K, Ongena P; EORTC GU Group. Zoladex and flutamide versus bilateral orchiectomy: a randomized phase III EORTC 30853 study. Cancer. 1990 Sep 1;66(5 Suppl):1045-57. [https://doi.org/10.1002/cncr.1990.66.s5.1045 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2144206/ PubMed]<br />
##'''Update:''' Denis LJ, Carnelro de Moura JL, Bono A, Sylvester R, Whelan P, Newling D, Depauw M; [[Study_Groups#EORTC|EORTC]] GU Group. Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III EORTC trial (30853). Urology. 1993 Aug;42(2):119-29. [https://www.goldjournal.net/article/0090-4295(93)90634-M/pdf link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8367920 PubMed]<br />
##'''Update:''' Denis LJ, Keuppens F, Smith PH, Whelan P, de Moura JL, Newling D, Bono A, Sylvester R; [[Study_Groups#EORTC|EORTC]] Genito-Urinary Tract Cancer Cooperative Group and the EORTC Data Center. Maximal androgen blockade: final analysis of EORTC phase III trial 30853. Eur Urol. 1998;33(2):144-51. [https://doi.org/10.1159/000019546 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9519355 PubMed]<br />
#Iversen P, Christensen MG, Friis E, Hornbøl P, Hvidt V, Iversen HG, Klarskov P, Krarup T, Lund F, Mogensen P, et al. A phase III trial of zoladex and flutamide versus orchiectomy in the treatment of patients with advanced carcinoma of the prostate. Cancer. 1990 Sep 1;66(5 Suppl):1058-66. [https://doi.org/10.1002/cncr.1990.66.s5.1058 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2144207/ PubMed]<br />
#Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Urology. 1995 May;45(5):745-52. [http://www.goldjournal.net/article/S0090-4295(99)80077-6/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7538237 PubMed]<br />
##'''Update:''' Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Chen Y, Kolvenbag GJ; CASODEX Combination Study Group. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: analysis of time to progression. Cancer. 1996 Nov 15;78(10):2164-9. [https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0142(19961115)78:10%3C2164::AID-CNCR18%3E3.0.CO;2-X/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8918410 PubMed]<br />
##'''Update:''' Soloway MS, Schellhammer P, Sharifi R, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of Casodex (bicalutamide) vs flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Eur Urol. 1996;29 Suppl 2:105-9. [https://doi.org/10.1159/000473848 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8717471 PubMed]<br />
##'''Update:''' Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ; Casodex Combination Study Group. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology. 1997 Sep;50(3):330-6. [https://www.goldjournal.net/article/S0090-4295(97)00279-3/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9301693 PubMed]<br />
#'''SWOG-9346:''' Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, Wilding G, Prescott S, Kanaga Sundaram S, Small EJ, Dawson NA, Donnelly BJ, Venner PM, Vaishampayan UN, Schellhammer PF, Quinn DI, Raghavan D, Ely B, Moinpour CM, Vogelzang NJ, Thompson IM Jr. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013 Apr 4;368(14):1314-25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1212299 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682658/ link to PMC article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1212299/suppl_file/nejmoa1212299_protocol.pdf supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23550669 PubMed] NCT00002651<br />
<br />
==Flutamide & Leuprolide {{#subobject:14 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, daily Lupron {{#subobject:5b0861 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM198908173210702 Crawford et al. 1989 (SWOG-8494)]<br />
|1985-1986<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Leuprolide_monotherapy_2|Leuprolide]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: this is likely of historic importance only, given the formulation of leuoprolide.''<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]] 250 mg PO three times per day<br />
*[[Leuprolide (Lupron)]] 1 mg SC once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen variant #2, 1-month depot Lupron {{#subobject:14 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.goldjournal.net/article/S0090-4295(99)80077-6/abstract Schellhammer et al. 1995]<br />
| rowspan="2" |1992-1993<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Bicalutamide_.26_Goserelin_2|Bicalutamide & Goserelin]]<br> 2. [[#Bicalutamide_.26_Leuprolide|Bicalutamide & Leuprolide]]<br />
| style="background-color:#eeee01" |Equivalent TTP<sup>1</sup><br />
|-<br />
|3. [[#Flutamide_.26_Goserelin_2|Flutamide & Goserelin]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682658/ Hussain et al. 2013 (SWOG-9346)]<br />
|1995-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Intermittent_ADT|Intermittent ADT]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for Schellhammer et al. 1995 is based on the 1997 final update.''<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]] 250 mg PO three times per day<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 1-month depot]] 7.5 mg IM once on day 1<br />
<br />
'''28-day cycles'''<br />
===References===<br />
<br />
#'''SWOG-8494:''' Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, Blumenstein BA, Davis MA, Goodman PJ. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989 Aug 17;321(7):419-24. Erratum in: N Engl J Med 1989 Nov 16;321(20):1420. [https://www.nejm.org/doi/full/10.1056/NEJM198908173210702 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2503724 PubMed]<br />
#Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer; Casodex Combination Study Group. Urology. 1995 May;45(5):745-52. [http://www.goldjournal.net/article/S0090-4295(99)80077-6/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7538237 PubMed]<br />
##'''Update:''' Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Chen Y, Kolvenbag GJ. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: analysis of time to progression; CASODEX Combination Study Group. Cancer. 1996 Nov 15;78(10):2164-9. [https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0142(19961115)78:10%3C2164::AID-CNCR18%3E3.0.CO;2-X/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8918410 PubMed]<br />
##'''Update:''' Soloway MS, Schellhammer P, Sharifi R, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of Casodex (bicalutamide) vs flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Eur Urol. 1996;29 Suppl 2:105-9. [https://doi.org/10.1159/000473848 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8717471 PubMed]<br />
##'''Update:''' Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ; Casodex Combination Study Group. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology. 1997 Sep;50(3):330-6. [https://www.goldjournal.net/article/S0090-4295(97)00279-3/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9301693 PubMed]<br />
#'''SWOG-9346:''' Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, Wilding G, Prescott S, Kanaga Sundaram S, Small EJ, Dawson NA, Donnelly BJ, Venner PM, Vaishampayan UN, Schellhammer PF, Quinn DI, Raghavan D, Ely B, Moinpour CM, Vogelzang NJ, Thompson IM Jr. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013 Apr 4;368(14):1314-25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1212299 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682658/ link to PMC article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1212299/suppl_file/nejmoa1212299_protocol.pdf supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23550669 PubMed] NCT00002651<br />
<br />
==Goserelin monotherapy {{#subobject:9 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Goserelin (Zoladex) in prostate cancer]]<br />
<br />
===Regimen variant #1, 28-day cycles {{#subobject:9 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.goldjournal.net/article/0090-4295(91)80077-K/pdf Soloway et al. 1991]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Prostate_cancer_-_historical#Castration|Bilateral orchiectomy]]<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1464-410X.1991.tb15195.x Kaisary et al. 1991]<br />
|1983-1986<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Prostate_cancer_-_historical#Castration|Bilateral orchiectomy]]<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1464-410X.1992.tb15633.x Waymont et al. 1992]<br />
|1985-1987<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|DES<br />
| style="background-color:#91cf60" |Seems to have superior time to first response<br />
|-<br />
|[https://doi.org/10.1016/s0022-5347(17)38080-1 Tyrrell et al. 1991 (IPCSG)]<br />
|1986-1987<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Flutamide_.26_Goserelin_2|Flutamide & Goserelin]]<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(05)80293-X/abstract Boccardo et al. 1993 (PONCAP)]<br />
|1987-1990<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Flutamide_.26_Goserelin_2|Flutamide & Goserelin]]<br />
| style="background-color:#fee08b" |Might have inferior PFS50%<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Goserelin (Zoladex)]] 3.6 mg SC once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 12-week cycles {{#subobject:7afffe |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989846/ Ozono et al. 2018 (3550-CL-0010)]<br />
|2015-NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Degarelix_monotherapy|Degarelix]]<br />
| style="background-color:#eeee01" |Non-inferior testosterone suppression<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Goserelin (Zoladex)]] as follows:<br />
**Cycle 1: 3.6 mg SC once on day 1<br />
**Cycle 2 onwards: 10.8 mg SC once on day 1<br />
<br />
'''28-day cycle for 1 cycle, then 12-week cycles'''<br />
<br />
===References===<br />
<br />
#Soloway MS, Chodak G, Vogelzang NJ, Block NL, Schellhammer PF, Smith JA Jr, Scott M, Kennealey G, Gau TC; Zoladex Prostate Study Group. Zoladex versus orchiectomy in treatment of advanced prostate cancer: a randomized trial. Urology. 1991 Jan;37(1):46-51. [https://www.goldjournal.net/article/0090-4295(91)80077-K/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1824732 PubMed]<br />
##'''Update:''' Vogelzang NJ, Chodak GW, Soloway MS, Block NL, Schellhammer PF, Smith JA Jr, Caplan RJ, Kennealey GT; Zoladex Prostate Study Group. Goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial. Urology. 1995 Aug;46(2):220-6. [http://www.goldjournal.net/article/S0090-4295(99)80197-6/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7624991 PubMed]<br />
#Kaisary AV, Tyrrell CJ, Peeling WB, Griffiths K. Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostatic carcinoma. Br J Urol. 1991 May;67(5):502-8. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1464-410X.1991.tb15195.x link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1828183 PubMed]<br />
#'''IPCSG:''' Tyrrell CJ, Altwein JE, Klippel F, Varenhorst E, Lunglmayr G, Boccardo F, Holdaway IM, Haefliger JM, Jordaan JP; International Prostate Cancer Study Group. A multicenter randomized trial comparing the luteinizing hormone-releasing hormone analogue goserelin acetate alone and with flutamide in the treatment of advanced prostate cancer. J Urol. 1991 Nov;146(5):1321-6. [https://doi.org/10.1016/s0022-5347(17)38080-1 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1834864 PubMed]<br />
#Waymont B, Lynch TH, Dunn JA, Emtage LA, Arkell DG, Wallace DM, Blackledge GR. Phase III randomised study of zoladex versus stilboestrol in the treatment of advanced prostate cancer. Br J Urol. 1992 Jun;69(6):614-20. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1464-410X.1992.tb15633.x link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1386272 PubMed]<br />
#'''PONCAP:''' Boccardo F, Pace M, Rubagotti A, Guarneri D, Decensi A, Oneto F, Martorana G, Giuliani L, Selvaggi F, Battaglia M, Delli Ponti U, Petracco S, Cortellini P, Ziveri M, Ferraris V, Bruttini GP, Epis R, Comeri G, Gallo G; Italian Prostatic Cancer Project (PONCAP) Study Group. Goserelin acetate with or without flutamide in the treatment of patients with locally advanced or metastatic prostate cancer. Eur J Cancer. 1993;29A(8):1088-93. [https://www.ejcancer.com/article/S0959-8049(05)80293-X/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8518017 PubMed]<br />
#'''3550-CL-0010:''' Ozono S, Tsukamoto T, Naito S, Horie S, Ohashi Y, Uemura H, Yokomizo Y, Fukasawa S, Kusuoka H, Akazawa R, Saito M, Akaza H. Efficacy and safety of 3-month dosing regimen of degarelix in Japanese subjects with prostate cancer: a phase III study. Cancer Sci. 2018 Jun;109(6):1920-1929. Epub 2018 May 23. [https://onlinelibrary.wiley.com/doi/abs/10.1111/cas.13600 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989846/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29624800 PubMed] NCT01964170<br />
<br />
==Histrelin monotherapy {{#subobject:97agub |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:918gya|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.auajournals.org/doi/full/10.1016/S0022-5347%2805%2900649-X Schlegel 2006]<br />
|NR<br />
| style="background-color:#91cf61" |Non-randomized (RT)<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Histrelin (Vantas)]]<br />
<br />
===References===<br />
<br />
#Schlegel PN; Histrelin Study Group. Efficacy and safety of histrelin subdermal implant in patients with advanced prostate cancer. J Urol. 2006 Apr;175(4):1353-8. [https://www.auajournals.org/doi/full/10.1016/S0022-5347%2805%2900649-X link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16515997 PubMed]<br />
<br />
==Intermittent ADT==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
IHT: '''<u>I</u>'''ntermittent '''<u>H</u>'''ormone '''<u>T</u>'''herapy<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(09)00159-6/fulltext Calais da Silva et al. 2009 (SEUG 9401)]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|Continuous ADT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682658/ Hussain et al. 2013 (SWOG-9346)]<br />
|1995-2008<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|Continuous ADT<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521033/ Crook et al. 2012 (NCIC-CTG PR.7)]<br />
|1999-2005<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|Continuous ADT<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(13)00342-4/fulltext Calais da Silva et al. 2013 (SEUG 9901)]<br />
|2000-2007<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|Continuous ADT<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
''See papers for details about treatment holidays.''<br />
====Endocrine therapy====<br />
<br />
*[[:Category:GnRH agonists|LHRH agonist]]<br />
*[[:Category:Nonsteroidal_antiandrogens|Nonsteroidal antiandrogen]] for at least 4 weeks<br />
<br />
'''8-month cycles'''<br />
===References===<br />
<br />
#'''SEUG 9401:''' Calais da Silva FE, Bono AV, Whelan P, Brausi M, Marques Queimadelos A, Martin JA, Kirkali Z, Calais da Silva FM, Robertson C. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group. Eur Urol. 2009 Jun;55(6):1269-77. Epub 2009 Feb 21. [https://www.europeanurology.com/article/S0302-2838(09)00159-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19249153 PubMed]<br />
#'''NCIC-CTG PR.7:''' Crook JM, O'Callaghan CJ, Duncan G, Dearnaley DP, Higano CS, Horwitz EM, Frymire E, Malone S, Chin J, Nabid A, Warde P, Corbett T, Angyalfi S, Goldenberg SL, Gospodarowicz MK, Saad F, Logue JP, Hall E, Schellhammer PF, Ding K, Klotz L. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med. 2012 Sep 6;367(10):895-903. Erratum in: N Engl J Med. 2012 Dec 6;367(23):2262. [https://www.nejm.org/doi/full/10.1056/NEJMoa1201546 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521033/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22931259 PubMed] NCT00003653<br />
#'''SWOG-9346:''' Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, Wilding G, Prescott S, Kanaga Sundaram S, Small EJ, Dawson NA, Donnelly BJ, Venner PM, Vaishampayan UN, Schellhammer PF, Quinn DI, Raghavan D, Ely B, Moinpour CM, Vogelzang NJ, Thompson IM Jr. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013 Apr 4;368(14):1314-25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1212299 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682658/ link to PMC article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1212299/suppl_file/nejmoa1212299_protocol.pdf supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23550669 PubMed] NCT00002651<br />
#'''SEUG 9901:''' Calais da Silva F, Calais da Silva FM, Gonçalves F, Santos A, Kliment J, Whelan P, Oliver T, Antoniou N, Pastidis S, Marques Queimadelos A, Robertson C. Locally advanced and metastatic prostate cancer treated with intermittent androgen monotherapy or maximal androgen blockade: results from a randomised phase 3 study by the South European Uroncological Group. Eur Urol. 2014 Aug;66(2):232-9. Epub 2013 Apr 4. [https://www.europeanurology.com/article/S0302-2838(13)00342-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23582949 PubMed]<br />
<br />
==Leuprolide monotherapy {{#subobject:12 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Leuprolide (Lupron) in prostate cancer]]<br />
<br />
===Regimen variant #1, daily {{#subobject:c6f258 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM198411153112004 Garnick et al. 1984]<br />
|1981-NR<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|DES<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
| style="background-color:#1a9850" |Less toxic<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM198908173210702 Crawford et al. 1989 (SWOG-8494)]<br />
|1985-1986<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Flutamide_.26_Leuprolide|Flutamide & Leuprolide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|<br />
|-<br />
|}<br />
''Note: this is of historic importance only, given the wide availability of depot formulations of leuoprolide.''<br />
====Endocrine therapy====<br />
<br />
*[[Leuprolide (Lupron)]] 1 mg SC once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen variant #2, 1-month depot, 3.75 mg {{#subobject:172cb3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jjco.oxfordjournals.org/content/34/1/20.full Akaza et al. 2004]<br />
|2000-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Bicalutamide_.26_Goserelin_2|Bicalutamide & Goserelin]]<br> 2. [[#Bicalutamide_.26_Leuprolide|Bicalutamide & Leuprolide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2009 update.''<br />
====Endocrine therapy====<br />
<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 1-month depot]] 3.75 mg SC once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3, 1-month depot, 7.5 mg {{#subobject:172cb4|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2817%2939868-3 Sharifi & Soloway 1990]<br />
|1986-NR<br />
| style="background-color:#91cf61" |Non-randomized (RT)<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2008.08183.x/full Klotz et al. 2008 (CS21)]<br />
| rowspan="2" |2006-2007<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Degarelix_monotherapy|Degarelix 240/80]]<br />
| style="background-color:#eeee01" |Non-inferior testosterone suppression<br />
|-<br />
|2. [[#Degarelix_monotherapy|Degarelix 240/160]]<br />
| style="background-color:#eeee01" |Non-inferior testosterone suppression<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 1-month depot]] 7.5 mg IM once on day 1<br />
<br />
'''28-day cycles'''<br />
===Regimen variant #4, 3-month depot {{#subobject:5415fc |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.clinicaltherapeutics.com/article/S0149-2918(96)80215-3/pdf Sharifi et al. 1996]<br />
|NR<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://pubmed.ncbi.nlm.nih.gov/32469183/ Shore et al. 2020 (HERO)]<br />
|2017-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Relugolix_monotherapy|Relugolix]]<br />
| style="background-color:#d73027" |Inferior testosterone suppression<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 3-month depot]] 22.5 mg IM once on day 1<br />
<br />
'''84-day cycles'''<br />
<br />
===Regimen variant #5, 4-month depot {{#subobject:21b60f |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295(97)00500-1/pdf Sharifi et al. 1998]<br />
|NR<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 4-month depot]] 30 mg IM once on day 1<br />
<br />
'''16-week cycles'''<br />
<br />
===Regimen variant #6, 6-month depot {{#subobject:21720f |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278745/ Spitz et al. 2011 (L-PC07-169)]<br />
|2008-2009<br />
| style="background-color:#91cf61" |Non-randomized (RT)<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 6-month depot]] 45 mg IM once on day 1<br />
<br />
'''26-week cycles'''<br />
<br />
===References===<br />
<br />
#Garnick MB, Glode LM; Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med. 1984 Nov 15;311(20):1281-6. [https://www.nejm.org/doi/full/10.1056/NEJM198411153112004 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/6436700 PubMed]<br />
#'''SWOG-8494:''' Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, Blumenstein BA, Davis MA, Goodman PJ. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989 Aug 17;321(7):419-24. Erratum in: N Engl J Med 1989 Nov 16;321(20):1420. [https://www.nejm.org/doi/full/10.1056/NEJM198908173210702 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2503724 PubMed]<br />
#Sharifi R, Soloway M; Leuprolide Study Group. Clinical study of leuprolide depot formulation in the treatment of advanced prostate cancer. J Urol. 1990 Jan;143(1):68-71. [https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2817%2939868-3 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2104638 PubMed]<br />
#Sharifi R, Bruskewitz RC, Gittleman MC, Graham SD Jr, Hudson PB, Stein B. Leuprolide acetate 22.5 mg 12-week depot formulation in the treatment of patients with advanced prostate cancer. Clin Ther. 1996 Jul-Aug;18(4):647-57. [http://www.clinicaltherapeutics.com/article/S0149-2918(96)80215-3/pdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8879893 PubMed]<br />
#Sharifi R, Knoll LD, Smith J, Kramolowsky E. Leuprolide acetate (30-mg depot every four months) in the treatment of advanced prostate cancer. Urology. 1998 Feb;51(2):271-6. [http://www.goldjournal.net/article/S0090-4295(97)00500-1/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9495710 PubMed]<br />
#Akaza H, Yamaguchi A, Matsuda T, Igawa M, Kumon H, Soeda A, Arai Y, Usami M, Naito S, Kanetake H, Ohashi Y. Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: interim results of a randomized study in Japanese patients. Jpn J Clin Oncol. 2004 Jan;34(1):20-8. [http://jjco.oxfordjournals.org/content/34/1/20.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15020659 PubMed]<br />
##'''Update:''' Akaza H, Hinotsu S, Usami M, Arai Y, Kanetake H, Naito S, Hirao Y; Study Group for the Combined Androgen Blockade Therapy of Prostate Cancer. Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival. Cancer. 2009 Aug 1;115(15):3437-45. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.24395 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19536889 PubMed]<br />
#'''CS21:''' Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, Jensen JK, Olesen TK, Schröder FH. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008 Dec;102(11):1531-8. [https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2008.08183.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19035858 PubMed]<br />
##'''Update:''' Tombal B, Miller K, Boccon-Gibod L, Schröder F, Shore N, Crawford ED, Moul J, Jensen JK, Kold Olesen T, Persson BE. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. 2010 May;57(5):836-42. Epub 2009 Nov 20. [http://www.europeanurology.com/article/S0302-2838%2809%2901171-3 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19962227 PubMed]<br />
#'''L-PC07-169:''' Spitz A, Young JM, Larsen L, Mattia-Goldberg C, Donnelly J, Chwalisz K. Efficacy and safety of leuprolide acetate 6-month depot for suppression of testosterone in patients with prostate cancer. Prostate Cancer Prostatic Dis. 2012 Mar;15(1):93-9. Epub 2011 Oct 25. [https://www.nature.com/articles/pcan201150 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278745/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22025196 PubMed]<br />
#'''HERO:''' Shore ND, Saad F, Cookson MS, George DJ, Saltzstein DR, Tutrone R, Akaza H, Bossi A, van Veenhuyzen DF, Selby B, Fan X, Kang V, Walling J, Tombal B; HERO Study Investigators. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med. 2020 Jun 4;382(23):2187-2196. [https://doi.org/10.1056/NEJMoa2004325 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32469183/ PubMed] NCT03085095<br />
<br />
==Nilutamide & Orchiectomy {{#subobject:15 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:15 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/s0022-5347(17)36003-2 Janknegt et al. 1993 (International Anandron Study)]<br />
|1986-NR<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Prostate_cancer_-_historical#Castration|Bilateral orchiectomy]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
''Nilutamide to start the day of, or day after surgical castration/orchiectomy.''<br />
====Endocrine therapy====<br />
<br />
*[[Nilutamide (Nilandron)]] 300 mg PO once per day x 1 month, then 150 mg PO once per day<br />
*[[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]]<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''International Anandron Study:''' Janknegt RA, Abbou CC, Bartoletti R, Bernstein-Hahn L, Bracken B, Brisset JM, Da Silva FC, Chisholm G, Crawford ED, Debruyne FM, Dijkman GD, Frick J, Goedhals J, Knönagel H, Venner PM. Orchiectomy and nilutamide or placebo as treatment of metastatic prostatic cancer in a multinational double-blind randomized trial. J Urol. 1993 Jan;149(1):77-82. [https://doi.org/10.1016/s0022-5347(17)36003-2 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7678043 PubMed]<br />
##'''Update:''' Janknegt RA; Anandron International Study Group. Total androgen blockade with the use of orchiectomy and nilutamide (Anandron) or placebo as treatment of metastatic prostate cancer. Cancer. 1993 Dec 15;72(12 Suppl):3874-7. [https://www.ncbi.nlm.nih.gov/pubmed/8252507 PubMed]<br />
##'''Update:''' Dijkman GA, Janknegt RA, De Reijke TM, Debruyne FM; International Anandron Study Group. Long-term efficacy and safety of nilutamide plus castration in advanced prostate cancer, and the significance of early prostate specific antigen normalization. J Urol. 1997 Jul;158(1):160-3. [https://www.ncbi.nlm.nih.gov/pubmed/9186345 PubMed]<br />
##'''Update:''' de Reijke T, Derobert E; Anandron /Nilutamide Study Group. Prognostic factor analysis in patients with advanced prostate cancer treated by castration plus anandron or placebo: a final update. Eur Urol. 2002 Aug;42(2):139-46. [http://www.europeanurology.com/article/S0302-2838%2802%2900272-5 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12160584 PubMed]<br />
<br />
==Relugolix monotherapy {{#subobject:5jagu9 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:gaghc5 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://pubmed.ncbi.nlm.nih.gov/32469183/ Shore et al. 2020 (HERO)]<br />
|2017-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Leuprolide_monotherapy_2|Leuprolide]]<br />
| style="background-color:#1a9850" |Superior testosterone suppression<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
*[[Relugolix (Orgovyx)]] 360 mg PO once on day 1, then 120 mg PO once per day<br />
<br />
'''48-week course'''<br />
===References===<br />
#'''HERO:''' Shore ND, Saad F, Cookson MS, George DJ, Saltzstein DR, Tutrone R, Akaza H, Bossi A, van Veenhuyzen DF, Selby B, Fan X, Kang V, Walling J, Tombal B; HERO Study Investigators. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med. 2020 Jun 4;382(23):2187-2196. [https://doi.org/10.1056/NEJMoa2004325 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32469183/ PubMed] NCT03085095<br />
<br />
==Triptorelin monotherapy {{#subobject:15acjb |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1596sc |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1046/j.1464-410X.2003.04308.x Heyns et al. 2003]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Leuprolide_monotherapy_2|Leuprolide]]<br />
| style="background-color:#91cf60" |Seems to have superior 9-month OS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Survival was a secondary endpoint.''<br />
====Endocrine therapy====<br />
<br />
*[[Triptorelin (Trelstar LA)]] 3.75 mg IM once on day 1<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
===References===<br />
<br />
#Heyns CF, Simonin MP, Grosgurin P, Schall R, Porchet HC; South African Triptorelin Study Group. Comparative efficacy of triptorelin pamoate and leuprolide acetate in men with advanced prostate cancer. BJU Int. 2003 Aug;92(3):226-31. [https://onlinelibrary.wiley.com/doi/full/10.1046/j.1464-410X.2003.04308.x link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12887472 PubMed]<br />
<br />
=Metastatic disease, second-line hormonal therapy=<br />
==Abiraterone monotherapy {{#subobject:16 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:16 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''', PSA RR]]<br />
!Comparator [[Overall response rate|'''ORR''', PSA RR]]<br />
!Pt Population<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471149/ de Bono et al. 2011 (COU-AA-301)]<br />
|2008-2009<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|14% (95% CI n/a), 29%<br />
|3% (95% CI n/a), 6%<br />
|Chemo-exposed<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683570/ Ryan et al. 2013 (COU-AA-302)]<br />
|2009-2010<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|36% (95% CI n/a), 62%<br />
|16% (95% CI n/a), 24%<br />
|Chemo-naive<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717983/ Ye et al. 2017 (ABI-PRO-3002)]<br />
|2012-2013<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#1a9850" |Superior TTPP<br />
|<br />
|<br />
|Chemo-naive<br />
|-<br />
|[https://doi.org/10.1200/JCO.2018.77.9827 Attard et al. 2018 (PLATO)]<br />
|2013-NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Abiraterone, Enzalutamide, Prednisone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|<br />
|<br />
|Chemo-naive<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30860-X/fulltext Smith et al. 2019 (ERA 223)]<br />
|2014-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Abiraterone, Radium-223, Prednisone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of symptomatic skeletal EFS<br />
|<br />
|<br />
|Chemo-naive<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*PLATO: [[#Enzalutamide_monotherapy_2|Enzalutamide]], with rising PSA<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Abiraterone (Zytiga)]] 1000 mg PO once per day, 1 hour before or 2 hours after meals<br />
<br />
====Supportive medications====<br />
<br />
*[[Prednisone (Sterapred)]] 5 mg PO twice per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''COU-AA-301:''' de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005. [https://www.nejm.org/doi/full/10.1056/NEJMoa1014618 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471149/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21612468 PubMed] NCT00638690<br />
##'''Update:''' Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, Staffurth JN, North S, Vogelzang NJ, Saad F, Mainwaring P, Harland S, Goodman OB Jr, Sternberg CN, Li JH, Kheoh T, Haqq CM, de Bono JS; COU-AA-301 Investigators. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012 Oct;13(10):983-92. Epub 2012 Sep 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70379-0/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22995653 PubMed]<br />
##'''Update:''' Logothetis CJ, Basch E, Molina A, Fizazi K, North SA, Chi KN, Jones RJ, Goodman OB, Mainwaring PN, Sternberg CN, Efstathiou E, Gagnon DD, Rothman M, Hao Y, Liu CS, Kheoh TS, Haqq CM, Scher HI, de Bono JS. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol. 2012 Dec;13(12):1210-7. Epub 2012 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70473-4/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23142059 PubMed]<br />
#'''COU-AA-302:''' Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE; COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48. Epub 2012 Dec 10. [https://www.nejm.org/doi/full/10.1056/NEJMoa1209096 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683570/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23228172 PubMed] NCT00887198<br />
##'''Update:''' Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, Carles J, Flaig TW, Taplin ME, Higano CS, de Souza P, de Bono JS, Griffin TW, De Porre P, Yu MK, Park YC, Li J, Kheoh T, Naini V, Molina A, Rathkopf DE; COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015 Feb;16(2):152-60. Epub 2015 Jan 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71205-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25601341 PubMed]<br />
#'''ABI-PRO-3002:''' Ye D, Huang Y, Zhou F, Xie K, Matveev V, Li C, Alexeev B, Tian Y, Qiu M, Li H, Zhou T, De Porre P, Yu M, Naini V, Liang H, Wu Z, Sun Y. A phase 3, double-blind, randomized placebo-controlled efficacy and safety study of abiraterone acetate in chemotherapy-naïve patients with mCRPC in China, Malaysia, Thailand and Russia. Asian J Urol. 2017 Apr;4(2):75-85. Epub 2017 Jan 23. [https://doi.org/10.1016/j.ajur.2017.01.002 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717983/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29264210 PubMed] NCT01591122<br />
#'''PLATO:''' Attard G, Borre M, Gurney H, Loriot Y, Andresen-Daniil C, Kalleda R, Pham T, Taplin ME; PLATO collaborators. Abiraterone alone or in combination with enzalutamide in metastatic castration-resistant prostate cancer with rising prostate-specific antigen during enzalutamide treatment. J Clin Oncol. 2018 Sep 1;36(25):2639-2646. Epub 2018 Jul 20. [https://doi.org/10.1200/JCO.2018.77.9827 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30028657 PubMed] NCT01995513<br />
#'''ERA 223:''' Smith M, Parker C, Saad F, Miller K, Tombal B, Ng QS, Boegemann M, Matveev V, Piulats JM, Zucca LE, Karyakin O, Kimura G, Matsubara N, Nahas WC, Nolè F, Rosenbaum E, Heidenreich A, Kakehi Y, Zhang A, Krissel H, Teufel M, Shen J, Wagner V, Higano C. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):408-419. Epub 2019 Feb 6. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30860-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30738780 PubMed] NCT02043678<br />
#'''PROfound:''' de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 May 28;382(22):2091-2102. Epub 2020 Apr 28. [http://doi.org/10.1056/NEJMoa1911440 link to original article] '''contains verified protocol''' [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1911440/suppl_file/nejmoa1911440_appendix.pdf link to supplementary appendix] [https://pubmed.ncbi.nlm.nih.gov/32343890/ PubMed] NCT02987543<br />
#'''PROpel:''' NCT03732820<br />
#'''KEYLYNK-010:''' NCT03834519<br />
#'''AMPLITUDE:''' NCT04497844<br />
<br />
==Antiandrogen withdrawal {{#subobject:17 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:17 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2004.06.037 Small et al. 2004 (CALGB 9583)]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ketoconazole_.26_Hydrocortisone|Ketoconazole & Hydrocortisone]]<br />
| style="background-color:#d73027" |Inferior PSA response<br />
|-<br />
|}<br />
<br />
''Refers to cessation of antiandrogen therapy.''<br />
<br />
===References===<br />
<br />
#'''CALGB 9583:''' Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P, Torti FM, Kaplan E, Vogelzang NJ. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004 Mar 15;22(6):1025-33. [https://doi.org/10.1200/jco.2004.06.037 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15020604 PubMed]<br />
<br />
==Apalutamide monotherapy {{#subobject:acc40a |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cf9ghi|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543693/ Rathkopf et al. 2017 (ARN-509-001)]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Apalutamide (Erleada)]] 240 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''ARN-509-001:''' Rathkopf DE, Antonarakis ES, Shore ND, Tutrone RF, Alumkal JJ, Ryan CJ, Saleh M, Hauke RJ, Bandekar R, Maneval EC, de Boer CJ, Yu MK, Scher HI. Safety and Antitumor Activity of Apalutamide (ARN-509) in Metastatic Castration-Resistant Prostate Cancer with and without Prior Abiraterone Acetate and Prednisone. Clin Cancer Res. 2017 Jul 15;23(14):3544-3551. Epub 2017 Feb 17. [http://clincancerres.aacrjournals.org/content/23/14/3544.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543693/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28213364 PubMed]<br />
<br />
==BAT {{#subobject:aoc10a |Regimen=1}}==<br />
BAT: '''<u>B</u>'''ipolar '''<u>A</u>'''ndrogen '''<u>T</u>'''herapy <br />
===Regimen {{#subobject:#e085c7 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.02759 Denmeade et al. 2021 (TRANSFORMER)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[Prostate_cancer#Enzalutamide_monotherapy|Enzalutamide]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<sup>1</sup><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Progression-free survival<br />
! style="width: 33%" |Comparator progression-free survival<br />
! style="width: 33%" |Pt Population<br />
|-<br />
|5.7 months<br />
|5.7 months<br />
|Castrate-resistant, metastatic, asymptomatic, progressed after abiraterone<br />
|-<br />
|}<br />
''<sup>1</sup>Study not powered for equivalency. Secondary endpoint of PFS2 after crossover was superior in BAT to enzalutamide arm.''<br />
<br />
====Endocrine therapy====<br />
*ADT: All patients maintained on continuous testosterone suppression via surgical castration or [[:Category:GnRH_agonists|GnRH agonist]] or [[:Category:GnRH antagonists|GnRH antagonist]]<br />
*Bipolar Androgen Therapy (BAT): [[Testosterone cypionate]] 400 mg IM once every 28 days<br />
*[[Enzalutamide_(Xtandi)|Enzalutamide]]: 160 mg by mouth daily<br />
<br />
====Subsequent treatment====<br />
*At progression, asymptomatic patients were allowed to cross over to alternative therapy<br />
<br />
===References===<br />
# '''TRANSFORMER:''' Denmeade SR, Wang H, Agarwal N, Smith D, Schweizer MT, Stein MN, Assikis V, Twardowski P, Flaig T, Szmulewitz R, Holzbeierlein J, Hauke R, Sonpavde G, Garcia J, Hussain A, Sartor O, Mao S, Cao H, Fu W, Wang T, Abdallah R, Lim SJ, Bolejack V, Paller C, Carducci M, Markowski MC, Eisenberger MA, Antonarakis ES; TRANSFORMER investigators. TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Prostate Cancer. J Clin Oncol. Epub 2021 Feb 22 [https://doi.org/10.1200/jco.20.02759 link to original article] [https://ascopubs.org/doi/suppl/10.1200/JCO.20.02759 link to protocol] [https://pubmed.ncbi.nlm.nih.gov/33617303/ PubMed] NCT02286921<br />
<br />
==Bicalutamide monotherapy {{#subobject:abb40a |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cf9def|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''', PSA RR]]<br />
!Comparator [[Overall response rate|'''ORR''', PSA RR]]<br />
!Pt Population<br />
|-<br />
|[https://doi.org/10.1200/jco.2015.64.9285 Penson et al. 2016 (STRIVE)]<br />
|2012-2014<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Enzalutamide_monotherapy_2|Enzalutamide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|pts w/ measurable disease: '''14%''' (95% CI n/a), '''31%''' (95% CI n/a)<br />
|pts w/ measurable disease: '''60%''' (95% CI n/a), '''81%''' (95% CI n/a)<br />
|Chemo-naive, abi and keto-naive<br />
|-<br />
|}<br />
''Patients continued ADT while on study; details not provided.''<br />
====Endocrine therapy====<br />
<br />
*[[Bicalutamide (Casodex)]] 50 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<!-- Presented in part at the American Urological Association 2015 Annual Meeting, New Orleans, LA, May 15-19, 2015. --><br />
<br />
#'''STRIVE:''' Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, Dunshee C, Wang F, Wu K, Krivoshik A, Phung D, Higano CS. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J Clin Oncol. 2016 Jun 20;34(18):2098-106. Epub 2016 Jan 25. [https://doi.org/10.1200/jco.2015.64.9285 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26811535 PubMed] NCT01664923<br />
<br />
==Enzalutamide monotherapy {{#subobject:18 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 160 mg/day {{#subobject:18 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Levels_of_Evidence#Efficacy|Efficacy]], PSA RR<br />
!Comparator [[Overall response rate|'''ORR''']], PSA RR<br />
!Pt Population<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1207506 Scher et al. 2012 (AFFIRM)]<br />
|2009-2010<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Prostate_cancer_-_null_regimens#Placebo_3|Placebo]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|29% (95% CI n/a), 54%<br />
|4% (95% CI n/a), 2%<br />
|Chemo-exposed (docetaxel)<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418931/ Beer et al. 2014 (PREVAIL)]<br />
|2010-2012<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Prostate_cancer_-_null_regimens#Placebo_3|Placebo]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|59% (95% CI n/a), 78%<br />
|5% (95% CI n/a), 3%<br />
|Chemo and abiraterone naive<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00518-5/fulltext Shore et al. 2016 (TERRAIN)]<br />
|2011-2013<br />
| style="background-color:#1a9851" |Randomized Phase II (E-RT-switch-ic)<br />
|[[#Bicalutamide_monotherapy_2|Bicalutamide]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|<br />
|<br />
|<br />
|-<br />
|[https://doi.org/10.1200/jco.2015.64.9285 Penson et al. 2016 (STRIVE)]<br />
|2012-2014<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Bicalutamide_monotherapy_2|Bicalutamide]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|60% (95% CI n/a), 81%<br />
|14% (95% CI n/a), 31%<br />
|Chemo and bicalutamide naive<br />
|-<br />
|[https://doi.org/10.1200/JCO.2018.77.9827 Attard et al. 2018 (PLATO)]<br />
|2013-NR<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|Chemo-naive<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.20.02759 Denmeade et al. 2021 (TRANSFORMER)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[Prostate_cancer#BAT|BAT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| Post-abiraterone, asymptomatic<br />
|-<br />
|}<br />
''Patients in STRIVE, PLATO, & TRANSFORMER continued ADT while on study or had a history of bilateral orchiectomy; details not provided.''<br />
====Endocrine therapy====<br />
<br />
*[[Enzalutamide (Xtandi)]] 160 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
====Subsequent treatment====<br />
<br />
*PLATO, with rising PSA: [[#Abiraterone_monotherapy|Abiraterone]] versus [[Stub#Abiraterone_.26_Enzalutamide|Abiraterone & Enzalutamide]]<br />
*TRANSFORMER, asymptomatic PSA or radiographic progression: crossover to alternative arm. Secondary endpoint of PFS2 was statistically longer with BAT to Enzalutamide compared to Enzalutamide to BAT<br />
<br />
===Regimen variant #2, 240 mg/day {{#subobject:7bf35b |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948179/ Scher et al. 2010 (S-3100-1-01)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Note: this is the reported MTD from the phase I portion of the trial; however, it is NOT the dose used in subsequent phase III studies.''<br />
====Endocrine therapy====<br />
<br />
*[[Enzalutamide (Xtandi)]] 240 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
<br />
#'''S-3100-1-01:''' Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, Rathkopf D, Shelkey J, Yu EY, Alumkal J, Hung D, Hirmand M, Seely L, Morris MJ, Danila DC, Humm J, Larson S, Fleisher M, Sawyers CL; Prostate Cancer Foundation/Department of Defense Prostate Cancer Clinical Trials Consortium. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010 Apr 24;375(9724):1437-46. Epub 2010 Apr 14. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60172-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948179/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20398925 PubMed] NCT00510718<br />
#'''AFFIRM:''' Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Fléchon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS; AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012 Sep 27;367(13):1187-97. Epub 2012 Aug 15. [https://www.nejm.org/doi/full/10.1056/NEJMoa1207506 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22894553 PubMed] NCT00974311<br />
<!-- # Beer TM, Armstrong AJ, Sternberg CN, Higano CS, Iversen P, Loriot Y, et al. Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study. ASCO Meeting Abstracts. 2014 February 5, 2014;32(4_suppl):LBA1. [http://abstracts.asco.org/142/AbstView_142_123836.html link to original article] '''contains verified protocol''' --><br />
#'''PREVAIL:''' Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B; PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014 Jul 31;371(5):424-33. Epub 2014 Jun 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1405095 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418931/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24881730 PubMed] NCT01212991<br />
##'''Update:''' Beer TM, Armstrong AJ, Rathkopf D, Loriot Y, Sternberg CN, Higano CS, Iversen P, Evans CP, Kim CS, Kimura G, Miller K, Saad F, Bjartell AS, Borre M, Mulders P, Tammela TL, Parli T, Sari S, van Os S, Theeuwes A, Tombal B. Enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate cancer: Extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017 Feb;71(2):151-154. Epub 2016 Jul 28. [http://www.europeanurology.com/article/S0302-2838(16)30437-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570461/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27477525 PubMed]<br />
##'''HRQoL analysis:''' Devlin N, Herdman M, Pavesi M, Phung D, Naidoo S, Beer TM, Tombal B, Loriot Y, Ivanescu C, Parli T, Balk M, Holmstrom S. Health-related quality of life effects of enzalutamide in patients with metastatic castration-resistant prostate cancer: an in-depth post hoc analysis of EQ-5D data from the PREVAIL trial. Health Qual Life Outcomes. 2017 Jun 23;15(1):130. [https://hqlo.biomedcentral.com/articles/10.1186/s12955-017-0704-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481866/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28645287 PubMed]<br />
#'''TERRAIN:''' Shore ND, Chowdhury S, Villers A, Klotz L, Siemens DR, Phung, van Os S, Hasabou N, Wang F, Bhattacharya S, Heidenreich A. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol. 2016 Feb;17(2):153-163. Epub 2016 Jan 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00518-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26774508 PubMed] NCT01288911<br />
<!-- Presented in part at the American Urological Association 2015 Annual Meeting, New Orleans, LA, May 15-19, 2015. --><br />
#'''STRIVE:''' Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, Dunshee C, Wang F, Wu K, Krivoshik A, Phung D, Higano CS. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J Clin Oncol. 2016 Jun 20;34(18):2098-106. Epub 2016 Jan 25. [https://doi.org/10.1200/jco.2015.64.9285 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26811535 PubMed] NCT01664923<br />
#'''PLATO:''' Attard G, Borre M, Gurney H, Loriot Y, Andresen-Daniil C, Kalleda R, Pham T, Taplin ME; PLATO collaborators. Abiraterone alone or in combination with enzalutamide in metastatic castration-resistant prostate cancer with rising prostate-specific antigen during enzalutamide treatment. J Clin Oncol. 2018 Sep 1;36(25):2639-2646. Epub 2018 Jul 20. [https://doi.org/10.1200/JCO.2018.77.9827 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30028657 PubMed] NCT01995513<br />
#'''PROfound:''' de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 May 28;382(22):2091-2102. Epub 2020 Apr 28. [http://doi.org/10.1056/NEJMoa1911440 link to original article] '''contains verified protocol''' [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1911440/suppl_file/nejmoa1911440_appendix.pdf link to supplementary appendix] [https://pubmed.ncbi.nlm.nih.gov/32343890/ PubMed] NCT02987543<br />
# '''TRANSFORMER:''' Denmeade SR, Wang H, Agarwal N, Smith D, Schweizer MT, Stein MN, Assikis V, Twardowski P, Flaig T, Szmulewitz R, Holzbeierlein J, Hauke R, Sonpavde G, Garcia J, Hussain A, Sartor O, Mao S, Cao H, Fu W, Wang T, Abdallah R, Lim SJ, Bolejack V, Paller C, Carducci M, Markowski MC, Eisenberger MA, Antonarakis ES; TRANSFORMER investigators. TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Prostate Cancer. J Clin Oncol. Epub 2021 Feb 22 [https://doi.org/10.1200/jco.20.02759 link to original article] [https://ascopubs.org/doi/suppl/10.1200/JCO.20.02759 link to protocol] [https://pubmed.ncbi.nlm.nih.gov/33617303/ PubMed] NCT02286921<br />
#'''CASPAR:''' NCT04455750<br />
#'''KEYLYNK-010:''' NCT03834519<br />
<br />
==Hydrocortisone monotherapy {{#subobject:f48fb4 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:da4be9 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1999.17.8.2506 Kantoff et al. 1999 (CALGB 9182)]<br />
|1992-1995<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Mitoxantrone_.26_Hydrocortisone|Mitoxantrone & Hydrocortisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.7.1440 Small et al. 2000]<br />
|1994-1996<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Suramin & Hydrocortisone<br />
| style="background-color:#d73027" |Inferior TTP<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdh429 Abratt et al. 2004]<br />
|1997-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Vinorelbine_.26_Hydrocortisone|Vinorelbine & Hydrocortisone]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Hydrocortisone (Cortef)]] 40 mg/day PO<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''CALGB 9182:''' Kantoff PW, Halabi S, Conaway M, Picus J, Kirshner J, Hars V, Trump D, Winer EP, Vogelzang NJ. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol. 1999 Aug;17(8):2506-13. [https://doi.org/10.1200/JCO.1999.17.8.2506 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10561316 PubMed]<br />
#Small EJ, Meyer M, Marshall ME, Reyno LM, Meyers FJ, Natale RB, Lenehan PF, Chen L, Slichenmyer WJ, Eisenberger M. Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: results of a randomized phase III trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone. J Clin Oncol. 2000 Apr;18(7):1440-50. [https://doi.org/10.1200/JCO.2000.18.7.1440 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10735891 PubMed]<br />
#Abratt RP, Brune D, Dimopoulos MA, Kliment J, Breza J, Selvaggi FP, Beuzeboc P, Demkow T, Oudard S. Randomised phase III study of intravenous vinorelbine plus hormone therapy versus hormone therapy alone in hormone-refractory prostate cancer. Ann Oncol. 2004 Nov;15(11):1613-21. [https://doi.org/10.1093/annonc/mdh429 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15520061 PubMed]<br />
<br />
==Ketoconazole & Hydrocortisone {{#subobject:19 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:19 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''', PSA RR]]<br />
!Comparator [[Overall response rate|'''ORR''', PSA RR]]<br />
!Pt Population<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(84)92909-X/fulltext Trachtenberg & Pont 1984]<br />
|NR<br />
| style="background-color:#ffffbe" |Pilot<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|<br />
|<br />
|<br />
|-<br />
|[https://doi.org/10.1200/jco.2004.06.037 Small et al. 2004 (CALGB 9583)]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Antiandrogen_withdrawal|Antiandrogen withdrawal]]<br />
| style="background-color:#1a9850" |Superior PSA response<br />
|pts w/ measurable disease: '''20%''' (95% CI 11 - 32), '''27%''' (95% CI 20 - 35)<br />
|pts w/ measurable disease: '''2%''' (95% CI 0 - 11), '''11%''' (95% CI 7 - 17)<br />
|Progression at ADT, i.e. CRPC<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Ketoconazole (Nizoral)]] 400 mg PO three times per day<br />
*[[Hydrocortisone (Cortef)]] 30 mg PO QAM and 10 mg PO QPM<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#Trachtenberg J, Pont A. Ketoconazole therapy for advanced prostate cancer. Lancet. 1984 Aug 25;2(8400):433-5. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(84)92909-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6147504 PubMed]<br />
#'''CALGB 9583:''' Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P, Torti FM, Kaplan E, Vogelzang NJ. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004 Mar 15;22(6):1025-33. [https://doi.org/10.1200/jco.2004.06.037 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15020604 PubMed]<br />
<br />
==Ketoconazole, Hydrocortisone, Dutasteride {{#subobject:20 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:20 |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644858/ Taplin et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Ketoconazole (Nizoral)]] 400 mg PO three times per day<br />
*[[Hydrocortisone (Cortef)]] 30 mg PO QAM and 10 mg PO QPM<br />
*[[Dutasteride (Avodart)]] 0.5 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#Taplin ME, Regan MM, Ko YJ, Bubley GJ, Duggan SE, Werner L, Beer TM, Ryan CW, Mathew P, Tu SM, Denmeade SR, Oh WK, Sartor O, Mantzoros CS, Rittmaster R, Kantoff PW, Balk SP. Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer. Clin Cancer Res. 2009 Nov 15;15(22):7099-105. Epub 2009 Nov 3. [http://clincancerres.aacrjournals.org/content/15/22/7099.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644858/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19887483 PubMed]<br />
<br />
==Prednisone monotherapy {{#subobject:22 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 5 mg twice per day {{#subobject:22 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.1989.7.5.590 Tannock et al. 1989]<br />
|1976-1980<br />
| style="background-color:#ffffbe" |Retrospective<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/JCO.1996.14.6.1756 Tannock et al. 1996 (CCI-NOV22)]<br />
|1990-1994<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Mitoxantrone_.26_Prednisone|Mitoxantrone & Prednisone]]<br />
| style="background-color:#d73027" |Inferior palliation<br />
|-<br />
|[https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2964163-8 Berry et al. 2002]<br />
|1997-1999<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Mitoxantrone_.26_Prednisone|Mitoxantrone & Prednisone]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTTF<br />
|-<br />
|[https://doi.org/10.1200/JCO.2008.20.1228 Sternberg et al. 2009 (SPARC)]<br />
|2003-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Satraplatin & Prednisone<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471149/ de Bono et al. 2011 (COU-AA-301)]<br />
|2008-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Abiraterone_monotherapy|Abiraterone]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2012.48.5268 Michaelson et al. 2013 (SUN 1120)]<br />
|2008-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Sunitinib & Prednisone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683570/ Ryan et al. 2013 (COU-AA-302)]<br />
|2009-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Abiraterone_monotherapy|Abiraterone]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70027-6/fulltext Saad et al. 2015 (ELM-PC 4)]<br />
|2010-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Orteronel & Prednisone<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879718/ Fizazi et al. 2015 (ELM-PC 5)]<br />
|2010-NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Orteronel & Prednisone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2015.65.5597 Smith et al. 2016 (COMET-1)]<br />
|2012-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cabozantinib_monotherapy|Cabozantinib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 5 mg PO twice per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen variant #2, 5 mg QID {{#subobject:5055a7 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2001.19.1.62 Fosså et al. 2001 (EORTC 30903)]<br />
|1992-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Flutamide_monotherapy|Flutamide]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of TTP/OS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 5 mg PO four times per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart L, Rider W. Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol. 1989 May;7(5):590-7. [https://doi.org/10.1200/jco.1989.7.5.590 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2709088 PubMed]<br />
#'''CCI-NOV22:''' Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, Armitage GR, Wilson JJ, Venner PM, Coppin CM, Murphy KC. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996 Jun;14(6):1756-64. [https://doi.org/10.1200/JCO.1996.14.6.1756 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8656243 PubMed]<br />
##'''HRQoL analysis:''' Osoba D, Tannock IF, Ernst DS, Neville AJ. Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol. 1999 Jun;17(6):1654-63. [https://doi.org/10.1200/JCO.1999.17.6.1654 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10561201 PubMed]<br />
#'''EORTC 30903:''' Fosså SD, Slee PH, Brausi M, Horenblas S, Hall RR, Hetherington JW, Aaronson N, de Prijck L, Collette L. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol. 2001 Jan 1;19(1):62-71. [https://doi.org/10.1200/JCO.2001.19.1.62 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11134196 PubMed]<br />
#Berry W, Dakhil S, Modiano M, Gregurich M, Asmar L. Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol. 2002 Dec;168(6):2439-43. [https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2964163-8 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12441935 PubMed]<br />
#'''SPARC:''' Sternberg CN, Petrylak DP, Sartor O, Witjes JA, Demkow T, Ferrero JM, Eymard JC, Falcon S, Calabrò F, James N, Bodrogi I, Harper P, Wirth M, Berry W, Petrone ME, McKearn TJ, Noursalehi M, George M, Rozencweig M. Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial. J Clin Oncol. 2009 Nov 10;27(32):5431-8. Epub 2009 Oct 5. [https://doi.org/10.1200/JCO.2008.20.1228 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19805692 PubMed] NCT00069745<br />
#'''COU-AA-301:''' de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005. [https://www.nejm.org/doi/full/10.1056/NEJMoa1014618 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471149/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21612468 PubMed] NCT00638690<br />
##'''Update:''' Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, Staffurth JN, North S, Vogelzang NJ, Saad F, Mainwaring P, Harland S, Goodman OB Jr, Sternberg CN, Li JH, Kheoh T, Haqq CM, de Bono JS; COU-AA-301 Investigators. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012 Oct;13(10):983-92. Epub 2012 Sep 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70379-0/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22995653 PubMed]<br />
##'''Update:''' Logothetis CJ, Basch E, Molina A, Fizazi K, North SA, Chi KN, Jones RJ, Goodman OB, Mainwaring PN, Sternberg CN, Efstathiou E, Gagnon DD, Rothman M, Hao Y, Liu CS, Kheoh TS, Haqq CM, Scher HI, de Bono JS. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol. 2012 Dec;13(12):1210-7. Epub 2012 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70473-4/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23142059 PubMed]<br />
#'''COU-AA-302:''' Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE; COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48. Epub 2012 Dec 10. [https://www.nejm.org/doi/full/10.1056/NEJMoa1209096 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683570/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23228172 PubMed] NCT00887198<br />
##'''Update:''' Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, Carles J, Flaig TW, Taplin ME, Higano CS, de Souza P, de Bono JS, Griffin TW, De Porre P, Yu MK, Park YC, Li J, Kheoh T, Naini V, Molina A, Rathkopf DE; COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015 Feb;16(2):152-60. Epub 2015 Jan 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71205-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25601341 PubMed]<br />
#'''SUN 1120:''' Michaelson MD, Oudard S, Ou YC, Sengeløv L, Saad F, Houede N, Ostler P, Stenzl A, Daugaard G, Jones R, Laestadius F, Ullèn A, Bahl A, Castellano D, Gschwend J, Maurina T, Chow Maneval E, Wang SL, Lechuga MJ, Paolini J, Chen I. Randomized, placebo-controlled, phase III trial of sunitinib plus prednisone versus prednisone alone in progressive, metastatic, castration-resistant prostate cancer. J Clin Oncol. 2014 Jan 10;32(2):76-82. Epub 2013 Dec 9. [https://doi.org/10.1200/JCO.2012.48.5268 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24323035 PubMed] NCT00676650<br />
#'''ELM-PC 5:''' Fizazi K, Jones R, Oudard S, Efstathiou E, Saad F, de Wit R, De Bono J, Cruz FM, Fountzilas G, Ulys A, Carcano F, Agarwal N, Agus D, Bellmunt J, Petrylak DP, Lee SY, Webb IJ, Tejura B, Borgstein N, Dreicer R. Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. J Clin Oncol. 2015 Mar 1;33(7):723-31. Epub 2015 Jan 26. [https://doi.org/10.1200/JCO.2014.56.5119 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879718/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25624429 PubMed] NCT01193257<br />
#'''ELM-PC 4:''' Saad F, Fizazi K, Jinga V, Efstathiou E, Fong PC, Hart LL, Jones R, McDermott R, Wirth M, Suzuki K, MacLean DB, Wang L, Akaza H, Nelson J, Scher HI, Dreicer R, Webb IJ, de Wit R; ELM-PC 4 investigators. Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. Lancet Oncol. 2015 Mar;16(3):338-48. Epub 2015 Feb 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70027-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25701170 PubMed] NCT01193244<br />
#'''COMET-1:''' Smith M, De Bono J, Sternberg C, Le Moulec S, Oudard S, De Giorgi U, Krainer M, Bergman A, Hoelzer W, De Wit R, Bögemann M, Saad F, Cruciani G, Thiery-Vuillemin A, Feyerabend S, Miller K, Houédé N, Hussain S, Lam E, Polikoff J, Stenzl A, Mainwaring P, Ramies D, Hessel C, Weitzman A, Fizazi K. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016 Sep 1;34(25):3005-13. Epub 2016 Jul 11. [https://doi.org/10.1200/JCO.2015.65.5597 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27400947 PubMed] NCT01605227<br />
<br />
=Chemotherapy for metastatic castrate-sensitive disease=<br />
==Cabazitaxel & Prednisone {{#subobject:23jbuz |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Cabazitaxel (Jevtana) in prostate cancer]]<br />
<br />
===Regimen {{#subobject:2hcb1b |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1911206 de Wit et al. 2019 (CARD)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|1. [[#Abiraterone_monotherapy|Abiraterone]]<br> 2. [[#Enzalutamide_monotherapy|Enzalutamide]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: patients in CARD had already received and progressed on the alternate androgen signaling targeted inhibitor.''<br />
====Chemotherapy====<br />
<br />
*[[Cabazitaxel (Jevtana)]] 25 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 10 mg PO once per day<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Antihistamines|Antihistamine]] once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
*[[:Category:Steroids|Corticosteroid]] ([[Dexamethasone (Decadron)|dexamethasone]] 8 mg or equivalent) once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
*[[:Category:Antihistamines|Histamine H2-antagonist]] (except cimetidine) once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''CARD:''' de Wit R, de Bono J, Sternberg CN, Fizazi K, Tombal B, Wülfing C, Kramer G, Eymard JC, Bamias A, Carles J, Iacovelli R, Melichar B, Sverrisdóttir Á, Theodore C, Feyerabend S, Helissey C, Ozatilgan A, Geffriaud-Ricouard C, Castellano D; CARD Investigators. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med. 2019 Dec 26;381(26):2506-2518. Epub 2019 Sep 30. [https://www.nejm.org/doi/full/10.1056/NEJMoa1911206 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31566937 PubMed]<br />
<br />
=Chemotherapy for metastatic castrate-resistant disease=<br />
==Cabazitaxel & Prednisolone {{#subobject:23aug19 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Cabazitaxel (Jevtana) in prostate cancer]]<br />
<br />
===Regimen {{#subobject:fa5jfa |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/s0140-6736(21)00237-3 Hofman et al. 2021 (TheraP)]<br />
|2018-2019<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[<sup>177</sup>Lu]Lu-PSMA-617<br />
| style="background-color:#d73027" |Inferior PSA response<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cabazitaxel (Jevtana)]] 20 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisolone (Millipred)]] 10 mg PO once per day<br />
<br />
'''21-day cycle for up to 10 cycles'''<br />
<br />
===References===<br />
# '''TheraP:''' Hofman MS, Emmett L, Sandhu S, Iravani A, Joshua AM, Goh JC, Pattison DA, Tan TH, Kirkwood ID, Ng S, Francis RJ, Gedye C, Rutherford NK, Weickhardt A, Scott AM, Lee ST, Kwan EM, Azad AA, Ramdave S, Redfern AD, Macdonald W, Guminski A, Hsiao E, Chua W, Lin P, Zhang AY, McJannett MM, Stockler MR, Violet JA, Williams SG, Martin AJ, Davis ID; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021 Feb 11:S0140-6736(21)00237-3. Epub ahead of print. [https://doi.org/10.1016/s0140-6736(21)00237-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33581798/ PubMed] NCT03392428<br />
<br />
==Cabazitaxel & Prednisone {{#subobject:23 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Cabazitaxel (Jevtana) in prostate cancer]]<br />
<br />
===Regimen variant #1, 20/10, indefinite {{#subobject:fa59fa |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2016.72.1068 Oudard et al. 2017 (FIRSTANA)]<br />
| rowspan="2" |2011-2013<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cabazitaxel_.26_Prednisone_2|Cabazitaxel & Prednisone]]; 25/10<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[[#Docetaxel_.26_Prednisone|Docetaxel & Prednisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2016.72.1076 Eisenberger et al. 2017 (PROSELICA)]<br />
|2011-2013<br />
| style="background-color:#1a9851" |Phase III (E-RT-de-esc)<br />
|[[#Cabazitaxel_.26_Prednisone_2|Cabazitaxel & Prednisone]]; 25/10<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cabazitaxel (Jevtana)]] 20 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 10 mg PO once per day<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 25/10 x 10 {{#subobject:23 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''', PSA RR]]<br />
!Comparator [[Overall response rate|'''ORR''', PSA RR]]<br />
!Pt Population<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961389-X/fulltext de Bono et al. 2010 (TROPIC)]<br />
|2007-2008<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Mitoxantrone_.26_Prednisone|Mitoxantrone & Prednisone]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|14% (95% CI 10-19)<br> 39% (95% CI 34-44)<sup>1</sup><br />
|4% (95% CI 2-7)<br> 18% (95% CI 14-22)<sup>1</sup><br />
|Progressed on docetaxel<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30605-8/fulltext Beer et al. 2017 (AFFINITY)]<br />
|2012-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cabazitaxel, Prednisone, Custirsen<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|<br />
|Progressed on docetaxel<br />
|-<br />
|}<br />
''<sup>1</sup>ORRs in TROPIC were only reported for patients with measurable disease.''<br />
====Chemotherapy====<br />
<br />
*[[Cabazitaxel (Jevtana)]] 25 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 10 mg PO once per day<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Antihistamines|Antihistamine]] once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
*[[:Category:Steroids|Corticosteroid]] ([[Dexamethasone (Decadron)|dexamethasone]] 8 mg or equivalent) once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
*[[:Category:Antihistamines|Histamine H2-antagonist]] (except cimetidine) once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
<br />
'''21-day cycle for up to 10 cycles'''<br />
<br />
===Regimen variant #3, 25/10, indefinite {{#subobject:23sa2b |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2016.72.1068 Oudard et al. 2017 (FIRSTANA)]<br />
| rowspan="2" |2011-2013<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cabazitaxel_.26_Prednisone_2|Cabazitaxel & Prednisone]]; 20/10<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[[#Docetaxel_.26_Prednisone|Docetaxel & Prednisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2016.72.1076 Eisenberger et al. 2017 (PROSELICA)]<br />
|2011-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cabazitaxel_.26_Prednisone_2|Cabazitaxel & Prednisone]]; 20/10<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cabazitaxel (Jevtana)]] 25 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 10 mg PO once per day<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Antihistamines|Antihistamine]] once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
*[[:Category:Steroids|Corticosteroid]] ([[Dexamethasone (Decadron)|dexamethasone]] 8 mg or equivalent) once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
*[[:Category:Antihistamines|Histamine H2-antagonist]] (except cimetidine) once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''TROPIC:''' de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010 Oct 2;376(9747):1147-54. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961389-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20888992 PubMed] NCT00417079<br />
#'''FIRSTANA:''' Oudard S, Fizazi K, Sengeløv L, Daugaard G, Saad F, Hansen S, Hjälm-Eriksson M, Jassem J, Thiery-Vuillemin A, Caffo O, Castellano D, Mainwaring PN, Bernard J, Shen L, Chadjaa M, Sartor O. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: A randomized phase III Trial-FIRSTANA. J Clin Oncol. 2017 Oct 1;35(28):3189-3197. Epub 2017 Jul 28. [https://doi.org/10.1200/JCO.2016.72.1068 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28753384 PubMed] NCT01308567<br />
#'''PROSELICA:''' Eisenberger M, Hardy-Bessard AC, Kim CS, Géczi L, Ford D, Mourey L, Carles J, Parente P, Font A, Kacso G, Chadjaa M, Zhang W, Bernard J, de Bono J. Phase III study comparing a reduced dose of cabazitaxel (20 mg/m(2)) and the currently approved dose (25 mg/m(2)) in postdocetaxel patients with metastatic castration-resistant prostate cancer-PROSELICA. J Clin Oncol. 2017 Oct 1;35(28):3198-3206. Epub 2017 Aug 15 [https://doi.org/10.1200/JCO.2016.72.1076 link to original article] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/28809610 PubMed]<br />
#'''AFFINITY:''' Beer TM, Hotte SJ, Saad F, Alekseev B, Matveev V, Fléchon A, Gravis G, Joly F, Chi KN, Malik Z, Blumenstein B, Stewart PS, Jacobs CA, Fizazi K. Custirsen (OGX-011) combined with cabazitaxel and prednisone versus cabazitaxel and prednisone alone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel (AFFINITY): a randomised, open-label, international, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1532-1542. Epub 2017 Oct 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30605-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29033099 PubMed] NCT01578655<br />
<br />
==Cabozantinib monotherapy {{#subobject:a20f66 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 60 mg/day {{#subobject:0eb568 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2015.65.5597 Smith et al. 2016 (COMET-1)]<br />
|2012-2014<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
<br />
*[[Cabozantinib (Cometriq)]] 60 mg PO once per day<br />
<br />
===Regimen variant #2, 100 mg/day {{#subobject:2efaa6 |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110249/ Smith et al. 2012 (XL184-203)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
<br />
*[[Cabozantinib (Cometriq)]] 100 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
<br />
#'''XL184-203:''' Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, Vogelzang NJ, Small EJ, Harzstark AL, Gordon MS, Vaishampayan UN, Haas NB, Spira AI, Lara PN Jr, Lin CC, Srinivas S, Sella A, Schöffski P, Scheffold C, Weitzman AL, Hussain M. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013 Feb 1;31(4):412-9. Epub 2012 Nov 19. [https://doi.org/10.1200/jco.2012.45.0494 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110249/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23169517 PubMed] NCT00940225<br />
#'''COMET-1:''' Smith M, De Bono J, Sternberg C, Le Moulec S, Oudard S, De Giorgi U, Krainer M, Bergman A, Hoelzer W, De Wit R, Bögemann M, Saad F, Cruciani G, Thiery-Vuillemin A, Feyerabend S, Miller K, Houédé N, Hussain S, Lam E, Polikoff J, Stenzl A, Mainwaring P, Ramies D, Hessel C, Weitzman A, Fizazi K. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016 Sep 1;34(25):3005-13. Epub 2016 Jul 11. [https://doi.org/10.1200/JCO.2015.65.5597 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27400947 PubMed] NCT01605227<br />
<br />
==Carboplatin & Docetaxel {{#subobject:28 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Example orders===<br />
<br />
*[[Example orders for Docetaxel & Carboplatin in prostate cancer]]<br />
<br />
===Regimen {{#subobject:31 |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.23195/full Ross et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients enrolled in the trial had hormone-refractory prostate cancer and progression of disease during docetaxel treatment or within 45 days of stopping docetaxel treatment.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 4 (Calvert formula) IV over 60 minutes once on day 1, '''given second'''<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*"Standard dexamethasone premedication was used"<br />
*Patients continued to receive androgen deprivation therapy<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Ross RW, Beer TM, Jacobus S, Bubley GJ, Taplin ME, Ryan CW, Huang J, Oh WK; Prostate Cancer Clinical Trials Consortium. A phase 2 study of carboplatin plus docetaxel in men with metastatic hormone-refractory prostate cancer who are refractory to docetaxel. Cancer. 2008 Feb 1;112(3):521-6. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.23195/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18085595 PubMed]<br />
#'''Retrospective:''' Nakabayashi M, Sartor O, Jacobus S, Regan MM, McKearn D, Ross RW, Kantoff PW, Taplin ME, Oh WK. Response to docetaxel/carboplatin-based chemotherapy as first- and second-line therapy in patients with metastatic hormone-refractory prostate cancer. BJU Int. 2008 Feb;101(3):308-12. [https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2007.07331.x/full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18184327 PubMed]<br />
<br />
==Carboplatin, Docetaxel, Prednisone {{#subobject:28a1b4 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:32 |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00345-010-0527-5 Reuter et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients enrolled in the trial had progression of disease on docetaxel chemotherapy and castration-resistant disease.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 30 minutes once on day 1<br />
*[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15<br />
**Note: In contrast to its abstract, Reuter et al. 2010 sometimes used "days 1, 8, (15)" to describe when docetaxel was given. The paper did not specifically say what "(15)" meant, such as whether this meant that the day 15 dose was optional.<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 5 mg PO twice per day<br />
<br />
====Supportive medications====<br />
<br />
*"Standard dexamethasone premedication was used"<br />
*Patients continued to receive LHRH (luteinizing hormone releasing hormone) agonists<br />
*No routine use of granulocyte colony-stimulating factor (G-CSF)<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Reuter CW, Morgan MA, Ivanyi P, Fenner M, Ganser A, Grünwald V. Carboplatin plus weekly docetaxel as salvage chemotherapy in docetaxel-resistant and castration-resistant prostate cancer. World J Urol. 2010 Jun;28(3):391-8. Epub 2010 Mar 14. [http://link.springer.com/article/10.1007%2Fs00345-010-0527-5 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20229232 PubMed]<br />
<br />
==Carboplatin & Paclitaxel (CP) {{#subobject:30 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1 {{#subobject:34 |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1896-9 Kentepozidis et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 3 (Calvert formula) IV once per day on days 1 & 15, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 135 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*"All patients received a concomitant anti-emetic prophylaxis"<br />
*[[Dexamethasone (Decadron)]] 20 mg PO given twice, 12 and 6 hours prior to [[Paclitaxel (Taxol)]]<br />
*[[Diphenhydramine (Benadryl)]] 50 mg IV once per day on days 1 & 15, "prior to each dose" (there was nothing else after this in Kentepozidis et al. 2012, and it is assumed to mean prior to each dose of [[Paclitaxel (Taxol)]])<br />
*[[Cimetidine (Tagamet)]] 300 mg IV once per day on days 1 & 15, "prior to each dose" (there was nothing else after this in Kentepozidis et al. 2012, and it is assumed to mean prior to each dose of [[Paclitaxel (Taxol)]])<br />
*No prophylactic G-CSF<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:35 |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.urologiconcology.org/article/S1078-1439%2810%2900003-7/abstract Jeske et al. 2010]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 4 to 6 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 60 to 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Retrospective:''' Jeske S, Tagawa ST, Olowokure O, Selzer J, Giannakakou P, Nanus DM. Carboplatin plus paclitaxel therapy after docetaxel in men with metastatic castrate resistant prostate cancer. Urol Oncol. 2011 Nov-Dec;29(6):676-81. Epub 2010 May 7. [http://www.urologiconcology.org/article/S1078-1439%2810%2900003-7/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20451413 PubMed]<br />
#Kentepozidis N, Soultati A, Giassas S, Vardakis N, Kalykaki A, Kotsakis A, Papadimitraki E, Pantazopoulos N, Bozionellou V, Georgoulias V; Hellenic Oncology Research Group. Paclitaxel in combination with carboplatin as salvage treatment in patients with castration-resistant prostate cancer: a Hellenic Oncology Research Group multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jul;70(1):161-8. Epub 2012 Jun 3. [http://link.springer.com/article/10.1007%2Fs00280-012-1896-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22660737 PubMed]<br />
<br />
==Cyclophosphamide, Prednisone, Diethylstilbestrol {{#subobject:26 |Regimen=1}}==<br />
CPD: '''<u>C</u>'''yclophosphamide, '''<u>P</u>'''rednisone, '''<u>D</u>'''iethylstilbestrol<br />
<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:26 |Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.11686/abstract Hellerstedt et al. 2003]<br />
| style="background-color:#91cf61" |Phase II<br />
|50% or greater decline in PSA: 42%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 20<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 10 mg PO once per day<br />
*[[Diethylstilbestrol (DES)]] 1 mg PO once per day<br />
<br />
====Supportive medications====<br />
<br />
*[[Warfarin (Coumadin)]] 1 mg PO once per day to decrease risk of DVT<br />
<br />
'''30-day cycles'''<br />
<br />
===References===<br />
<br />
#Hellerstedt B, Pienta KJ, Redman BG, Esper P, Dunn R, Fardig J, Olson K, Smith DC. Phase II trial of oral cyclophosphamide, prednisone, and diethylstilbestrol for androgen-independent prostate carcinoma. Cancer. 2003 Oct 15;98(8):1603-10. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.11686/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14534875 PubMed]<br />
<br />
==Docetaxel & Estramustine {{#subobject:27a1bc |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:51bc1c |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa041318 Petrylak et al. 2004 (SWOG S9916)]<br />
|1999-2003<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Mitoxantrone_.26_Prednisone|Mitoxantrone & Prednisone]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]]<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Estramustine (Emcyt)]]<br />
<br />
===References===<br />
<br />
#'''SWOG S9916:''' Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1513-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa041318 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15470214 PubMed]<br />
<br />
==Docetaxel & Prednisone {{#subobject:27 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Docetaxel (Taxotere) in prostate cancer]]<br />
<br />
===Regimen variant #1, 30 mg/m<sup>2</sup> weekly {{#subobject:29 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa040720 Tannock et al. 2004 (TAX 327)]<br />
| rowspan="2" |2000-2002<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Docetaxel_.26_Prednisone|Docetaxel & Prednisone]]; q3wk<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Mitoxantrone_.26_Prednisone|Mitoxantrone & Prednisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 5 mg PO twice per day<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 8 mg (route not specified) once 1 hour before [[Docetaxel (Taxotere)]]<br />
*Antiemetics "according to local practice"<br />
<br />
'''42-day cycle for up to 5 cycles'''<br />
<br />
===Regimen variant #2, 75 mg/m<sup>2</sup> q3wk x 10 {{#subobject:27 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''', PSA RR]]<br />
!Comparator [[Overall response rate|'''ORR''', PSA RR]]<br />
!Pt Population<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa040720 Tannock et al. 2004 (TAX 327)]<br />
| rowspan="2" |2000-2002<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Docetaxel_.26_Prednisone|Docetaxel & Prednisone]]; weekly<br />
| style="background-color:#d3d3d3" |Not reported<br />
| rowspan="2" |pts w/ measurable disease:'''12%''' (95% CI, 7-19), '''45%''' (95% CI, 40-51)<br />
|pts w/ measurable disease:'''8%''' (95% CI, 4-14), '''48%''' (95% CI, 42-54)<br />
|Chemo-naive<br />
|-<br />
|2. [[#Mitoxantrone_.26_Prednisone|Mitoxantrone & Prednisone]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|pts w/ measurable disease:'''7%''' (95% CI, 3-12), '''32%''' (95% CI, 26-37)<br />
|Chemo-naive<br />
|-<br />
|[https://doi.org/10.1200/JCO.2006.06.8197 Beer et al. 2011 (ASCENT)]<br />
|2002-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Calcitriol, Docetaxel, Prednisone<br />
| style="background-color:#1a9850" |Superior OS<sup>1</sup><br />
|<br />
|<br />
|<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(12)00428-5/fulltext Meulenbeld et al. 2012 (NePro)]<br />
|2004-2010<br />
| style="background-color:#1a9851" |Phase II/III (C)<br />
|Docetaxel, Prednisone, Risedronate<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP<br />
|<br />
|<br />
|<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for ASCENT is based on the 2011 update.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 5 mg PO twice per day<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 8 mg PO given three times; 12 hours, 3 hours, and 1 hour before [[Docetaxel (Taxotere)]]<br />
*[[:Category:Emesis_prevention|Antiemetics]] "according to local practice"<br />
<br />
'''21-day cycle for up to 10 cycles'''<br />
<br />
===Regimen variant #3, 75 mg/m<sup>2</sup> q3wk x 12 {{#subobject:27a1bc |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277263/ Quinn et al. 2013 (SWOG S0421)]<br />
|2006-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Atrasentan, Docetaxel, Prednisone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 5 mg PO twice per day<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 8 mg PO given three times; 12 hours, 3 hours, and 1 hour before [[Docetaxel (Taxotere)]]<br />
*[[:Category:Emesis_prevention|Antiemetics]] "according to local practice"<br />
<br />
'''21-day cycle for up to 12 cycles'''<br />
<br />
===Regimen variant #4, 75 mg/m<sup>2</sup> q3wk, indefinite {{#subobject:ea941e |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383121/ Kelly et al. 2012 (CALGB 90401)]<br />
|2005-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel, Prednisone, Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70184-0/abstract Tannock et al. 2013 (VENICE)]<br />
|2007-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Aflibercept, Docetaxel, Prednisone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478530/ Araujo et al. 2013 (READY)]<br />
|2008-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Dasatinib, Docetaxel, Prednisone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2012.46.4149 Fizazi et al. 2013 (ENTHUSE)]<br />
|2008-NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel, Prednisone, Zibotentan<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70025-2/abstract Petrylak et al. 2015 (MAINSAIL)]<br />
|2009-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel, Lenalidomide, Prednisone<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30168-7/fulltext Chi et al. 2017 (SYNERGY)]<br />
|2010-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Custirsen, Docetaxel, Prednisone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2016.72.1068 Oudard et al. 2017 (FIRSTANA)]<br />
| rowspan="2" |2011-2013<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cabazitaxel_.26_Prednisone_2|Cabazitaxel 20 mg/m<sup>2</sup> & Prednisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[[#Cabazitaxel_.26_Prednisone_2|Cabazitaxel 25 mg/m<sup>2</sup> & Prednisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: patients in CALGB 90401 discontinued treatment after a maximum of 2 years.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] as follows:<br />
**CALGB 90401: 5 mg PO once per day<br />
**Others: 10 mg/day; some regimens give as 5 mg PO twice per day, some as 10 mg PO once per day<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''TAX 327:''' Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1502-12. [https://www.nejm.org/doi/full/10.1056/NEJMoa040720 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15470213 PubMed]<br />
##'''Update:''' Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008 Jan 10;26(2):242-5. [https://doi.org/10.1200/jco.2007.12.4008 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18182665 PubMed]<br />
#'''ASCENT:''' Beer TM, Ryan CW, Venner PM, Petrylak DP, Chatta GS, Ruether JD, Redfern CH, Fehrenbacher L, Saleh MN, Waterhouse DM, Carducci MA, Vicario D, Dreicer R, Higano CS, Ahmann FR, Chi KN, Henner WD, Arroyo A, Clow FW; ASCENT Investigators. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol. 2007 Feb 20;25(6):669-74. [https://doi.org/10.1200/JCO.2006.06.8197 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17308271 PubMed] NCT00273338<br />
##'''Update:''' Scher HI, Jia X, Chi K, de Wit R, Berry WR, Albers P, Henick B, Waterhouse D, Ruether DJ, Rosen PJ, Meluch AA, Nordquist LT, Venner PM, Heidenreich A, Chu L, Heller G. Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer. J Clin Oncol. 2011 Jun 1;29(16):2191-8. Epub 2011 Apr 11. [https://doi.org/10.1200/JCO.2010.32.8815 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21483004 PubMed]<br />
<!-- Presented in part at the 48th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. --><br />
#'''CALGB 90401:''' Kelly WK, Halabi S, Carducci M, George D, Mahoney JF, Stadler WM, Morris M, Kantoff P, Monk JP, Kaplan E, Vogelzang NJ, Small EJ. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol. 2012 May 1;30(13):1534-40. Epub 2012 Mar 26. [https://doi.org/10.1200/JCO.2011.39.4767 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383121/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22454414 PubMed] NCT00110214<br />
#'''NePro:''' Meulenbeld HJ, van Werkhoven ED, Coenen JL, Creemers GJ, Loosveld OJ, de Jong PC, Ten Tije AJ, Fosså SD, Polee M, Gerritsen W, Dalesio O, de Wit R. Randomised phase II/III study of docetaxel with or without risedronate in patients with metastatic Castration Resistant Prostate Cancer (CRPC), the Netherlands Prostate Study (NePro). Eur J Cancer. 2012 Nov;48(16):2993-3000. Epub 2012 Jun 6. [https://www.ejcancer.com/article/S0959-8049(12)00428-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22677260 PubMed]<br />
#'''VENICE:''' Tannock IF, Fizazi K, Ivanov S, Karlsson CT, Fléchon A, Skoneczna I, Orlandi F, Gravis G, Matveev V, Bavbek S, Gil T, Viana L, Arén O, Karyakin O, Elliott T, Birtle A, Magherini E, Hatteville L, Petrylak D, Tombal B, Rosenthal M; VENICE investigators. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol. 2013 Jul;14(8):760-8. Epub 2013 Jun 4.[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70184-0/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23742877 PubMed] NCT00519285<br />
#'''SWOG S0421:''' Quinn DI, Tangen CM, Hussain M, Lara PN Jr, Goldkorn A, Moinpour CM, Garzotto MG, Mack PC, Carducci MA, Monk JP, Twardowski PW, Van Veldhuizen PJ, Agarwal N, Higano CS, Vogelzang NJ, Thompson IM Jr. Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial. Lancet Oncol. 2013 Aug;14(9):893-900. Epub 2013 Jul 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70294-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277263/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23871417 PubMed] NCT00134056<br />
#'''READY:''' Araujo JC, Trudel GC, Saad F, Armstrong AJ, Yu EY, Bellmunt J, Wilding G, McCaffrey J, Serrano SV, Matveev VB, Efstathiou E, Oudard S, Morris MJ, Sizer B, Goebell PJ, Heidenreich A, de Bono JS, Begbie S, Hong JH, Richardet E, Gallardo E, Paliwal P, Durham S, Cheng S, Logothetis CJ. Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1307-16. Epub 2013 Nov 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70479-0/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478530/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24211163 PubMed] NCT00744497<br />
#'''MAINSAIL:''' Petrylak DP, Vogelzang NJ, Budnik N, Wiechno PJ, Sternberg CN, Doner K, Bellmunt J, Burke JM, de Olza MO, Choudhury A, Gschwend JE, Kopyltsov E, Flechon A, Van As N, Houede N, Barton D, Fandi A, Jungnelius U, Li S, de Wit R, Fizazi K. Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2015 Apr;16(4):417-25. Epub 2015 Mar 3.[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70025-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25743937 PubMed] NCT00988208<br />
#'''SYNERGY:''' Chi KN, Higano CS, Blumenstein B, Ferrero JM, Reeves J, Feyerabend S, Gravis G, Merseburger AS, Stenzl A, Bergman AM, Mukherjee SD, Zalewski P, Saad F, Jacobs C, Gleave M, de Bono JS. Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2017 Apr;18(4):473-485. Epub 2017 Mar 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30168-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28283282 PubMed] NCT01188187<br />
#'''FIRSTANA:''' Oudard S, Fizazi K, Sengeløv L, Daugaard G, Saad F, Hansen S, Hjälm-Eriksson M, Jassem J, Thiery-Vuillemin A, Caffo O, Castellano D, Mainwaring PN, Bernard J, Shen L, Chadjaa M, Sartor O. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: A randomized phase III Trial-FIRSTANA. J Clin Oncol. 2017 Oct 1;35(28):3189-3197. Epub 2017 Jul 28. [https://doi.org/10.1200/JCO.2016.72.1068 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28753384 PubMed] NCT01308567<br />
#'''TRITON3:''' NCT02975934<br />
<br />
==Docetaxel & Prednisolone {{#subobject:8jfyz3 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Docetaxel (Taxotere) in prostate cancer]]<br />
<br />
===Regimen variant #1, 50 mg/m<sup>2</sup> bi-weekly {{#subobject:30 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2812%2970537-5/abstract Kellokumpu-Lehtinen et al. 2013 (PROSTY)]<br />
|2004-2009<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Docetaxel_.26_Prednisolone|Docetaxel & Prednisolone]]; q3wk<br />
| style="background-color:#91cf60" |Seems to have superior TTTF<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisolone (Millipred)]] 10 mg PO once per day<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 7.5 to 8 mg (route not specified) once per day, started 1 day before [[Docetaxel (Taxotere)]] and stopped 1 to 2 days after docetaxel infusion (in other words, from day -1 to day 2 or 3)<br />
*G-CSF not recommended unless patients developed febrile neutropenia or severe infection<br />
*"Treatment with bisphosphonates, erythropoietin, and palliative radiation therapy was allowed"<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 75 mg/m<sup>2</sup> q3wk, indefinite {{#subobject:28 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2812%2970537-5/abstract Kellokumpu-Lehtinen et al. 2013 (PROSTY)]<br />
|2004-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Prednisolone|Docetaxel & Prednisolone]]; q2wk<br />
| style="background-color:#fc8d59" |Seems to have inferior TTTF<br />
|-<br />
|[https://doi.org/10.1200/JCO.2012.46.4149 Fizazi et al. 2013 (ENTHUSE)]<br />
|2008-NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel, Zibotentan, Prednisolone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisolone (Millipred)]] 10 mg PO once per day<br />
**Fizazi et al. 2013: Given as 5 mg PO twice per day<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 7.5 to 8 mg daily, started 1 day before [[Docetaxel (Taxotere)]] and stopped 1 to 2 days after docetaxel infusion (in other words, from day -1 to day 2 or 3); reference did not specify route of administration<br />
*G-CSF not recommended unless patients developed febrile neutropenia or severe infection<br />
*"Treatment with bisphosphonates, erythropoietin, and palliative radiation therapy was allowed"<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''PROSTY:''' Kellokumpu-Lehtinen PL, Harmenberg U, Joensuu T, McDermott R, Hervonen P, Ginman C, Luukkaa M, Nyandoto P, Hemminki A, Nilsson S, McCaffrey J, Asola R, Turpeenniemi-Hujanen T, Laestadius F, Tasmuth T, Sandberg K, Keane M, Lehtinen I, Luukkaala T, Joensuu H; PROSTY study group. 2-weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial. Lancet Oncol. 2013 Feb;14(2):117-24. Epub 2013 Jan 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2812%2970537-5/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23294853 PubMed] NCT00255606<br />
#'''ENTHUSE:''' Fizazi K, Higano CS, Nelson JB, Gleave M, Miller K, Morris T, Nathan FE, McIntosh S, Pemberton K, Moul JW. Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2013 May 10;31(14):1740-7. Epub 2013 Apr 8. Erratum in: J Clin Oncol. 2014 Oct 20;32(30):3461. Fizazi, Karim S [Corrected to Fizazi, Karim]. [https://doi.org/10.1200/JCO.2012.46.4149 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23569308 PubMed] NCT00617669<br />
<br />
==Mitoxantrone & Hydrocortisone {{#subobject:f4eqv4 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:da47uz |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1999.17.8.2506 Kantoff et al. 1999 (CALGB 9182)]<br />
|1992-1995<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Hydrocortisone_monotherapy|Hydrocortisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Mitoxantrone (Novantrone)]]<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Hydrocortisone (Cortef)]]<br />
<br />
===References===<br />
<br />
#'''CALGB 9182:''' Kantoff PW, Halabi S, Conaway M, Picus J, Kirshner J, Hars V, Trump D, Winer EP, Vogelzang NJ. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol. 1999 Aug;17(8):2506-13. [https://doi.org/10.1200/JCO.1999.17.8.2506 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10561316 PubMed]<br />
<br />
==Mitoxantrone & Prednisone {{#subobject:29 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Mitoxantrone (Novantrone) in prostate cancer]]<br />
<br />
===Regimen {{#subobject:33 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''', PSA RR]]<br />
!Comparator [[Overall response rate|'''ORR''', PSA RR]]<br />
!Pt Population<br />
|-<br />
|[https://doi.org/10.1200/JCO.1994.12.4.689 Moore et al. 1994]<br />
|NR<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|<br />
|<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.1996.14.6.1756 Tannock et al. 1996 (CCI-NOV22)]<br />
|1990-1994<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#1a9850" |Superior palliation<br />
|<br />
|<br />
|<br />
|-<br />
|[https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2964163-8 Berry et al. 2002]<br />
|1997-1999<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#91cf60" |Seems to have superior TTTF<br />
|<br />
|<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa041318 Petrylak et al. 2004 (SWOG S9916)]<br />
|1999-2003<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Estramustine|Docetaxel & Estramustine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|<br />
|<br />
|<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa040720 Tannock et al. 2004 (TAX 327)]<br />
| rowspan="2" |2000-2002<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Docetaxel_.26_Prednisone|Weekly Docetaxel & Prednisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
| rowspan="2" |pts w/ measurable disease: '''7%''' (95% CI 3-12), '''32%''' (95% CI 26-37)<br />
|pts w/ measurable disease: '''8%''' (95% CI 4-14), '''48%''' (95% CI 42-54)<br />
|Chemo naive<br />
|-<br />
|2. [[#Docetaxel_.26_Prednisone|Every 3-week Docetaxel & Prednisone]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|pts w/ measurable disease: '''12%''' (95% CI 7-19), '''45%''' (95% CI 40-51)<br />
|Chemo naive<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961389-X/fulltext de Bono et al. 2010 (TROPIC)]<br />
|2007-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cabazitaxel_.26_Prednisone_2|Cabazitaxel & Prednisone]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|pts w/ measurable disease:<br>'''4.4%''' (95% CI 1.6 - 7.2), '''17.8%''' (95% CI 13.7 - 22.0)<br />
|pts w/ measurable disease:<br>'''14.4%''' (95% CI 9.6 - 19.3), '''39.2%''' (95% CI 33.9 - 44.5)<br />
|Progressed on docetaxel<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Mitoxantrone (Novantrone)]] 12 mg/m<sup>2</sup> IV over 15 to 30 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 10 mg PO once per day on days 1 to 21<br />
**Some protocols give 5 mg PO twice per day<br />
<br />
'''21-day cycle for up to 10 cycles'''<br />
<br />
===References===<br />
<br />
#Moore MJ, Osoba D, Murphy K, Tannock IF, Armitage A, Findlay B, Coppin C, Neville A, Venner P, Wilson J. Use of palliative end points to evaluate the effects of mitoxantrone and low-dose prednisone in patients with hormonally resistant prostate cancer. J Clin Oncol. 1994 Apr;12(4):689-94. [https://doi.org/10.1200/JCO.1994.12.4.689 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7512127 PubMed]<br />
#'''CCI-NOV22:''' Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, Armitage GR, Wilson JJ, Venner PM, Coppin CM, Murphy KC. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996 Jun;14(6):1756-64. [https://doi.org/10.1200/JCO.1996.14.6.1756 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8656243 PubMed]<br />
##'''HRQoL analysis:''' Osoba D, Tannock IF, Ernst DS, Neville AJ. Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol. 1999 Jun;17(6):1654-63. [https://doi.org/10.1200/JCO.1999.17.6.1654 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10561201 PubMed]<br />
#Berry W, Dakhil S, Modiano M, Gregurich M, Asmar L. Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol. 2002 Dec;168(6):2439-43. [https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2964163-8 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12441935 PubMed]<br />
#'''TAX 327:''' Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1502-12. [https://www.nejm.org/doi/full/10.1056/NEJMoa040720 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15470213 PubMed]<br />
##'''Update:''' Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008 Jan 10;26(2):242-5. [https://doi.org/10.1200/jco.2007.12.4008 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18182665 PubMed]<br />
#'''SWOG S9916:''' Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1513-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa041318 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15470214 PubMed]<br />
#'''TROPIC:''' de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010 Oct 2;376(9747):1147-54. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961389-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20888992 PubMed] NCT00417079<br />
<br />
==Olaparib monotherapy {{#subobject:defe72|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen Variant #1, 300 mg BID {{#subobject:8979a4|Variant=1}}===<br />
{| class="wikitable sortable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Levels_of_Evidence#Efficacy|Efficacy]], PFS<br />
!Comparator [[Overall response rate|'''ORR''']], PFS<br />
!Pt Population<br />
|-<br />
|[http://doi.org/10.1056/NEJMoa1911440 de Bono et al. 2020 (PROfound)]<br />
|2017-2018<br />
| style="background-color:#1a9851" |Phase III (E-RT-ooc)<br />
|1. [[#Abiraterone_monotherapy|Abiraterone]]<br> 2. [[#Enzalutamide_monotherapy|Enzalutamide]]<br />
| style="background-color:#1a9850" |Superior PFS<sup>1</sup><br />
|7.4 months (95% CI 0.25 to 0.47, p<0.001)<br />
|3.6 months<br />
|Progressed on abiraterone or enzalutamide, at least one alteration in BRCA1, BRCA2, or ATM<br />
|-<br />
|}<br />
''<sup>1</sup>Patients in Cohort A seemed to have superior OS in the 2020 update.''<br />
====Biomarker eligibility criteria====<br />
<br />
*Cohort A: 1+ alterations in BRCA1, BRCA2, or ATM<br />
*Cohort B: 1+ alterations in BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L<br />
<br />
====Targeted therapy====<br />
<br />
*[[Olaparib (Lynparza)]] 300 mg PO twice per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen Variant #2, 400 mg BID {{#subobject:8979a3|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6057749/ Kaufman et al. 2014 (Study 42)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts in subgroup<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228595/ Mateo et al. 2015 (TOPARP-A)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Biomarker eligibility criteria====<br />
*Study 42: Germline BRCA1/2 mutations and had progression on hormonal and one systemic therapy<br />
*TOPARP-A: Patients who were found to have homozygous deletions, deleterious mutations, or both in DNA-repair genes were much more likely to respond to olaparib<br />
<br />
====Targeted therapy====<br />
<br />
*[[Olaparib (Lynparza)]] 400 mg PO twice per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
<br />
#'''Study 42:''' Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.56.2728 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6057749/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed] NCT01078662<br />
#'''TOPARP-A:''' Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, Nava Rodrigues D, Robinson D, Omlin A, Tunariu N, Boysen G, Porta N, Flohr P, Gillman A, Figueiredo I, Paulding C, Seed G, Jain S, Ralph C, Protheroe A, Hussain S, Jones R, Elliott T, McGovern U, Bianchini D, Goodall J, Zafeiriou Z, Williamson CT, Ferraldeschi R, Riisnaes R, Ebbs B, Fowler G, Roda D, Yuan W, Wu YM, Cao X, Brough R, Pemberton H, A'Hern R, Swain A, Kunju LP, Eeles R, Attard G, Lord CJ, Ashworth A, Rubin MA, Knudsen KE, Feng FY, Chinnaiyan AM, Hall E, de Bono JS. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med. 2015 Oct 29;373(18):1697-708. [https://www.nejm.org/doi/full/10.1056/NEJMoa1506859Top link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228595/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26510020 PubMed] NCT01682772<br />
#'''PROfound:''' de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 May 28;382(22):2091-2102. Epub 2020 Apr 28. [http://doi.org/10.1056/NEJMoa1911440 link to original article] '''contains verified protocol''' [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1911440/suppl_file/nejmoa1911440_appendix.pdf link to supplementary appendix] [https://pubmed.ncbi.nlm.nih.gov/32343890/ PubMed] NCT02987543<br />
## ''Update:''' Hussain M, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Roubaud G, Özgüroğlu M, Kang J, Burgents J, Gresty C, Corcoran C, Adelman CA, de Bono J; PROfound Trial Investigators. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 Dec 10;383(24):2345-2357. Epub 2020 Sep 20. [https://doi.org/10.1056/nejmoa2022485 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32955174 PubMed]<br />
<br />
=Immunotherapy for metastatic castrate-resistant disease=<br />
<br />
==Ipilimumab & RT {{#subobject:33 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Ipilimumab & RT: Ipilimumab & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
<br />
===Regimen {{#subobject:38 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 25%" |Patient population<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707423/ Slovin et al. 2013]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 4% (95% CI n/a), PSA RR: 16%;<br />
|Most had ADT, some had docetaxel use. 10 mg/kg cohort reported here.<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Ipilimumab (Yervoy)]] 10 mg/kg IV over 90 minutes once on day 1<br />
**Lower doses including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended in this study<br />
<br />
====Radiotherapy====<br />
<br />
*[[External_beam_radiotherapy|Radiation therapy]] given focally at a single dose of 8 Gy per target bone lesion for up to three bone lesions per patient, '''given 24 to 48 h before the first ipilimumab dose'''<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, Scher HI, Chin K, Gagnier P, McHenry MB, Beer TM. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol. 2013 Jul;24(7):1813-21. [https://doi.org/10.1093/annonc/mdt107 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707423/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23535954 PubMed] NCT00323882<br />
<br />
==Sipuleucel-T monotherapy {{#subobject:32 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Sipuleucel-T (Provenge) in prostate cancer]]<br />
<br />
===Regimen {{#subobject:37 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.04.5252 Small et al. 2006 (D9901)]<br />
|2000-2001<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Prostate_cancer_-_null_regimens#Placebo_3|Placebo]]<br />
| style="background-color:#d9ef8b" |Might have superior TTP<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.24429 Higano et al. 2009 (D9902A)]<br />
|2000-2003<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_null_regimens#Placebo_3|Placebo]]<br />
| style="background-color:#d9ef8b" |Might have superior TTP<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1001294 Kantoff et al. 2010 (IMPACT<sub>prostate</sub>)]<br />
|2003-2007<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Prostate_cancer_-_null_regimens#Placebo_3|Placebo]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: Higano et al. 2009 was a pooled update but also the first publication to describe results of D9902A. IMPACT should not be confused with the studies of the same name in breast cancer and colorectal cancer.''<br />
====Immunotherapy====<br />
<br />
*[[Sipuleucel-T (Provenge)]]: leukapheresis followed 3 days later with at least 50 million autologous CD54+ cells activated with PAP-GM-CSF, to be done on weeks 0, 2, and 4<br />
<br />
====Supportive medications====<br />
<br />
*[[Acetaminophen (Tylenol)]] PO once per week on weeks 0, 2, 4; 30 minutes prior to [[Sipuleucel-T (Provenge)]]<br />
*[[:Category:Antihistamines|Antihistamine]] PO once per week on weeks 0, 2, 4; 30 minutes prior to [[Sipuleucel-T (Provenge)]]<br />
<br />
'''One course'''<br />
===References===<br />
<br />
#'''D9901:''' Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006 Jul 1;24(19):3089-94. [https://doi.org/10.1200/JCO.2005.04.5252 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16809734 PubMed]<br />
##'''Pooled Update:''' Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, Provost N, Frohlich MW. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009 Aug 15;115(16):3670-9. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.24429 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19536890 PubMed]<br />
#'''D9902A:''' Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, Provost N, Frohlich MW. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009 Aug 15;115(16):3670-9. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.24429 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19536890 PubMed]<br />
#'''IMPACT:''' Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010 Jul 29;363(5):411-22. [https://www.nejm.org/doi/full/10.1056/NEJMoa1001294 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20818862 PubMed]<br />
#'''Safety analysis:''' Hall SJ, Klotz L, Pantuck AJ, George DJ, Whitmore JB, Frohlich MW, Sims RB. Integrated safety data from 4 randomized, double-blind, controlled trials of autologous cellular immunotherapy with sipuleucel-T in patients with prostate cancer. J Urol. 2011 Sep;186(3):877-81. Epub 2011 Jul 23. [http://www.auajournals.org/article/S0022-5347(11)03851-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21788048 PubMed]<br />
<br />
=Radioactive agents for bony metastatic disease=<br />
<br />
==Radium-223 monotherapy {{#subobject:35 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1 {{#subobject:40 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1213755 Parker et al. 2013 (ALSYMPCA)]<br />
|2008-2011<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Prostate_cancer_-_null_regimens#Placebo_3|Placebo]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior EQ-5D score<br />
|-<br />
|}<br />
====Radiotherapy====<br />
<br />
*[[Radium-223 (Xofigo)]] 50 kBq/kg IV once on day 1<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:41 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70147-X/abstract Nilsson et al. 2007]<br />
|2004-2005<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[Prostate_cancer_-_null_regimens#Placebo_3|Placebo]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Patients in the study had "bone pain needing EBRT" (external beam radiation therapy). Treatment with radium 223 began within 7 days after EBRT.''<br />
====Radiotherapy====<br />
<br />
*[[Radium-223 (Xofigo)]] 50 kBq/kg IV once on day 1<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, Yachnin J, Garkavij M, Strang P, Harmenberg J, Bolstad B, Bruland OS. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007 Jul;8(7):587-94. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70147-X/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17544845 PubMed]<br />
##'''Update:''' Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, O'Bryan-Tear CG, Thuresson M, Bolstad B, Bruland ØS. Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases. Clin Genitourin Cancer. 2013 Mar;11(1):20-6. Epub 2012 Sep 26. [http://www.clinical-genitourinary-cancer.com/article/S1558-7673(12)00168-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23021204 PubMed]<br />
<!--<br />
# Chris Parker, Sten Nilsson, Daniel Heinrich, Joe M. O'Sullivan, Sophie D. Fossa, Ales Chodacki, Pawel J. Wiechno, John P. Logue, Mihalj Seke, Anders Widmark, Dag Clement Johannessen, Peter Hoskin, David Bottomley, Robert Edward Coleman, Nicholas J. Vogelzang, C. Gillies O'Bryan-Tear, Jose E. Garcia-Vargas, Minghua Shan, A. Oliver Sartor. Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer (CRPC) patients with bone metastases (ALSYMPCA). 2012 ASCO Annual Meeting Abstract LBA4512. [http://meetinglibrary.asco.org/content/95649-114 link to abstract] [http://meetinglibrary.asco.org/content/74842 link to oral abstract session]<br />
# A. Oliver Sartor, Daniel Heinrich, Joe M. O'Sullivan, Sophie D. Fossa, Ales Chodacki, Pawel J. Wiechno, John P. Logue, Mihalj Seke, Anders Widmark, Dag Clement Johannessen, Sten Nilsson, Peter Hoskin, David Bottomley, Robert Edward Coleman, Nicholas J. Vogelzang, C. Gillies O'Bryan-Tear, Jose E. Garcia-Vargas, Minghua Shan, Chris Parker. Radium-223 chloride (Ra-223) impact on skeletal-related events (SREs) and ECOG performance status (PS) in patients with castration-resistant prostate cancer (CRPC) with bone metastases: Interim results of a phase III trial (ALSYMPCA). 2012 ASCO Annual Meeting Abstract 4551. [http://meetinglibrary.asco.org/content/94891-114 link to abstract]<br />
# Nicholas J. Vogelzang, Chris Parker, Sten Nilsson, Robert Edward Coleman, C. Gillies O'Bryan-Tear, Minghua Shan, A. Oliver Sartor. Updated analysis of radium-223 dichloride (Ra-223) impact on skeletal-related events (SRE) in patients with castration-resistant prostate cancer (CRPC) and bone metastases from the phase III randomized trial (ALSYMPCA). 2013 ASCO Genitourinary Cancers Symposium Abstract 11. [https://meetinglibrary.asco.org/content/107117-134 link to abstract]<br />
# Sten Nilsson, A. Oliver Sartor, Oyvind S. Bruland, Fang Fang, Anne-Kirsti Aksnes, Chris Parker. Pain analysis from the phase III randomized ALSYMPCA study with radium-223 dichloride (Ra-223) in patients with castration-resistant prostate cancer (CRPC) with bone metastases. 2013 ASCO Genitourinary Cancers Symposium Abstract 19. [http://meetinglibrary.asco.org/content/107297-134 link to abstract]<br />
# '''Update:''' Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, O'Bryan-Tear CG, Thuresson M, Bolstad B, Bruland ØS. Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases. Clin Genitourin Cancer. 2013 Mar;11(1):20-6. Epub 2012 Sep 26. [http://www.clinical-genitourinary-cancer.com/article/S1558-7673(12)00168-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23021204 PubMed]<br />
--><br />
#'''ALSYMPCA:''' Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall'Oglio M, Franzén L, Coleman R, Vogelzang NJ, O'Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland ØS, Sartor O; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1213755 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23863050 PubMed]<br />
##'''Subgroup analysis:''' Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Widmark A, Johannessen DC, Hoskin P, James ND, Solberg A, Syndikus I, Vogelzang NJ, O'Bryan-Tear CG, Shan M, Bruland ØS, Parker C. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014 Jun;15(7):738-46. Epub 2014 May 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70183-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24836273 PubMed]<br />
##'''Subgroup analysis:''' Hoskin P, Sartor O, O'Sullivan JM, Johannessen DC, Helle SI, Logue J, Bottomley D, Nilsson S, Vogelzang NJ, Fang F, Wahba M, Aksnes AK, Parker C. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol. 2014 Nov;15(12):1397-406. Epub 2014 Oct 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2970474-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25439694 PubMed]<br />
##'''HRQoL analysis:''' Nilsson S, Cislo P, Sartor O, Vogelzang NJ, Coleman RE, O'Sullivan JM, Reuning-Scherer J, Shan M, Zhan L, Parker C. Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study. Ann Oncol. 2016 May;27(5):868-74. Epub 2016 Feb 23. [https://doi.org/10.1093/annonc/mdw065 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843190/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26912557 PubMed]<br />
<br />
==Samarium-153 monotherapy {{#subobject:36 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:42 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(97)00155-X/pdf Resche et al. 1997]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Samarium-153_monotherapy|Samarium-153]]; 0.5 mCi/kg<br />
| style="background-color:#91cf60" |Seems to have superior pain control at week 4<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2804%2900143-8/abstract Sartor et al. 2004]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Samarium-152 (non-radioactive)<br />
| style="background-color:#91cf60" |Seems to have superior pain control at week 4<br />
|-<br />
|}<br />
====Radiotherapy====<br />
<br />
*[[Samarium-153 (Quadramet)]] 1 mCi/kg IV over 1 minute once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*1000 mL of fluid IV or PO given twice, 4 hours before and 6 hours after treatment<br />
<br />
'''1 dose'''<br />
<br />
===References===<br />
<br />
#Resche I, Chatal JF, Pecking A, Ell P, Duchesne G, Rubens R, Fogelman I, Houston S, Fauser A, Fischer M, Wilkins D. A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer. 1997 Sep;33(10):1583-91. [https://www.ejcancer.com/article/S0959-8049(97)00155-X/pdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9389919 PubMed]<br />
#Sartor O, Reid RH, Hoskin PJ, Quick DP, Ell PJ, Coleman RE, Kotler JA, Freeman LM, Olivier P; Quadramet 424Sm10/11 Study Group. Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology. 2004 May;63(5):940-5. [http://www.goldjournal.net/article/S0090-4295%2804%2900143-8/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15134985 PubMed]<br />
<br />
=Measuring disease progression=<br />
<br />
*Criteria used for disease progression in prostate cancer clinical trials, Prostate Cancer Clinical Trials Working Group 2 (PCWG2):<ref>Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M; Prostate Cancer Clinical Trials Working Group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008 Mar 1;26(7):1148-59. [https://doi.org/10.1200/jco.2007.12.4487 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010133/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18309951 PubMed]</ref><br />
**Castrate level of serum testosterone is less than 50 ng/dL (less than 1.7 nmol/L)<br />
***However, there is controversy/disagreement in other references about whether a lower level should be used, such as less than 20 ng/dL (0.7 nmol/L)<ref>Oefelein MG, Feng A, Scolieri MJ, Ricchiutti D, Resnick MI. Reassessment of the definition of castrate levels of testosterone: implications for clinical decision making. Urology. 2000 Dec 20;56(6):1021-4. [http://www.goldjournal.net/article/S0090-4295%2800%2900793-7/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11113751 PubMed]</ref><br />
**PSA rise<br />
***Starting PSA of at least 2 ng/mL<br />
***Rising PSA values which are measured at least 1-week apart<br />
***Pretherapy PSA doubling times (PSA-DT) can be estimated if there are at least 3 PSA values measured at least 4 weeks apart<br />
**Bony metastases<br />
***At least 2 new lesions indicates progressive disease<br />
***It is recommended to assess ambiguous results with other imaging modalities such as CT or MRI<br />
**Measurable lesions (RECIST) - this is a lower priority criteria by the PCWG2 because fewer patients have measurable lesions as compared to, for example, bony metastases<br />
***Baseline imaging involves chest imaging with x-ray or CT, CT or MRI of the abdomen/pelvis, and radionuclide bone scan<br />
***It is recommended that local disease is assessed by endorectal MRI or prostatic ultrasound<br />
***Neurologic symptoms should be assessed with MRI of the spine and base of the skull<br />
***Positron emission tomography (PET) is not recommended and is considered investigational<br />
***Measurable lesions should be followed with [http://imaging.cancer.gov/clinicaltrials/imaging RECIST criteria]<br />
***"Up to 10 visceral and nodal lesions in total should be recorded (with a maximum of five in any one organ)"<br />
***It is suggested that a lymph node must be at least 2 cm in maximal dimension on spiral CT to count as a target lesion.<br />
<br />
=Statistics=<br />
<br />
*[http://jama.jamanetwork.com/article.aspx?articleid=198392 Four-Year Actuarial Progression-Free Probability (PFP) After Salvage Radiotherapy based on Gleason score, PSA, positive margins, etc.]<ref>Stephenson AJ, Shariat SF, Zelefsky MJ, Kattan MW, Butler EB, Teh BS, Klein EA, Kupelian PA, Roehrborn CG, Pistenmaa DA, Pacholke HD, Liauw SL, Katz MS, Leibel SA, Scardino PT, Slawin KM. Salvage Radiotherapy for Recurrent Prostate Cancer After Radical Prostatectomy. JAMA. 2004 Mar 17;291(11):1325-32. [http://jama.jamanetwork.com/article.aspx?articleid=198392 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15026399 PubMed]</ref> (flowchart is in Figure 2)<br />
*[http://seer.cancer.gov/statfacts/html/prost.html SEER Stat Fact Sheets: Prostate Cancer]<br />
*[http://www.cdc.gov/CANCER/prostate/statistics/ CDC Prostate Cancer Statistics]<br />
*[http://www.cancer.net/cancer-types/prostate-cancer/statistics Cancer.Net Prostate Cancer Statistics]<br />
<br />
=Links=<br />
<br />
*[http://genomedx.com/decipher-test/ Decipher], GenomeDx's genomic prognostic prostate cancer assay<br />
**"the Decipher Test uses the expression of these biomarkers to calculate the probability of clinical metastasis within 5 years of radical prostatectomy surgery, and within 3 years of successive PSA rise (biochemical recurrence)."<br />
*[http://www.mskcc.org/cancer-care/adult/prostate/prediction-tools MSKCC prostate cancer nomograms]<br />
*[http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx MSKCC PSA doubling time calculator]<br />
*[http://nomograms.mskcc.org/Prostate/Volume.aspx MSKCC Prostate volume calculator]<br />
*[http://prostate-cancer.oncotypedx.com/en-US/Professional.aspx Oncotype DX Prostate] Genomic Health's Genomic Prostate Score (GPS) & prognostic prostate cancer assay<br />
*[http://urology.jhu.edu/prostate/partintables.php Partin tables] to predict pathologic stage based on clinical TNM stage, PSA, and Gleason score<br />
*[http://www.diagnocure.com/en/products-projects/prostate-cancer/pca3-test-healthcare-practitioners.php PCA3 RNA urine test]<br />
**[http://www.pca3.org/ PCA3.org]<br />
*[http://www.prolaris.com/ Prolaris], Myriad's biomarker prognostic prostate cancer assay<br />
*[https://www.roswellpark.org/apps/prostate_cancer_estimator/ Roswell Park's Calculator for Estimating Overall Life Expectancy and Lifetime Risk for Prostate Cancer Death in Newly Diagnosed Men Managed without Definitive Local Therapy]<br />
*[http://urology.ucsf.edu/research/cancer/prostate-cancer-risk-assessment-and-the-ucsf-capra-score UCSF-CAPRA score]<br />
<br />
=Quality of life assessment tools=<br />
<br />
*[http://www.bidmc.org/~/media/Files/Centers%20and%20Departments/CancerCenter/prostateCancer/EPIC%20CP.pdf EPIC-CP: Expanded Prostate Cancer Index Composite for Clinical Practice] ([http://www.bidmc.org/epic twice per dayMC])<br />
*[http://www.oregonurology.com/pdfs/aua-symptom-score.pdf AUA Symptom Score (OR)] [//hemonc.org/w/images/1/1c/AUA-Symptom-Score_OR.pdf (local backup)]; [http://www.purclinic.com/wp-content/uploads/2014/05/AUA-Symptom-Score.pdf AUA Symptom Score (UCF)] [//hemonc.org/w/images/b/b0/AUA-Symptom-Score.pdf (local backup)]. Also known as International Prostate Symptom Score (I-PSS/IPSS) or AUASS<br />
<br />
=References=<br />
<references /><br />
<br />
[[Category:Prostate cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Genitourinary cancers]]</div>Karinehttps://hemonc.org/w/index.php?title=Prostate_cancer&diff=49689Prostate cancer2021-05-14T14:50:43Z<p>Karine: TITAN study final analysis reference</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" style="color:white; font-size:125%; background-color:#08519c" align="center" |'''Page editor'''<br />
! colspan="2" style="color:white; font-size:125%; background-color:#08519c" align="center" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:LauraGraham.jpg|frameless|upright=0.3|center]]<br />
|<big>Laura S. Graham, MD<br>University of Washington<br>Fred Hutchinson Cancer Research Center<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/LauraGrahamMD LauraGrahamMD]<br />
| style="background-color:#F0F0F0" |[[File:Alikhaki.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Alikhaki|Ali Raza Khaki, MD]]<br>Stanford University<br>Palo Alto, CA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/arkhaki arkhaki]<br />
|-<br />
|}<br />
''Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the [[Prostate_cancer_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Prostate cancer - null regimens|this page]]. If you still can't find it, please let us know so we can add it!'' <br><br />
'''Note: this page contains regimens for prostate cancer which were not tested in biomarker-specific populations. The following links will take you to biomarker-specific subpages:'''<br />
*Regimens for [[Prostate_cancer,_BRCA-mutated|'''BRCA-mutated prostate cancer are here''']].<br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/genitourinary-cancer ASCO]==<br />
<br />
*'''2018:''' Morris et al. [https://doi.org/10.1200/JCO.2018.78.0619 Optimizing Anticancer Therapy in Metastatic Non-Castrate Prostate Cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2017:''' Virgo et al. [https://doi.org/10.1200/JCO.2017.72.8030 Second-Line Hormonal Therapy for Men With Chemotherapy-Naïve, Castration-Resistant Prostate Cancer: American Society of Clinical Oncology Provisional Clinical Opinion] [https://www.ncbi.nlm.nih.gov/pubmed/28441112 PubMed]<br />
*'''2016:''' [https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/genitourinary-cancer#/9336 Active Surveillance for the Management of Localized Prostate Cancer Endorsement]<br />
*'''2015:''' [https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/genitourinary-cancer#/9426 Prostate Cancer Survivorship Care Guideline Endorsement]<br />
<br />
===Older===<br />
<br />
*'''2014:''' [https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/genitourinary-cancer#/9486 Adjuvant and Salvage Radiotherapy After Prostatectomy Endorsement]<br />
*'''2012:''' [https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/genitourinary-cancer#/9501 Screening for Prostate Cancer with Prostate-Specific Antigen (PSA) Testing PCO]<br />
*'''2009:''' [https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/genitourinary-cancer#/9511 Use of 5-alpha Reductase Inhibitors for Prostate Cancer Chemoprevention]<br />
*'''2007:''' [https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/genitourinary-cancer#/9516 Non-Hormonal Therapy for Men With Metastatic Hormone-Refractory (castration-resistant) Prostate Cancer Endorsement]<br />
<br />
==ASCO & CCO==<br />
<br />
*'''2014:''' Basch et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876355/ Systemic Therapy in Men With Metastatic Castration-Resistant Prostate Cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline]<br />
<br />
==AUA==<br />
<br />
*[https://www.auanet.org/education/guidelines/castration-resistant-prostate-cancer.cfm Castration-Resistant Prostate Cancer: AUA Guideline @ AUAnet] <br />
**[https://www.auanet.org/common/pdf/education/clinical-guidance/Castration-Resistant-Prostate-Cancer.pdf PDF (2015) @ AUAnet]<br />
*[https://www.auajournals.org/doi/full/10.1016/j.juro.2015.10.086 Castration-Resistant Prostate Cancer: AUA Guideline Amendment 2015] [https://www.ncbi.nlm.nih.gov/pubmed/26498056 PubMed]<br />
<br />
==EAU/ESTRO/SIOG==<br />
<br />
*'''2017:''' [http://www.europeanurology.com/article/S0302-2838(16)30469-9/fulltext EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer] [https://www.ncbi.nlm.nih.gov/pubmed/27591931 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2020:''' Parker et al. [https://doi.org/10.1016/j.annonc.2020.06.011 Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
===Older===<br />
*'''2015:''' Parker et al. [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Cancer-of-the-Prostate ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
*'''2013:''' Horwich et al. [https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mdt208 ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/23813930 PubMed]<br />
*'''2012:''' Horwich et al. [https://annonc.oxfordjournals.org/content/24/5/1141.full.pdf+html ESMO Consensus Conference Guidelines] [https://www.ncbi.nlm.nih.gov/pubmed/23303340 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf NCCN Guidelines - Prostate Cancer]<br />
<br />
==St Gallen==<br />
<br />
*'''2015:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511225/ Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC)]<br />
<br />
=Induction ADT=<br />
==ADT {{#subobject:8ab01b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:25b39f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2003.05.004 Roach et al. 2003 (RTOG 94-13)]<br />
|1995-1999<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#ADT|ADT]]; adjuvant<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2014.58.0662 Pisansky et al. 2014 (RTOG 9910)]<br />
|2000-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT|ADT]] x 28 weeks<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of disease-specific mortality<br />
|-<br />
|}<br />
''Note: these are clinical trials that did not specify a particular drug to be used for androgen deprivation. See papers for details.''<br />
====Endocrine therapy====<br />
<br />
*[[:Category:GnRH agonists|LHRH agonist]]<br />
*[[Bicalutamide (Casodex)]] or [[Flutamide (Eulexin)]]<br />
<br />
'''8-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[#ADT_.26_RT|ADT & RT]]<br />
<br />
===References===<br />
<br />
#'''RTOG 94-13:''' Roach M 3rd, DeSilvio M, Lawton C, Uhl V, Machtay M, Seider MJ, Rotman M, Jones C, Asbell SO, Valicenti RK, Han S, Thomas CR Jr, Shipley WS; Radiation Therapy Oncology Group. Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol. 2003 May 15;21(10):1904-11. [https://doi.org/10.1200/JCO.2003.05.004 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12743142 PubMed]<br />
##'''Update:''' Lawton CA, DeSilvio M, Roach M 3rd, Uhl V, Kirsch R, Seider M, Rotman M, Jones C, Asbell S, Valicenti R, Hahn S, Thomas CR Jr. An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions. Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):646-55. Epub 2007 May 24. [https://www.redjournal.org/article/S0360-3016(07)00641-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917177/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/17531401 PubMed]<br />
#'''RTOG 9910:''' Pisansky TM, Hunt D, Gomella LG, Amin MB, Balogh AG, Chinn DM, Seider MJ, Duclos M, Rosenthal SA, Bauman GS, Gore EM, Rotman MZ, Lukka HR, Shipley WU, Dignam JJ, Sandler HM. Duration of androgen suppression before radiotherapy for localized prostate cancer: Radiation Therapy Oncology Group randomized clinical trial 9910. J Clin Oncol. 2015 Feb 1;33(4):332-9. Epub 2014 Dec 22. [https://doi.org/10.1200/JCO.2014.58.0662 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302214/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25534388 PubMed] NCT00005044<br />
<br />
==Flutamide & Goserelin {{#subobject:b10d66 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:afbb9c |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.redjournal.org/article/S0360-3016(04)00264-0/fulltext Crook et al. 2004]<br />
|1995-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Flutamide_.26_Goserelin|Flutamide & Goserelin]] x 8 mo<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PSA-PFS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]]<br />
*[[Goserelin (Zoladex)]]<br />
<br />
'''3-month course'''<br />
====Subsequent treatment====<br />
<br />
*[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
<br />
===References===<br />
<br />
#Crook J, Ludgate C, Malone S, Lim J, Perry G, Eapen L, Bowen J, Robertson S, Lockwood G. Report of a multicenter Canadian phase III randomized trial of 3 months vs 8 months neoadjuvant androgen deprivation before standard-dose radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys. 2004 Sep 1;60(1):15-23. [https://www.redjournal.org/article/S0360-3016(04)00264-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15337535 PubMed]<br />
<br />
==Leuprolide monotherapy {{#subobject:1a6bc7 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:53abfc |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70328-6/fulltext Denham et al. 2014 (RADAR)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this trial had 4 arms including a randomization to zoledronic acid; see paper for details.''<br />
====Endocrine therapy====<br />
<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 3-month depot]] 22.5 mg IM once on day 1<br />
<br />
'''3-month cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Prostate_cancer_-_historical#Radiation_therapy|RT]], then [[#Leuprolide_monotherapy|Leuprolide]] x 12 mo versus [[Prostate_cancer_-_null_regimens#Observation|Observation]]<br />
<br />
===References===<br />
<br />
#'''RADAR:''' Denham JW, Joseph D, Lamb DS, Spry NA, Duchesne G, Matthews J, Atkinson C, Tai KH, Christie D, Kenny L, Turner S, Gogna NK, Diamond T, Delahunt B, Oldmeadow C, Attia J, Steigler A. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): an open-label, randomised, phase 3 factorial trial. Lancet Oncol. 2014 Sep;15(10):1076-89. Epub 2014 Aug 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70328-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25130995 PubMed] NCT00193856<br />
##'''Update:''' Denham JW, Joseph D, Lamb DS, Spry NA, Duchesne G, Matthews J, Atkinson C, Tai KH, Christie D, Kenny L, Turner S, Gogna NK, Diamond T, Delahunt B, Oldmeadow C, Attia J, Steigler A. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomised, phase 3, factorial trial. Lancet Oncol. 2019 Feb;20(2):267-281. Epub 2018 Dec 19. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30757-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30579763 PubMed]<br />
<br />
=Definitive therapy, including active surveillance=<br />
==Active surveillance==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa012794 Holmberg et al. 2002 (SPCG-4)]<br />
|1989-1999<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Surgery#Radical_prostatectomy|Radical prostatectomy]]<br />
| style="background-color:#d73027" |Inferior OS<sup>1</sup><br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429335/ Wilt et al. 2012 (PIVOT)]<br />
|1994-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Surgery#Radical_prostatectomy|Radical prostatectomy]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61619-X/fulltext Fleshner et al. 2012 (REDEEM)]<br />
|2006-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Dutasteride<br />
| style="background-color:#d73027" |Inferior TTP<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30661-1/fulltext Azzouzi et al. 2016 (CLIN1001 PCM301)]<br />
|2011-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Padeliporfin<br />
| style="background-color:#d73027" |Inferior TTP<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for SPCG-4 is based on the 2014 update.''<br><br />
''No antineoplastic therapy; consists of various strategies of close monitoring and re-biopsy.''<br />
===References===<br />
<br />
#'''SPCG-4:''' Holmberg L, Bill-Axelson A, Helgesen F, Salo JO, Folmerz P, Häggman M, Andersson SO, Spångberg A, Busch C, Nordling S, Palmgren J, Adami HO, Johansson JE, Norlén BJ; Scandinavian Prostatic Cancer Group. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med. 2002 Sep 12;347(11):781-9. [https://www.nejm.org/doi/10.1056/NEJMoa012794 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12226148 PubMed]<br />
##'''Update:''' Bill-Axelson A, Holmberg L, Ruutu M, Häggman M, Andersson SO, Bratell S, Spångberg A, Busch C, Nordling S, Garmo H, Palmgren J, Adami HO, Norlén BJ, Johansson JE; Scandinavian Prostate Cancer Group. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2005 May 12;352(19):1977-84. [https://www.nejm.org/doi/full/10.1056/NEJMoa043739 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15888698 PubMed]<br />
##'''Update:''' Bill-Axelson A, Holmberg L, Filén F, Ruutu M, Garmo H, Busch C, Nordling S, Häggman M, Andersson SO, Bratell S, Spångberg A, Palmgren J, Adami HO, Johansson JE; Scandinavian Prostate Cancer Group. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial. J Natl Cancer Inst. 2008 Aug 20;100(16):1144-54. Epub 2008 Aug 11. [https://academic.oup.com/jnci/article/100/16/1144/916419 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518167/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18695132 PubMed]<br />
##'''Update:''' Bill-Axelson A, Holmberg L, Ruutu M, Garmo H, Stark JR, Busch C, Nordling S, Häggman M, Andersson SO, Bratell S, Spångberg A, Palmgren J, Steineck G, Adami HO, Johansson JE; SPCG-4 Investigators. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2011 May 5;364(18):1708-17. [https://www.nejm.org/doi/10.1056/NEJMoa1011967 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21542742 PubMed]<br />
##'''Update:''' Bill-Axelson A, Holmberg L, Garmo H, Rider JR, Taari K, Busch C, Nordling S, Häggman M, Andersson SO, Spångberg A, Andrén O, Palmgren J, Steineck G, Adami HO, Johansson JE. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med. 2014 Mar 6;370(10):932-42. [https://www.nejm.org/doi/10.1056/NEJMoa1311593 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118145/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24597866 PubMed]<br />
##'''Update:''' Bill-Axelson A, Holmberg L, Garmo H, Taari K, Busch C, Nordling S, Häggman M, Andersson SO, Andrén O, Steineck G, Adami HO, Johansson JE. Radical Prostatectomy or Watchful Waiting in Prostate Cancer - 29-Year Follow-up. N Engl J Med. 2018 Dec 13;379(24):2319-2329. [https://www.nejm.org/doi/full/10.1056/NEJMoa1807801 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30575473 PubMed]<br />
#'''REDEEM:''' Fleshner NE, Lucia MS, Egerdie B, Aaron L, Eure G, Nandy I, Black L, Rittmaster RS. Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial. Lancet. 2012 Mar 24;379(9821):1103-11. Epub 2012 Jan 24. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61619-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22277570 PubMed] NCT00363311<br />
#'''PIVOT:''' Wilt TJ, Brawer MK, Jones KM, Barry MJ, Aronson WJ, Fox S, Gingrich JR, Wei JT, Gilhooly P, Grob BM, Nsouli I, Iyer P, Cartagena R, Snider G, Roehrborn C, Sharifi R, Blank W, Pandya P, Andriole GL, Culkin D, Wheeler T; Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012 Jul 19;367(3):203-13. Erratum in: N Engl J Med. 2012 Aug 9;367(6):582. [https://www.nejm.org/doi/10.1056/NEJMoa1113162 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429335/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22808955 PubMed] NCT00007644<br />
##'''Update:''' Wilt TJ, Jones KM, Barry MJ, Andriole GL, Culkin D, Wheeler T, Aronson WJ, Brawer MK. Follow-up of prostatectomy versus observation for early prostate cancer. N Engl J Med. 2017 Jul 13;377(2):132-142. [https://www.nejm.org/doi/10.1056/NEJMoa1615869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28700844 PubMed]<br />
#'''CLIN1001 PCM301:''' Azzouzi AR, Vincendeau S, Barret E, Cicco A, Kleinclauss F, van der Poel HG, Stief CG, Rassweiler J, Salomon G, Solsona E, Alcaraz A, Tammela TT, Rosario DJ, Gomez-Veiga F, Ahlgren G, Benzaghou F, Gaillac B, Amzal B, Debruyne FM, Fromont G, Gratzke C, Emberton M; PCM301 Study Group. Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial. Lancet Oncol. 2017 Feb;18(2):181-191. Epub 2016 Dec 20. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30661-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28007457 PubMed] NCT01310894<br />
<br />
==ADT {{#subobject:c3c2cb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c615a3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243932/ Warde et al. 2011 (NCIC-CTG PR.3/UK MRC PR07)]<br />
|1995-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_RT|ADT & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: these are clinical trials that did not specify a particular therapy to be used for androgen deprivation. See papers for details; the below are examples.''<br />
====Endocrine therapy====<br />
<br />
*ADT with ONE of the following:<br />
**[[:Category:GnRH agonists|LHRH agonist/analogue]]<br />
**[[:Category:GnRH antagonists|LHRH antagonist]]<br />
**[[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]]<br />
<br />
===References===<br />
<br />
#'''NCIC-CTG PR.3/UK MRC PR07:''' Warde P, Mason M, Ding K, Kirkbride P, Brundage M, Cowan R, Gospodarowicz M, Sanders K, Kostashuk E, Swanson G, Barber J, Hiltz A, Parmar MK, Sathya J, Anderson J, Hayter C, Hetherington J, Sydes MR, Parulekar W; NCIC-CTG; MRC. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011 Dec 17;378(9809):2104-11. Epub 2011 Nov 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61095-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243932/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22056152 PubMed] NCT00002633<br />
<br />
==ADT & RT {{#subobject:514ac2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT & RT: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:4aac55|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/199273 d'Amico et al. 2004]<br />
|1995-2001<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243932/ Warde et al. 2011 (NCIC-CTG PR.3/UK MRC PR07)]<br />
|1995-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#ADT_2|ADT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa0810095 Bolla et al. 2009 (EORTC 22961)]<br />
|1997-2001<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1016/j.ijrobp.2008.05.020 Rosenthal et al. 2008 (RTOG 9902)]<br />
|2000-2004<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/JCO.2014.58.0662 Pisansky et al. 2014 (RTOG 9910)]<br />
|2000-2004<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(18)30443-3/fulltext Nabid et al. 2018 (PCS IV)]<br />
|2000-2008<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|rowspan=2|[https://doi.org/10.1016/j.ejca.2020.10.023 Nabid et al. 2020 (PCS III)]<br />
|rowspan=2|2000-2010<br />
|rowspan=2 style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#1a9850" |Superior biochemical failure<br />
|-<br />
|2. [[#ADT_.26_RT|ADT & RT]]; dose-escalated RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of biochemical failure<br />
|-<br />
|[https://doi.org/10.1200/JCO.2015.64.8055 Bolla et al. 2016 (EORTC 22991)]<br />
|2001-2008<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7186584/ Malone et al. 2019]<br />
|2002-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70045-8/fulltext Zapatero et al. 2015 (DART01/05 GICOR)]<br />
|2005-2010<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: these are clinical trials that did not specify a particular drug to be used for androgen deprivation. See papers for details.''<br />
====Preceding treatment====<br />
<br />
*RTOG 9902 & DART01/05 GICOR: [[#ADT|ADT]] x 8 weeks<br />
*RTOG 9910: [[#ADT|ADT]] x 8 weeks versus [[#ADT|ADT]] x 28 weeks<br />
<br />
====Endocrine therapy====<br />
<br />
*ADT with ONE of the following:<br />
**[[:Category:GnRH agonists|LHRH agonist]]<br />
**Some protocols: [[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]]<br />
**Some protocols: [[Bicalutamide (Casodex)]] or [[Flutamide (Eulexin)]]<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]]<br />
<br />
'''8-week course'''<br />
====Subsequent treatment====<br />
<br />
*RTOG 9902: ADT x 2 y versus TEE x 4, then ADT x 2 y<br />
*EORTC 22961: ADT for 6 months versus ADT for 36 months<br />
*DART01/05 GICOR: ADT for 24 months versus no further treatment<br />
*PCS IV: ADT for 18 months versus ADT for 36 months<br />
<br />
===References===<br />
<br />
#D'Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA. 2004 Aug 18;292(7):821-7. [https://jamanetwork.com/journals/jama/fullarticle/199273 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15315996 PubMed]<br />
#'''RTOG 9902:''' Rosenthal SA, Bae K, Pienta KJ, Sobczak ML, Asbell SO, Rajan R, Kerlin KJ, Michalski JM, Sandler HM; Radiation Therapy Oncology Group. Phase III multi-institutional trial of adjuvant chemotherapy with paclitaxel, estramustine, and oral etoposide combined with long-term androgen suppression therapy and radiotherapy versus long-term androgen suppression plus radiotherapy alone for high-risk prostate cancer: preliminary toxicity analysis of RTOG 99-02. Int J Radiat Oncol Biol Phys. 2009 Mar 1;73(3):672-8. Epub 2008 Nov 5. [https://doi.org/10.1016/j.ijrobp.2008.05.020 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18990504 PubMed]<br />
##'''Update:''' Rosenthal SA, Hunt D, Sartor AO, Pienta KJ, Gomella L, Grignon D, Rajan R, Kerlin KJ, Jones CU, Dobelbower M, Shipley WU, Zeitzer K, Hamstra DA, Donavanik V, Rotman M, Hartford AC, Michalski J, Seider M, Kim H, Kuban DA, Moughan J, Sandler H. A phase 3 trial of 2 years of androgen suppression and radiation therapy with or without adjuvant chemotherapy for high-risk prostate cancer: final results of radiation therapy oncology group phase 3 randomized trial NRG Oncology RTOG 9902. Int J Radiat Oncol Biol Phys. 2015 Oct 1;93(2):294-302. Epub 2015 Jul 21. [https://www.redjournal.org/article/S0360-3016(15)00552-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719152/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26209502 PubMed]<br />
#'''EORTC 22961:''' Bolla M, de Reijke TM, Van Tienhoven G, Van den Bergh AC, Oddens J, Poortmans PM, Gez E, Kil P, Akdas A, Soete G, Kariakine O, van der Steen-Banasik EM, Musat E, Piérart M, Mauer ME, Collette L; [[Study_Groups#EORTC|EORTC]] Radiation Oncology Group; [[Study_Groups#EORTC|EORTC]] Genito-Urinary Tract Cancer Group. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med. 2009 Jun 11;360(24):2516-27. [https://www.nejm.org/doi/10.1056/NEJMoa0810095 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19516032 PubMed] NCT00003026<br />
#'''NCIC-CTG PR.3/UK MRC PR07:''' Warde P, Mason M, Ding K, Kirkbride P, Brundage M, Cowan R, Gospodarowicz M, Sanders K, Kostashuk E, Swanson G, Barber J, Hiltz A, Parmar MK, Sathya J, Anderson J, Hayter C, Hetherington J, Sydes MR, Parulekar W; NCIC; MRC. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011 Dec 17;378(9809):2104-11. Epub 2011 Nov 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61095-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243932/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22056152 PubMed] NCT00002633<br />
#'''RTOG 9910:''' Pisansky TM, Hunt D, Gomella LG, Amin MB, Balogh AG, Chinn DM, Seider MJ, Duclos M, Rosenthal SA, Bauman GS, Gore EM, Rotman MZ, Lukka HR, Shipley WU, Dignam JJ, Sandler HM. Duration of androgen suppression before radiotherapy for localized prostate cancer: Radiation Therapy Oncology Group randomized clinical trial 9910. J Clin Oncol. 2015 Feb 1;33(4):332-9. Epub 2014 Dec 22. [https://doi.org/10.1200/JCO.2014.58.0662 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302214/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25534388 PubMed] NCT00005044<br />
#'''DART01/05 GICOR:''' Zapatero A, Guerrero A, Maldonado X, Alvarez A, Gonzalez San Segundo C, Cabeza Rodríguez MA, Macias V, Pedro Olive A, Casas F, Boladeras A, de Vidales CM, Vazquez de la Torre ML, Villà S, Perez de la Haza A, Calvo FA. High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Mar;16(3):320-7. Epub 2015 Feb 19. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70045-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25702876 PubMed] NCT02175212<br />
#'''EORTC 22991:''' Bolla M, Maingon P, Carrie C, Villa S, Kitsios P, Poortmans PM, Sundar S, van der Steen-Banasik EM, Armstrong J, Bosset JF, Herrera FG, Pieters B, Slot A, Bahl A, Ben-Yosef R, Boehmer D, Scrase C, Renard L, Shash E, Coens C, van den Bergh AC, Collette L. Short androgen suppression and radiation dose escalation for intermediate- and high-risk localized prostate cancer: results of EORTC trial 22991. J Clin Oncol. 2016 May 20;34(15):1748-56. Epub 2016 Mar 14. [https://doi.org/10.1200/JCO.2015.64.8055 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26976418 PubMed] NCT00021450<br />
#'''PCS IV:''' Nabid A, Carrier N, Martin AG, Bahary JP, Lemaire C, Vass S, Bahoric B, Archambault R, Vincent F, Bettahar R, Duclos M, Garant MP, Souhami L. Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial. Eur Urol. 2018 Oct;74(4):432-441. Epub 2018 Jul 3. [https://www.europeanurology.com/article/S0302-2838(18)30443-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29980331 PubMed] NCT00223171<br />
#Malone S, Roy S, Eapen L, E C, MacRae R, Perry G, Bowen J, Samant R, Morgan S, Craig J, Malone K, Grimes S. Sequencing of Androgen-Deprivation Therapy With External-Beam Radiotherapy in Localized Prostate Cancer: A Phase III Randomized Controlled Trial. J Clin Oncol. 2020 Feb 20;38(6):593-601. Epub 2019 Dec 12. Erratum in: J Clin Oncol. 2020 Jun 10;38(17):2005. [https://doi.org/10.1200/jco.19.01904 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7186584/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31829912/ PubMed]<br />
#'''PCS III:''' Nabid A, Carrier N, Vigneault E, Van Nguyen T, Vavassis P, Brassard MA, Bahoric B, Archambault R, Vincent F, Bettahar R, Wilke D, Souhami L. Androgen deprivation therapy and radiotherapy in intermediate-risk prostate cancer: A randomised phase III trial. Eur J Cancer. 2021 Jan;143:64-74. Epub 2020 Dec 3. [https://doi.org/10.1016/j.ejca.2020.10.023 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33279855/ PubMed] NCT00223145<br />
<br />
==Flutamide, Goserelin, RT {{#subobject:2 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Flutamide, Goserelin, RT: Flutamide, Goserelin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:2 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.goldjournal.net/article/S0090-4295(99)80053-3/pdf Pilepich et al. 1995]<br />
|1987-1991<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|[http://www.redjournal.org/article/S0360-3016(01)01579-6/fulltext Pilepich et al. 2001 (RTOG 86-10)]<br />
|1987-1991<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#91cf60" |Seems to have superior cause-specific mortality<br />
|-<br />
|[https://doi.org/10.1200/jco.2003.11.023 Hanks et al. 2003 (RTOG 92-02)]<br />
|1992-1995<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1012348 Jones et al. 2011 (RTOG 94-08)]<br />
|1994-2001<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/299/3/289.long D'Amico et al. 2008 (DFCI 95-096)]<br />
|1995-2001<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70348-X/abstract Denham et al. 2005 (TTROG 96.01)]<br />
| rowspan="2" |1996-2000<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. Flutamide & Goserelin x 6 mo, RT<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#1a9850" |Superior EFS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]] 250 mg PO three times per day<br />
*[[Goserelin (Zoladex)]] 3.6 mg SC once on day 1<br />
<br />
'''28-day cycles, starting 2 months prior to radiation therapy and continuing at least through the end of radiation therapy'''<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] is started 2 months after start of androgen deprivation therapy (ADT), 1.8 to 2 Gy per fraction, with an initial 44 to 46 Gy to the pelvis, then an additional conedown to the prostate that resulted in a total dose of 65 to 70 Gy<br />
<br />
'''7-week course'''<br />
<br />
====Subsequent treatment====<br />
<br />
*RTOG 92-02: [[#Goserelin_monotherapy|adjuvant goserelin]] x 2 y versus [[Prostate_cancer_-_null_regimens#Observation|no further treatment]]<br />
<br />
===References===<br />
<br />
#Pilepich MV, Krall JM, al-Sarraf M, John MJ, Doggett RL, Sause WT, Lawton CA, Abrams RA, Rotman M, Rubin P, Soloway MS; Radiation Therapy Oncology Group. Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology. 1995 Apr;45(4):616-23. [https://www.goldjournal.net/article/S0090-4295(99)80053-3/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7716842 PubMed]<br />
#'''RTOG 86-10:''' Pilepich MV, Winter K, John MJ, Mesic JB, Sause W, Rubin P, Lawton C, Machtay M, Grignon D. Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 2001 Aug 1;50(5):1243-52. [http://www.redjournal.org/article/S0360-3016(01)01579-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11483335 PubMed]<br />
##'''Update:''' Roach M 3rd, Bae K, Speight J, Wolkov HB, Rubin P, Lee RJ, Lawton C, Valicenti R, Grignon D, Pilepich MV. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J Clin Oncol. 2008 Feb 1;26(4):585-91. Epub 2008 Jan 2. [https://doi.org/10.1200/jco.2007.13.9881 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18172188 PubMed]<br />
#'''RTOG 92-02:''' Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, Horwitz EM, Lawton C, Rosenthal SA, Sandler HM, Shipley WU; Radiation Therapy Oncology Group. Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol. 2003 Nov 1;21(21):3972-8. Erratum in: J Clin Oncol. 2004 Jan 15;22(2):386. [https://doi.org/10.1200/jco.2003.11.023 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14581419 PubMed]<br />
##'''Update:''' Horwitz EM, Bae K, Hanks GE, Porter A, Grignon DJ, Brereton HD, Venkatesan V, Lawton CA, Rosenthal SA, Sandler HM, Shipley WU. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol. 2008 May 20;26(15):2497-504. Epub 2008 Apr 14. [https://doi.org/10.1200/jco.2007.14.9021 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18413638 PubMed]<br />
##'''Update:''' Lawton CAF, Lin X, Hanks GE, Lepor H, Grignon DJ, Brereton HD, Bedi M, Rosenthal SA, Zeitzer KL, Venkatesan VM, Horwitz EM, Pisansky TM, Kim H, Parliament MB, Rabinovitch R, Roach M 3rd, Kwok Y, Dignam JJ, Sandler HM. Duration of androgen deprivation in locally advanced prostate cancer: long-term update of NRG Oncology RTOG 9202. Int J Radiat Oncol Biol Phys. 2017 Jun 1;98(2):296-303. Epub 2017 Feb 12. [https://doi.org/10.1016/j.ijrobp.2017.02.004 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5603177/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28463149 PubMed]<br />
#'''TTROG 96.01:''' Denham JW, Steigler A, Lamb DS, Joseph D, Mameghan H, Turner S, Matthews J, Franklin I, Atkinson C, North J, Poulsen M, Christie D, Spry NA, Tai KH, Wynne C, Duchesne G, Kovacev O, D'Este C; Trans-Tasman Radiation Oncology Group. Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial. Lancet Oncol. 2005 Nov;6(11):841-50. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70348-X/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16257791 PubMed]<br />
##'''Update:''' Denham JW, Steigler A, Lamb DS, Joseph D, Turner S, Matthews J, Atkinson C, North J, Christie D, Spry NA, Tai KH, Wynne C, D'Este C. Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial. Lancet Oncol. 2011 May;12(5):451-9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70063-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21440505 PubMed]<br />
#'''DFCI 95-096:''' D'Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA. 2008 Jan 23;299(3):289-95. [http://jama.ama-assn.org/content/299/3/289.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18212313 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
##'''Update:''' D'Amico AV, Chen MH, Renshaw A, Loffredo M, Kantoff PW. Long-term Follow-up of a Randomized Trial of Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer. JAMA. 2015 Sep 22-29;314(12):1291-3. [https://jamanetwork.com/journals/jama/fullarticle/2442924 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26393854 PubMed]<br />
#'''RTOG 94-08:''' Jones CU, Hunt D, McGowan DG, Amin MB, Chetner MP, Bruner DW, Leibenhaut MH, Husain SM, Rotman M, Souhami L, Sandler HM, Shipley WU. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med. 2011 Jul 14;365(2):107-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1012348 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21751904 PubMed] NCT00002597<br />
<br />
==Flutamide, Leuprolide, RT {{#subobject:3 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Flutamide, Leuprolide, RT: Flutamide, Leuprolide, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen variant #1, 4 months of ADT {{#subobject:3 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1012348 Jones et al. 2011 (RTOG 94-08)]<br />
|1994-2001<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]] 250 mg PO three times per day, to start 2 months prior to radiation therapy<br />
*[[Leuprolide (Lupron)]] 7.5 mg SC once on day 1, to start 2 months prior to radiation therapy<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] is started 2 months after start of androgen deprivation therapy (ADT), 1.8 to 2 Gy per fraction, with an initial 44 to 46 Gy to the pelvis, then an additional conedown to the prostate that resulted in a total dose of 65 to 70 Gy<br />
<br />
===Regimen variant #2, 3 years of ADT {{#subobject:38huac |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/j.eururo.2012.03.053 Mottet et al. 2012 (TAP 32)]<br />
|2000-2003<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Flutamide_.26_Leuprolide|Flutamide & Leuprolide]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]] 750 mg/day PO for one month<br />
*[[Leuprolide (Lupron)]] 11.25 mg SC once on day 1<br />
<br />
'''3-month cycle for 12 cycles (3 years)'''<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] started within 90 days of initiation of ADT, as follows:<br />
**Pelvis: 44 to 48 Gy given in 25 fractions over 5 weeks<br />
**Prostate: 20 to 28 Gy boost given in 10 to 12 fractions over 15 to 20 days<br />
<br />
'''One course'''<br />
<br />
===Regimen variant #3, indefinite ADT {{#subobject:5bddaf |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61815-2/fulltext Widmark et al. 2008 (SPCG-7/SFUO-3)]<br />
|1996-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Flutamide & Leuprolide<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]] 250 mg PO three times per day, to start 3 months prior to radiation therapy<br />
*[[Leuprolide (Lupron)]] by one of the following, to start 3 months prior to radiation therapy:<br />
**3.75 mg SC once per month for 3 months<br />
**11.25 mg SC once<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] 50 Gy + 20 Gy boost (total dose minimum of 70 Gy)<br />
<br />
===References===<br />
<br />
#'''SPCG-7/SFUO-3:''' Widmark A, Klepp O, Solberg A, Damber JE, Angelsen A, Fransson P, Lund JA, Tasdemir I, Hoyer M, Wiklund F, Fosså SD; Scandinavian Prostate Cancer Group; Swedish Association for Urological Oncology. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet. 2009 Jan 24;373(9660):301-8. Epub 2008 Dec 16. Erratum in: Lancet. 2009 Apr 4;373(9670):1174. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61815-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19091394 PubMed] ISRCTN01534787<br />
#'''RTOG 94-08:''' Jones CU, Hunt D, McGowan DG, Amin MB, Chetner MP, Bruner DW, Leibenhaut MH, Husain SM, Rotman M, Souhami L, Sandler HM, Shipley WU. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med. 2011 Jul 14;365(2):107-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1012348 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21751904 PubMed] NCT00002597<br />
#'''TAP 32:''' Mottet N, Peneau M, Mazeron JJ, Molinie V, Richaud P. Addition of radiotherapy to long-term androgen deprivation in locally advanced prostate cancer: an open randomised phase 3 trial. Eur Urol. 2012 Aug;62(2):213-9. Epub 2012 Apr 3. [https://doi.org/10.1016/j.eururo.2012.03.053 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22502942 PubMed] NCT01122121<br />
##'''Update:''' Sargos P, Mottet N, Bellera C, Richaud P. Long-term androgen deprivation, with or without radiotherapy, in locally advanced prostate cancer: updated results from a phase III randomised trial. BJU Int. 2020 Jun;125(6):810-816. Epub 2020 Mar 2. [https://doi.org/10.1111/bju.14768 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30946523 PubMed]<br />
<br />
==Goserelin & RT {{#subobject:1 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
Goserelin & RT: Goserelin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
<br />
===Regimen {{#subobject:1 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.1997.15.3.1013 Pilepich et al. 2005 (RTOG 85-31)]<br />
|1987-1992<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199707313370502 Bolla et al. 1997 (EORTC 22863)]<br />
|1987-1995<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_historical#Radiation_therapy|RT]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Goserelin (Zoladex)]] 3.6 mg SC once on day 1, started during the last week of radiation therapy<br />
<br />
'''28-day cycles'''<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]], 1.8 to 2 Gy per fraction, with an initial 44 to 46 Gy to the pelvis, then an additional boost to the prostate that resulted in a total dose of 65 to 70 Gy in definitive radiation patients; 60 to 65 Gy total dose for post-prostatectomy patients<br />
<br />
'''One course'''<br />
<br />
===References===<br />
<br />
#'''RTOG 85-31:''' Pilepich MV, Caplan R, Byhardt RW, Lawton CA, Gallagher MJ, Mesic JB, Hanks GE, Coughlin CT, Porter A, Shipley WU, Grignon D. Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group protocol 85-31. J Clin Oncol. 1997 Mar;15(3):1013-21. [https://doi.org/10.1200/jco.1997.15.3.1013 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9060541 PubMed]<br />
##'''Update:''' Lawton CA, Winter K, Murray K, Machtay M, Mesic JB, Hanks GE, Coughlin CT, Pilepich MV. Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 2001 Mar 15;49(4):937-46. [http://www.redjournal.org/article/S0360-3016%2800%2901516-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11240234 PubMed]<br />
##'''Update:''' Pilepich MV, Winter K, Lawton CA, Krisch RE, Wolkov HB, Movsas B, Hug EB, Asbell SO, Grignon D. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1285-90. [http://www.redjournal.org/article/S0360-3016(04)02468-X/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15817329 PubMed]<br />
#'''EORTC 22863:''' Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Gil T, Collette L, Pierart M. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med. 1997 Jul 31;337(5):295-300. [https://www.nejm.org/doi/full/10.1056/NEJM199707313370502 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9233866 PubMed]<br />
##'''Update:''' Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Mattelaer J, Lopez Torecilla J, Pfeffer JR, Lino Cutajar C, Zurlo A, Pierart M. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet. 2002 Jul 13;360(9327):103-6. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)09408-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12126818 PubMed]<br />
##'''Update:''' Bolla M, Van Tienhoven G, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Billiet I, Torecilla JL, Pfeffer R, Cutajar CL, Van der Kwast T, Collette L. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol. 2010 Nov;11(11):1066-73. Epub 2010 Oct 7. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70223-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20933466 PubMed]<br />
<br />
=Adjuvant therapy=<br />
==Bicalutamide & Goserelin {{#subobject:611758|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:bdfd60|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107759/ Dorff et al. 2011 (SWOG S9921)]<br />
|2000-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ADT & Mitoxantrone<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Dosing details are not available in the manuscript; this is the common dosing used.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Radical_prostatectomy|Radical prostatectomy]]<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Bicalutamide (Casodex)]] 50 mg PO once per day<br />
*[[Goserelin (Zoladex)]] 10.8 mg SC once on day 1<br />
<br />
'''12-week cycle for 9 cycles (2 years)'''<br />
<br />
===References===<br />
<br />
#'''SWOG S9921:''' Dorff TB, Flaig TW, Tangen CM, Hussain MH, Swanson GP, Wood DP Jr, Sakr WA, Dawson NA, Haas NB, Crawford ED, Vogelzang NJ, Thompson IM, Glode LM. Adjuvant androgen deprivation for high-risk prostate cancer after radical prostatectomy: SWOG S9921 study. J Clin Oncol. 2011 May 20;29(15):2040-5. Epub 2011 Apr 18. [https://doi.org/10.1200/JCO.2010.32.2776 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107759/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21502546 PubMed] NCT00004124<br />
<br />
==Goserelin monotherapy {{#subobject:267ff5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:53d064|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199912093412401 Messing et al. 1999 (ECOG E3886)]<br />
|1988-1993<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_null_regimens#Observation|No further treatment]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://doi.org/10.1200/jco.2003.11.023 Hanks et al. 2003 (RTOG 92-02)]<br />
|1992-1995<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_null_regimens#Observation|No further treatment]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy of RTOG 92-02 based on the 2017 update.''<br />
====Preceding treatment====<br />
<br />
*ECOG E3886: [[Surgery#Radical_prostatectomy|Radical prostatectomy]]<br />
*RTOG 92-02: [[#Flutamide.2C_Goserelin.2C_RT|Flutamide, Goserelin, RT]]<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Goserelin (Zoladex)]] 3.6 mg SC once per month<br />
<br />
'''2-year course (RTOG 92-02) or until rising PSA detected (ECOG E3886)'''<br />
<br />
===References===<br />
<br />
#'''ECOG E3886:''' Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D; [[Study_Groups#ECOG|ECOG]]. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 1999 Dec 9;341(24):1781-8. [https://www.nejm.org/doi/full/10.1056/NEJM199912093412401 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10588962 PubMed]<br />
##'''Update:''' Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, di'SantAgnese PA, Trump D; [[Study_Groups#ECOG|ECOG]]. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol. 2006 Jun;7(6):472-9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(06)70700-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16750497 PubMed]<br />
#'''RTOG 92-02:''' Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, Horwitz EM, Lawton C, Rosenthal SA, Sandler HM, Shipley WU; Radiation Therapy Oncology Group. Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol. 2003 Nov 1;21(21):3972-8. Erratum in: J Clin Oncol. 2004 Jan 15;22(2):386. [https://doi.org/10.1200/jco.2003.11.023 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14581419 PubMed]<br />
##'''Update:''' Horwitz EM, Bae K, Hanks GE, Porter A, Grignon DJ, Brereton HD, Venkatesan V, Lawton CA, Rosenthal SA, Sandler HM, Shipley WU. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol. 2008 May 20;26(15):2497-504. Epub 2008 Apr 14. [https://doi.org/10.1200/jco.2007.14.9021 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18413638 PubMed]<br />
##'''Update:''' Lawton CAF, Lin X, Hanks GE, Lepor H, Grignon DJ, Brereton HD, Bedi M, Rosenthal SA, Zeitzer KL, Venkatesan VM, Horwitz EM, Pisansky TM, Kim H, Parliament MB, Rabinovitch R, Roach M 3rd, Kwok Y, Dignam JJ, Sandler HM. Duration of androgen deprivation in locally advanced prostate cancer: long-term update of NRG Oncology RTOG 9202. Int J Radiat Oncol Biol Phys. 2017 Jun 1;98(2):296-303. Epub 2017 Feb 12. [https://doi.org/10.1016/j.ijrobp.2017.02.004 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5603177/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28463149 PubMed]<br />
<br />
==Triptorelin & RT {{#subobject:611758|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:bdfd60|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30454-X/fulltext/ Sargos et al. 2020 (GETUG-AFU 17)]<br />
|2008-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Triptorelin & RT; salvage<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS<br />
|-<br />
|}<br />
''Statistical power was compromised due to unexpectedly low event rate. GETUG-AFU 17 was published concurrently along with two other Phase III trials looking at timing of radiotherapy following radical prostatectomy: [https://pubmed.ncbi.nlm.nih.gov/33002429/ RADICALS-RT] and [https://pubmed.ncbi.nlm.nih.gov/33002437/ ANZUP RAVES]. All three trials were also analyzed as part of a pre-planned meta-analysis [https://pubmed.ncbi.nlm.nih.gov/33002431/ ARTISTIC] which failed to show an EFS benefit with adjuvant radiotherapy vs. salvage radiotherapy.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Radical_prostatectomy|Radical prostatectomy]]<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Triptorelin (Trelstar LA)]] 11.25 mg IM once on day 1<br />
<br />
'''12-week cycle for 2 cycles (6 months)'''<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]]<br />
<br />
===References===<br />
<br />
#'''GETUG-AFU 17:''' Sargos P, Chabaud S, Latorzeff I, Magne N, Benyoucef A, Supiot S, Pasquier D, Abdiche MS, Gilliot O, Graff-Cailleaud P, Silva M, Bergerot P, Baumann P, Belkacemi Y, Azria D, Brihoum M, Soulie M, Richaud P. Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localized prostate cancer after radical prostatectomy (GETUG-AFU 17): a randomised, phase 3 trial. Lancet Oncol. 2020 Oct; 21(10):1341-1352. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30454-X/fulltext link to original article] '''does not contain protocol''' [https://pubmed.ncbi.nlm.nih.gov/33002438/ PubMed] NCT00667069<br />
<br />
=Salvage ADT & radiotherapy=<br />
==Bicalutamide & RT {{#subobject:2c64f0 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Bicalutamide & RT: Bicalutamide & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:4f2e28 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444881/ Shipley et al. 2017 (RTOG 9601)]<br />
|1998-2003<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|RT<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Prostatectomy|Prostatectomy]] with [[Surgery#Lymphadenectomy|lymphadenectomy]], with a postoperative detectable PSA level of 0.2 to 4.0 ng/mL<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Bicalutamide (Casodex)]] 150 mg PO once per day<br />
<br />
'''2-year course'''<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]], 64.8 Gy in 36 daily fractions of 1.8 Gy<br />
<br />
'''7-week course'''<br />
<br />
===References===<br />
<br />
#'''RTOG 9601:''' Shipley WU, Seiferheld W, Lukka HR, Major PP, Heney NM, Grignon DJ, Sartor O, Patel MP, Bahary JP, Zietman AL, Pisansky TM, Zeitzer KL, Lawton CA, Feng FY, Lovett RD, Balogh AG, Souhami L, Rosenthal SA, Kerlin KJ, Dignam JJ, Pugh SL, Sandler HM; NRG Oncology RTOG. Radiation with or without antiandrogen therapy in recurrent prostate cancer. N Engl J Med. 2017 Feb 2;376(5):417-428. [https://www.nejm.org/doi/full/10.1056/NEJMoa1607529 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444881/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28146658 PubMed] NCT00002874<br />
<br />
==Goserelin & RT {{#subobject:88575c |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Goserelin & RT: Goserelin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:fac0bd |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00111-X/fulltext Carrie et al. 2016 (GETUG-AFU 16)]<br />
|2006-2010<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Salvage RT<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Prostatectomy|Prostatectomy]], with rising PSA<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Goserelin (Zoladex)]] 0.8 mg SC once on day 1<br />
<br />
'''3-month cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]], 66 Gy in 33 daily fractions of 2 Gy<br />
<br />
'''7-week course'''<br />
<br />
===References===<br />
<br />
#'''GETUG-AFU 16:''' Carrie C, Hasbini A, de Laroche G, Richaud P, Guerif S, Latorzeff I, Supiot S, Bosset M, Lagrange JL, Beckendorf V, Lesaunier F, Dubray B, Wagner JP, N'Guyen TD, Suchaud JP, Créhange G, Barbier N, Habibian M, Ferlay C, Fourneret P, Ruffion A, Dussart S. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2016 Jun;17(6):747-756. Epub 2016 May 6. Erratum in: Lancet Oncol. 2016 Jun;17 (6):e223. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00111-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27160475 PubMed] NCT00423475<br />
##'''Update:''' Carrie C, Magné N, Burban-Provost P, Sargos P, Latorzeff I, Lagrange JL, Supiot S, Belkacemi Y, Peiffert D, Allouache N, Dubray BM, Servagi-Vernat S, Suchaud JP, Crehange G, Guerif S, Brihoum M, Barbier N, Graff-Cailleaud P, Ruffion A, Dussart S, Ferlay C, Chabaud S. Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial. Lancet Oncol. 2019 Dec;20(12):1740-1749. Epub 2019 Oct 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30486-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31629656 PubMed]<br />
<br />
<br /><br />
=Hormonal therapy for non-metastatic castrate sensitive disease=<br />
==ADT {{#subobject:6e0da9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:0415d3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jamaoncology/article-abstract/2723273 Oudard et al. 2019 (RisingPSA)]<br />
|2003-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ADT & Docetaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PSA-PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00107-8/fulltext Duchesne et al. 2016 (TOAD)]<br />
|2004-2012<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|Delayed ADT<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(15)00977-X/fulltext Schulman et al. 2015 (ICELAND)]<br />
|2006-NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Intermittent ADT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP<br />
|-<br />
|}<br />
''Note: these are clinical trials that did not specify a particular drug to be used for androgen deprivation. See papers for details.''<br />
====Endocrine therapy====<br />
<br />
*[[:Category:GnRH agonists|LHRH agonist]]<br />
*[[Bicalutamide (Casodex)]] or [[Flutamide (Eulexin)]]<br />
<br />
'''12-month course (RisingPSA) or continued indefinitely'''<br />
===References===<br />
<br />
#'''ICELAND:''' Schulman C, Cornel E, Matveev V, Tammela TL, Schraml J, Bensadoun H, Warnack W, Persad R, Salagierski M, Gómez Veiga F, Baskin-Bey E, López B, Tombal B. Intermittent versus continuous androgen deprivation therapy in patients with relapsing or locally advanced prostate cancer: a phase 3b randomised study (ICELAND). Eur Urol. 2016 Apr;69(4):720-727. Epub 2015 Oct 29. [https://www.europeanurology.com/article/S0302-2838(15)00977-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26520703 PubMed] NCT00378690<br />
#'''TOAD:''' Duchesne GM, Woo HH, Bassett JK, Bowe SJ, D'Este C, Frydenberg M, King M, Ledwich L, Loblaw A, Malone S, Millar J, Milne R, Smith RG, Spry N, Stockler M, Syme RA, Tai KH, Turner S. Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Lancet Oncol. 2016 Jun;17(6):727-737. Epub 2016 May 4. Erratum in: Lancet Oncol. 2016 Jun;17 (6):e223. Lancet Oncol. 2017 Sep;18(9):e510. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00107-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27155740 PubMed] NCT00110162<br />
#'''RisingPSA:''' Oudard S, Latorzeff I, Caty A, Miglianico L, Sevin E, Hardy-Bessard AC, Delva R, Rolland F, Mouret L, Priou F, Beuzeboc P, Gravis G, Linassier C, Gomez P, Voog E, Muracciole X, Abraham C, Banu E, Ferrero JM, Ravaud A, Krakowski I, Lagrange JL, Deplanque G, Zylberait D, Bozec L, Houede N, Culine S, Elaidi R. Effect of adding docetaxel to androgen-deprivation therapy in patients with high-risk prostate cancer with rising prostate-specific antigen levels after primary local therapy: a randomized clinical trial. JAMA Oncol. 2019 May 1;5(5):623-632. Epub 2019 Jan 31. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2723273 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512307/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30703190 PubMed] NCT00764166<br />
<br />
=Hormonal therapy for non-metastatic castrate resistant disease=<br />
==ADT {{#subobject:68ajcbz|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:0a9b7x3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1715546 Smith et al. 2017 (SPARTAN)]<br />
|2013-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_Apalutamide|ADT & Apalutamide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup><br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1800536 Hussain et al. 2018 (PROSPER)]<br />
|2013-2017<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_Enzalutamide|ADT & Enzalutamide]]<br />
| style="background-color:#d73027" |Inferior MFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1815671 Fizazi et al. 2019 (ARAMIS)]<br />
|2014-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_Darolutamide|ADT & Darolutamide]]<br />
| style="background-color:#d73027" |Inferior OS<sup>2</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for SPARTAN is based on the 2019 update.''<br><br />
''<sup>2</sup>Reported efficacy for ARAMIS is based on the 2020 update.''<br><br />
''Note: these are clinical trials that did not specify a particular drug to be used for androgen deprivation. See papers for details.''<br />
====Endocrine therapy====<br />
<br />
*[[:Category:GnRH_agonists|GnRH agonist]] or [[:Category:GnRH antagonists|GnRH antagonist]] or a history of [[Endocrine_ablation_surgery#Bilateral_orchiectomy|bilateral orchiectomy]]<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
<br />
#'''SPARTAN:''' Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, Lopez-Gitlitz A, Trudel GC, Espina BM, Shu Y, Park YC, Rackoff WR, Yu MK, Small EJ; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018 Apr 12;378(15):1408-1418. [https://www.nejm.org/doi/10.1056/NEJMoa1715546 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1715546/suppl_file/nejmoa1715546_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29420164 PubMed] NCT01946204<br />
##'''Update:''' Small EJ, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, De Porre P, Smith AA, Zhang K, Lopez-Gitlitz A, Smith MR. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. Ann Oncol. 2019 Nov 1;30(11):1813-1820. [https://doi.org/10.1093/annonc/mdz397 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927320/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/31560066 PubMed]<br />
#'''PROSPER:''' Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, Ivashchenko P, Demirhan E, Modelska K, Phung D, Krivoshik A, Sternberg CN. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018 Jun 28;378(26):2465-2474. [https://www.nejm.org/doi/full/10.1056/NEJMoa1800536 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29949494 PubMed]<br />
#'''ARAMIS:''' Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Kappeler C, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019 Mar 28;380(13):1235-1246. Epub 2019 Feb 14. [https://www.nejm.org/doi/full/10.1056/NEJMoa1815671 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30763142 PubMed] NCT02200614<br />
##'''Update:''' Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Le Berre MA, Petrenciuc O, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. N Engl J Med. 2020 Sep 10;383(11):1040-1049. [https://doi.org/10.1056/nejmoa2001342 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32905676 PubMed]<br />
<br />
==ADT & Apalutamide {{#subobject:a70eae |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT & Apalutamide: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy & Apalutamide<br />
===Regimen {{#subobject:#e085c7 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJMoa1715546 Smith et al. 2017 (SPARTAN)]<br />
|2013-2016<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup> <br>(HR 0.75, 95% CI 0.59-0.96)<br />
|-<br />
|}<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Metastasis-free survival<br />
! style="width: 33%" |Comparator metastasis-free survival<br />
! style="width: 33%" |Pt Population<br />
|-<br />
|40.5 months<br />
|16.2 months<br />
|Castrate-resistant, non-metastatic, PSA doubling time <10 months<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2019 update.''<br />
====Endocrine therapy====<br />
<br />
*[[Apalutamide (Erleada)]] 240 mg PO once per day<br />
*Patients should concurrently be receiving [[:Category:GnRH_agonists|GnRH analog]] or have had [[Endocrine_ablation_surgery#Bilateral_orchiectomy|bilateral orchiectomy]]<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''SPARTAN:''' Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, Lopez-Gitlitz A, Trudel GC, Espina BM, Shu Y, Park YC, Rackoff WR, Yu MK, Small EJ; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018 Apr 12;378(15):1408-1418. [https://www.nejm.org/doi/10.1056/NEJMoa1715546 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1715546/suppl_file/nejmoa1715546_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29420164 PubMed] NCT01946204<br />
##'''Update:''' Small EJ, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, De Porre P, Smith AA, Zhang K, Lopez-Gitlitz A, Smith MR. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. Ann Oncol. 2019 Nov 1;30(11):1813-1820. [https://doi.org/10.1093/annonc/mdz397 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927320/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/31560066 PubMed]<br />
<br />
==ADT & Darolutamide {{#subobject:d39ncb |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:#9276df |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1815671 Fizazi et al. 2019 (ARAMIS)]<br />
|2014-2018<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#1a9850" |Superior OS<sup>1</sup> <br>(HR 0.69, 95% CI 0.53-0.88)<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2020 update.''<br />
====Endocrine therapy====<br />
<br />
*[[:Category:GnRH_agonists|GnRH agonist]] or [[:Category:GnRH antagonists|GnRH antagonist]]<br />
*[[Darolutamide (Nubeqa)]] 600 mg PO twice per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''ARAMIS:''' Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Kappeler C, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019 Mar 28;380(13):1235-1246. Epub 2019 Feb 14. [https://www.nejm.org/doi/full/10.1056/NEJMoa1815671 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30763142 PubMed] NCT02200614<br />
##'''Update:''' Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Le Berre MA, Petrenciuc O, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. N Engl J Med. 2020 Sep 10;383(11):1040-1049. [https://doi.org/10.1056/nejmoa2001342 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32905676 PubMed]<br />
<br />
==ADT & Enzalutamide {{#subobject:d34e0b |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT & Enzalutamide: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy & Enzalutamide<br />
===Regimen {{#subobject:#80614f |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1800536 Hussain et al. 2018 (PROSPER)]<br />
|2013-2017<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#1a9850" |Superior MFS<br />
|-<br />
|}<br />
''Patients had castrate-resistant, non-metastatic, prostate cancer with PSA doubling time less than 10 months.''<br />
====Endocrine therapy====<br />
<br />
*[[Enzalutamide (Xtandi)]] 160 mg PO once per day<br />
*Patients should concurrently be receiving [[:Category:GnRH_agonists|GnRH agonist]] or [[:Category:GnRH antagonists|GnRH antagonist]] or have had [[Endocrine_ablation_surgery#Bilateral_orchiectomy|bilateral orchiectomy]]<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''PROSPER:''' Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, Ivashchenko P, Demirhan E, Modelska K, Phung D, Krivoshik A, Sternberg CN. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018 Jun 28;378(26):2465-2474. [https://www.nejm.org/doi/full/10.1056/NEJMoa1800536 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29949494 PubMed]<br />
<br />
=Hormonal therapy for metastatic or locally advanced disease=<br />
==ADT {{#subobject:45fc98|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:bd66bd|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.auajournals.org/doi/full/10.1097/01.ju.0000135742.13171.d2 Schröder et al. 2004 (EORTC 30846)]<br />
|1986-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Delayed ADT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00011-X/fulltext Fizazi et al. 2015 (GETUG 12)]<br />
|2002-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT.2C_Docetaxel.2C_Estramustine|ADT, Docetaxel, Estramustine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior RFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70560-0/fulltext Gravis et al. 2013 (GETUG-AFU 15)]<br />
|2004-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_Docetaxel|ADT & Docetaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398767/ James et al. 2012 (STAMPEDE)]<br />
|2005-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ADT & Celecoxib<br />
| style="background-color:#ffffbf" |Did not meet intermediate primary endpoint of FFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800035/ James et al. 2015 (STAMPEDE)]<br />
|2005-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_Docetaxel|ADT & Docetaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533216 James et al. 2017 (STAMPEDE)]<br />
|2005-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_Abiraterone|ADT & Abiraterone]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4562797/ Sweeney et al. 2015 (CHAARTED)]<br />
|2006-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_Docetaxel|ADT & Docetaxel]]<br />
| style="background-color:#d73027" |Inferior OS<sup>1</sup><br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs10147-016-1037-2 Kamba et al. 2016 (ZAPCA)]<br />
|2008-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ADT & Zoledronic acid<br />
| style="background-color:#fee08b" |Might have inferior TTTF<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1704174 Fizazi et al. 2017 (LATITUDE)]<br />
|2013-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADT_.26_Abiraterone|ADT & Abiraterone]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''<sup>1</sup>In the 2018 update of CHAARTED, only patients with high-volume disease had inferior survival in the control arm.''<br><br />
''Note: these are clinical trials that did not specify a particular therapy to be used for androgen deprivation. See papers for details; the below are examples.''<br />
====Endocrine therapy====<br />
<br />
*ADT with ONE of the following:<br />
**[[:Category:GnRH agonists|LHRH agonist/analogue]]<br />
**[[:Category:GnRH antagonists|LHRH antagonist]]<br />
**[[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]]<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''EORTC 30846:''' Schröder FH, Kurth KH, Fosså SD, Hoekstra W, Karthaus PP, Debois M, Collette L; European Organisation for the Research and Treatment of Cancer Genito-urinary Group. Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local treatment of the primary tumor: results of European Organisation for the Research and Treatment of Cancer 30846--a phase III study. J Urol. 2004 Sep;172(3):923-7. [https://www.auajournals.org/doi/full/10.1097/01.ju.0000135742.13171.d2 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15310999 PubMed]<br />
#'''STAMPEDE:''' James ND, Sydes MR, Mason MD, Clarke NW, Anderson J, Dearnaley DP, Dwyer J, Jovic G, Ritchie AW, Russell JM, Sanders K, Thalmann GN, Bertelli G, Birtle AJ, O'Sullivan JM, Protheroe A, Sheehan D, Srihari N, Parmar MK; STAMPEDE Investigators. Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial. Lancet Oncol. 2012 May;13(5):549-58. Epub 2012 Mar 26. Erratum in: Lancet Oncol. 2013 Jan;14(1):e5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70088-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398767/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22452894 PubMed] NCT00268476<br />
#'''GETUG-AFU 15:''' Gravis G, Fizazi K, Joly F, Oudard S, Priou F, Esterni B, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Théodore C, Deplanque G, Ferrero JM, Pouessel D, Mourey L, Beuzeboc P, Zanetta S, Habibian M, Berdah JF, Dauba J, Baciuchka M, Platini C, Linassier C, Labourey JL, Machiels JP, El Kouri C, Ravaud A, Suc E, Eymard JC, Hasbini A, Bousquet G, Soulie M. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Feb;14(2):149-58. Epub 2013 Jan 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70560-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23306100 PubMed] NCT00104715<br />
##'''Update:''' Gravis G, Boher JM, Joly F, Soulié M, Albiges L, Priou F, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Théodore C, Deplanque G, Ferrero JM, Culine S, Mourey L, Beuzeboc P, Habibian M, Oudard S, Fizazi K; GETUG. Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: Impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial. Eur Urol. 2016 Aug;70(2):256-62. Epub 2015 Nov 21. [http://www.europeanurology.com/article/S0302-2838(15)01103-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26610858 PubMed]<br />
#'''GETUG 12:''' Fizazi K, Faivre L, Lesaunier F, Delva R, Gravis G, Rolland F, Priou F, Ferrero JM, Houede N, Mourey L, Theodore C, Krakowski I, Berdah JF, Baciuchka M, Laguerre B, Fléchon A, Ravaud A, Cojean-Zelek I, Oudard S, Labourey JL, Chinet-Charrot P, Legouffe E, Lagrange JL, Linassier C, Deplanque G, Beuzeboc P, Davin JL, Martin AL, Habibian M, Laplanche A, Culine S. Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial. Lancet Oncol. 2015 Jul;16(7):787-94. Epub 2015 May 28. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00011-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26028518 PubMed] NCT00055731<br />
#'''CHAARTED:''' Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015 Aug 20;373(8):737-46. Epub 2015 Aug 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1503747 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4562797/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26244877 Pubmed] NCT00309985<br />
##'''Update:''' Kyriakopoulos CE, Chen YH, Carducci MA, Liu G, Jarrard DF, Hahn NM, Shevrin DH, Dreicer R, Hussain M, Eisenberger M, Kohli M, Plimack ER, Vogelzang NJ, Picus J, Cooney MM, Garcia JA, DiPaola RS, Sweeney CJ. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018 Apr 10;36(11):1080-1087. Epub 2018 Jan 31. [https://doi.org/10.1200/JCO.2017.75.3657 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891129/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29384722 PubMed]<br />
##'''QoL analysis:''' Morgans AK, Chen YH, Sweeney CJ, Jarrard DF, Plimack ER, Gartrell BA, Carducci MA, Hussain M, Garcia JA, Cella D, DiPaola RS, Patrick-Miller LJ. Quality of life during treatment with chemohormonal therapy: analysis of E3805 chemohormonal androgen ablation randomized trial in prostate cancer. J Clin Oncol. 2018 Apr 10;36(11):1088-1095. Epub 2018 Mar 9. [https://doi.org/10.1200/JCO.2017.75.3335 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891128/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29522362 PubMed]<br />
#'''STAMPEDE:''' James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, Ritchie AW, Parker CC, Russell JM, Attard G, de Bono J, Cross W, Jones RJ, Thalmann G, Amos C, Matheson D, Millman R, Alzouebi M, Beesley S, Birtle AJ, Brock S, Cathomas R, Chakraborti P, Chowdhury S, Cook A, Elliott T, Gale J, Gibbs S, Graham JD, Hetherington J, Hughes R, Laing R, McKinna F, McLaren DB, O'Sullivan JM, Parikh O, Peedell C, Protheroe A, Robinson AJ, Srihari N, Srinivasan R, Staffurth J, Sundar S, Tolan S, Tsang D, Wagstaff J, Parmar MK; STAMPEDE Investigators. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016 Mar 19;387(10024):1163-77. Epub 2015 Dec 21. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01037-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800035/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26719232 PubMed] NCT00268476<br />
##'''Update:''' Clarke NW, Ali A, Ingleby FC, Hoyle A, Amos CL, Attard G, Brawley CD, Calvert J, Chowdhury S, Cook A, Cross W, Dearnaley DP, Douis H, Gilbert D, Gillessen S, Jones RJ, Langley RE, MacNair A, Malik Z, Mason MD, Matheson D, Millman R, Parker CC, Ritchie AWS, Rush H, Russell JM, Brown J, Beesley S, Birtle A, Capaldi L, Gale J, Gibbs S, Lydon A, Nikapota A, Omlin A, O'Sullivan JM, Parikh O, Protheroe A, Rudman S, Srihari NN, Simms M, Tanguay JS, Tolan S, Wagstaff J, Wallace J, Wylie J, Zarkar A, Sydes MR, Parmar MKB, James ND. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol. 2019 Dec 1;30(12):1992-2003. [https://doi.org/10.1093/annonc/mdz396 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938598/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/31560068 PubMed]<br />
#'''ZAPCA:''' Kamba T, Kamoto T, Maruo S, Kikuchi T, Shimizu Y, Namiki S, Fujimoto K, Kawanishi H, Sato F, Narita S, Satoh T, Saito H, Sugimoto M, Teishima J, Masumori N, Egawa S, Sakai H, Okada Y, Terachi T, Ogawa O; ZAPCA Study Group. A phase III multicenter, randomized, controlled study of combined androgen blockade with versus without zoledronic acid in prostate cancer patients with metastatic bone disease: results of the ZAPCA trial. Int J Clin Oncol. 2017 Feb;22(1):166-173. Epub 2016 Sep 10. [https://link.springer.com/article/10.1007%2Fs10147-016-1037-2 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27614621 PubMed] NCT00685646<br />
#'''STAMPEDE:''' James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, Ritchie AWS, Amos CL, Gilson C, Jones RJ, Matheson D, Millman R, Attard G, Chowdhury S, Cross WR, Gillessen S, Parker CC, Russell JM, Berthold DR, Brawley C, Adab F, Aung S, Birtle AJ, Bowen J, Brock S, Chakraborti P, Ferguson C, Gale J, Gray E, Hingorani M, Hoskin PJ, Lester JF, Malik ZI, McKinna F, McPhail N, Money-Kyrle J, O'Sullivan J, Parikh O, Protheroe A, Robinson A, Srihari NN, Thomas C, Wagstaff J, Wylie J, Zarkar A, Parmar MKB, Sydes MR; STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017 Jul 27;377(4):338-351. Epub 2017 Jun 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1702900 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533216 link to PMC article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1702900/suppl_file/nejmoa1702900_protocol.pdf supplementary protocol] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/28578639 PubMed] NCT00268476<br />
#'''LATITUDE:''' Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, De Porre P, Kheoh T, Park YC, Todd MB, Chi KN; LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017 Jul 27;377(4):352-360. Epub 2017 Jun 4. [https://www.nejm.org/doi/full/10.1056/NEJMoa1704174 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1704174/suppl_file/nejmoa1704174_protocol.pdf supplementary protocol] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/28578607 PubMed]<br />
##'''HRQoL analysis:''' Chi KN, Protheroe A, Rodríguez-Antolín A, Facchini G, Suttman H, Matsubara N, Ye Z, Keam B, Damião R, Li T, McQuarrie K, Jia B, De Porre P, Martin J, Todd MB, Fizazi K. Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial. Lancet Oncol. 2018 Feb;19(2):194-206. Epub 2018 Jan 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30911-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29326030 PubMed]<br />
##'''Update:''' Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, Sulur G, Luna Y, Li S, Mundle S, Chi KN. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019 May;20(5):686-700. Epub 2019 Apr 12. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30082-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30987939 PubMed]<br />
<br />
==ADT & Abiraterone {{#subobject:02afb7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT & Abiraterone: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy & Abiraterone<br />
===Regimen {{#subobject:31ffca|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533216 James et al. 2017 (STAMPEDE)]<br />
|2005-2011<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1704174 Fizazi et al. 2017 (LATITUDE)]<br />
|2013-2014<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: while LATITUDE allowed for a dose increase in prednisone, the FDA recommended dose is 5 mg PO once per day.''<br />
====Endocrine therapy====<br />
<br />
*[[Abiraterone (Zytiga)]] 1000 mg PO once per day<br />
*ADT with ONE of the following:<br />
**[[:Category:GnRH agonists|LHRH agonist/analogue]]<br />
**'''STAMPEDE only:''' [[:Category:GnRH antagonists|LHRH antagonist]]<br />
**[[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]]<br />
<br />
====Supportive medications====<br />
<br />
*Prevention of mineralocorticoid excess with ONE of the following:<br />
**'''STAMPEDE except Switzerland:''' [[Prednisolone (Millipred)]] 5 mg PO once per day<br />
**'''LATITUDE and STAMPEDE in Switzerland:''' [[Prednisone (Sterapred)]] 5 mg PO once per day<br />
***'''LATITUDE:''' "dose increase of up to 10 mg/day is permitted to manage refractory mineralocorticoid related toxicities"<br />
<br />
'''Continued indefinitely unless radiotherapy planned, in which case continued for up to 2 years'''<br />
<br />
===References===<br />
<br />
#'''STAMPEDE:''' James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, Ritchie AWS, Amos CL, Gilson C, Jones RJ, Matheson D, Millman R, Attard G, Chowdhury S, Cross WR, Gillessen S, Parker CC, Russell JM, Berthold DR, Brawley C, Adab F, Aung S, Birtle AJ, Bowen J, Brock S, Chakraborti P, Ferguson C, Gale J, Gray E, Hingorani M, Hoskin PJ, Lester JF, Malik ZI, McKinna F, McPhail N, Money-Kyrle J, O'Sullivan J, Parikh O, Protheroe A, Robinson A, Srihari NN, Thomas C, Wagstaff J, Wylie J, Zarkar A, Parmar MKB, Sydes MR; STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017 Jul 27;377(4):338-351. Epub 2017 Jun 3. [https://www.nejm.org/doi/full/10.1056/NEJMoa1702900 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533216 link to PMC article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1702900/suppl_file/nejmoa1702900_protocol.pdf supplementary protocol] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/28578639 PubMed] NCT00268476<br />
#'''LATITUDE:''' Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, De Porre P, Kheoh T, Park YC, Todd MB, Chi KN; LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017 Jul 27;377(4):352-360. Epub 2017 Jun 4. [https://www.nejm.org/doi/full/10.1056/NEJMoa1704174 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1704174/suppl_file/nejmoa1704174_protocol.pdf supplementary protocol] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/28578607 PubMed]<br />
##'''HRQoL analysis:''' Chi KN, Protheroe A, Rodríguez-Antolín A, Facchini G, Suttman H, Matsubara N, Ye Z, Keam B, Damião R, Li T, McQuarrie K, Jia B, De Porre P, Martin J, Todd MB, Fizazi K. Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial. Lancet Oncol. 2018 Feb;19(2):194-206. Epub 2018 Jan 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30911-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29326030 PubMed]<br />
##'''Update:''' Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, Sulur G, Luna Y, Li S, Mundle S, Chi KN. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019 May;20(5):686-700. Epub 2019 Apr 12. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30082-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30987939 PubMed]<br />
<br />
==ADT & Apalutamide {{#subobject:02eac3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT & Apalutamide: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy & Apalutamide<br />
===Regimen {{#subobject:31baz9|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1903307 Chi et al. 2019 (TITAN<sub>prostate</sub>)]<br />
|2015-2017<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: there are several other trials in other cancer subtypes named TITAN.''<br />
====Endocrine therapy====<br />
<br />
*[[Apalutamide (Erleada)]] 240 mg PO once per day<br />
*[[:Category:GnRH agonists|LHRH agonist/analogue]]<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''TITAN:''' Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, Juárez Soto Á, Merseburger AS, Özgüroğlu M, Uemura H, Ye D, Deprince K, Naini V, Li J, Cheng S, Yu MK, Zhang K, Larsen JS, McCarthy S, Chowdhury S; TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019 Jul 4;381(1):13-24. Epub 2019 May 31. [https://www.nejm.org/doi/full/10.1056/NEJMoa1903307 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31150574 PubMed] NCT02489318<br />
##'''Update:''' Chi KN, Chowdhury S, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, Juárez A, Merseburger AS, Özgüroğlu M, Uemura H, Ye D, Brookman-May S, Mundle SD, McCarthy SA, Larsen JS, Sun W, Bevans KB, Zhang K, Bandyopadhyay N, Agarwal N. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J Clin Oncol. 2021 Apr 29<br />
[https://ascopubs.org/doi/full/10.1200/JCO.20.03488 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33914595/ PubMed] NCT02489318<br />
<br />
==ADT & Docetaxel {{#subobject:EJCADTdoceR|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT & Docetaxel: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy & Docetaxel<br />
===Regimen variant #1, 6 cycles {{#subobject:EJCADTdoceV|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800035/ James et al. 2015 (STAMPEDE)]<br />
|2005-2011<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4562797/ Sweeney et al. 2015 (CHAARTED)]<br />
|2006-2012<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#1a9850" |Superior OS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>In the 2018 update of CHAARTED, only patients with high-volume disease had superior survival in the experimental arm.''<br><br />
''Patients already on androgen deprivation therapy were eligible to participate in CHAARTED if there was no evidence of disease progression and if they had started ADT no more than 120 days before randomization.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*ADT with ONE of the following:<br />
**[[:Category:GnRH agonists|LHRH agonist/analogue]]<br />
**[[:Category:GnRH antagonists|LHRH antagonist]]<br />
**[[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]]<br />
**Intermittent hormonal therapy was not allowed. Antiandrogens e.g. [[Bicalutamide (Casodex)|bicalutamide]] were allowed at the start of therapy "at the discretion of the investigator."<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 8 mg PO given three times; 12 hours, 3 hours, and 1 hour before [[Docetaxel (Taxotere)]]<br />
*Daily prednisone was not required<br />
*At least calcium 500 mg and vitamin D 400 IU PO once per day<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #2, 9 cycles {{#subobject:257951|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70560-0/fulltext Gravis et al. 2013 (GETUG-AFU 15)]<br />
|2004-2008<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*ADT with one of the following:<br />
**[[:Category:GnRH agonists|LHRH agonist/analogue]] with or without [[:Category:Nonsteroidal_androgen_receptor_inhibitors|nonsteroidal androgen receptor inhibitors]]<br />
**[[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]] with or without [[:Category:Nonsteroidal_androgen_receptor_inhibitors|nonsteroidal androgen receptor inhibitors]]<br />
<br />
'''21-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<br />
#'''GETUG-AFU 15:''' Gravis G, Fizazi K, Joly F, Oudard S, Priou F, Esterni B, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Théodore C, Deplanque G, Ferrero JM, Pouessel D, Mourey L, Beuzeboc P, Zanetta S, Habibian M, Berdah JF, Dauba J, Baciuchka M, Platini C, Linassier C, Labourey JL, Machiels JP, El Kouri C, Ravaud A, Suc E, Eymard JC, Hasbini A, Bousquet G, Soulie M. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Feb;14(2):149-58. Epub 2013 Jan 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70560-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23306100 PubMed] NCT00104715<br />
##'''Update:''' Gravis G, Boher JM, Joly F, Soulié M, Albiges L, Priou F, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Théodore C, Deplanque G, Ferrero JM, Culine S, Mourey L, Beuzeboc P, Habibian M, Oudard S, Fizazi K; GETUG. Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: Impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial. Eur Urol. 2016 Aug;70(2):256-62. Epub 2015 Nov 21. [http://www.europeanurology.com/article/S0302-2838(15)01103-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26610858 PubMed]<br />
#'''CHAARTED:''' Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015 Aug 20;373(8):737-46. Epub 2015 Aug 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1503747 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4562797/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26244877 Pubmed] NCT00309985<br />
##'''Update:''' Kyriakopoulos CE, Chen YH, Carducci MA, Liu G, Jarrard DF, Hahn NM, Shevrin DH, Dreicer R, Hussain M, Eisenberger M, Kohli M, Plimack ER, Vogelzang NJ, Picus J, Cooney MM, Garcia JA, DiPaola RS, Sweeney CJ. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018 Apr 10;36(11):1080-1087. Epub 2018 Jan 31. [https://doi.org/10.1200/JCO.2017.75.3657 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891129/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29384722 PubMed]<br />
##'''QoL analysis:''' Morgans AK, Chen YH, Sweeney CJ, Jarrard DF, Plimack ER, Gartrell BA, Carducci MA, Hussain M, Garcia JA, Cella D, DiPaola RS, Patrick-Miller LJ. Quality of life during treatment with chemohormonal therapy: analysis of E3805 chemohormonal androgen ablation randomized trial in prostate cancer. J Clin Oncol. 2018 Apr 10;36(11):1088-1095. Epub 2018 Mar 9. [https://doi.org/10.1200/JCO.2017.75.3335 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891128/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29522362 PubMed]<br />
#'''STAMPEDE:''' James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, Ritchie AW, Parker CC, Russell JM, Attard G, de Bono J, Cross W, Jones RJ, Thalmann G, Amos C, Matheson D, Millman R, Alzouebi M, Beesley S, Birtle AJ, Brock S, Cathomas R, Chakraborti P, Chowdhury S, Cook A, Elliott T, Gale J, Gibbs S, Graham JD, Hetherington J, Hughes R, Laing R, McKinna F, McLaren DB, O'Sullivan JM, Parikh O, Peedell C, Protheroe A, Robinson AJ, Srihari N, Srinivasan R, Staffurth J, Sundar S, Tolan S, Tsang D, Wagstaff J, Parmar MK; STAMPEDE Investigators. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016 Mar 19;387(10024):1163-77. Epub 2015 Dec 21. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01037-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800035/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26719232 PubMed] NCT00268476<br />
##'''Update:''' Clarke NW, Ali A, Ingleby FC, Hoyle A, Amos CL, Attard G, Brawley CD, Calvert J, Chowdhury S, Cook A, Cross W, Dearnaley DP, Douis H, Gilbert D, Gillessen S, Jones RJ, Langley RE, MacNair A, Malik Z, Mason MD, Matheson D, Millman R, Parker CC, Ritchie AWS, Rush H, Russell JM, Brown J, Beesley S, Birtle A, Capaldi L, Gale J, Gibbs S, Lydon A, Nikapota A, Omlin A, O'Sullivan JM, Parikh O, Protheroe A, Rudman S, Srihari NN, Simms M, Tanguay JS, Tolan S, Wagstaff J, Wallace J, Wylie J, Zarkar A, Sydes MR, Parmar MKB, James ND. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol. 2019 Dec 1;30(12):1992-2003. [https://doi.org/10.1093/annonc/mdz396 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938598/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/31560068 PubMed]<br />
<br />
==ADT, Docetaxel, Estramustine {{#subobject:7nc12c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT, Docetaxel, Estramustine: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy, Docetaxel, Estramustine<br />
===Regimen {{#subobject:3ac6bc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00011-X/fulltext Fizazi et al. 2015 (GETUG 12)]<br />
|2002-2006<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#ADT_4|ADT]]<br />
| style="background-color:#91cf60" |Seems to have superior RFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]]<br />
*[[Estramustine (Emcyt)]]<br />
<br />
====Endocrine therapy====<br />
<br />
*ADT with one of the following:<br />
**[[:Category:GnRH agonists|LHRH agonist/analogue]] with or without [[:Category:Nonsteroidal_androgen_receptor_inhibitors|nonsteroidal androgen receptor inhibitors]]<br />
**[[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]] with or without [[:Category:Nonsteroidal_androgen_receptor_inhibitors|nonsteroidal androgen receptor inhibitors]]<br />
<br />
===References===<br />
<br />
#'''GETUG 12:''' Fizazi K, Faivre L, Lesaunier F, Delva R, Gravis G, Rolland F, Priou F, Ferrero JM, Houede N, Mourey L, Theodore C, Krakowski I, Berdah JF, Baciuchka M, Laguerre B, Fléchon A, Ravaud A, Cojean-Zelek I, Oudard S, Labourey JL, Chinet-Charrot P, Legouffe E, Lagrange JL, Linassier C, Deplanque G, Beuzeboc P, Davin JL, Martin AL, Habibian M, Laplanche A, Culine S. Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial. Lancet Oncol. 2015 Jul;16(7):787-94. Epub 2015 May 28. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00011-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26028518 PubMed] NCT00055731<br />
<br />
==ADT & Enzalutamide {{#subobject:79lq3c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADT & Enzalutamide: '''<u>A</u>'''ndrogen '''<u>D</u>'''eprivation '''<u>T</u>'''herapy & Enzalutamide<br />
===Regimen {{#subobject:29ncbc|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1903835 Davis et al. 2019 (ENZAMET)]<br />
|2014-2017<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. ADT & Bicalutamide<br> 2. ADT & Flutamide<br> 3. ADT & Niluatmide<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.00799 Armstrong et al. 2019 (ARCHES)]<br />
|2016-2018<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#ADT_5|ADT]]<br />
| style="background-color:#1a9850" |Superior rPFS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Enzalutamide (Xtandi)]] 160 mg PO once per day<br />
*ADT with one of the following:<br />
**[[:Category:GnRH agonists|LHRH agonist/analogue]]<br />
**[[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]]<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''ENZAMET:''' Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, Coskinas X, Frydenberg M, Hague WE, Horvath LG, Joshua AM, Lawrence NJ, Marx G, McCaffrey J, McDermott R, McJannett M, North SA, Parnis F, Parulekar W, Pook DW, Reaume MN, Sandhu SK, Tan A, Tan TH, Thomson A, Tu E, Vera-Badillo F, Williams SG, Yip S, Zhang AY, Zielinski RR, Sweeney CJ; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019 Jul 11;381(2):121-131. Epub 2019 Jun 2. [https://www.nejm.org/doi/full/10.1056/NEJMoa1903835 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31157964 PubMed] NCT02446405<br />
#'''ARCHES:''' Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, Alcaraz A, Alekseev B, Iguchi T, Shore ND, Rosbrook B, Sugg J, Baron B, Chen L, Stenzl A. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019 Nov 10;37(32):2974-2986. Epub 2019 Jul 22. [https://doi.org/10.1200/JCO.19.00799 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31329516 PubMed]<br />
<br />
==Bicalutamide monotherapy {{#subobject:5 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.karger.com/Article/Abstract/19634 Tyrrell et al. 1998]<br />
|NR in abstract<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Prostate_cancer_-_historical#Castration|Castration]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS<sup>1</sup><br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(02)00311-1/fulltext Iversen et al. 2002 (SPCG-6)]<br />
|1995-1998<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Placebo<br />
| style="background-color:#1a9850" |Superior OS<sup>2</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for Tyrrell et al. 1998 is based on the 2000 update.''<br><br />
''<sup>2</sup>Reported efficacy for SPCG-6 is based on the 2006 update and is only for the locally advanced subgroup.''<br><br />
''Not approved for monotherapy in the United States. See combination regimens with goserelin & leuprolide.''<br />
====Endocrine therapy====<br />
<br />
*[[Bicalutamide (Casodex)]] 150 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
<br />
#Tyrrell CJ, Kaisary AV, Iversen P, Anderson JB, Baert L, Tammela T, Chamberlain M, Webster A, Blackledge G. A randomised comparison of 'Casodex' (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol. 1998;33(5):447-56. [https://www.karger.com/Article/Abstract/19634 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9643663 PubMed]<br />
##'''Update:''' Iversen P, Tyrrell CJ, Kaisary AV, Anderson JB, Van Poppel H, Tammela TL, Chamberlain M, Carroll K, Melezinek I. Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup. J Urol. 2000 Nov;164(5):1579-82. [https://www.auajournals.org/article/S0022-5347(05)67032-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11025708 PubMed]<br />
#'''SPCG-6:''' Iversen P, Tammela TL, Vaage S, Lukkarinen O, Lodding P, Bull-Njaa T, Viitanen J, Hoisaeter P, Lundmo P, Rasmussen F, Johansson JE, Persson BE, Carroll K; Scandinavian Prostatic Cancer Group. A randomised comparison of bicalutamide ('Casodex') 150 mg versus placebo as immediate therapy either alone or as adjuvant to standard care for early non-metastatic prostate cancer: first report from the Scandinavian Prostatic Cancer Group Study No 6. Eur Urol. 2002 Sep;42(3):204-11. [https://www.europeanurology.com/article/S0302-2838(02)00311-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12234503 PubMed]<br />
##'''Update:''' Iversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Carroll K; Scandinavian Prostatic Cancer Group. Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6. J Urol. 2004 Nov;172(5 Pt 1):1871-6. [https://www.auajournals.org/article/S0022-5347(05)60880-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15540741 PubMed]<br />
##'''Update:''' Iversen P, Johansson JE, Lodding P, Kylmälä T, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Armstrong J; Scandinavian Prostate Cancer Group. Bicalutamide 150 mg in addition to standard care for patients with early non-metastatic prostate cancer: updated results from the Scandinavian Prostate Cancer Period Group-6 Study after a median follow-up period of 7.1 years. Scand J Urol Nephrol. 2006;40(6):441-52. [https://www.tandfonline.com/doi/abs/10.1080/00365590601017329 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17130095 PubMed]<br />
<br />
==Bicalutamide & Goserelin {{#subobject:10 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 50/3.6 {{#subobject:10 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.goldjournal.net/article/S0090-4295(99)80077-6/abstract Schellhammer et al. 1995]<br />
| rowspan="2" |1992-1993<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Bicalutamide_.26_Leuprolide|Bicalutamide & Leuprolide]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Flutamide_.26_Goserelin_2|Flutamide & Goserelin]]<br> 3. [[#Flutamide_.26_Leuprolide|Flutamide & Leuprolide]]<br />
| style="background-color:#eeee01" |Equivalent TTP<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for Schellhammer et al. 1995 is based on the 1997 final update.''<br />
====Endocrine therapy====<br />
<br />
*[[Bicalutamide (Casodex)]] 50 mg PO once per day<br />
*[[Goserelin (Zoladex)]] 3.6 mg SC once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 80/3.6 {{#subobject:a8fe78|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jjco.oxfordjournals.org/content/34/1/20.full Akaza et al. 2004]<br />
|2000-2001<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Goserelin_monotherapy_2|Goserelin]]<br> 2. [[#Leuprolide_monotherapy_2|Leuprolide]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2009 update.''<br />
====Endocrine therapy====<br />
<br />
*[[Bicalutamide (Casodex)]] 80 mg PO once per day<br />
*[[Goserelin (Zoladex)]] 3.6 mg SC once on day 1<br />
<br />
'''28-day cycles'''<br />
===References===<br />
<br />
#Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer; Casodex Combination Study Group. Urology. 1995 May;45(5):745-52. [http://www.goldjournal.net/article/S0090-4295(99)80077-6/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7538237 PubMed]<br />
##'''Update:''' Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Chen Y, Kolvenbag GJ. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: analysis of time to progression; CASODEX Combination Study Group. Cancer. 1996 Nov 15;78(10):2164-9. [https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0142(19961115)78:10%3C2164::AID-CNCR18%3E3.0.CO;2-X/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8918410 PubMed]<br />
##'''Update:''' Soloway MS, Schellhammer P, Sharifi R, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of Casodex (bicalutamide) vs flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Eur Urol. 1996;29 Suppl 2:105-9. [https://doi.org/10.1159/000473848 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8717471 PubMed]<br />
##'''Update:''' Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ; Casodex Combination Study Group. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology. 1997 Sep;50(3):330-6. [https://www.goldjournal.net/article/S0090-4295(97)00279-3/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9301693 PubMed]<br />
#Akaza H, Yamaguchi A, Matsuda T, Igawa M, Kumon H, Soeda A, Arai Y, Usami M, Naito S, Kanetake H, Ohashi Y. Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: interim results of a randomized study in Japanese patients. Jpn J Clin Oncol. 2004 Jan;34(1):20-8. [http://jjco.oxfordjournals.org/content/34/1/20.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15020659 PubMed]<br />
##'''Update:''' Akaza H, Hinotsu S, Usami M, Arai Y, Kanetake H, Naito S, Hirao Y; Study Group for the Combined Androgen Blockade Therapy of Prostate Cancer. Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival. Cancer. 2009 Aug 1;115(15):3437-45. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.24395 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19536889 PubMed]<br />
<br />
==Bicalutamide & Leuprolide {{#subobject:13 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 50/7.5 {{#subobject:13 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.goldjournal.net/article/S0090-4295(99)80077-6/abstract Schellhammer et al. 1995]<br />
| rowspan="2" |1992-1993<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Bicalutamide_.26_Goserelin_2|Bicalutamide & Goserelin]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Flutamide_.26_Goserelin_2|Flutamide & Goserelin]]<br> 3. [[#Flutamide_.26_Leuprolide|Flutamide & Leuprolide]]<br />
| style="background-color:#eeee01" |Equivalent TTP<sup>1</sup><br />
|-<br />
|[https://www.auajournals.org/doi/full/10.1016/S0022-5347%2805%2965175-0 Trachtenberg et al. 2002]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Abarelix<br />
| style="background-color:#d73027" |Inferior primary endpoint<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for Schellhammer et al. 1995 is based on the 1997 final update.''<br />
====Endocrine therapy====<br />
<br />
*[[Bicalutamide (Casodex)]] 50 mg PO once per day<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 1-month depot]] 7.5 mg IM once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 80/3.75 {{#subobject:28699c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jjco.oxfordjournals.org/content/34/1/20.full Akaza et al. 2004]<br />
|2000-2001<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Goserelin_monotherapy|Goserelin]]<br> 2. [[#Leuprolide_monotherapy_2|Leuprolide]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2009 update.''<br />
====Endocrine therapy====<br />
<br />
*[[Bicalutamide (Casodex)]] 80 mg PO once per day<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 1-month depot]] 3.75 mg SC once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer; Casodex Combination Study Group. Urology. 1995 May;45(5):745-52. [http://www.goldjournal.net/article/S0090-4295(99)80077-6/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7538237 PubMed]<br />
##'''Update:''' Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Chen Y, Kolvenbag GJ. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: analysis of time to progression; CASODEX Combination Study Group. Cancer. 1996 Nov 15;78(10):2164-9. [https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0142(19961115)78:10%3C2164::AID-CNCR18%3E3.0.CO;2-X/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8918410 PubMed]<br />
##'''Update:''' Soloway MS, Schellhammer P, Sharifi R, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of Casodex (bicalutamide) vs flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Eur Urol. 1996;29 Suppl 2:105-9. [https://doi.org/10.1159/000473848 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8717471 PubMed]<br />
##'''Update:''' Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ; Casodex Combination Study Group. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology. 1997 Sep;50(3):330-6. [https://www.goldjournal.net/article/S0090-4295(97)00279-3/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9301693 PubMed]<br />
#Trachtenberg J, Gittleman M, Steidle C, Barzell W, Friedel W, Pessis D, Fotheringham N, Campion M, Garnick MB; Abarelix Study Group. A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. J Urol. 2002 Apr;167(4):1670-4. [https://www.auajournals.org/doi/full/10.1016/S0022-5347%2805%2965175-0 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11912385 PubMed]<br />
#Akaza H, Yamaguchi A, Matsuda T, Igawa M, Kumon H, Soeda A, Arai Y, Usami M, Naito S, Kanetake H, Ohashi Y. Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: interim results of a randomized study in Japanese patients. Jpn J Clin Oncol. 2004 Jan;34(1):20-8. [http://jjco.oxfordjournals.org/content/34/1/20.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15020659 PubMed]<br />
##'''Update:''' Akaza H, Hinotsu S, Usami M, Arai Y, Kanetake H, Naito S, Hirao Y; Study Group for the Combined Androgen Blockade Therapy of Prostate Cancer. Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival. Cancer. 2009 Aug 1;115(15):3437-45. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.24395 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19536889 PubMed]<br />
<br />
==Degarelix monotherapy {{#subobject:7 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Degarelix (Firmagon) in prostate cancer]]<br />
<br />
===Regimen variant #1, 240/80 {{#subobject:7 |Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2008.08183.x/full Klotz et al. 2008 (CS21)]<br />
| rowspan="2" |2006-2007<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Degarelix_monotherapy|Degarelix]]; 240/160<br />
| style="background-color:#eeee01" |Non-inferior testosterone suppression<br />
|-<br />
|2. [[#Leuprolide_monotherapy_2|Leuprolide]]<br />
| style="background-color:#eeee01" |Non-inferior testosterone suppression<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Degarelix (Firmagon)]] as follows:<br />
**Cycle 1: 240 mg SC once on day 1<br />
**Cycle 2 onwards: 80 mg SC once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 240/160 {{#subobject:7b |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2008.08183.x/full Klotz et al. 2008 (CS21)]<br />
| rowspan="2" |2006-2007<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Degarelix_monotherapy|Degarelix]]; 240/80<br />
| style="background-color:#eeee01" |Non-inferior testosterone suppression<br />
|-<br />
|2. [[#Leuprolide_monotherapy_2|Leuprolide]]<br />
| style="background-color:#eeee01" |Non-inferior testosterone suppression<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Degarelix (Firmagon)]] as follows:<br />
**Cycle 1: 240 mg SC once on day 1<br />
**Cycle 2 onwards: 160 mg SC once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3, 240/480 {{#subobject:01864f |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989846/ Ozono et al. 2018 (3550-CL-0010)]<br />
|2013-NR<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Goserelin_monotherapy_2|Goserelin]]<br />
| style="background-color:#eeee01" |Non-inferior testosterone suppression<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Degarelix (Firmagon)]] as follows:<br />
**Cycle 1: 240 mg SC once on day 1<br />
**Cycle 2 onwards: 480 mg SC once on day 1<br />
<br />
'''28-day cycle for 1 cycle, then 12-week cycles'''<br />
<br />
===References===<br />
<br />
#'''CS21:''' Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, Jensen JK, Olesen TK, Schröder FH. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008 Dec;102(11):1531-8. [https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2008.08183.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19035858 PubMed]<br />
##'''Update:''' Tombal B, Miller K, Boccon-Gibod L, Schröder F, Shore N, Crawford ED, Moul J, Jensen JK, Kold Olesen T, Persson BE. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. 2010 May;57(5):836-42. Epub 2009 Nov 20. [http://www.europeanurology.com/article/S0302-2838%2809%2901171-3 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19962227 PubMed]<br />
#'''3550-CL-0010:''' Ozono S, Tsukamoto T, Naito S, Horie S, Ohashi Y, Uemura H, Yokomizo Y, Fukasawa S, Kusuoka H, Akazawa R, Saito M, Akaza H. Efficacy and safety of 3-month dosing regimen of degarelix in Japanese subjects with prostate cancer: a phase III study. Cancer Sci. 2018 Jun;109(6):1920-1929. Epub 2018 May 23. [https://onlinelibrary.wiley.com/doi/abs/10.1111/cas.13600 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989846/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29624800 PubMed] NCT01964170<br />
<br />
==Flutamide monotherapy {{#subobject:8 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.karger.com/Article/Abstract/480795 Boccon-Gibod et al. 1997]<br />
|1989-1991<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Prostate_cancer_-_historical#Castration|Bilateral orchiectomy]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2001.19.1.62 Fosså et al. 2001 (EORTC 30903)]<br />
|1992-1998<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of TTP/OS<br />
|-<br />
|}<br />
''Not approved for monotherapy in the United States. See combination regimens with Goserelin & Leuprolide.''<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]] 250 mg PO three times per day<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
<br />
#Boccon-Gibod L, Fournier G, Bottet P, Marechal JM, Guiter J, Rischman P, Hubert J, Soret JY, Mangin P, Mallo C, Fraysse CE. Flutamide versus orchidectomy in the treatment of metastatic prostate carcinoma. Eur Urol. 1997;32(4):391-5. [https://www.karger.com/Article/Abstract/480795 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9412794 PubMed]<br />
#'''EORTC 30903:''' Fosså SD, Slee PH, Brausi M, Horenblas S, Hall RR, Hetherington JW, Aaronson N, de Prijck L, Collette L. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol. 2001 Jan 1;19(1):62-71. [https://doi.org/10.1200/JCO.2001.19.1.62 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11134196 PubMed]<br />
<br />
==Flutamide & Goserelin {{#subobject:11 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:11 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1002/cncr.1990.66.s5.1058 Iversen et al. 1990]<br />
|1986-1987<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Prostate_cancer_-_historical#Castration|Bilateral orchiectomy]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of OS/PFS/TTP<br />
|-<br />
|[https://doi.org/10.1002/cncr.1990.66.s5.1045 Keuppens et al. 1990 (EORTC 30853)]<br />
|1986-1988<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Prostate_cancer_-_historical#Castration|Bilateral orchiectomy]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br />
|-<br />
| rowspan="2" |[http://www.goldjournal.net/article/S0090-4295(99)80077-6/abstract Schellhammer et al. 1995]<br />
| rowspan="2" |1992-1993<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Bicalutamide_.26_Goserelin_2|Bicalutamide & Goserelin]]<br> 2. [[#Bicalutamide_.26_Leuprolide|Bicalutamide & Leuprolide]]<br />
| style="background-color:#eeee01" |Equivalent TTP<sup>2</sup><br />
|-<br />
|3. [[#Flutamide_.26_Leuprolide|Flutamide & Leuprolide]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682658/ Hussain et al. 2013 (SWOG-9346)]<br />
|1995-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Intermittent_ADT|Intermittent ADT]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for EORTC 30853 is based on the 1998 final update.''<br><br />
''<sup>2</sup>Reported efficacy for Schellhammer et al. 1995 is based on the 1997 final update.''<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]] 250 mg PO three times per day<br />
*[[Goserelin (Zoladex)]] 3.6 mg SC once on day 1<br />
<br />
'''28-day cycles'''<br />
===References===<br />
#'''EORTC 30853:''' Keuppens F, Denis L, Smith P, Carvalho AP, Newling D, Bond A, Sylvester R, De Pauw M, Vermeylen K, Ongena P; EORTC GU Group. Zoladex and flutamide versus bilateral orchiectomy: a randomized phase III EORTC 30853 study. Cancer. 1990 Sep 1;66(5 Suppl):1045-57. [https://doi.org/10.1002/cncr.1990.66.s5.1045 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2144206/ PubMed]<br />
##'''Update:''' Denis LJ, Carnelro de Moura JL, Bono A, Sylvester R, Whelan P, Newling D, Depauw M; [[Study_Groups#EORTC|EORTC]] GU Group. Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III EORTC trial (30853). Urology. 1993 Aug;42(2):119-29. [https://www.goldjournal.net/article/0090-4295(93)90634-M/pdf link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8367920 PubMed]<br />
##'''Update:''' Denis LJ, Keuppens F, Smith PH, Whelan P, de Moura JL, Newling D, Bono A, Sylvester R; [[Study_Groups#EORTC|EORTC]] Genito-Urinary Tract Cancer Cooperative Group and the EORTC Data Center. Maximal androgen blockade: final analysis of EORTC phase III trial 30853. Eur Urol. 1998;33(2):144-51. [https://doi.org/10.1159/000019546 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9519355 PubMed]<br />
#Iversen P, Christensen MG, Friis E, Hornbøl P, Hvidt V, Iversen HG, Klarskov P, Krarup T, Lund F, Mogensen P, et al. A phase III trial of zoladex and flutamide versus orchiectomy in the treatment of patients with advanced carcinoma of the prostate. Cancer. 1990 Sep 1;66(5 Suppl):1058-66. [https://doi.org/10.1002/cncr.1990.66.s5.1058 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2144207/ PubMed]<br />
#Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Urology. 1995 May;45(5):745-52. [http://www.goldjournal.net/article/S0090-4295(99)80077-6/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7538237 PubMed]<br />
##'''Update:''' Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Chen Y, Kolvenbag GJ; CASODEX Combination Study Group. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: analysis of time to progression. Cancer. 1996 Nov 15;78(10):2164-9. [https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0142(19961115)78:10%3C2164::AID-CNCR18%3E3.0.CO;2-X/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8918410 PubMed]<br />
##'''Update:''' Soloway MS, Schellhammer P, Sharifi R, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of Casodex (bicalutamide) vs flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Eur Urol. 1996;29 Suppl 2:105-9. [https://doi.org/10.1159/000473848 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8717471 PubMed]<br />
##'''Update:''' Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ; Casodex Combination Study Group. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology. 1997 Sep;50(3):330-6. [https://www.goldjournal.net/article/S0090-4295(97)00279-3/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9301693 PubMed]<br />
#'''SWOG-9346:''' Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, Wilding G, Prescott S, Kanaga Sundaram S, Small EJ, Dawson NA, Donnelly BJ, Venner PM, Vaishampayan UN, Schellhammer PF, Quinn DI, Raghavan D, Ely B, Moinpour CM, Vogelzang NJ, Thompson IM Jr. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013 Apr 4;368(14):1314-25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1212299 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682658/ link to PMC article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1212299/suppl_file/nejmoa1212299_protocol.pdf supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23550669 PubMed] NCT00002651<br />
<br />
==Flutamide & Leuprolide {{#subobject:14 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, daily Lupron {{#subobject:5b0861 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM198908173210702 Crawford et al. 1989 (SWOG-8494)]<br />
|1985-1986<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Leuprolide_monotherapy_2|Leuprolide]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: this is likely of historic importance only, given the formulation of leuoprolide.''<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]] 250 mg PO three times per day<br />
*[[Leuprolide (Lupron)]] 1 mg SC once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen variant #2, 1-month depot Lupron {{#subobject:14 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.goldjournal.net/article/S0090-4295(99)80077-6/abstract Schellhammer et al. 1995]<br />
| rowspan="2" |1992-1993<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Bicalutamide_.26_Goserelin_2|Bicalutamide & Goserelin]]<br> 2. [[#Bicalutamide_.26_Leuprolide|Bicalutamide & Leuprolide]]<br />
| style="background-color:#eeee01" |Equivalent TTP<sup>1</sup><br />
|-<br />
|3. [[#Flutamide_.26_Goserelin_2|Flutamide & Goserelin]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682658/ Hussain et al. 2013 (SWOG-9346)]<br />
|1995-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Intermittent_ADT|Intermittent ADT]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for Schellhammer et al. 1995 is based on the 1997 final update.''<br />
====Endocrine therapy====<br />
<br />
*[[Flutamide (Eulexin)]] 250 mg PO three times per day<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 1-month depot]] 7.5 mg IM once on day 1<br />
<br />
'''28-day cycles'''<br />
===References===<br />
<br />
#'''SWOG-8494:''' Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, Blumenstein BA, Davis MA, Goodman PJ. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989 Aug 17;321(7):419-24. Erratum in: N Engl J Med 1989 Nov 16;321(20):1420. [https://www.nejm.org/doi/full/10.1056/NEJM198908173210702 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2503724 PubMed]<br />
#Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer; Casodex Combination Study Group. Urology. 1995 May;45(5):745-52. [http://www.goldjournal.net/article/S0090-4295(99)80077-6/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7538237 PubMed]<br />
##'''Update:''' Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Chen Y, Kolvenbag GJ. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: analysis of time to progression; CASODEX Combination Study Group. Cancer. 1996 Nov 15;78(10):2164-9. [https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0142(19961115)78:10%3C2164::AID-CNCR18%3E3.0.CO;2-X/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8918410 PubMed]<br />
##'''Update:''' Soloway MS, Schellhammer P, Sharifi R, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of Casodex (bicalutamide) vs flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Eur Urol. 1996;29 Suppl 2:105-9. [https://doi.org/10.1159/000473848 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8717471 PubMed]<br />
##'''Update:''' Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ; Casodex Combination Study Group. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology. 1997 Sep;50(3):330-6. [https://www.goldjournal.net/article/S0090-4295(97)00279-3/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9301693 PubMed]<br />
#'''SWOG-9346:''' Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, Wilding G, Prescott S, Kanaga Sundaram S, Small EJ, Dawson NA, Donnelly BJ, Venner PM, Vaishampayan UN, Schellhammer PF, Quinn DI, Raghavan D, Ely B, Moinpour CM, Vogelzang NJ, Thompson IM Jr. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013 Apr 4;368(14):1314-25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1212299 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682658/ link to PMC article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1212299/suppl_file/nejmoa1212299_protocol.pdf supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23550669 PubMed] NCT00002651<br />
<br />
==Goserelin monotherapy {{#subobject:9 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Goserelin (Zoladex) in prostate cancer]]<br />
<br />
===Regimen variant #1, 28-day cycles {{#subobject:9 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.goldjournal.net/article/0090-4295(91)80077-K/pdf Soloway et al. 1991]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Prostate_cancer_-_historical#Castration|Bilateral orchiectomy]]<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1464-410X.1991.tb15195.x Kaisary et al. 1991]<br />
|1983-1986<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Prostate_cancer_-_historical#Castration|Bilateral orchiectomy]]<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1464-410X.1992.tb15633.x Waymont et al. 1992]<br />
|1985-1987<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|DES<br />
| style="background-color:#91cf60" |Seems to have superior time to first response<br />
|-<br />
|[https://doi.org/10.1016/s0022-5347(17)38080-1 Tyrrell et al. 1991 (IPCSG)]<br />
|1986-1987<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Flutamide_.26_Goserelin_2|Flutamide & Goserelin]]<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(05)80293-X/abstract Boccardo et al. 1993 (PONCAP)]<br />
|1987-1990<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Flutamide_.26_Goserelin_2|Flutamide & Goserelin]]<br />
| style="background-color:#fee08b" |Might have inferior PFS50%<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Goserelin (Zoladex)]] 3.6 mg SC once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 12-week cycles {{#subobject:7afffe |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989846/ Ozono et al. 2018 (3550-CL-0010)]<br />
|2015-NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Degarelix_monotherapy|Degarelix]]<br />
| style="background-color:#eeee01" |Non-inferior testosterone suppression<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Goserelin (Zoladex)]] as follows:<br />
**Cycle 1: 3.6 mg SC once on day 1<br />
**Cycle 2 onwards: 10.8 mg SC once on day 1<br />
<br />
'''28-day cycle for 1 cycle, then 12-week cycles'''<br />
<br />
===References===<br />
<br />
#Soloway MS, Chodak G, Vogelzang NJ, Block NL, Schellhammer PF, Smith JA Jr, Scott M, Kennealey G, Gau TC; Zoladex Prostate Study Group. Zoladex versus orchiectomy in treatment of advanced prostate cancer: a randomized trial. Urology. 1991 Jan;37(1):46-51. [https://www.goldjournal.net/article/0090-4295(91)80077-K/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1824732 PubMed]<br />
##'''Update:''' Vogelzang NJ, Chodak GW, Soloway MS, Block NL, Schellhammer PF, Smith JA Jr, Caplan RJ, Kennealey GT; Zoladex Prostate Study Group. Goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial. Urology. 1995 Aug;46(2):220-6. [http://www.goldjournal.net/article/S0090-4295(99)80197-6/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7624991 PubMed]<br />
#Kaisary AV, Tyrrell CJ, Peeling WB, Griffiths K. Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostatic carcinoma. Br J Urol. 1991 May;67(5):502-8. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1464-410X.1991.tb15195.x link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1828183 PubMed]<br />
#'''IPCSG:''' Tyrrell CJ, Altwein JE, Klippel F, Varenhorst E, Lunglmayr G, Boccardo F, Holdaway IM, Haefliger JM, Jordaan JP; International Prostate Cancer Study Group. A multicenter randomized trial comparing the luteinizing hormone-releasing hormone analogue goserelin acetate alone and with flutamide in the treatment of advanced prostate cancer. J Urol. 1991 Nov;146(5):1321-6. [https://doi.org/10.1016/s0022-5347(17)38080-1 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1834864 PubMed]<br />
#Waymont B, Lynch TH, Dunn JA, Emtage LA, Arkell DG, Wallace DM, Blackledge GR. Phase III randomised study of zoladex versus stilboestrol in the treatment of advanced prostate cancer. Br J Urol. 1992 Jun;69(6):614-20. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1464-410X.1992.tb15633.x link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1386272 PubMed]<br />
#'''PONCAP:''' Boccardo F, Pace M, Rubagotti A, Guarneri D, Decensi A, Oneto F, Martorana G, Giuliani L, Selvaggi F, Battaglia M, Delli Ponti U, Petracco S, Cortellini P, Ziveri M, Ferraris V, Bruttini GP, Epis R, Comeri G, Gallo G; Italian Prostatic Cancer Project (PONCAP) Study Group. Goserelin acetate with or without flutamide in the treatment of patients with locally advanced or metastatic prostate cancer. Eur J Cancer. 1993;29A(8):1088-93. [https://www.ejcancer.com/article/S0959-8049(05)80293-X/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8518017 PubMed]<br />
#'''3550-CL-0010:''' Ozono S, Tsukamoto T, Naito S, Horie S, Ohashi Y, Uemura H, Yokomizo Y, Fukasawa S, Kusuoka H, Akazawa R, Saito M, Akaza H. Efficacy and safety of 3-month dosing regimen of degarelix in Japanese subjects with prostate cancer: a phase III study. Cancer Sci. 2018 Jun;109(6):1920-1929. Epub 2018 May 23. [https://onlinelibrary.wiley.com/doi/abs/10.1111/cas.13600 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989846/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29624800 PubMed] NCT01964170<br />
<br />
==Histrelin monotherapy {{#subobject:97agub |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:918gya|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.auajournals.org/doi/full/10.1016/S0022-5347%2805%2900649-X Schlegel 2006]<br />
|NR<br />
| style="background-color:#91cf61" |Non-randomized (RT)<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Histrelin (Vantas)]]<br />
<br />
===References===<br />
<br />
#Schlegel PN; Histrelin Study Group. Efficacy and safety of histrelin subdermal implant in patients with advanced prostate cancer. J Urol. 2006 Apr;175(4):1353-8. [https://www.auajournals.org/doi/full/10.1016/S0022-5347%2805%2900649-X link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16515997 PubMed]<br />
<br />
==Intermittent ADT==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
IHT: '''<u>I</u>'''ntermittent '''<u>H</u>'''ormone '''<u>T</u>'''herapy<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(09)00159-6/fulltext Calais da Silva et al. 2009 (SEUG 9401)]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|Continuous ADT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682658/ Hussain et al. 2013 (SWOG-9346)]<br />
|1995-2008<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|Continuous ADT<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521033/ Crook et al. 2012 (NCIC-CTG PR.7)]<br />
|1999-2005<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|Continuous ADT<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(13)00342-4/fulltext Calais da Silva et al. 2013 (SEUG 9901)]<br />
|2000-2007<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|Continuous ADT<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
''See papers for details about treatment holidays.''<br />
====Endocrine therapy====<br />
<br />
*[[:Category:GnRH agonists|LHRH agonist]]<br />
*[[:Category:Nonsteroidal_antiandrogens|Nonsteroidal antiandrogen]] for at least 4 weeks<br />
<br />
'''8-month cycles'''<br />
===References===<br />
<br />
#'''SEUG 9401:''' Calais da Silva FE, Bono AV, Whelan P, Brausi M, Marques Queimadelos A, Martin JA, Kirkali Z, Calais da Silva FM, Robertson C. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group. Eur Urol. 2009 Jun;55(6):1269-77. Epub 2009 Feb 21. [https://www.europeanurology.com/article/S0302-2838(09)00159-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19249153 PubMed]<br />
#'''NCIC-CTG PR.7:''' Crook JM, O'Callaghan CJ, Duncan G, Dearnaley DP, Higano CS, Horwitz EM, Frymire E, Malone S, Chin J, Nabid A, Warde P, Corbett T, Angyalfi S, Goldenberg SL, Gospodarowicz MK, Saad F, Logue JP, Hall E, Schellhammer PF, Ding K, Klotz L. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med. 2012 Sep 6;367(10):895-903. Erratum in: N Engl J Med. 2012 Dec 6;367(23):2262. [https://www.nejm.org/doi/full/10.1056/NEJMoa1201546 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521033/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22931259 PubMed] NCT00003653<br />
#'''SWOG-9346:''' Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, Wilding G, Prescott S, Kanaga Sundaram S, Small EJ, Dawson NA, Donnelly BJ, Venner PM, Vaishampayan UN, Schellhammer PF, Quinn DI, Raghavan D, Ely B, Moinpour CM, Vogelzang NJ, Thompson IM Jr. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013 Apr 4;368(14):1314-25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1212299 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682658/ link to PMC article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1212299/suppl_file/nejmoa1212299_protocol.pdf supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23550669 PubMed] NCT00002651<br />
#'''SEUG 9901:''' Calais da Silva F, Calais da Silva FM, Gonçalves F, Santos A, Kliment J, Whelan P, Oliver T, Antoniou N, Pastidis S, Marques Queimadelos A, Robertson C. Locally advanced and metastatic prostate cancer treated with intermittent androgen monotherapy or maximal androgen blockade: results from a randomised phase 3 study by the South European Uroncological Group. Eur Urol. 2014 Aug;66(2):232-9. Epub 2013 Apr 4. [https://www.europeanurology.com/article/S0302-2838(13)00342-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23582949 PubMed]<br />
<br />
==Leuprolide monotherapy {{#subobject:12 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Leuprolide (Lupron) in prostate cancer]]<br />
<br />
===Regimen variant #1, daily {{#subobject:c6f258 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM198411153112004 Garnick et al. 1984]<br />
|1981-NR<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|DES<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
| style="background-color:#1a9850" |Less toxic<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM198908173210702 Crawford et al. 1989 (SWOG-8494)]<br />
|1985-1986<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Flutamide_.26_Leuprolide|Flutamide & Leuprolide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|<br />
|-<br />
|}<br />
''Note: this is of historic importance only, given the wide availability of depot formulations of leuoprolide.''<br />
====Endocrine therapy====<br />
<br />
*[[Leuprolide (Lupron)]] 1 mg SC once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen variant #2, 1-month depot, 3.75 mg {{#subobject:172cb3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jjco.oxfordjournals.org/content/34/1/20.full Akaza et al. 2004]<br />
|2000-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Bicalutamide_.26_Goserelin_2|Bicalutamide & Goserelin]]<br> 2. [[#Bicalutamide_.26_Leuprolide|Bicalutamide & Leuprolide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2009 update.''<br />
====Endocrine therapy====<br />
<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 1-month depot]] 3.75 mg SC once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3, 1-month depot, 7.5 mg {{#subobject:172cb4|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2817%2939868-3 Sharifi & Soloway 1990]<br />
|1986-NR<br />
| style="background-color:#91cf61" |Non-randomized (RT)<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2008.08183.x/full Klotz et al. 2008 (CS21)]<br />
| rowspan="2" |2006-2007<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Degarelix_monotherapy|Degarelix 240/80]]<br />
| style="background-color:#eeee01" |Non-inferior testosterone suppression<br />
|-<br />
|2. [[#Degarelix_monotherapy|Degarelix 240/160]]<br />
| style="background-color:#eeee01" |Non-inferior testosterone suppression<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 1-month depot]] 7.5 mg IM once on day 1<br />
<br />
'''28-day cycles'''<br />
===Regimen variant #4, 3-month depot {{#subobject:5415fc |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.clinicaltherapeutics.com/article/S0149-2918(96)80215-3/pdf Sharifi et al. 1996]<br />
|NR<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://pubmed.ncbi.nlm.nih.gov/32469183/ Shore et al. 2020 (HERO)]<br />
|2017-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Relugolix_monotherapy|Relugolix]]<br />
| style="background-color:#d73027" |Inferior testosterone suppression<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 3-month depot]] 22.5 mg IM once on day 1<br />
<br />
'''84-day cycles'''<br />
<br />
===Regimen variant #5, 4-month depot {{#subobject:21b60f |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295(97)00500-1/pdf Sharifi et al. 1998]<br />
|NR<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 4-month depot]] 30 mg IM once on day 1<br />
<br />
'''16-week cycles'''<br />
<br />
===Regimen variant #6, 6-month depot {{#subobject:21720f |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278745/ Spitz et al. 2011 (L-PC07-169)]<br />
|2008-2009<br />
| style="background-color:#91cf61" |Non-randomized (RT)<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Leuprolide (Lupron)|Leuprolide (Lupron) 6-month depot]] 45 mg IM once on day 1<br />
<br />
'''26-week cycles'''<br />
<br />
===References===<br />
<br />
#Garnick MB, Glode LM; Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med. 1984 Nov 15;311(20):1281-6. [https://www.nejm.org/doi/full/10.1056/NEJM198411153112004 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/6436700 PubMed]<br />
#'''SWOG-8494:''' Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, Blumenstein BA, Davis MA, Goodman PJ. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989 Aug 17;321(7):419-24. Erratum in: N Engl J Med 1989 Nov 16;321(20):1420. [https://www.nejm.org/doi/full/10.1056/NEJM198908173210702 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2503724 PubMed]<br />
#Sharifi R, Soloway M; Leuprolide Study Group. Clinical study of leuprolide depot formulation in the treatment of advanced prostate cancer. J Urol. 1990 Jan;143(1):68-71. [https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2817%2939868-3 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2104638 PubMed]<br />
#Sharifi R, Bruskewitz RC, Gittleman MC, Graham SD Jr, Hudson PB, Stein B. Leuprolide acetate 22.5 mg 12-week depot formulation in the treatment of patients with advanced prostate cancer. Clin Ther. 1996 Jul-Aug;18(4):647-57. [http://www.clinicaltherapeutics.com/article/S0149-2918(96)80215-3/pdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8879893 PubMed]<br />
#Sharifi R, Knoll LD, Smith J, Kramolowsky E. Leuprolide acetate (30-mg depot every four months) in the treatment of advanced prostate cancer. Urology. 1998 Feb;51(2):271-6. [http://www.goldjournal.net/article/S0090-4295(97)00500-1/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9495710 PubMed]<br />
#Akaza H, Yamaguchi A, Matsuda T, Igawa M, Kumon H, Soeda A, Arai Y, Usami M, Naito S, Kanetake H, Ohashi Y. Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: interim results of a randomized study in Japanese patients. Jpn J Clin Oncol. 2004 Jan;34(1):20-8. [http://jjco.oxfordjournals.org/content/34/1/20.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15020659 PubMed]<br />
##'''Update:''' Akaza H, Hinotsu S, Usami M, Arai Y, Kanetake H, Naito S, Hirao Y; Study Group for the Combined Androgen Blockade Therapy of Prostate Cancer. Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival. Cancer. 2009 Aug 1;115(15):3437-45. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.24395 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19536889 PubMed]<br />
#'''CS21:''' Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, Jensen JK, Olesen TK, Schröder FH. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008 Dec;102(11):1531-8. [https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2008.08183.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19035858 PubMed]<br />
##'''Update:''' Tombal B, Miller K, Boccon-Gibod L, Schröder F, Shore N, Crawford ED, Moul J, Jensen JK, Kold Olesen T, Persson BE. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. 2010 May;57(5):836-42. Epub 2009 Nov 20. [http://www.europeanurology.com/article/S0302-2838%2809%2901171-3 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19962227 PubMed]<br />
#'''L-PC07-169:''' Spitz A, Young JM, Larsen L, Mattia-Goldberg C, Donnelly J, Chwalisz K. Efficacy and safety of leuprolide acetate 6-month depot for suppression of testosterone in patients with prostate cancer. Prostate Cancer Prostatic Dis. 2012 Mar;15(1):93-9. Epub 2011 Oct 25. [https://www.nature.com/articles/pcan201150 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278745/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22025196 PubMed]<br />
#'''HERO:''' Shore ND, Saad F, Cookson MS, George DJ, Saltzstein DR, Tutrone R, Akaza H, Bossi A, van Veenhuyzen DF, Selby B, Fan X, Kang V, Walling J, Tombal B; HERO Study Investigators. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med. 2020 Jun 4;382(23):2187-2196. [https://doi.org/10.1056/NEJMoa2004325 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32469183/ PubMed] NCT03085095<br />
<br />
==Nilutamide & Orchiectomy {{#subobject:15 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:15 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/s0022-5347(17)36003-2 Janknegt et al. 1993 (International Anandron Study)]<br />
|1986-NR<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Prostate_cancer_-_historical#Castration|Bilateral orchiectomy]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
''Nilutamide to start the day of, or day after surgical castration/orchiectomy.''<br />
====Endocrine therapy====<br />
<br />
*[[Nilutamide (Nilandron)]] 300 mg PO once per day x 1 month, then 150 mg PO once per day<br />
*[[Endocrine_ablation_surgery#Bilateral_orchiectomy|Bilateral orchiectomy]]<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''International Anandron Study:''' Janknegt RA, Abbou CC, Bartoletti R, Bernstein-Hahn L, Bracken B, Brisset JM, Da Silva FC, Chisholm G, Crawford ED, Debruyne FM, Dijkman GD, Frick J, Goedhals J, Knönagel H, Venner PM. Orchiectomy and nilutamide or placebo as treatment of metastatic prostatic cancer in a multinational double-blind randomized trial. J Urol. 1993 Jan;149(1):77-82. [https://doi.org/10.1016/s0022-5347(17)36003-2 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7678043 PubMed]<br />
##'''Update:''' Janknegt RA; Anandron International Study Group. Total androgen blockade with the use of orchiectomy and nilutamide (Anandron) or placebo as treatment of metastatic prostate cancer. Cancer. 1993 Dec 15;72(12 Suppl):3874-7. [https://www.ncbi.nlm.nih.gov/pubmed/8252507 PubMed]<br />
##'''Update:''' Dijkman GA, Janknegt RA, De Reijke TM, Debruyne FM; International Anandron Study Group. Long-term efficacy and safety of nilutamide plus castration in advanced prostate cancer, and the significance of early prostate specific antigen normalization. J Urol. 1997 Jul;158(1):160-3. [https://www.ncbi.nlm.nih.gov/pubmed/9186345 PubMed]<br />
##'''Update:''' de Reijke T, Derobert E; Anandron /Nilutamide Study Group. Prognostic factor analysis in patients with advanced prostate cancer treated by castration plus anandron or placebo: a final update. Eur Urol. 2002 Aug;42(2):139-46. [http://www.europeanurology.com/article/S0302-2838%2802%2900272-5 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12160584 PubMed]<br />
<br />
==Relugolix monotherapy {{#subobject:5jagu9 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:gaghc5 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://pubmed.ncbi.nlm.nih.gov/32469183/ Shore et al. 2020 (HERO)]<br />
|2017-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Leuprolide_monotherapy_2|Leuprolide]]<br />
| style="background-color:#1a9850" |Superior testosterone suppression<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
*[[Relugolix (Orgovyx)]] 360 mg PO once on day 1, then 120 mg PO once per day<br />
<br />
'''48-week course'''<br />
===References===<br />
#'''HERO:''' Shore ND, Saad F, Cookson MS, George DJ, Saltzstein DR, Tutrone R, Akaza H, Bossi A, van Veenhuyzen DF, Selby B, Fan X, Kang V, Walling J, Tombal B; HERO Study Investigators. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med. 2020 Jun 4;382(23):2187-2196. [https://doi.org/10.1056/NEJMoa2004325 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32469183/ PubMed] NCT03085095<br />
<br />
==Triptorelin monotherapy {{#subobject:15acjb |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1596sc |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1046/j.1464-410X.2003.04308.x Heyns et al. 2003]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Leuprolide_monotherapy_2|Leuprolide]]<br />
| style="background-color:#91cf60" |Seems to have superior 9-month OS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Survival was a secondary endpoint.''<br />
====Endocrine therapy====<br />
<br />
*[[Triptorelin (Trelstar LA)]] 3.75 mg IM once on day 1<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
===References===<br />
<br />
#Heyns CF, Simonin MP, Grosgurin P, Schall R, Porchet HC; South African Triptorelin Study Group. Comparative efficacy of triptorelin pamoate and leuprolide acetate in men with advanced prostate cancer. BJU Int. 2003 Aug;92(3):226-31. [https://onlinelibrary.wiley.com/doi/full/10.1046/j.1464-410X.2003.04308.x link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12887472 PubMed]<br />
<br />
=Metastatic disease, second-line hormonal therapy=<br />
==Abiraterone monotherapy {{#subobject:16 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:16 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''', PSA RR]]<br />
!Comparator [[Overall response rate|'''ORR''', PSA RR]]<br />
!Pt Population<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471149/ de Bono et al. 2011 (COU-AA-301)]<br />
|2008-2009<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|14% (95% CI n/a), 29%<br />
|3% (95% CI n/a), 6%<br />
|Chemo-exposed<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683570/ Ryan et al. 2013 (COU-AA-302)]<br />
|2009-2010<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|36% (95% CI n/a), 62%<br />
|16% (95% CI n/a), 24%<br />
|Chemo-naive<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717983/ Ye et al. 2017 (ABI-PRO-3002)]<br />
|2012-2013<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#1a9850" |Superior TTPP<br />
|<br />
|<br />
|Chemo-naive<br />
|-<br />
|[https://doi.org/10.1200/JCO.2018.77.9827 Attard et al. 2018 (PLATO)]<br />
|2013-NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Abiraterone, Enzalutamide, Prednisone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|<br />
|<br />
|Chemo-naive<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30860-X/fulltext Smith et al. 2019 (ERA 223)]<br />
|2014-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Abiraterone, Radium-223, Prednisone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of symptomatic skeletal EFS<br />
|<br />
|<br />
|Chemo-naive<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*PLATO: [[#Enzalutamide_monotherapy_2|Enzalutamide]], with rising PSA<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Abiraterone (Zytiga)]] 1000 mg PO once per day, 1 hour before or 2 hours after meals<br />
<br />
====Supportive medications====<br />
<br />
*[[Prednisone (Sterapred)]] 5 mg PO twice per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''COU-AA-301:''' de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005. [https://www.nejm.org/doi/full/10.1056/NEJMoa1014618 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471149/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21612468 PubMed] NCT00638690<br />
##'''Update:''' Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, Staffurth JN, North S, Vogelzang NJ, Saad F, Mainwaring P, Harland S, Goodman OB Jr, Sternberg CN, Li JH, Kheoh T, Haqq CM, de Bono JS; COU-AA-301 Investigators. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012 Oct;13(10):983-92. Epub 2012 Sep 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70379-0/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22995653 PubMed]<br />
##'''Update:''' Logothetis CJ, Basch E, Molina A, Fizazi K, North SA, Chi KN, Jones RJ, Goodman OB, Mainwaring PN, Sternberg CN, Efstathiou E, Gagnon DD, Rothman M, Hao Y, Liu CS, Kheoh TS, Haqq CM, Scher HI, de Bono JS. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol. 2012 Dec;13(12):1210-7. Epub 2012 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70473-4/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23142059 PubMed]<br />
#'''COU-AA-302:''' Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE; COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48. Epub 2012 Dec 10. [https://www.nejm.org/doi/full/10.1056/NEJMoa1209096 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683570/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23228172 PubMed] NCT00887198<br />
##'''Update:''' Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, Carles J, Flaig TW, Taplin ME, Higano CS, de Souza P, de Bono JS, Griffin TW, De Porre P, Yu MK, Park YC, Li J, Kheoh T, Naini V, Molina A, Rathkopf DE; COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015 Feb;16(2):152-60. Epub 2015 Jan 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71205-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25601341 PubMed]<br />
#'''ABI-PRO-3002:''' Ye D, Huang Y, Zhou F, Xie K, Matveev V, Li C, Alexeev B, Tian Y, Qiu M, Li H, Zhou T, De Porre P, Yu M, Naini V, Liang H, Wu Z, Sun Y. A phase 3, double-blind, randomized placebo-controlled efficacy and safety study of abiraterone acetate in chemotherapy-naïve patients with mCRPC in China, Malaysia, Thailand and Russia. Asian J Urol. 2017 Apr;4(2):75-85. Epub 2017 Jan 23. [https://doi.org/10.1016/j.ajur.2017.01.002 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717983/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29264210 PubMed] NCT01591122<br />
#'''PLATO:''' Attard G, Borre M, Gurney H, Loriot Y, Andresen-Daniil C, Kalleda R, Pham T, Taplin ME; PLATO collaborators. Abiraterone alone or in combination with enzalutamide in metastatic castration-resistant prostate cancer with rising prostate-specific antigen during enzalutamide treatment. J Clin Oncol. 2018 Sep 1;36(25):2639-2646. Epub 2018 Jul 20. [https://doi.org/10.1200/JCO.2018.77.9827 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30028657 PubMed] NCT01995513<br />
#'''ERA 223:''' Smith M, Parker C, Saad F, Miller K, Tombal B, Ng QS, Boegemann M, Matveev V, Piulats JM, Zucca LE, Karyakin O, Kimura G, Matsubara N, Nahas WC, Nolè F, Rosenbaum E, Heidenreich A, Kakehi Y, Zhang A, Krissel H, Teufel M, Shen J, Wagner V, Higano C. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):408-419. Epub 2019 Feb 6. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30860-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30738780 PubMed] NCT02043678<br />
#'''PROfound:''' de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 May 28;382(22):2091-2102. Epub 2020 Apr 28. [http://doi.org/10.1056/NEJMoa1911440 link to original article] '''contains verified protocol''' [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1911440/suppl_file/nejmoa1911440_appendix.pdf link to supplementary appendix] [https://pubmed.ncbi.nlm.nih.gov/32343890/ PubMed] NCT02987543<br />
#'''PROpel:''' NCT03732820<br />
#'''KEYLYNK-010:''' NCT03834519<br />
#'''AMPLITUDE:''' NCT04497844<br />
<br />
==Antiandrogen withdrawal {{#subobject:17 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:17 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2004.06.037 Small et al. 2004 (CALGB 9583)]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ketoconazole_.26_Hydrocortisone|Ketoconazole & Hydrocortisone]]<br />
| style="background-color:#d73027" |Inferior PSA response<br />
|-<br />
|}<br />
<br />
''Refers to cessation of antiandrogen therapy.''<br />
<br />
===References===<br />
<br />
#'''CALGB 9583:''' Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P, Torti FM, Kaplan E, Vogelzang NJ. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004 Mar 15;22(6):1025-33. [https://doi.org/10.1200/jco.2004.06.037 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15020604 PubMed]<br />
<br />
==Apalutamide monotherapy {{#subobject:acc40a |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cf9ghi|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543693/ Rathkopf et al. 2017 (ARN-509-001)]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Apalutamide (Erleada)]] 240 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''ARN-509-001:''' Rathkopf DE, Antonarakis ES, Shore ND, Tutrone RF, Alumkal JJ, Ryan CJ, Saleh M, Hauke RJ, Bandekar R, Maneval EC, de Boer CJ, Yu MK, Scher HI. Safety and Antitumor Activity of Apalutamide (ARN-509) in Metastatic Castration-Resistant Prostate Cancer with and without Prior Abiraterone Acetate and Prednisone. Clin Cancer Res. 2017 Jul 15;23(14):3544-3551. Epub 2017 Feb 17. [http://clincancerres.aacrjournals.org/content/23/14/3544.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543693/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28213364 PubMed]<br />
<br />
==BAT {{#subobject:aoc10a |Regimen=1}}==<br />
BAT: '''<u>B</u>'''ipolar '''<u>A</u>'''ndrogen '''<u>T</u>'''herapy <br />
===Regimen {{#subobject:#e085c7 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.02759 Denmeade et al. 2021 (TRANSFORMER)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[Prostate_cancer#Enzalutamide_monotherapy|Enzalutamide]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<sup>1</sup><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Progression-free survival<br />
! style="width: 33%" |Comparator progression-free survival<br />
! style="width: 33%" |Pt Population<br />
|-<br />
|5.7 months<br />
|5.7 months<br />
|Castrate-resistant, metastatic, asymptomatic, progressed after abiraterone<br />
|-<br />
|}<br />
''<sup>1</sup>Study not powered for equivalency. Secondary endpoint of PFS2 after crossover was superior in BAT to enzalutamide arm.''<br />
<br />
====Endocrine therapy====<br />
*ADT: All patients maintained on continuous testosterone suppression via surgical castration or [[:Category:GnRH_agonists|GnRH agonist]] or [[:Category:GnRH antagonists|GnRH antagonist]]<br />
*Bipolar Androgen Therapy (BAT): [[Testosterone cypionate]] 400 mg IM once every 28 days<br />
*[[Enzalutamide_(Xtandi)|Enzalutamide]]: 160 mg by mouth daily<br />
<br />
====Subsequent treatment====<br />
*At progression, asymptomatic patients were allowed to cross over to alternative therapy<br />
<br />
===References===<br />
# '''TRANSFORMER:''' Denmeade SR, Wang H, Agarwal N, Smith D, Schweizer MT, Stein MN, Assikis V, Twardowski P, Flaig T, Szmulewitz R, Holzbeierlein J, Hauke R, Sonpavde G, Garcia J, Hussain A, Sartor O, Mao S, Cao H, Fu W, Wang T, Abdallah R, Lim SJ, Bolejack V, Paller C, Carducci M, Markowski MC, Eisenberger MA, Antonarakis ES; TRANSFORMER investigators. TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Prostate Cancer. J Clin Oncol. Epub 2021 Feb 22 [https://doi.org/10.1200/jco.20.02759 link to original article] [https://ascopubs.org/doi/suppl/10.1200/JCO.20.02759 link to protocol] [https://pubmed.ncbi.nlm.nih.gov/33617303/ PubMed] NCT02286921<br />
<br />
==Bicalutamide monotherapy {{#subobject:abb40a |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cf9def|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''', PSA RR]]<br />
!Comparator [[Overall response rate|'''ORR''', PSA RR]]<br />
!Pt Population<br />
|-<br />
|[https://doi.org/10.1200/jco.2015.64.9285 Penson et al. 2016 (STRIVE)]<br />
|2012-2014<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Enzalutamide_monotherapy_2|Enzalutamide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|pts w/ measurable disease: '''14%''' (95% CI n/a), '''31%''' (95% CI n/a)<br />
|pts w/ measurable disease: '''60%''' (95% CI n/a), '''81%''' (95% CI n/a)<br />
|Chemo-naive, abi and keto-naive<br />
|-<br />
|}<br />
''Patients continued ADT while on study; details not provided.''<br />
====Endocrine therapy====<br />
<br />
*[[Bicalutamide (Casodex)]] 50 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<!-- Presented in part at the American Urological Association 2015 Annual Meeting, New Orleans, LA, May 15-19, 2015. --><br />
<br />
#'''STRIVE:''' Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, Dunshee C, Wang F, Wu K, Krivoshik A, Phung D, Higano CS. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J Clin Oncol. 2016 Jun 20;34(18):2098-106. Epub 2016 Jan 25. [https://doi.org/10.1200/jco.2015.64.9285 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26811535 PubMed] NCT01664923<br />
<br />
==Enzalutamide monotherapy {{#subobject:18 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 160 mg/day {{#subobject:18 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Levels_of_Evidence#Efficacy|Efficacy]], PSA RR<br />
!Comparator [[Overall response rate|'''ORR''']], PSA RR<br />
!Pt Population<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1207506 Scher et al. 2012 (AFFIRM)]<br />
|2009-2010<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Prostate_cancer_-_null_regimens#Placebo_3|Placebo]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|29% (95% CI n/a), 54%<br />
|4% (95% CI n/a), 2%<br />
|Chemo-exposed (docetaxel)<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418931/ Beer et al. 2014 (PREVAIL)]<br />
|2010-2012<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Prostate_cancer_-_null_regimens#Placebo_3|Placebo]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|59% (95% CI n/a), 78%<br />
|5% (95% CI n/a), 3%<br />
|Chemo and abiraterone naive<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00518-5/fulltext Shore et al. 2016 (TERRAIN)]<br />
|2011-2013<br />
| style="background-color:#1a9851" |Randomized Phase II (E-RT-switch-ic)<br />
|[[#Bicalutamide_monotherapy_2|Bicalutamide]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|<br />
|<br />
|<br />
|-<br />
|[https://doi.org/10.1200/jco.2015.64.9285 Penson et al. 2016 (STRIVE)]<br />
|2012-2014<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Bicalutamide_monotherapy_2|Bicalutamide]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|60% (95% CI n/a), 81%<br />
|14% (95% CI n/a), 31%<br />
|Chemo and bicalutamide naive<br />
|-<br />
|[https://doi.org/10.1200/JCO.2018.77.9827 Attard et al. 2018 (PLATO)]<br />
|2013-NR<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|Chemo-naive<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.20.02759 Denmeade et al. 2021 (TRANSFORMER)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[Prostate_cancer#BAT|BAT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| Post-abiraterone, asymptomatic<br />
|-<br />
|}<br />
''Patients in STRIVE, PLATO, & TRANSFORMER continued ADT while on study or had a history of bilateral orchiectomy; details not provided.''<br />
====Endocrine therapy====<br />
<br />
*[[Enzalutamide (Xtandi)]] 160 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
====Subsequent treatment====<br />
<br />
*PLATO, with rising PSA: [[#Abiraterone_monotherapy|Abiraterone]] versus [[Stub#Abiraterone_.26_Enzalutamide|Abiraterone & Enzalutamide]]<br />
*TRANSFORMER, asymptomatic PSA or radiographic progression: crossover to alternative arm. Secondary endpoint of PFS2 was statistically longer with BAT to Enzalutamide compared to Enzalutamide to BAT<br />
<br />
===Regimen variant #2, 240 mg/day {{#subobject:7bf35b |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948179/ Scher et al. 2010 (S-3100-1-01)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Note: this is the reported MTD from the phase I portion of the trial; however, it is NOT the dose used in subsequent phase III studies.''<br />
====Endocrine therapy====<br />
<br />
*[[Enzalutamide (Xtandi)]] 240 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
<br />
#'''S-3100-1-01:''' Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, Rathkopf D, Shelkey J, Yu EY, Alumkal J, Hung D, Hirmand M, Seely L, Morris MJ, Danila DC, Humm J, Larson S, Fleisher M, Sawyers CL; Prostate Cancer Foundation/Department of Defense Prostate Cancer Clinical Trials Consortium. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010 Apr 24;375(9724):1437-46. Epub 2010 Apr 14. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60172-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948179/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20398925 PubMed] NCT00510718<br />
#'''AFFIRM:''' Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Fléchon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS; AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012 Sep 27;367(13):1187-97. Epub 2012 Aug 15. [https://www.nejm.org/doi/full/10.1056/NEJMoa1207506 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22894553 PubMed] NCT00974311<br />
<!-- # Beer TM, Armstrong AJ, Sternberg CN, Higano CS, Iversen P, Loriot Y, et al. Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study. ASCO Meeting Abstracts. 2014 February 5, 2014;32(4_suppl):LBA1. [http://abstracts.asco.org/142/AbstView_142_123836.html link to original article] '''contains verified protocol''' --><br />
#'''PREVAIL:''' Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B; PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014 Jul 31;371(5):424-33. Epub 2014 Jun 1. [https://www.nejm.org/doi/full/10.1056/NEJMoa1405095 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418931/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24881730 PubMed] NCT01212991<br />
##'''Update:''' Beer TM, Armstrong AJ, Rathkopf D, Loriot Y, Sternberg CN, Higano CS, Iversen P, Evans CP, Kim CS, Kimura G, Miller K, Saad F, Bjartell AS, Borre M, Mulders P, Tammela TL, Parli T, Sari S, van Os S, Theeuwes A, Tombal B. Enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate cancer: Extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017 Feb;71(2):151-154. Epub 2016 Jul 28. [http://www.europeanurology.com/article/S0302-2838(16)30437-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570461/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27477525 PubMed]<br />
##'''HRQoL analysis:''' Devlin N, Herdman M, Pavesi M, Phung D, Naidoo S, Beer TM, Tombal B, Loriot Y, Ivanescu C, Parli T, Balk M, Holmstrom S. Health-related quality of life effects of enzalutamide in patients with metastatic castration-resistant prostate cancer: an in-depth post hoc analysis of EQ-5D data from the PREVAIL trial. Health Qual Life Outcomes. 2017 Jun 23;15(1):130. [https://hqlo.biomedcentral.com/articles/10.1186/s12955-017-0704-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481866/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28645287 PubMed]<br />
#'''TERRAIN:''' Shore ND, Chowdhury S, Villers A, Klotz L, Siemens DR, Phung, van Os S, Hasabou N, Wang F, Bhattacharya S, Heidenreich A. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol. 2016 Feb;17(2):153-163. Epub 2016 Jan 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00518-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26774508 PubMed] NCT01288911<br />
<!-- Presented in part at the American Urological Association 2015 Annual Meeting, New Orleans, LA, May 15-19, 2015. --><br />
#'''STRIVE:''' Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, Dunshee C, Wang F, Wu K, Krivoshik A, Phung D, Higano CS. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J Clin Oncol. 2016 Jun 20;34(18):2098-106. Epub 2016 Jan 25. [https://doi.org/10.1200/jco.2015.64.9285 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26811535 PubMed] NCT01664923<br />
#'''PLATO:''' Attard G, Borre M, Gurney H, Loriot Y, Andresen-Daniil C, Kalleda R, Pham T, Taplin ME; PLATO collaborators. Abiraterone alone or in combination with enzalutamide in metastatic castration-resistant prostate cancer with rising prostate-specific antigen during enzalutamide treatment. J Clin Oncol. 2018 Sep 1;36(25):2639-2646. Epub 2018 Jul 20. [https://doi.org/10.1200/JCO.2018.77.9827 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30028657 PubMed] NCT01995513<br />
#'''PROfound:''' de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 May 28;382(22):2091-2102. Epub 2020 Apr 28. [http://doi.org/10.1056/NEJMoa1911440 link to original article] '''contains verified protocol''' [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1911440/suppl_file/nejmoa1911440_appendix.pdf link to supplementary appendix] [https://pubmed.ncbi.nlm.nih.gov/32343890/ PubMed] NCT02987543<br />
# '''TRANSFORMER:''' Denmeade SR, Wang H, Agarwal N, Smith D, Schweizer MT, Stein MN, Assikis V, Twardowski P, Flaig T, Szmulewitz R, Holzbeierlein J, Hauke R, Sonpavde G, Garcia J, Hussain A, Sartor O, Mao S, Cao H, Fu W, Wang T, Abdallah R, Lim SJ, Bolejack V, Paller C, Carducci M, Markowski MC, Eisenberger MA, Antonarakis ES; TRANSFORMER investigators. TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Prostate Cancer. J Clin Oncol. Epub 2021 Feb 22 [https://doi.org/10.1200/jco.20.02759 link to original article] [https://ascopubs.org/doi/suppl/10.1200/JCO.20.02759 link to protocol] [https://pubmed.ncbi.nlm.nih.gov/33617303/ PubMed] NCT02286921<br />
#'''CASPAR:''' NCT04455750<br />
#'''KEYLYNK-010:''' NCT03834519<br />
<br />
==Hydrocortisone monotherapy {{#subobject:f48fb4 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:da4be9 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1999.17.8.2506 Kantoff et al. 1999 (CALGB 9182)]<br />
|1992-1995<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Mitoxantrone_.26_Hydrocortisone|Mitoxantrone & Hydrocortisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2000.18.7.1440 Small et al. 2000]<br />
|1994-1996<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Suramin & Hydrocortisone<br />
| style="background-color:#d73027" |Inferior TTP<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdh429 Abratt et al. 2004]<br />
|1997-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Vinorelbine_.26_Hydrocortisone|Vinorelbine & Hydrocortisone]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Hydrocortisone (Cortef)]] 40 mg/day PO<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''CALGB 9182:''' Kantoff PW, Halabi S, Conaway M, Picus J, Kirshner J, Hars V, Trump D, Winer EP, Vogelzang NJ. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol. 1999 Aug;17(8):2506-13. [https://doi.org/10.1200/JCO.1999.17.8.2506 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10561316 PubMed]<br />
#Small EJ, Meyer M, Marshall ME, Reyno LM, Meyers FJ, Natale RB, Lenehan PF, Chen L, Slichenmyer WJ, Eisenberger M. Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: results of a randomized phase III trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone. J Clin Oncol. 2000 Apr;18(7):1440-50. [https://doi.org/10.1200/JCO.2000.18.7.1440 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10735891 PubMed]<br />
#Abratt RP, Brune D, Dimopoulos MA, Kliment J, Breza J, Selvaggi FP, Beuzeboc P, Demkow T, Oudard S. Randomised phase III study of intravenous vinorelbine plus hormone therapy versus hormone therapy alone in hormone-refractory prostate cancer. Ann Oncol. 2004 Nov;15(11):1613-21. [https://doi.org/10.1093/annonc/mdh429 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15520061 PubMed]<br />
<br />
==Ketoconazole & Hydrocortisone {{#subobject:19 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:19 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''', PSA RR]]<br />
!Comparator [[Overall response rate|'''ORR''', PSA RR]]<br />
!Pt Population<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(84)92909-X/fulltext Trachtenberg & Pont 1984]<br />
|NR<br />
| style="background-color:#ffffbe" |Pilot<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|<br />
|<br />
|<br />
|-<br />
|[https://doi.org/10.1200/jco.2004.06.037 Small et al. 2004 (CALGB 9583)]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Antiandrogen_withdrawal|Antiandrogen withdrawal]]<br />
| style="background-color:#1a9850" |Superior PSA response<br />
|pts w/ measurable disease: '''20%''' (95% CI 11 - 32), '''27%''' (95% CI 20 - 35)<br />
|pts w/ measurable disease: '''2%''' (95% CI 0 - 11), '''11%''' (95% CI 7 - 17)<br />
|Progression at ADT, i.e. CRPC<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Ketoconazole (Nizoral)]] 400 mg PO three times per day<br />
*[[Hydrocortisone (Cortef)]] 30 mg PO QAM and 10 mg PO QPM<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#Trachtenberg J, Pont A. Ketoconazole therapy for advanced prostate cancer. Lancet. 1984 Aug 25;2(8400):433-5. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(84)92909-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6147504 PubMed]<br />
#'''CALGB 9583:''' Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P, Torti FM, Kaplan E, Vogelzang NJ. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004 Mar 15;22(6):1025-33. [https://doi.org/10.1200/jco.2004.06.037 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15020604 PubMed]<br />
<br />
==Ketoconazole, Hydrocortisone, Dutasteride {{#subobject:20 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:20 |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644858/ Taplin et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Ketoconazole (Nizoral)]] 400 mg PO three times per day<br />
*[[Hydrocortisone (Cortef)]] 30 mg PO QAM and 10 mg PO QPM<br />
*[[Dutasteride (Avodart)]] 0.5 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#Taplin ME, Regan MM, Ko YJ, Bubley GJ, Duggan SE, Werner L, Beer TM, Ryan CW, Mathew P, Tu SM, Denmeade SR, Oh WK, Sartor O, Mantzoros CS, Rittmaster R, Kantoff PW, Balk SP. Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer. Clin Cancer Res. 2009 Nov 15;15(22):7099-105. Epub 2009 Nov 3. [http://clincancerres.aacrjournals.org/content/15/22/7099.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644858/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19887483 PubMed]<br />
<br />
==Prednisone monotherapy {{#subobject:22 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 5 mg twice per day {{#subobject:22 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.1989.7.5.590 Tannock et al. 1989]<br />
|1976-1980<br />
| style="background-color:#ffffbe" |Retrospective<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/JCO.1996.14.6.1756 Tannock et al. 1996 (CCI-NOV22)]<br />
|1990-1994<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Mitoxantrone_.26_Prednisone|Mitoxantrone & Prednisone]]<br />
| style="background-color:#d73027" |Inferior palliation<br />
|-<br />
|[https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2964163-8 Berry et al. 2002]<br />
|1997-1999<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Mitoxantrone_.26_Prednisone|Mitoxantrone & Prednisone]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTTF<br />
|-<br />
|[https://doi.org/10.1200/JCO.2008.20.1228 Sternberg et al. 2009 (SPARC)]<br />
|2003-2006<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Satraplatin & Prednisone<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471149/ de Bono et al. 2011 (COU-AA-301)]<br />
|2008-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Abiraterone_monotherapy|Abiraterone]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2012.48.5268 Michaelson et al. 2013 (SUN 1120)]<br />
|2008-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Sunitinib & Prednisone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683570/ Ryan et al. 2013 (COU-AA-302)]<br />
|2009-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Abiraterone_monotherapy|Abiraterone]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70027-6/fulltext Saad et al. 2015 (ELM-PC 4)]<br />
|2010-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Orteronel & Prednisone<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879718/ Fizazi et al. 2015 (ELM-PC 5)]<br />
|2010-NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Orteronel & Prednisone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2015.65.5597 Smith et al. 2016 (COMET-1)]<br />
|2012-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cabozantinib_monotherapy|Cabozantinib]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 5 mg PO twice per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen variant #2, 5 mg QID {{#subobject:5055a7 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2001.19.1.62 Fosså et al. 2001 (EORTC 30903)]<br />
|1992-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Flutamide_monotherapy|Flutamide]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of TTP/OS<br />
|-<br />
|}<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 5 mg PO four times per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart L, Rider W. Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol. 1989 May;7(5):590-7. [https://doi.org/10.1200/jco.1989.7.5.590 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2709088 PubMed]<br />
#'''CCI-NOV22:''' Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, Armitage GR, Wilson JJ, Venner PM, Coppin CM, Murphy KC. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996 Jun;14(6):1756-64. [https://doi.org/10.1200/JCO.1996.14.6.1756 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8656243 PubMed]<br />
##'''HRQoL analysis:''' Osoba D, Tannock IF, Ernst DS, Neville AJ. Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol. 1999 Jun;17(6):1654-63. [https://doi.org/10.1200/JCO.1999.17.6.1654 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10561201 PubMed]<br />
#'''EORTC 30903:''' Fosså SD, Slee PH, Brausi M, Horenblas S, Hall RR, Hetherington JW, Aaronson N, de Prijck L, Collette L. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol. 2001 Jan 1;19(1):62-71. [https://doi.org/10.1200/JCO.2001.19.1.62 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11134196 PubMed]<br />
#Berry W, Dakhil S, Modiano M, Gregurich M, Asmar L. Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol. 2002 Dec;168(6):2439-43. [https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2964163-8 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12441935 PubMed]<br />
#'''SPARC:''' Sternberg CN, Petrylak DP, Sartor O, Witjes JA, Demkow T, Ferrero JM, Eymard JC, Falcon S, Calabrò F, James N, Bodrogi I, Harper P, Wirth M, Berry W, Petrone ME, McKearn TJ, Noursalehi M, George M, Rozencweig M. Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial. J Clin Oncol. 2009 Nov 10;27(32):5431-8. Epub 2009 Oct 5. [https://doi.org/10.1200/JCO.2008.20.1228 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19805692 PubMed] NCT00069745<br />
#'''COU-AA-301:''' de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005. [https://www.nejm.org/doi/full/10.1056/NEJMoa1014618 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471149/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21612468 PubMed] NCT00638690<br />
##'''Update:''' Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, Staffurth JN, North S, Vogelzang NJ, Saad F, Mainwaring P, Harland S, Goodman OB Jr, Sternberg CN, Li JH, Kheoh T, Haqq CM, de Bono JS; COU-AA-301 Investigators. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012 Oct;13(10):983-92. Epub 2012 Sep 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70379-0/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22995653 PubMed]<br />
##'''Update:''' Logothetis CJ, Basch E, Molina A, Fizazi K, North SA, Chi KN, Jones RJ, Goodman OB, Mainwaring PN, Sternberg CN, Efstathiou E, Gagnon DD, Rothman M, Hao Y, Liu CS, Kheoh TS, Haqq CM, Scher HI, de Bono JS. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol. 2012 Dec;13(12):1210-7. Epub 2012 Nov 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70473-4/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23142059 PubMed]<br />
#'''COU-AA-302:''' Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE; COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48. Epub 2012 Dec 10. [https://www.nejm.org/doi/full/10.1056/NEJMoa1209096 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683570/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23228172 PubMed] NCT00887198<br />
##'''Update:''' Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, Carles J, Flaig TW, Taplin ME, Higano CS, de Souza P, de Bono JS, Griffin TW, De Porre P, Yu MK, Park YC, Li J, Kheoh T, Naini V, Molina A, Rathkopf DE; COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015 Feb;16(2):152-60. Epub 2015 Jan 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71205-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25601341 PubMed]<br />
#'''SUN 1120:''' Michaelson MD, Oudard S, Ou YC, Sengeløv L, Saad F, Houede N, Ostler P, Stenzl A, Daugaard G, Jones R, Laestadius F, Ullèn A, Bahl A, Castellano D, Gschwend J, Maurina T, Chow Maneval E, Wang SL, Lechuga MJ, Paolini J, Chen I. Randomized, placebo-controlled, phase III trial of sunitinib plus prednisone versus prednisone alone in progressive, metastatic, castration-resistant prostate cancer. J Clin Oncol. 2014 Jan 10;32(2):76-82. Epub 2013 Dec 9. [https://doi.org/10.1200/JCO.2012.48.5268 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24323035 PubMed] NCT00676650<br />
#'''ELM-PC 5:''' Fizazi K, Jones R, Oudard S, Efstathiou E, Saad F, de Wit R, De Bono J, Cruz FM, Fountzilas G, Ulys A, Carcano F, Agarwal N, Agus D, Bellmunt J, Petrylak DP, Lee SY, Webb IJ, Tejura B, Borgstein N, Dreicer R. Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. J Clin Oncol. 2015 Mar 1;33(7):723-31. Epub 2015 Jan 26. [https://doi.org/10.1200/JCO.2014.56.5119 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879718/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25624429 PubMed] NCT01193257<br />
#'''ELM-PC 4:''' Saad F, Fizazi K, Jinga V, Efstathiou E, Fong PC, Hart LL, Jones R, McDermott R, Wirth M, Suzuki K, MacLean DB, Wang L, Akaza H, Nelson J, Scher HI, Dreicer R, Webb IJ, de Wit R; ELM-PC 4 investigators. Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. Lancet Oncol. 2015 Mar;16(3):338-48. Epub 2015 Feb 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70027-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25701170 PubMed] NCT01193244<br />
#'''COMET-1:''' Smith M, De Bono J, Sternberg C, Le Moulec S, Oudard S, De Giorgi U, Krainer M, Bergman A, Hoelzer W, De Wit R, Bögemann M, Saad F, Cruciani G, Thiery-Vuillemin A, Feyerabend S, Miller K, Houédé N, Hussain S, Lam E, Polikoff J, Stenzl A, Mainwaring P, Ramies D, Hessel C, Weitzman A, Fizazi K. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016 Sep 1;34(25):3005-13. Epub 2016 Jul 11. [https://doi.org/10.1200/JCO.2015.65.5597 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27400947 PubMed] NCT01605227<br />
<br />
=Chemotherapy for metastatic castrate-sensitive disease=<br />
==Cabazitaxel & Prednisone {{#subobject:23jbuz |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Cabazitaxel (Jevtana) in prostate cancer]]<br />
<br />
===Regimen {{#subobject:2hcb1b |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1911206 de Wit et al. 2019 (CARD)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|1. [[#Abiraterone_monotherapy|Abiraterone]]<br> 2. [[#Enzalutamide_monotherapy|Enzalutamide]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: patients in CARD had already received and progressed on the alternate androgen signaling targeted inhibitor.''<br />
====Chemotherapy====<br />
<br />
*[[Cabazitaxel (Jevtana)]] 25 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 10 mg PO once per day<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Antihistamines|Antihistamine]] once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
*[[:Category:Steroids|Corticosteroid]] ([[Dexamethasone (Decadron)|dexamethasone]] 8 mg or equivalent) once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
*[[:Category:Antihistamines|Histamine H2-antagonist]] (except cimetidine) once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''CARD:''' de Wit R, de Bono J, Sternberg CN, Fizazi K, Tombal B, Wülfing C, Kramer G, Eymard JC, Bamias A, Carles J, Iacovelli R, Melichar B, Sverrisdóttir Á, Theodore C, Feyerabend S, Helissey C, Ozatilgan A, Geffriaud-Ricouard C, Castellano D; CARD Investigators. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med. 2019 Dec 26;381(26):2506-2518. Epub 2019 Sep 30. [https://www.nejm.org/doi/full/10.1056/NEJMoa1911206 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31566937 PubMed]<br />
<br />
=Chemotherapy for metastatic castrate-resistant disease=<br />
==Cabazitaxel & Prednisolone {{#subobject:23aug19 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Cabazitaxel (Jevtana) in prostate cancer]]<br />
<br />
===Regimen {{#subobject:fa5jfa |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/s0140-6736(21)00237-3 Hofman et al. 2021 (TheraP)]<br />
|2018-2019<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[<sup>177</sup>Lu]Lu-PSMA-617<br />
| style="background-color:#d73027" |Inferior PSA response<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cabazitaxel (Jevtana)]] 20 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisolone (Millipred)]] 10 mg PO once per day<br />
<br />
'''21-day cycle for up to 10 cycles'''<br />
<br />
===References===<br />
# '''TheraP:''' Hofman MS, Emmett L, Sandhu S, Iravani A, Joshua AM, Goh JC, Pattison DA, Tan TH, Kirkwood ID, Ng S, Francis RJ, Gedye C, Rutherford NK, Weickhardt A, Scott AM, Lee ST, Kwan EM, Azad AA, Ramdave S, Redfern AD, Macdonald W, Guminski A, Hsiao E, Chua W, Lin P, Zhang AY, McJannett MM, Stockler MR, Violet JA, Williams SG, Martin AJ, Davis ID; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021 Feb 11:S0140-6736(21)00237-3. Epub ahead of print. [https://doi.org/10.1016/s0140-6736(21)00237-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33581798/ PubMed] NCT03392428<br />
<br />
==Cabazitaxel & Prednisone {{#subobject:23 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Cabazitaxel (Jevtana) in prostate cancer]]<br />
<br />
===Regimen variant #1, 20/10, indefinite {{#subobject:fa59fa |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2016.72.1068 Oudard et al. 2017 (FIRSTANA)]<br />
| rowspan="2" |2011-2013<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cabazitaxel_.26_Prednisone_2|Cabazitaxel & Prednisone]]; 25/10<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[[#Docetaxel_.26_Prednisone|Docetaxel & Prednisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2016.72.1076 Eisenberger et al. 2017 (PROSELICA)]<br />
|2011-2013<br />
| style="background-color:#1a9851" |Phase III (E-RT-de-esc)<br />
|[[#Cabazitaxel_.26_Prednisone_2|Cabazitaxel & Prednisone]]; 25/10<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cabazitaxel (Jevtana)]] 20 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 10 mg PO once per day<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 25/10 x 10 {{#subobject:23 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''', PSA RR]]<br />
!Comparator [[Overall response rate|'''ORR''', PSA RR]]<br />
!Pt Population<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961389-X/fulltext de Bono et al. 2010 (TROPIC)]<br />
|2007-2008<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Mitoxantrone_.26_Prednisone|Mitoxantrone & Prednisone]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|14% (95% CI 10-19)<br> 39% (95% CI 34-44)<sup>1</sup><br />
|4% (95% CI 2-7)<br> 18% (95% CI 14-22)<sup>1</sup><br />
|Progressed on docetaxel<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30605-8/fulltext Beer et al. 2017 (AFFINITY)]<br />
|2012-2014<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cabazitaxel, Prednisone, Custirsen<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|<br />
|Progressed on docetaxel<br />
|-<br />
|}<br />
''<sup>1</sup>ORRs in TROPIC were only reported for patients with measurable disease.''<br />
====Chemotherapy====<br />
<br />
*[[Cabazitaxel (Jevtana)]] 25 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 10 mg PO once per day<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Antihistamines|Antihistamine]] once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
*[[:Category:Steroids|Corticosteroid]] ([[Dexamethasone (Decadron)|dexamethasone]] 8 mg or equivalent) once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
*[[:Category:Antihistamines|Histamine H2-antagonist]] (except cimetidine) once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
<br />
'''21-day cycle for up to 10 cycles'''<br />
<br />
===Regimen variant #3, 25/10, indefinite {{#subobject:23sa2b |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2016.72.1068 Oudard et al. 2017 (FIRSTANA)]<br />
| rowspan="2" |2011-2013<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cabazitaxel_.26_Prednisone_2|Cabazitaxel & Prednisone]]; 20/10<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[[#Docetaxel_.26_Prednisone|Docetaxel & Prednisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2016.72.1076 Eisenberger et al. 2017 (PROSELICA)]<br />
|2011-2013<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cabazitaxel_.26_Prednisone_2|Cabazitaxel & Prednisone]]; 20/10<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cabazitaxel (Jevtana)]] 25 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 10 mg PO once per day<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Antihistamines|Antihistamine]] once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
*[[:Category:Steroids|Corticosteroid]] ([[Dexamethasone (Decadron)|dexamethasone]] 8 mg or equivalent) once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
*[[:Category:Antihistamines|Histamine H2-antagonist]] (except cimetidine) once on day 1, at least 30 minutes prior to [[Cabazitaxel (Jevtana)]]<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''TROPIC:''' de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010 Oct 2;376(9747):1147-54. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961389-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20888992 PubMed] NCT00417079<br />
#'''FIRSTANA:''' Oudard S, Fizazi K, Sengeløv L, Daugaard G, Saad F, Hansen S, Hjälm-Eriksson M, Jassem J, Thiery-Vuillemin A, Caffo O, Castellano D, Mainwaring PN, Bernard J, Shen L, Chadjaa M, Sartor O. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: A randomized phase III Trial-FIRSTANA. J Clin Oncol. 2017 Oct 1;35(28):3189-3197. Epub 2017 Jul 28. [https://doi.org/10.1200/JCO.2016.72.1068 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28753384 PubMed] NCT01308567<br />
#'''PROSELICA:''' Eisenberger M, Hardy-Bessard AC, Kim CS, Géczi L, Ford D, Mourey L, Carles J, Parente P, Font A, Kacso G, Chadjaa M, Zhang W, Bernard J, de Bono J. Phase III study comparing a reduced dose of cabazitaxel (20 mg/m(2)) and the currently approved dose (25 mg/m(2)) in postdocetaxel patients with metastatic castration-resistant prostate cancer-PROSELICA. J Clin Oncol. 2017 Oct 1;35(28):3198-3206. Epub 2017 Aug 15 [https://doi.org/10.1200/JCO.2016.72.1076 link to original article] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/28809610 PubMed]<br />
#'''AFFINITY:''' Beer TM, Hotte SJ, Saad F, Alekseev B, Matveev V, Fléchon A, Gravis G, Joly F, Chi KN, Malik Z, Blumenstein B, Stewart PS, Jacobs CA, Fizazi K. Custirsen (OGX-011) combined with cabazitaxel and prednisone versus cabazitaxel and prednisone alone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel (AFFINITY): a randomised, open-label, international, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1532-1542. Epub 2017 Oct 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30605-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29033099 PubMed] NCT01578655<br />
<br />
==Cabozantinib monotherapy {{#subobject:a20f66 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 60 mg/day {{#subobject:0eb568 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2015.65.5597 Smith et al. 2016 (COMET-1)]<br />
|2012-2014<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
<br />
*[[Cabozantinib (Cometriq)]] 60 mg PO once per day<br />
<br />
===Regimen variant #2, 100 mg/day {{#subobject:2efaa6 |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110249/ Smith et al. 2012 (XL184-203)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
<br />
*[[Cabozantinib (Cometriq)]] 100 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
<br />
#'''XL184-203:''' Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, Vogelzang NJ, Small EJ, Harzstark AL, Gordon MS, Vaishampayan UN, Haas NB, Spira AI, Lara PN Jr, Lin CC, Srinivas S, Sella A, Schöffski P, Scheffold C, Weitzman AL, Hussain M. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013 Feb 1;31(4):412-9. Epub 2012 Nov 19. [https://doi.org/10.1200/jco.2012.45.0494 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110249/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23169517 PubMed] NCT00940225<br />
#'''COMET-1:''' Smith M, De Bono J, Sternberg C, Le Moulec S, Oudard S, De Giorgi U, Krainer M, Bergman A, Hoelzer W, De Wit R, Bögemann M, Saad F, Cruciani G, Thiery-Vuillemin A, Feyerabend S, Miller K, Houédé N, Hussain S, Lam E, Polikoff J, Stenzl A, Mainwaring P, Ramies D, Hessel C, Weitzman A, Fizazi K. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016 Sep 1;34(25):3005-13. Epub 2016 Jul 11. [https://doi.org/10.1200/JCO.2015.65.5597 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27400947 PubMed] NCT01605227<br />
<br />
==Carboplatin & Docetaxel {{#subobject:28 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Example orders===<br />
<br />
*[[Example orders for Docetaxel & Carboplatin in prostate cancer]]<br />
<br />
===Regimen {{#subobject:31 |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.23195/full Ross et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients enrolled in the trial had hormone-refractory prostate cancer and progression of disease during docetaxel treatment or within 45 days of stopping docetaxel treatment.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 4 (Calvert formula) IV over 60 minutes once on day 1, '''given second'''<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*"Standard dexamethasone premedication was used"<br />
*Patients continued to receive androgen deprivation therapy<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Ross RW, Beer TM, Jacobus S, Bubley GJ, Taplin ME, Ryan CW, Huang J, Oh WK; Prostate Cancer Clinical Trials Consortium. A phase 2 study of carboplatin plus docetaxel in men with metastatic hormone-refractory prostate cancer who are refractory to docetaxel. Cancer. 2008 Feb 1;112(3):521-6. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.23195/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18085595 PubMed]<br />
#'''Retrospective:''' Nakabayashi M, Sartor O, Jacobus S, Regan MM, McKearn D, Ross RW, Kantoff PW, Taplin ME, Oh WK. Response to docetaxel/carboplatin-based chemotherapy as first- and second-line therapy in patients with metastatic hormone-refractory prostate cancer. BJU Int. 2008 Feb;101(3):308-12. [https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2007.07331.x/full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18184327 PubMed]<br />
<br />
==Carboplatin, Docetaxel, Prednisone {{#subobject:28a1b4 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:32 |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00345-010-0527-5 Reuter et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients enrolled in the trial had progression of disease on docetaxel chemotherapy and castration-resistant disease.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 30 minutes once on day 1<br />
*[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15<br />
**Note: In contrast to its abstract, Reuter et al. 2010 sometimes used "days 1, 8, (15)" to describe when docetaxel was given. The paper did not specifically say what "(15)" meant, such as whether this meant that the day 15 dose was optional.<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 5 mg PO twice per day<br />
<br />
====Supportive medications====<br />
<br />
*"Standard dexamethasone premedication was used"<br />
*Patients continued to receive LHRH (luteinizing hormone releasing hormone) agonists<br />
*No routine use of granulocyte colony-stimulating factor (G-CSF)<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Reuter CW, Morgan MA, Ivanyi P, Fenner M, Ganser A, Grünwald V. Carboplatin plus weekly docetaxel as salvage chemotherapy in docetaxel-resistant and castration-resistant prostate cancer. World J Urol. 2010 Jun;28(3):391-8. Epub 2010 Mar 14. [http://link.springer.com/article/10.1007%2Fs00345-010-0527-5 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20229232 PubMed]<br />
<br />
==Carboplatin & Paclitaxel (CP) {{#subobject:30 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1 {{#subobject:34 |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1896-9 Kentepozidis et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 3 (Calvert formula) IV once per day on days 1 & 15, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 135 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*"All patients received a concomitant anti-emetic prophylaxis"<br />
*[[Dexamethasone (Decadron)]] 20 mg PO given twice, 12 and 6 hours prior to [[Paclitaxel (Taxol)]]<br />
*[[Diphenhydramine (Benadryl)]] 50 mg IV once per day on days 1 & 15, "prior to each dose" (there was nothing else after this in Kentepozidis et al. 2012, and it is assumed to mean prior to each dose of [[Paclitaxel (Taxol)]])<br />
*[[Cimetidine (Tagamet)]] 300 mg IV once per day on days 1 & 15, "prior to each dose" (there was nothing else after this in Kentepozidis et al. 2012, and it is assumed to mean prior to each dose of [[Paclitaxel (Taxol)]])<br />
*No prophylactic G-CSF<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:35 |Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.urologiconcology.org/article/S1078-1439%2810%2900003-7/abstract Jeske et al. 2010]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 4 to 6 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 60 to 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Retrospective:''' Jeske S, Tagawa ST, Olowokure O, Selzer J, Giannakakou P, Nanus DM. Carboplatin plus paclitaxel therapy after docetaxel in men with metastatic castrate resistant prostate cancer. Urol Oncol. 2011 Nov-Dec;29(6):676-81. Epub 2010 May 7. [http://www.urologiconcology.org/article/S1078-1439%2810%2900003-7/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20451413 PubMed]<br />
#Kentepozidis N, Soultati A, Giassas S, Vardakis N, Kalykaki A, Kotsakis A, Papadimitraki E, Pantazopoulos N, Bozionellou V, Georgoulias V; Hellenic Oncology Research Group. Paclitaxel in combination with carboplatin as salvage treatment in patients with castration-resistant prostate cancer: a Hellenic Oncology Research Group multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jul;70(1):161-8. Epub 2012 Jun 3. [http://link.springer.com/article/10.1007%2Fs00280-012-1896-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22660737 PubMed]<br />
<br />
==Cyclophosphamide, Prednisone, Diethylstilbestrol {{#subobject:26 |Regimen=1}}==<br />
CPD: '''<u>C</u>'''yclophosphamide, '''<u>P</u>'''rednisone, '''<u>D</u>'''iethylstilbestrol<br />
<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:26 |Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.11686/abstract Hellerstedt et al. 2003]<br />
| style="background-color:#91cf61" |Phase II<br />
|50% or greater decline in PSA: 42%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 20<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 10 mg PO once per day<br />
*[[Diethylstilbestrol (DES)]] 1 mg PO once per day<br />
<br />
====Supportive medications====<br />
<br />
*[[Warfarin (Coumadin)]] 1 mg PO once per day to decrease risk of DVT<br />
<br />
'''30-day cycles'''<br />
<br />
===References===<br />
<br />
#Hellerstedt B, Pienta KJ, Redman BG, Esper P, Dunn R, Fardig J, Olson K, Smith DC. Phase II trial of oral cyclophosphamide, prednisone, and diethylstilbestrol for androgen-independent prostate carcinoma. Cancer. 2003 Oct 15;98(8):1603-10. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.11686/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14534875 PubMed]<br />
<br />
==Docetaxel & Estramustine {{#subobject:27a1bc |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:51bc1c |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa041318 Petrylak et al. 2004 (SWOG S9916)]<br />
|1999-2003<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Mitoxantrone_.26_Prednisone|Mitoxantrone & Prednisone]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]]<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Estramustine (Emcyt)]]<br />
<br />
===References===<br />
<br />
#'''SWOG S9916:''' Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1513-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa041318 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15470214 PubMed]<br />
<br />
==Docetaxel & Prednisone {{#subobject:27 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Docetaxel (Taxotere) in prostate cancer]]<br />
<br />
===Regimen variant #1, 30 mg/m<sup>2</sup> weekly {{#subobject:29 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa040720 Tannock et al. 2004 (TAX 327)]<br />
| rowspan="2" |2000-2002<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Docetaxel_.26_Prednisone|Docetaxel & Prednisone]]; q3wk<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Mitoxantrone_.26_Prednisone|Mitoxantrone & Prednisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 5 mg PO twice per day<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 8 mg (route not specified) once 1 hour before [[Docetaxel (Taxotere)]]<br />
*Antiemetics "according to local practice"<br />
<br />
'''42-day cycle for up to 5 cycles'''<br />
<br />
===Regimen variant #2, 75 mg/m<sup>2</sup> q3wk x 10 {{#subobject:27 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''', PSA RR]]<br />
!Comparator [[Overall response rate|'''ORR''', PSA RR]]<br />
!Pt Population<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa040720 Tannock et al. 2004 (TAX 327)]<br />
| rowspan="2" |2000-2002<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#Docetaxel_.26_Prednisone|Docetaxel & Prednisone]]; weekly<br />
| style="background-color:#d3d3d3" |Not reported<br />
| rowspan="2" |pts w/ measurable disease:'''12%''' (95% CI, 7-19), '''45%''' (95% CI, 40-51)<br />
|pts w/ measurable disease:'''8%''' (95% CI, 4-14), '''48%''' (95% CI, 42-54)<br />
|Chemo-naive<br />
|-<br />
|2. [[#Mitoxantrone_.26_Prednisone|Mitoxantrone & Prednisone]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|pts w/ measurable disease:'''7%''' (95% CI, 3-12), '''32%''' (95% CI, 26-37)<br />
|Chemo-naive<br />
|-<br />
|[https://doi.org/10.1200/JCO.2006.06.8197 Beer et al. 2011 (ASCENT)]<br />
|2002-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Calcitriol, Docetaxel, Prednisone<br />
| style="background-color:#1a9850" |Superior OS<sup>1</sup><br />
|<br />
|<br />
|<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(12)00428-5/fulltext Meulenbeld et al. 2012 (NePro)]<br />
|2004-2010<br />
| style="background-color:#1a9851" |Phase II/III (C)<br />
|Docetaxel, Prednisone, Risedronate<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP<br />
|<br />
|<br />
|<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for ASCENT is based on the 2011 update.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 5 mg PO twice per day<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 8 mg PO given three times; 12 hours, 3 hours, and 1 hour before [[Docetaxel (Taxotere)]]<br />
*[[:Category:Emesis_prevention|Antiemetics]] "according to local practice"<br />
<br />
'''21-day cycle for up to 10 cycles'''<br />
<br />
===Regimen variant #3, 75 mg/m<sup>2</sup> q3wk x 12 {{#subobject:27a1bc |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277263/ Quinn et al. 2013 (SWOG S0421)]<br />
|2006-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Atrasentan, Docetaxel, Prednisone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 5 mg PO twice per day<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 8 mg PO given three times; 12 hours, 3 hours, and 1 hour before [[Docetaxel (Taxotere)]]<br />
*[[:Category:Emesis_prevention|Antiemetics]] "according to local practice"<br />
<br />
'''21-day cycle for up to 12 cycles'''<br />
<br />
===Regimen variant #4, 75 mg/m<sup>2</sup> q3wk, indefinite {{#subobject:ea941e |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383121/ Kelly et al. 2012 (CALGB 90401)]<br />
|2005-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel, Prednisone, Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70184-0/abstract Tannock et al. 2013 (VENICE)]<br />
|2007-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Aflibercept, Docetaxel, Prednisone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478530/ Araujo et al. 2013 (READY)]<br />
|2008-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Dasatinib, Docetaxel, Prednisone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2012.46.4149 Fizazi et al. 2013 (ENTHUSE)]<br />
|2008-NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel, Prednisone, Zibotentan<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70025-2/abstract Petrylak et al. 2015 (MAINSAIL)]<br />
|2009-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel, Lenalidomide, Prednisone<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30168-7/fulltext Chi et al. 2017 (SYNERGY)]<br />
|2010-2012<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Custirsen, Docetaxel, Prednisone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2016.72.1068 Oudard et al. 2017 (FIRSTANA)]<br />
| rowspan="2" |2011-2013<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cabazitaxel_.26_Prednisone_2|Cabazitaxel 20 mg/m<sup>2</sup> & Prednisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[[#Cabazitaxel_.26_Prednisone_2|Cabazitaxel 25 mg/m<sup>2</sup> & Prednisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: patients in CALGB 90401 discontinued treatment after a maximum of 2 years.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] as follows:<br />
**CALGB 90401: 5 mg PO once per day<br />
**Others: 10 mg/day; some regimens give as 5 mg PO twice per day, some as 10 mg PO once per day<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''TAX 327:''' Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1502-12. [https://www.nejm.org/doi/full/10.1056/NEJMoa040720 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15470213 PubMed]<br />
##'''Update:''' Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008 Jan 10;26(2):242-5. [https://doi.org/10.1200/jco.2007.12.4008 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18182665 PubMed]<br />
#'''ASCENT:''' Beer TM, Ryan CW, Venner PM, Petrylak DP, Chatta GS, Ruether JD, Redfern CH, Fehrenbacher L, Saleh MN, Waterhouse DM, Carducci MA, Vicario D, Dreicer R, Higano CS, Ahmann FR, Chi KN, Henner WD, Arroyo A, Clow FW; ASCENT Investigators. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol. 2007 Feb 20;25(6):669-74. [https://doi.org/10.1200/JCO.2006.06.8197 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17308271 PubMed] NCT00273338<br />
##'''Update:''' Scher HI, Jia X, Chi K, de Wit R, Berry WR, Albers P, Henick B, Waterhouse D, Ruether DJ, Rosen PJ, Meluch AA, Nordquist LT, Venner PM, Heidenreich A, Chu L, Heller G. Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer. J Clin Oncol. 2011 Jun 1;29(16):2191-8. Epub 2011 Apr 11. [https://doi.org/10.1200/JCO.2010.32.8815 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21483004 PubMed]<br />
<!-- Presented in part at the 48th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. --><br />
#'''CALGB 90401:''' Kelly WK, Halabi S, Carducci M, George D, Mahoney JF, Stadler WM, Morris M, Kantoff P, Monk JP, Kaplan E, Vogelzang NJ, Small EJ. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol. 2012 May 1;30(13):1534-40. Epub 2012 Mar 26. [https://doi.org/10.1200/JCO.2011.39.4767 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383121/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22454414 PubMed] NCT00110214<br />
#'''NePro:''' Meulenbeld HJ, van Werkhoven ED, Coenen JL, Creemers GJ, Loosveld OJ, de Jong PC, Ten Tije AJ, Fosså SD, Polee M, Gerritsen W, Dalesio O, de Wit R. Randomised phase II/III study of docetaxel with or without risedronate in patients with metastatic Castration Resistant Prostate Cancer (CRPC), the Netherlands Prostate Study (NePro). Eur J Cancer. 2012 Nov;48(16):2993-3000. Epub 2012 Jun 6. [https://www.ejcancer.com/article/S0959-8049(12)00428-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22677260 PubMed]<br />
#'''VENICE:''' Tannock IF, Fizazi K, Ivanov S, Karlsson CT, Fléchon A, Skoneczna I, Orlandi F, Gravis G, Matveev V, Bavbek S, Gil T, Viana L, Arén O, Karyakin O, Elliott T, Birtle A, Magherini E, Hatteville L, Petrylak D, Tombal B, Rosenthal M; VENICE investigators. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol. 2013 Jul;14(8):760-8. Epub 2013 Jun 4.[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70184-0/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23742877 PubMed] NCT00519285<br />
#'''SWOG S0421:''' Quinn DI, Tangen CM, Hussain M, Lara PN Jr, Goldkorn A, Moinpour CM, Garzotto MG, Mack PC, Carducci MA, Monk JP, Twardowski PW, Van Veldhuizen PJ, Agarwal N, Higano CS, Vogelzang NJ, Thompson IM Jr. Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial. Lancet Oncol. 2013 Aug;14(9):893-900. Epub 2013 Jul 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70294-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277263/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23871417 PubMed] NCT00134056<br />
#'''READY:''' Araujo JC, Trudel GC, Saad F, Armstrong AJ, Yu EY, Bellmunt J, Wilding G, McCaffrey J, Serrano SV, Matveev VB, Efstathiou E, Oudard S, Morris MJ, Sizer B, Goebell PJ, Heidenreich A, de Bono JS, Begbie S, Hong JH, Richardet E, Gallardo E, Paliwal P, Durham S, Cheng S, Logothetis CJ. Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1307-16. Epub 2013 Nov 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70479-0/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478530/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24211163 PubMed] NCT00744497<br />
#'''MAINSAIL:''' Petrylak DP, Vogelzang NJ, Budnik N, Wiechno PJ, Sternberg CN, Doner K, Bellmunt J, Burke JM, de Olza MO, Choudhury A, Gschwend JE, Kopyltsov E, Flechon A, Van As N, Houede N, Barton D, Fandi A, Jungnelius U, Li S, de Wit R, Fizazi K. Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2015 Apr;16(4):417-25. Epub 2015 Mar 3.[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70025-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25743937 PubMed] NCT00988208<br />
#'''SYNERGY:''' Chi KN, Higano CS, Blumenstein B, Ferrero JM, Reeves J, Feyerabend S, Gravis G, Merseburger AS, Stenzl A, Bergman AM, Mukherjee SD, Zalewski P, Saad F, Jacobs C, Gleave M, de Bono JS. Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2017 Apr;18(4):473-485. Epub 2017 Mar 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30168-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28283282 PubMed] NCT01188187<br />
#'''FIRSTANA:''' Oudard S, Fizazi K, Sengeløv L, Daugaard G, Saad F, Hansen S, Hjälm-Eriksson M, Jassem J, Thiery-Vuillemin A, Caffo O, Castellano D, Mainwaring PN, Bernard J, Shen L, Chadjaa M, Sartor O. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: A randomized phase III Trial-FIRSTANA. J Clin Oncol. 2017 Oct 1;35(28):3189-3197. Epub 2017 Jul 28. [https://doi.org/10.1200/JCO.2016.72.1068 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28753384 PubMed] NCT01308567<br />
#'''TRITON3:''' NCT02975934<br />
<br />
==Docetaxel & Prednisolone {{#subobject:8jfyz3 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Docetaxel (Taxotere) in prostate cancer]]<br />
<br />
===Regimen variant #1, 50 mg/m<sup>2</sup> bi-weekly {{#subobject:30 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2812%2970537-5/abstract Kellokumpu-Lehtinen et al. 2013 (PROSTY)]<br />
|2004-2009<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Docetaxel_.26_Prednisolone|Docetaxel & Prednisolone]]; q3wk<br />
| style="background-color:#91cf60" |Seems to have superior TTTF<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisolone (Millipred)]] 10 mg PO once per day<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 7.5 to 8 mg (route not specified) once per day, started 1 day before [[Docetaxel (Taxotere)]] and stopped 1 to 2 days after docetaxel infusion (in other words, from day -1 to day 2 or 3)<br />
*G-CSF not recommended unless patients developed febrile neutropenia or severe infection<br />
*"Treatment with bisphosphonates, erythropoietin, and palliative radiation therapy was allowed"<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 75 mg/m<sup>2</sup> q3wk, indefinite {{#subobject:28 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2812%2970537-5/abstract Kellokumpu-Lehtinen et al. 2013 (PROSTY)]<br />
|2004-2009<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Prednisolone|Docetaxel & Prednisolone]]; q2wk<br />
| style="background-color:#fc8d59" |Seems to have inferior TTTF<br />
|-<br />
|[https://doi.org/10.1200/JCO.2012.46.4149 Fizazi et al. 2013 (ENTHUSE)]<br />
|2008-NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel, Zibotentan, Prednisolone<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisolone (Millipred)]] 10 mg PO once per day<br />
**Fizazi et al. 2013: Given as 5 mg PO twice per day<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 7.5 to 8 mg daily, started 1 day before [[Docetaxel (Taxotere)]] and stopped 1 to 2 days after docetaxel infusion (in other words, from day -1 to day 2 or 3); reference did not specify route of administration<br />
*G-CSF not recommended unless patients developed febrile neutropenia or severe infection<br />
*"Treatment with bisphosphonates, erythropoietin, and palliative radiation therapy was allowed"<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''PROSTY:''' Kellokumpu-Lehtinen PL, Harmenberg U, Joensuu T, McDermott R, Hervonen P, Ginman C, Luukkaa M, Nyandoto P, Hemminki A, Nilsson S, McCaffrey J, Asola R, Turpeenniemi-Hujanen T, Laestadius F, Tasmuth T, Sandberg K, Keane M, Lehtinen I, Luukkaala T, Joensuu H; PROSTY study group. 2-weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial. Lancet Oncol. 2013 Feb;14(2):117-24. Epub 2013 Jan 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2812%2970537-5/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23294853 PubMed] NCT00255606<br />
#'''ENTHUSE:''' Fizazi K, Higano CS, Nelson JB, Gleave M, Miller K, Morris T, Nathan FE, McIntosh S, Pemberton K, Moul JW. Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2013 May 10;31(14):1740-7. Epub 2013 Apr 8. Erratum in: J Clin Oncol. 2014 Oct 20;32(30):3461. Fizazi, Karim S [Corrected to Fizazi, Karim]. [https://doi.org/10.1200/JCO.2012.46.4149 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23569308 PubMed] NCT00617669<br />
<br />
==Mitoxantrone & Hydrocortisone {{#subobject:f4eqv4 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:da47uz |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1999.17.8.2506 Kantoff et al. 1999 (CALGB 9182)]<br />
|1992-1995<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Hydrocortisone_monotherapy|Hydrocortisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Mitoxantrone (Novantrone)]]<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Hydrocortisone (Cortef)]]<br />
<br />
===References===<br />
<br />
#'''CALGB 9182:''' Kantoff PW, Halabi S, Conaway M, Picus J, Kirshner J, Hars V, Trump D, Winer EP, Vogelzang NJ. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol. 1999 Aug;17(8):2506-13. [https://doi.org/10.1200/JCO.1999.17.8.2506 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10561316 PubMed]<br />
<br />
==Mitoxantrone & Prednisone {{#subobject:29 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Mitoxantrone (Novantrone) in prostate cancer]]<br />
<br />
===Regimen {{#subobject:33 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''', PSA RR]]<br />
!Comparator [[Overall response rate|'''ORR''', PSA RR]]<br />
!Pt Population<br />
|-<br />
|[https://doi.org/10.1200/JCO.1994.12.4.689 Moore et al. 1994]<br />
|NR<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|<br />
|<br />
|<br />
|-<br />
|[https://doi.org/10.1200/JCO.1996.14.6.1756 Tannock et al. 1996 (CCI-NOV22)]<br />
|1990-1994<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#1a9850" |Superior palliation<br />
|<br />
|<br />
|<br />
|-<br />
|[https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2964163-8 Berry et al. 2002]<br />
|1997-1999<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Prednisone_monotherapy|Prednisone]]<br />
| style="background-color:#91cf60" |Seems to have superior TTTF<br />
|<br />
|<br />
|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa041318 Petrylak et al. 2004 (SWOG S9916)]<br />
|1999-2003<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Estramustine|Docetaxel & Estramustine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|<br />
|<br />
|<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa040720 Tannock et al. 2004 (TAX 327)]<br />
| rowspan="2" |2000-2002<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Docetaxel_.26_Prednisone|Weekly Docetaxel & Prednisone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
| rowspan="2" |pts w/ measurable disease: '''7%''' (95% CI 3-12), '''32%''' (95% CI 26-37)<br />
|pts w/ measurable disease: '''8%''' (95% CI 4-14), '''48%''' (95% CI 42-54)<br />
|Chemo naive<br />
|-<br />
|2. [[#Docetaxel_.26_Prednisone|Every 3-week Docetaxel & Prednisone]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|pts w/ measurable disease: '''12%''' (95% CI 7-19), '''45%''' (95% CI 40-51)<br />
|Chemo naive<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961389-X/fulltext de Bono et al. 2010 (TROPIC)]<br />
|2007-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cabazitaxel_.26_Prednisone_2|Cabazitaxel & Prednisone]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|pts w/ measurable disease:<br>'''4.4%''' (95% CI 1.6 - 7.2), '''17.8%''' (95% CI 13.7 - 22.0)<br />
|pts w/ measurable disease:<br>'''14.4%''' (95% CI 9.6 - 19.3), '''39.2%''' (95% CI 33.9 - 44.5)<br />
|Progressed on docetaxel<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Mitoxantrone (Novantrone)]] 12 mg/m<sup>2</sup> IV over 15 to 30 minutes once on day 1<br />
<br />
====Endocrine therapy====<br />
<br />
*[[Prednisone (Sterapred)]] 10 mg PO once per day on days 1 to 21<br />
**Some protocols give 5 mg PO twice per day<br />
<br />
'''21-day cycle for up to 10 cycles'''<br />
<br />
===References===<br />
<br />
#Moore MJ, Osoba D, Murphy K, Tannock IF, Armitage A, Findlay B, Coppin C, Neville A, Venner P, Wilson J. Use of palliative end points to evaluate the effects of mitoxantrone and low-dose prednisone in patients with hormonally resistant prostate cancer. J Clin Oncol. 1994 Apr;12(4):689-94. [https://doi.org/10.1200/JCO.1994.12.4.689 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7512127 PubMed]<br />
#'''CCI-NOV22:''' Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, Armitage GR, Wilson JJ, Venner PM, Coppin CM, Murphy KC. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996 Jun;14(6):1756-64. [https://doi.org/10.1200/JCO.1996.14.6.1756 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8656243 PubMed]<br />
##'''HRQoL analysis:''' Osoba D, Tannock IF, Ernst DS, Neville AJ. Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol. 1999 Jun;17(6):1654-63. [https://doi.org/10.1200/JCO.1999.17.6.1654 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10561201 PubMed]<br />
#Berry W, Dakhil S, Modiano M, Gregurich M, Asmar L. Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol. 2002 Dec;168(6):2439-43. [https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2964163-8 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12441935 PubMed]<br />
#'''TAX 327:''' Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1502-12. [https://www.nejm.org/doi/full/10.1056/NEJMoa040720 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15470213 PubMed]<br />
##'''Update:''' Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008 Jan 10;26(2):242-5. [https://doi.org/10.1200/jco.2007.12.4008 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18182665 PubMed]<br />
#'''SWOG S9916:''' Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1513-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa041318 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15470214 PubMed]<br />
#'''TROPIC:''' de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010 Oct 2;376(9747):1147-54. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961389-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20888992 PubMed] NCT00417079<br />
<br />
==Olaparib monotherapy {{#subobject:defe72|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen Variant #1, 300 mg BID {{#subobject:8979a4|Variant=1}}===<br />
{| class="wikitable sortable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Levels_of_Evidence#Efficacy|Efficacy]], PFS<br />
!Comparator [[Overall response rate|'''ORR''']], PFS<br />
!Pt Population<br />
|-<br />
|[http://doi.org/10.1056/NEJMoa1911440 de Bono et al. 2020 (PROfound)]<br />
|2017-2018<br />
| style="background-color:#1a9851" |Phase III (E-RT-ooc)<br />
|1. [[#Abiraterone_monotherapy|Abiraterone]]<br> 2. [[#Enzalutamide_monotherapy|Enzalutamide]]<br />
| style="background-color:#1a9850" |Superior PFS<sup>1</sup><br />
|7.4 months (95% CI 0.25 to 0.47, p<0.001)<br />
|3.6 months<br />
|Progressed on abiraterone or enzalutamide, at least one alteration in BRCA1, BRCA2, or ATM<br />
|-<br />
|}<br />
''<sup>1</sup>Patients in Cohort A seemed to have superior OS in the 2020 update.''<br />
====Biomarker eligibility criteria====<br />
<br />
*Cohort A: 1+ alterations in BRCA1, BRCA2, or ATM<br />
*Cohort B: 1+ alterations in BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L<br />
<br />
====Targeted therapy====<br />
<br />
*[[Olaparib (Lynparza)]] 300 mg PO twice per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen Variant #2, 400 mg BID {{#subobject:8979a3|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6057749/ Kaufman et al. 2014 (Study 42)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts in subgroup<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228595/ Mateo et al. 2015 (TOPARP-A)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Biomarker eligibility criteria====<br />
*Study 42: Germline BRCA1/2 mutations and had progression on hormonal and one systemic therapy<br />
*TOPARP-A: Patients who were found to have homozygous deletions, deleterious mutations, or both in DNA-repair genes were much more likely to respond to olaparib<br />
<br />
====Targeted therapy====<br />
<br />
*[[Olaparib (Lynparza)]] 400 mg PO twice per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
<br />
#'''Study 42:''' Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.56.2728 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6057749/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed] NCT01078662<br />
#'''TOPARP-A:''' Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, Nava Rodrigues D, Robinson D, Omlin A, Tunariu N, Boysen G, Porta N, Flohr P, Gillman A, Figueiredo I, Paulding C, Seed G, Jain S, Ralph C, Protheroe A, Hussain S, Jones R, Elliott T, McGovern U, Bianchini D, Goodall J, Zafeiriou Z, Williamson CT, Ferraldeschi R, Riisnaes R, Ebbs B, Fowler G, Roda D, Yuan W, Wu YM, Cao X, Brough R, Pemberton H, A'Hern R, Swain A, Kunju LP, Eeles R, Attard G, Lord CJ, Ashworth A, Rubin MA, Knudsen KE, Feng FY, Chinnaiyan AM, Hall E, de Bono JS. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med. 2015 Oct 29;373(18):1697-708. [https://www.nejm.org/doi/full/10.1056/NEJMoa1506859Top link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228595/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26510020 PubMed] NCT01682772<br />
#'''PROfound:''' de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 May 28;382(22):2091-2102. Epub 2020 Apr 28. [http://doi.org/10.1056/NEJMoa1911440 link to original article] '''contains verified protocol''' [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1911440/suppl_file/nejmoa1911440_appendix.pdf link to supplementary appendix] [https://pubmed.ncbi.nlm.nih.gov/32343890/ PubMed] NCT02987543<br />
## ''Update:''' Hussain M, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Roubaud G, Özgüroğlu M, Kang J, Burgents J, Gresty C, Corcoran C, Adelman CA, de Bono J; PROfound Trial Investigators. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 Dec 10;383(24):2345-2357. Epub 2020 Sep 20. [https://doi.org/10.1056/nejmoa2022485 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32955174 PubMed]<br />
<br />
=Immunotherapy for metastatic castrate-resistant disease=<br />
<br />
==Ipilimumab & RT {{#subobject:33 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Ipilimumab & RT: Ipilimumab & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
<br />
===Regimen {{#subobject:38 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 25%" |Patient population<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707423/ Slovin et al. 2013]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 4% (95% CI n/a), PSA RR: 16%;<br />
|Most had ADT, some had docetaxel use. 10 mg/kg cohort reported here.<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Ipilimumab (Yervoy)]] 10 mg/kg IV over 90 minutes once on day 1<br />
**Lower doses including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended in this study<br />
<br />
====Radiotherapy====<br />
<br />
*[[External_beam_radiotherapy|Radiation therapy]] given focally at a single dose of 8 Gy per target bone lesion for up to three bone lesions per patient, '''given 24 to 48 h before the first ipilimumab dose'''<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, Scher HI, Chin K, Gagnier P, McHenry MB, Beer TM. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol. 2013 Jul;24(7):1813-21. [https://doi.org/10.1093/annonc/mdt107 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707423/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23535954 PubMed] NCT00323882<br />
<br />
==Sipuleucel-T monotherapy {{#subobject:32 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Example orders===<br />
<br />
*[[Example orders for Sipuleucel-T (Provenge) in prostate cancer]]<br />
<br />
===Regimen {{#subobject:37 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.04.5252 Small et al. 2006 (D9901)]<br />
|2000-2001<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Prostate_cancer_-_null_regimens#Placebo_3|Placebo]]<br />
| style="background-color:#d9ef8b" |Might have superior TTP<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.24429 Higano et al. 2009 (D9902A)]<br />
|2000-2003<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Prostate_cancer_-_null_regimens#Placebo_3|Placebo]]<br />
| style="background-color:#d9ef8b" |Might have superior TTP<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1001294 Kantoff et al. 2010 (IMPACT<sub>prostate</sub>)]<br />
|2003-2007<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Prostate_cancer_-_null_regimens#Placebo_3|Placebo]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: Higano et al. 2009 was a pooled update but also the first publication to describe results of D9902A. IMPACT should not be confused with the studies of the same name in breast cancer and colorectal cancer.''<br />
====Immunotherapy====<br />
<br />
*[[Sipuleucel-T (Provenge)]]: leukapheresis followed 3 days later with at least 50 million autologous CD54+ cells activated with PAP-GM-CSF, to be done on weeks 0, 2, and 4<br />
<br />
====Supportive medications====<br />
<br />
*[[Acetaminophen (Tylenol)]] PO once per week on weeks 0, 2, 4; 30 minutes prior to [[Sipuleucel-T (Provenge)]]<br />
*[[:Category:Antihistamines|Antihistamine]] PO once per week on weeks 0, 2, 4; 30 minutes prior to [[Sipuleucel-T (Provenge)]]<br />
<br />
'''One course'''<br />
===References===<br />
<br />
#'''D9901:''' Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006 Jul 1;24(19):3089-94. [https://doi.org/10.1200/JCO.2005.04.5252 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16809734 PubMed]<br />
##'''Pooled Update:''' Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, Provost N, Frohlich MW. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009 Aug 15;115(16):3670-9. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.24429 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19536890 PubMed]<br />
#'''D9902A:''' Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, Provost N, Frohlich MW. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009 Aug 15;115(16):3670-9. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.24429 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19536890 PubMed]<br />
#'''IMPACT:''' Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010 Jul 29;363(5):411-22. [https://www.nejm.org/doi/full/10.1056/NEJMoa1001294 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20818862 PubMed]<br />
#'''Safety analysis:''' Hall SJ, Klotz L, Pantuck AJ, George DJ, Whitmore JB, Frohlich MW, Sims RB. Integrated safety data from 4 randomized, double-blind, controlled trials of autologous cellular immunotherapy with sipuleucel-T in patients with prostate cancer. J Urol. 2011 Sep;186(3):877-81. Epub 2011 Jul 23. [http://www.auajournals.org/article/S0022-5347(11)03851-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21788048 PubMed]<br />
<br />
=Radioactive agents for bony metastatic disease=<br />
<br />
==Radium-223 monotherapy {{#subobject:35 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1 {{#subobject:40 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1213755 Parker et al. 2013 (ALSYMPCA)]<br />
|2008-2011<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[Prostate_cancer_-_null_regimens#Placebo_3|Placebo]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior EQ-5D score<br />
|-<br />
|}<br />
====Radiotherapy====<br />
<br />
*[[Radium-223 (Xofigo)]] 50 kBq/kg IV once on day 1<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:41 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70147-X/abstract Nilsson et al. 2007]<br />
|2004-2005<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[Prostate_cancer_-_null_regimens#Placebo_3|Placebo]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Patients in the study had "bone pain needing EBRT" (external beam radiation therapy). Treatment with radium 223 began within 7 days after EBRT.''<br />
====Radiotherapy====<br />
<br />
*[[Radium-223 (Xofigo)]] 50 kBq/kg IV once on day 1<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, Yachnin J, Garkavij M, Strang P, Harmenberg J, Bolstad B, Bruland OS. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007 Jul;8(7):587-94. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70147-X/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17544845 PubMed]<br />
##'''Update:''' Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, O'Bryan-Tear CG, Thuresson M, Bolstad B, Bruland ØS. Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases. Clin Genitourin Cancer. 2013 Mar;11(1):20-6. Epub 2012 Sep 26. [http://www.clinical-genitourinary-cancer.com/article/S1558-7673(12)00168-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23021204 PubMed]<br />
<!--<br />
# Chris Parker, Sten Nilsson, Daniel Heinrich, Joe M. O'Sullivan, Sophie D. Fossa, Ales Chodacki, Pawel J. Wiechno, John P. Logue, Mihalj Seke, Anders Widmark, Dag Clement Johannessen, Peter Hoskin, David Bottomley, Robert Edward Coleman, Nicholas J. Vogelzang, C. Gillies O'Bryan-Tear, Jose E. Garcia-Vargas, Minghua Shan, A. Oliver Sartor. Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer (CRPC) patients with bone metastases (ALSYMPCA). 2012 ASCO Annual Meeting Abstract LBA4512. [http://meetinglibrary.asco.org/content/95649-114 link to abstract] [http://meetinglibrary.asco.org/content/74842 link to oral abstract session]<br />
# A. Oliver Sartor, Daniel Heinrich, Joe M. O'Sullivan, Sophie D. Fossa, Ales Chodacki, Pawel J. Wiechno, John P. Logue, Mihalj Seke, Anders Widmark, Dag Clement Johannessen, Sten Nilsson, Peter Hoskin, David Bottomley, Robert Edward Coleman, Nicholas J. Vogelzang, C. Gillies O'Bryan-Tear, Jose E. Garcia-Vargas, Minghua Shan, Chris Parker. Radium-223 chloride (Ra-223) impact on skeletal-related events (SREs) and ECOG performance status (PS) in patients with castration-resistant prostate cancer (CRPC) with bone metastases: Interim results of a phase III trial (ALSYMPCA). 2012 ASCO Annual Meeting Abstract 4551. [http://meetinglibrary.asco.org/content/94891-114 link to abstract]<br />
# Nicholas J. Vogelzang, Chris Parker, Sten Nilsson, Robert Edward Coleman, C. Gillies O'Bryan-Tear, Minghua Shan, A. Oliver Sartor. Updated analysis of radium-223 dichloride (Ra-223) impact on skeletal-related events (SRE) in patients with castration-resistant prostate cancer (CRPC) and bone metastases from the phase III randomized trial (ALSYMPCA). 2013 ASCO Genitourinary Cancers Symposium Abstract 11. [https://meetinglibrary.asco.org/content/107117-134 link to abstract]<br />
# Sten Nilsson, A. Oliver Sartor, Oyvind S. Bruland, Fang Fang, Anne-Kirsti Aksnes, Chris Parker. Pain analysis from the phase III randomized ALSYMPCA study with radium-223 dichloride (Ra-223) in patients with castration-resistant prostate cancer (CRPC) with bone metastases. 2013 ASCO Genitourinary Cancers Symposium Abstract 19. [http://meetinglibrary.asco.org/content/107297-134 link to abstract]<br />
# '''Update:''' Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, O'Bryan-Tear CG, Thuresson M, Bolstad B, Bruland ØS. Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases. Clin Genitourin Cancer. 2013 Mar;11(1):20-6. Epub 2012 Sep 26. [http://www.clinical-genitourinary-cancer.com/article/S1558-7673(12)00168-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23021204 PubMed]<br />
--><br />
#'''ALSYMPCA:''' Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall'Oglio M, Franzén L, Coleman R, Vogelzang NJ, O'Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland ØS, Sartor O; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1213755 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23863050 PubMed]<br />
##'''Subgroup analysis:''' Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Widmark A, Johannessen DC, Hoskin P, James ND, Solberg A, Syndikus I, Vogelzang NJ, O'Bryan-Tear CG, Shan M, Bruland ØS, Parker C. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014 Jun;15(7):738-46. Epub 2014 May 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70183-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24836273 PubMed]<br />
##'''Subgroup analysis:''' Hoskin P, Sartor O, O'Sullivan JM, Johannessen DC, Helle SI, Logue J, Bottomley D, Nilsson S, Vogelzang NJ, Fang F, Wahba M, Aksnes AK, Parker C. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol. 2014 Nov;15(12):1397-406. Epub 2014 Oct 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2970474-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25439694 PubMed]<br />
##'''HRQoL analysis:''' Nilsson S, Cislo P, Sartor O, Vogelzang NJ, Coleman RE, O'Sullivan JM, Reuning-Scherer J, Shan M, Zhan L, Parker C. Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study. Ann Oncol. 2016 May;27(5):868-74. Epub 2016 Feb 23. [https://doi.org/10.1093/annonc/mdw065 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843190/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26912557 PubMed]<br />
<br />
==Samarium-153 monotherapy {{#subobject:36 |Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:42 |Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(97)00155-X/pdf Resche et al. 1997]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Samarium-153_monotherapy|Samarium-153]]; 0.5 mCi/kg<br />
| style="background-color:#91cf60" |Seems to have superior pain control at week 4<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2804%2900143-8/abstract Sartor et al. 2004]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Samarium-152 (non-radioactive)<br />
| style="background-color:#91cf60" |Seems to have superior pain control at week 4<br />
|-<br />
|}<br />
====Radiotherapy====<br />
<br />
*[[Samarium-153 (Quadramet)]] 1 mCi/kg IV over 1 minute once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*1000 mL of fluid IV or PO given twice, 4 hours before and 6 hours after treatment<br />
<br />
'''1 dose'''<br />
<br />
===References===<br />
<br />
#Resche I, Chatal JF, Pecking A, Ell P, Duchesne G, Rubens R, Fogelman I, Houston S, Fauser A, Fischer M, Wilkins D. A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer. 1997 Sep;33(10):1583-91. [https://www.ejcancer.com/article/S0959-8049(97)00155-X/pdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9389919 PubMed]<br />
#Sartor O, Reid RH, Hoskin PJ, Quick DP, Ell PJ, Coleman RE, Kotler JA, Freeman LM, Olivier P; Quadramet 424Sm10/11 Study Group. Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology. 2004 May;63(5):940-5. [http://www.goldjournal.net/article/S0090-4295%2804%2900143-8/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15134985 PubMed]<br />
<br />
=Measuring disease progression=<br />
<br />
*Criteria used for disease progression in prostate cancer clinical trials, Prostate Cancer Clinical Trials Working Group 2 (PCWG2):<ref>Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M; Prostate Cancer Clinical Trials Working Group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008 Mar 1;26(7):1148-59. [https://doi.org/10.1200/jco.2007.12.4487 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010133/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18309951 PubMed]</ref><br />
**Castrate level of serum testosterone is less than 50 ng/dL (less than 1.7 nmol/L)<br />
***However, there is controversy/disagreement in other references about whether a lower level should be used, such as less than 20 ng/dL (0.7 nmol/L)<ref>Oefelein MG, Feng A, Scolieri MJ, Ricchiutti D, Resnick MI. Reassessment of the definition of castrate levels of testosterone: implications for clinical decision making. Urology. 2000 Dec 20;56(6):1021-4. [http://www.goldjournal.net/article/S0090-4295%2800%2900793-7/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11113751 PubMed]</ref><br />
**PSA rise<br />
***Starting PSA of at least 2 ng/mL<br />
***Rising PSA values which are measured at least 1-week apart<br />
***Pretherapy PSA doubling times (PSA-DT) can be estimated if there are at least 3 PSA values measured at least 4 weeks apart<br />
**Bony metastases<br />
***At least 2 new lesions indicates progressive disease<br />
***It is recommended to assess ambiguous results with other imaging modalities such as CT or MRI<br />
**Measurable lesions (RECIST) - this is a lower priority criteria by the PCWG2 because fewer patients have measurable lesions as compared to, for example, bony metastases<br />
***Baseline imaging involves chest imaging with x-ray or CT, CT or MRI of the abdomen/pelvis, and radionuclide bone scan<br />
***It is recommended that local disease is assessed by endorectal MRI or prostatic ultrasound<br />
***Neurologic symptoms should be assessed with MRI of the spine and base of the skull<br />
***Positron emission tomography (PET) is not recommended and is considered investigational<br />
***Measurable lesions should be followed with [http://imaging.cancer.gov/clinicaltrials/imaging RECIST criteria]<br />
***"Up to 10 visceral and nodal lesions in total should be recorded (with a maximum of five in any one organ)"<br />
***It is suggested that a lymph node must be at least 2 cm in maximal dimension on spiral CT to count as a target lesion.<br />
<br />
=Statistics=<br />
<br />
*[http://jama.jamanetwork.com/article.aspx?articleid=198392 Four-Year Actuarial Progression-Free Probability (PFP) After Salvage Radiotherapy based on Gleason score, PSA, positive margins, etc.]<ref>Stephenson AJ, Shariat SF, Zelefsky MJ, Kattan MW, Butler EB, Teh BS, Klein EA, Kupelian PA, Roehrborn CG, Pistenmaa DA, Pacholke HD, Liauw SL, Katz MS, Leibel SA, Scardino PT, Slawin KM. Salvage Radiotherapy for Recurrent Prostate Cancer After Radical Prostatectomy. JAMA. 2004 Mar 17;291(11):1325-32. [http://jama.jamanetwork.com/article.aspx?articleid=198392 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15026399 PubMed]</ref> (flowchart is in Figure 2)<br />
*[http://seer.cancer.gov/statfacts/html/prost.html SEER Stat Fact Sheets: Prostate Cancer]<br />
*[http://www.cdc.gov/CANCER/prostate/statistics/ CDC Prostate Cancer Statistics]<br />
*[http://www.cancer.net/cancer-types/prostate-cancer/statistics Cancer.Net Prostate Cancer Statistics]<br />
<br />
=Links=<br />
<br />
*[http://genomedx.com/decipher-test/ Decipher], GenomeDx's genomic prognostic prostate cancer assay<br />
**"the Decipher Test uses the expression of these biomarkers to calculate the probability of clinical metastasis within 5 years of radical prostatectomy surgery, and within 3 years of successive PSA rise (biochemical recurrence)."<br />
*[http://www.mskcc.org/cancer-care/adult/prostate/prediction-tools MSKCC prostate cancer nomograms]<br />
*[http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx MSKCC PSA doubling time calculator]<br />
*[http://nomograms.mskcc.org/Prostate/Volume.aspx MSKCC Prostate volume calculator]<br />
*[http://prostate-cancer.oncotypedx.com/en-US/Professional.aspx Oncotype DX Prostate] Genomic Health's Genomic Prostate Score (GPS) & prognostic prostate cancer assay<br />
*[http://urology.jhu.edu/prostate/partintables.php Partin tables] to predict pathologic stage based on clinical TNM stage, PSA, and Gleason score<br />
*[http://www.diagnocure.com/en/products-projects/prostate-cancer/pca3-test-healthcare-practitioners.php PCA3 RNA urine test]<br />
**[http://www.pca3.org/ PCA3.org]<br />
*[http://www.prolaris.com/ Prolaris], Myriad's biomarker prognostic prostate cancer assay<br />
*[https://www.roswellpark.org/apps/prostate_cancer_estimator/ Roswell Park's Calculator for Estimating Overall Life Expectancy and Lifetime Risk for Prostate Cancer Death in Newly Diagnosed Men Managed without Definitive Local Therapy]<br />
*[http://urology.ucsf.edu/research/cancer/prostate-cancer-risk-assessment-and-the-ucsf-capra-score UCSF-CAPRA score]<br />
<br />
=Quality of life assessment tools=<br />
<br />
*[http://www.bidmc.org/~/media/Files/Centers%20and%20Departments/CancerCenter/prostateCancer/EPIC%20CP.pdf EPIC-CP: Expanded Prostate Cancer Index Composite for Clinical Practice] ([http://www.bidmc.org/epic twice per dayMC])<br />
*[http://www.oregonurology.com/pdfs/aua-symptom-score.pdf AUA Symptom Score (OR)] [//hemonc.org/w/images/1/1c/AUA-Symptom-Score_OR.pdf (local backup)]; [http://www.purclinic.com/wp-content/uploads/2014/05/AUA-Symptom-Score.pdf AUA Symptom Score (UCF)] [//hemonc.org/w/images/b/b0/AUA-Symptom-Score.pdf (local backup)]. Also known as International Prostate Symptom Score (I-PSS/IPSS) or AUASS<br />
<br />
=References=<br />
<references /><br />
<br />
[[Category:Prostate cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Genitourinary cancers]]</div>Karinehttps://hemonc.org/w/index.php?title=Breast_cancer,_HER2-positive&diff=49686Breast cancer, HER2-positive2021-05-13T19:59:53Z<p>Karine: Tolaney 7 year update reference</p>
<hr />
<div>{{#lst:Section editor transclusions|breast}}<br />
''Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the [[Breast_cancer,_HER2-positive_-_historical|historical regimens page]]. If you still can't find it, please let us know so we can add it!''<br />
<br><big>'''Note: these are regimens tested in biomarker-specific populations, please see the [[breast cancer|main breast cancer page]] for other regimens.'''</big><br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[http://www.asco.org/ ASCO]==<br />
*'''2021:''' Korde et al. [https://doi.org/10.1200/jco.20.03399 Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline]<br />
*'''2020:''' Denduluri et al. [https://doi.org/10.1200/jco.20.02510 Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update]<br />
*'''2018:''' Ramakrishna et al. [https://doi.org/10.1200/JCO.2018.79.2713 Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline update] [https://pubmed.ncbi.nlm.nih.gov/29939840 PubMed]<br />
*'''2018:''' Giordano et al. [https://doi.org/10.1200/JCO.2018.79.2697 Systemic therapy for patients with advanced human epidermal growth factor receptor 2–positive breast cancer: ASCO Clinical Practice Guideline update] [https://pubmed.ncbi.nlm.nih.gov/29939838 PubMed]<br />
===Older===<br />
*'''2018:''' Denduluri et al. [https://doi.org/10.1200/JCO.2018.78.8604 Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO clinical practice guideline focused update] [https://pubmed.ncbi.nlm.nih.gov/29787356 PubMed]<br />
*'''2016:''' Harris et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933134/ Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2015:''' Van Poznak et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478102/ Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2014:''' Giordano et al. [https://doi.org/10.1200/JCO.2013.54.0948 Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline] [https://pubmed.ncbi.nlm.nih.gov/24799465 PubMed]<br />
*'''2014:''' Ramakrishna et al. [https://doi.org/10.1200/JCO.2013.54.0955 Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline] [https://pubmed.ncbi.nlm.nih.gov/24799487 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2017:''' Cardoso et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378224/ 3rd ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3).] [https://pubmed.ncbi.nlm.nih.gov/28177437 PubMed]<br />
*'''2015:''' Senkus et al. [http://annonc.oxfordjournals.org/content/26/suppl_5/v8.full.pdf+html Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.] [https://pubmed.ncbi.nlm.nih.gov/26314782 PubMed]<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf NCCN Guidelines - Breast Cancer]<br />
<br />
== St Gallen Breast Guidelines ==<br />
*'''2019:''' Burstein et al. [https://academic.oup.com/annonc/article/30/10/1541/5543097 Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019]<br />
===Older===<br />
*'''2017:''' Curigliano et al. [https://pubmed.ncbi.nlm.nih.gov/28838210 St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2017]<br />
*'''2015:''' Coates et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511219/ Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015]<br />
<br />
=Neoadjuvant chemotherapy=<br />
==Cyclophosphamide & Doxorubicin (AC) {{#subobject:647f67|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
AC: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1, 4 cycles {{#subobject:b18877|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70411-X/fulltext Robidoux et al. 2013 (NSABP B-41)]<br />
|2007-2011<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259558/ Park et al. 2016 (I-SPY 2)]<br />
|2010-2013<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*I-SPY 2: [[#Neratinib_.26_Paclitaxel|Neratinib & Paclitaxel]] x 12 wk versus [[#TH_.28Taxol.29|TH]] x 12 wk<br />
====Chemotherapy====<br />
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
====Subsequent treatment====<br />
*NSABP B-41: [[#TH_.28Taxol.29|TH]] versus [[#THL_.28Taxol.29|THL]] versus [[#TL_.28Taxol.29|TL]], then [[Surgery#Breast_cancer_surgery|surgery]]<br />
*I-SPY 2: [[Surgery#Breast_cancer_surgery|Surgery]]<br />
<br />
===References===<br />
# '''NSABP B-41:''' Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1183-92. Epub 2013 Oct 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70411-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24095300 PubMed] NCT00486668<br />
<!-- Presented in part by Dr. Park at the 104th annual meeting of the American Association for Cancer Research, Washington, DC, April 6–10, 2013. --><br />
# '''I-SPY 2:''' Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016 Jul 7;375(1):11-22. [https://www.nejm.org/doi/full/10.1056/NEJMoa1513750 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259558/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27406346 PubMed] NCT01042379<br />
<br />
==Dose-dense Cyclophosphamide & Doxorubicin (ddAC) {{#subobject:dcfdd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ddAC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>A</u>'''driamycin (Doxorubicin) and '''<u>C</u>'''yclophosphamide<br />
===Regimen {{#subobject:daff10|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259558/ Park et al. 2016 (I-SPY 2)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[#Neratinib_.26_Paclitaxel|Neratinib & Paclitaxel]] x 12 wk versus [[#TH_.28Taxol.29|TH]] x 12 wk<br />
====Chemotherapy====<br />
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2, given 24 hours after chemotherapy<br />
<br />
'''14-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
<br />
===References===<br />
<!-- Presented in part by Dr. Park at the 104th annual meeting of the American Association for Cancer Research, Washington, DC, April 6–10, 2013. --><br />
# '''I-SPY 2:''' Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016 Jul 7;375(1):11-22. [https://www.nejm.org/doi/full/10.1056/NEJMoa1513750 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259558/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27406346 PubMed] NCT01042379<br />
<br />
==ECH {{#subobject:6828f5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
ECH: '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''erceptin (Trastuzumab)<br />
===Regimen {{#subobject:436755|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70397-7/fulltext Untch et al. 2012 (GeparQuinto)]<br />
|2007-2010<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[Complex_multipart_regimens#GeparQuinto|See link]]<br />
| style="background-color:#91cf60" |[[Complex_multipart_regimens#GeparQuinto|See link]]<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Chemotherapy====<br />
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycles 2 to 4: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[#TH_.28Taxotere.29|TH (Taxotere)]] x 4, then [[Surgery#Breast_cancer_surgery|surgery]]<br />
===References===<br />
# '''GeparQuinto:''' Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, Hilfrich J, Strumberg D, Fasching PA, Kreienberg R, Tesch H, Hanusch C, Gerber B, Rezai M, Jackisch C, Huober J, Kühn T, Nekljudova V, von Minckwitz G; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie-Breast Study Group. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 2012 Feb;13(2):135-44. Epub 2012 Jan 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70397-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22257523 PubMed] NCT00567554<br />
## '''Update:''' Untch M, von Minckwitz G, Gerber B, Schem C, Rezai M, Fasching PA, Tesch H, Eggemann H, Hanusch C, Huober J, Solbach C, Jackisch C, Kunz G, Blohmer JU, Hauschild M, Fehm T, Nekljudova V, Loibl S; GBG; AGO-B Study Group. Survival analysis after neoadjuvant chemotherapy with trastuzumab or lapatinib in patients with human epidermal growth factor receptor 2-positive breast cancer in the GeparQuinto (G5) study (GBG 44). J Clin Oncol. 2018 May 1;36(13):1308-1316. Epub 2018 Mar 15. [https://doi.org/10.1200/JCO.2017.75.9175 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29543566 PubMed]<br />
<br />
==FEC {{#subobject:ec48df|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FEC: '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1, 500/75/500 ("FEC-75") {{#subobject:9e61ad|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176878/ Buzdar et al. 2013 (ACOSOG Z1041)]<br />
|2007-2011<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#ACOSOG_Z1041|See link]]<br />
| style="background-color:#ffffbf" |[[Complex_multipart_regimens#ACOSOG_Z1041|See link]]<br />
|-<br />
|}<br />
''Note: This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[#TH_.28Taxol.29|TH (Taxol)]] x 12 wk, then [[Surgery#Breast_cancer_surgery|surgery]]<br />
<br />
===Regimen variant #2, 500/100/600 x 3 {{#subobject:7ddba5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdt182 Schneeweiss et al. 2013 (TRYPHAENA)]<br />
|2009-2011<br />
|style="background-color:#1a9851"|Randomized Phase II (C)<br />
|[[Complex_multipart_regimens#TRYPHAENA|See link]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|}<br />
''Note: This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
*[[Epirubicin (Ellence)]] 100 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[#THP_.28Taxotere.29|THP]] x 3, then [[Surgery#Breast_cancer_surgery|surgery]]<br />
<br />
===Regimen variant #3, 1000/75/500 x 4 {{#subobject:1350d9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.07.032 Buzdar et al. 2005]<br />
|2001-2003<br />
|style="background-color:#1a9851"|Randomized (C)<br />
|[[Complex_multipart_regimens#Buzdar_et_al._2005|See link]]<br />
| style="background-color:#fc8d59" |[[Complex_multipart_regimens#Buzdar_et_al._2005|See link]]<br />
|-<br />
|}<br />
''Note: This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*CI paclitaxel x 4<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 4<br />
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
<br />
===References===<br />
# Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005 Jun 1;23(16):3676-85. Epub 2005 Feb 28. [https://doi.org/10.1200/jco.2005.07.032 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15738535 PubMed]<br />
## '''Update:''' Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, Pusztai L, Green MC, Singletary SE, Hunt KK, Sahin AA, Esteva F, Symmans WF, Ewer MS, Buchholz TA, Hortobagyi GN. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007 Jan 1;13(1):228-33. [http://clincancerres.aacrjournals.org/content/13/1/228.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17200359 PubMed]<br />
# '''TRYPHAENA:''' Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortés J. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013 Sep;24(9):2278-84. Epub 2013 May 22. [https://doi.org/10.1093/annonc/mdt182 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23704196 PubMed] NCT00976989<br />
# '''ACOSOG Z1041:''' Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig G, Royce M, McCall LM, Ewer MS, Hunt KK; American College of Surgeons Oncology Group. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1317-25. Epub 2013 Nov 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70502-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176878/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24239210 PubMed] NCT00513292<br />
## '''Update:''' Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig GW, Royce ME, Hunt KK. Disease-Free and Overall Survival Among Patients With Operable HER2-Positive Breast Cancer Treated With Sequential vs Concurrent Chemotherapy: The ACOSOG Z1041 (Alliance) Randomized Clinical Trial. JAMA Oncol. 2019 Jan 1;5(1):45-50. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2698846 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331049/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30193295 PubMed]<br />
<br />
==FEC & H {{#subobject:d2476f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FEC & H: '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''erceptin (Trastuzumab)<br />
===Regimen variant #1, q3wk trastuzumab {{#subobject:b4f490|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70329-7/fulltext Ismael et al. 2012 (HannaH)]<br />
|2009-2010<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[Complex_multipart_regimens#HannaH|See link]]<br />
|style="background-color:#eeee01"|[[Complex_multipart_regimens#HannaH|See link]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2017.74.0126 Pivot et al. 2018 (SB3-G31-BC)]<br />
|2014-2015<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[Complex_multipart_regimens#SB3-G31-BC|See link]]<br />
|style="background-color:#eeee01"|[[Complex_multipart_regimens#SB3-G31-BC|See link]]<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[#TH_.28Taxotere.29|TH (IV)]] x 4<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*HannaH: [[Surgery#Breast_cancer_surgery|Surgery]]<br />
*SB3-G31-BC: [[Surgery#Breast_cancer_surgery|Surgery]], then [[#Trastuzumab_monotherapy_2|adjuvant trastuzumab]] x 30 wk<br />
<br />
===Regimen variant #2, weekly trastuzumab {{#subobject:8e388e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.07.032 Buzdar et al. 2005]<br />
|2001-2003<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Complex_multipart_regimens#Buzdar_et_al._2005|See link]]<br />
| style="background-color:#91cf60" |[[Complex_multipart_regimens#Buzdar_et_al._2005|See link]]<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[#TH_.28Taxol.29|TH]] x 4<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 4<br />
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] 2 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
<br />
===References===<br />
# Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005 Jun 1;23(16):3676-85. Epub 2005 Feb 28. [https://doi.org/10.1200/jco.2005.07.032 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15738535 PubMed]<br />
## '''Update:''' Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, Pusztai L, Green MC, Singletary SE, Hunt KK, Sahin AA, Esteva F, Symmans WF, Ewer MS, Buchholz TA, Hortobagyi GN. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007 Jan 1;13(1):228-33. [http://clincancerres.aacrjournals.org/content/13/1/228.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17200359 PubMed]<br />
# '''HannaH:''' Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012 Sep;13(9):869-78. Epub 2012 Aug 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70329-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22884505 PubMed] NCT00950300<br />
## '''Update:''' Jackisch C, Kim SB, Semiglazov V, Melichar B, Pivot X, Hillenbach C, Stroyakovskiy D, Lum BL, Elliott R, Weber HA, Ismael G. Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study. Ann Oncol. 2015 Feb;26(2):320-5. Epub 2014 Nov 17. [https://doi.org/10.1093/annonc/mdu524 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25403587 PubMed]<br />
## '''Update:''' Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen SC, Meyenberg C, Al-Sakaff N, Heinzmann D, Hegg R. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol. 2019 May 1;5(5):e190339. Epub 2019 May 9. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2730632 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512301/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30998824 PubMed]<br />
# '''SB3-G31-BC:''' Pivot X, Bondarenko I, Nowecki Z, Dvorkin M, Trishkina E, Ahn JH, Vinnyk Y, Im SA, Sarosiek T, Chatterjee S, Wojtukiewicz MZ, Moiseyenko V, Shparyk Y, Bello M 3rd, Semiglazov V, Song S, Lim J. Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients treated with neoadjuvant therapy for human epidermal growth factor receptor 2-positive early breast cancer. J Clin Oncol. 2018 Apr 1;36(10):968-974. Epub 2018 Jan 26. [https://doi.org/10.1200/JCO.2017.74.0126 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29373094 PubMed]<br />
<br />
==FEC & H (SC) {{#subobject:d28hof|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FEC & H: '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''erceptin Hylecta (Trastuzumab and hyaluronidase)<br />
===Regimen {{#subobject:febd45|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70329-7/fulltext Ismael et al. 2012 (HannaH)]<br />
|2009-2010<br />
|style="background-color:#1a9851"|Phase III (E-RT-switch-ic)<br />
|[[Complex_multipart_regimens#HannaH|See link]]<br />
|style="background-color:#eeee01"|[[Complex_multipart_regimens#HannaH|See link]]<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[#TH_.28Taxotere.2FSC.29|TH (SC)]] x 4<br />
<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab and hyaluronidase (Herceptin Hylecta)]] 600 mg/10,000 units SC once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
<br />
===References===<br />
# '''HannaH:''' Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012 Sep;13(9):869-78. Epub 2012 Aug 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70329-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22884505 PubMed] NCT00950300<br />
## '''Update:''' Jackisch C, Kim SB, Semiglazov V, Melichar B, Pivot X, Hillenbach C, Stroyakovskiy D, Lum BL, Elliott R, Weber HA, Ismael G. Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study. Ann Oncol. 2015 Feb;26(2):320-5. Epub 2014 Nov 17. [https://doi.org/10.1093/annonc/mdu524 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25403587 PubMed]<br />
## '''Update:''' Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen SC, Meyenberg C, Al-Sakaff N, Heinzmann D, Hegg R. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol. 2019 May 1;5(5):e190339. Epub 2019 May 9. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2730632 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512301/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30998824 PubMed]<br />
<br />
==Lapatinib & Trastuzumab {{#subobject:9cbcb2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ac66b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext Baselga et al. 2012 (NeoALTTO)]<br />
|2008-2010<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Complex_multipart_regimens#NeoALTTO|See link]]<br />
|[[Complex_multipart_regimens#NeoALTTO|See link]]<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Targeted therapy====<br />
*[[Lapatinib (Tykerb)]] 1000 mg PO once per day<br />
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22, 29, 36<br />
<br />
'''6-week course'''<br />
====Subsequent treatment====<br />
*[[#THL_.28Taxol.29|THL (Taxol)]] x 12 wk, then [[Surgery#Breast_cancer_surgery|surgery]]<br />
<br />
===References===<br />
# '''NeoALTTO:''' Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705192/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22257673 PubMed] NCT00553358<br />
## '''Update:''' de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70320-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/25130998 PubMed]<br />
## '''Update:''' Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. [https://doi.org/10.1016/j.ejca.2019.04.038 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31377477 PubMed]<br />
<br />
==Neratinib & Paclitaxel {{#subobject:bd4482|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3751fa|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259558/ Park et al. 2016 (I-SPY 2)]<br />
|2010-2013<br />
|style="background-color:#1a9851"|Adaptively Randomized Phase II (E-switch-ic)<br />
|[[#TH_.28Taxol.29|TH]]<br />
|style="background-color:#91cf60"|Seems to have superior pCR rate<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Neratinib (Nerlynx)]] 240 mg PO once per day<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
*[[Loperamide (Imodium)]] 4 mg PO once on day 1, then 2 mg PO once 8 hours later, then 2 mg PO twice per day for two weeks, then decreased per patient choice, started on day 1 of [[Neratinib (Nerlynx)]]<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]] or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29|ddAC]], then [[Surgery#Breast_cancer_surgery|surgery]]<br />
<br />
===References===<br />
<!-- Presented in part by Dr. Park at the 104th annual meeting of the American Association for Cancer Research, Washington, DC, April 6–10, 2013. --><br />
# '''I-SPY 2:''' Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016 Jul 7;375(1):11-22. [https://www.nejm.org/doi/full/10.1056/NEJMoa1513750 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259558/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27406346 PubMed] NCT01042379<br />
<br />
==TCHP (Taxol) {{#subobject:ab8cj1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TCHP: '''<u>T</u>'''axol (Paclitaxel), '''<u>C</u>'''arboplatin, '''<u>H</u>'''erceptin (Trastuzumab), '''<u>P</u>'''ertuzumab<br><br />
===Regimen variant #1, standard carboplatin {{#subobject:a0cbj1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/s1470-2045(18)30570-9 van Ramshorst et al. 2018 (TRAIN-2)]<br />
|2013-2016<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[Stub#FEC_.26_HP|FEC & HP]] x 3, then [[#TCHP_.28Taxol.29|TCHP]] x 6<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of pCR rate<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycles 2 to 9: 6 mg/kg IV once on day 1<br />
*[[Pertuzumab (Perjeta)]] as follows:<br />
**Cycle 1: 840 mg IV once on day 1<br />
**Cycles 2 to 9: 420 mg IV once on day 1<br />
<br />
'''21-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
<br />
===Regimen variant #2, split carboplatin {{#subobject:a1ibj1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/s1470-2045(18)30570-9 van Ramshorst et al. 2018 (TRAIN-2)]<br />
|2013-2016<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[Stub#FEC_.26_HP|FEC & HP]] x 3, then [[#TCHP_.28Taxol.29|TCHP]] x 6<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of pCR rate<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Carboplatin (Paraplatin)]] AUC 3 IV once per day on days 1 & 8<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycles 2 to 9: 6 mg/kg IV once on day 1<br />
*[[Pertuzumab (Perjeta)]] as follows:<br />
**Cycle 1: 840 mg IV once on day 1<br />
**Cycles 2 to 9: 420 mg IV once on day 1<br />
<br />
'''21-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
<br />
===References===<br />
# '''TRAIN-2:''' van Ramshorst MS, van der Voort A, van Werkhoven ED, Mandjes IA, Kemper I, Dezentjé VO, Oving IM, Honkoop AH, Tick LW, van de Wouw AJ, Mandigers CM, van Warmerdam LJ, Wesseling J, Vrancken Peeters MT, Linn SC, Sonke GS; Dutch Breast Cancer Research Group. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018 Dec;19(12):1630-1640. Epub 2018 Nov 6. [https://doi.org/10.1016/s1470-2045(18)30570-9 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/30413379 PubMed] NCT01996267<br />
<br />
==TCHP (Taxotere) {{#subobject:CMR1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TCHP: '''<u>T</u>'''axotere (Docetaxel), '''<u>C</u>'''arboplatin, '''<u>H</u>'''erceptin (Trastuzumab), '''<u>P</u>'''ertuzumab<br><br />
===Regimen {{#subobject:CMV1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdt182 Schneeweiss et al. 2013 (TRYPHAENA)]<br />
|2009-2011<br />
|style="background-color:#1a9851"|Randomized Phase II (E-RT-switch-ic)<br />
|[[Complex_multipart_regimens#TRYPHAENA|See link]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30716-7/fulltext Hurvitz et al. 2017 (KRISTINE)]<br />
|2014-2015<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Pertuzumab_.26_T-DM1|Pertuzumab & T-DM1]]<br />
| style="background-color:#1a9850" |Superior EFS<sup>1</sup> <br>(HR 0.38, 95% CI 0.20-0.74)<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for KRISTINE is based on the 2019 update. EFS was a secondary endpoint.''<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycles 2 to 6: 6 mg/kg IV once on day 1<br />
*[[Pertuzumab (Perjeta)]] as follows:<br />
**Cycle 1: 840 mg IV once on day 1<br />
**Cycles 2 to 6: 420 mg IV once on day 1<br />
<br />
'''21-day cycle for 6 cycles'''<br />
<br />
====Subsequent treatment====<br />
*TRYPHAENA: [[Surgery#Breast_cancer_surgery|Surgery]], then further adjuvant treatment (radiotherapy, chemotherapy, hormonal treatment) according to local guidelines (a total of 1 year of trastuzumab was given)<br />
*KRISTINE: [[Surgery#Breast_cancer_surgery|Surgery]]<br />
===References===<br />
# '''TRYPHAENA:''' Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortés J. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013 Sep;24(9):2278-84. Epub 2013 May 22. [https://doi.org/10.1093/annonc/mdt182 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23704196 PubMed] NCT00976989<br />
# '''KRISTINE:''' Hurvitz SA, Martin M, Symmans WF, Jung KH, Huang CS, Thompson AM, Harbeck N, Valero V, Stroyakovskiy D, Wildiers H, Campone M, Boileau JF, Beckmann MW, Afenjar K, Fresco R, Helms HJ, Xu J, Lin YG, Sparano J, Slamon D. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2018 Jan;19(1):115-126. Epub 2017 Nov 23. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30716-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29175149 PubMed] NCT02131064<br />
## '''Update:''' Hurvitz SA, Martin M, Jung KH, Huang CS, Harbeck N, Valero V, Stroyakovskiy D, Wildiers H, Campone M, Boileau JF, Fasching PA, Afenjar K, Spera G, Lopez-Valverde V, Song C, Trask P, Boulet T, Sparano JA, Symmans WF, Thompson AM, Slamon D. Neoadjuvant trastuzumab emtansine and pertuzumab in human epidermal growth factor receptor 2-positive breast cancer: three-year outcomes from the phase III KRISTINE Study. J Clin Oncol. 2019 Sep 1;37(25):2206-2216. Epub 2019 Jun 3. [https://doi.org/10.1200/JCO.19.00882 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774816/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31157583 PubMed]<br />
<br />
==TH (Taxol) {{#subobject:647f67|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TH: '''<u>T</u>'''axol (Paclitaxel) & '''<u>H</u>'''erceptin (Trastuzumab)<br />
<br>T-T: '''<u>T</u>'''axol (Paclitaxel) & '''<u>T</u>'''rastuzumab<br />
===Regimen variant #1, weekly paclitaxel x 12, weekly trastuzumab {{#subobject:39d2af|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176878/ Buzdar et al. 2013 (ACOSOG Z1041)]<br />
|2007-2011<br />
|style="background-color:#1a9851"|Phase III<br />
|[[Complex_multipart_regimens#ACOSOG_Z1041|See link]]<br />
|style="background-color:#ffffbf"|[[Complex_multipart_regimens#ACOSOG_Z1041|See link]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext Baselga et al. 2012 (NeoALTTO)]<br />
|2008-2010<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[Complex_multipart_regimens#NeoALTTO|See link]]<br />
|[[Complex_multipart_regimens#NeoALTTO|See link]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259558/ Park et al. 2016 (I-SPY 2)]<br />
|2010-2013<br />
|style="background-color:#1a9851"|Adaptively Randomized Phase II (C)<br />
|[[#Neratinib_.26_Paclitaxel|Neratinib & Paclitaxel]]<br />
|style="background-color:#fc8d59"|Seems to have inferior pCR rate<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Patients in NeoALTTO had already undergone trastuzumab loading so would continue at the 2 mg/kg weekly dose. In ACOSOG Z1041, this portion of the regimen was used in both the control and experimental arms.''<br />
====Preceding treatment====<br />
*NeoALTTO: [[#Trastuzumab_monotherapy|Trastuzumab]] x 6 wk<br />
*ACOSOG Z1041: [[Breast_cancer#FEC|FEC]] x 4<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15<br />
**Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*NeoALTTO: [[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#FEC_2|adjuvant FEC]] x 3<br />
*ACOSOG Z1041: [[Surgery#Breast_cancer_surgery|Surgery]]<br />
*I-SPY 2: [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]] or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29|ddAC]], then [[Surgery#Breast_cancer_surgery|surgery]]<br />
<br />
===Regimen variant #2, weekly paclitaxel x 12, q3wk trastuzumab {{#subobject:b061d7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30241-9/fulltext von Minckwitz et al. 2018 (LILAC)]<br />
|2013-2015<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|Paclitaxel & ABP 980<br />
|style="background-color:#ffffbf"|Inconclusive whether equivalent pCR rate<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Regimen_classes#Anthracycline-based_regimen|Anthracycline-containing chemotherapy]] x 4<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycles 2 to 4: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
<br />
===Regimen variant #3, weekly paclitaxel x 16 {{#subobject:068233|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980567/ Carey et al. 2015 (CALGB 40601)]<br />
|rowspan=2|2008-2012<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (C)<br />
|1. [[#THL_.28Taxol.29|THL]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of pCR rate<br />
|-<br />
|2. [[#TL_.28Taxol.29|TL]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22<br />
**Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then adjuvant [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]] x 4, then [[#Trastuzumab_monotherapy_2|trastuzumab]] for 36 weeks was recommended but not mandated<br />
<br />
===Regimen variant #4, paclitaxel 3 out of 4 weeks {{#subobject:b18877|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70411-X/fulltext Robidoux et al. 2013 (NSABP B-41)]<br />
|rowspan=2|2007-2011<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (C)<br />
|1. [[#THL_.28Taxol.29|THL]]<br />
|style="background-color:#fee08b"|Might have inferior pCR rate<br />
|-<br />
|2. [[#TL_.28Taxol.29|TL]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of pCR rate<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]] x 4 <br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22<br />
**Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[#Trastuzumab_monotherapy_2|adjuvant trastuzumab]] for a total of 52 weeks of therapy.''<br />
<br />
===Regimen variant #5, q3wk, paclitaxel 175 mg/m<sup>2</sup> {{#subobject:7573a9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30241-9/fulltext von Minckwitz et al. 2018 (LILAC)]<br />
|2013-2015<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|Paclitaxel & ABP 980<br />
|style="background-color:#ffffbf"|Inconclusive whether equivalent pCR rate<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Regimen_classes#Anthracycline-based_regimen|Anthracycline-containing chemotherapy]] x 4<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once<br />
**Cycles 2 to 4: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
<br />
===Regimen variant #6, q3wk, paclitaxel 225 mg/m<sup>2</sup> {{#subobject:8e388e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.07.032 Buzdar et al. 2005]<br />
|2001-2003<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Complex_multipart_regimens#Buzdar_et_al._2005|See link]]<br />
| style="background-color:#91cf60" |[[Complex_multipart_regimens#Buzdar_et_al._2005|See link]]<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV continuous infusion over 24 hours on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1 prior to first dose of paclitaxel, then 2 mg/kg IV once per day on days 8 & 15<br />
**Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#FEC_.26_H|FEC & H]]<br />
<br />
===References===<br />
# Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005 Jun 1;23(16):3676-85. Epub 2005 Feb 28. [https://doi.org/10.1200/jco.2005.07.032 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15738535 PubMed]<br />
## '''Update:''' Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, Pusztai L, Green MC, Singletary SE, Hunt KK, Sahin AA, Esteva F, Symmans WF, Ewer MS, Buchholz TA, Hortobagyi GN. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007 Jan 1;13(1):228-33. [http://clincancerres.aacrjournals.org/content/13/1/228.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17200359 PubMed]<br />
# '''NeoALTTO:''' Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705192/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22257673 PubMed] NCT00553358<br />
## '''Update:''' de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70320-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/25130998 PubMed]<br />
## '''Update:''' Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. [https://doi.org/10.1016/j.ejca.2019.04.038 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31377477 PubMed]<br />
# '''NSABP B-41:''' Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1183-92. Epub 2013 Oct 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70411-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24095300 PubMed] NCT00486668<br />
# '''ACOSOG Z1041:''' Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig G, Royce M, McCall LM, Ewer MS, Hunt KK; American College of Surgeons Oncology Group. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1317-25. Epub 2013 Nov 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70502-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176878/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24239210 PubMed] NCT00513292<br />
## '''Update:''' Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig GW, Royce ME, Hunt KK. Disease-Free and Overall Survival Among Patients With Operable HER2-Positive Breast Cancer Treated With Sequential vs Concurrent Chemotherapy: The ACOSOG Z1041 (Alliance) Randomized Clinical Trial. JAMA Oncol. 2019 Jan 1;5(1):45-50. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2698846 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331049/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30193295 PubMed]<br />
# '''CALGB 40601:''' Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, Harris LN, Ollila DW, Krop IE, Henry NL, Weckstein DJ, Anders CK, Singh B, Hoadley KA, Iglesia M, Cheang MC, Perou CM, Winer EP, Hudis CA. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol. 2016 Feb 20;34(6):542-9. Epub 2015 Nov 2. [https://doi.org/10.1200/JCO.2015.62.1268 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980567/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26527775 PubMed] NCT00770809<br />
##'''Update:''' Fernandez-Martinez A, Krop IE, Hillman DW, Polley MY, Parker JS, Huebner L, Hoadley KA, Shepherd J, Tolaney S, Henry NL, Dang C, Harris L, Berry D, Hahn O, Hudis C, Winer E, Partridge A, Perou CM, Carey LA. Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer. J Clin Oncol. 2020 Dec 10;38(35):4184-4193. Epub 2020 Oct 23. [https://doi.org/10.1200/jco.20.01276 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723687/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33095682 PubMed]<br />
<!-- Presented in part by Dr. Park at the 104th annual meeting of the American Association for Cancer Research, Washington, DC, April 6–10, 2013. --><br />
# '''I-SPY 2:''' Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016 Jul 7;375(1):11-22. [https://www.nejm.org/doi/full/10.1056/NEJMoa1513750 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259558/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27406346 PubMed] NCT01042379<br />
# '''LILAC:''' von Minckwitz G, Colleoni M, Kolberg HC, Morales S, Santi P, Tomasevic Z, Zhang N, Hanes V. Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2018 Jul;19(7):987-998.Epub 2018 Jun 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30241-9/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29880292 PubMed] NCT01901146<br />
<br />
==TH (Taxotere) {{#subobject:ffc0e4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TH: '''<u>T</u>'''axotere (Docetaxel) & '''<u>H</u>'''erceptin (Trastuzumab)<br />
<br>DH: '''<u>D</u>'''ocetaxel & '''<u>H</u>'''erceptin (Trastuzumab)<br />
===Regimen variant #1, 75 mg/m<sup>2</sup> q3wk docetaxel, q3wk trastuzumab {{#subobject:7391c0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70329-7/fulltext Ismael et al. 2012 (HannaH)]<br />
|2009-2010<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[Complex_multipart_regimens#HannaH|See link]]<br />
|style="background-color:#eeee01"|[[Complex_multipart_regimens#HannaH|See link]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2017.74.0126 Pivot et al. 2018 (SB3-G31-BC)]<br />
|2014-2015<br />
|style="background-color:#1a9851"|Randomized (C)<br />
|[[Complex_multipart_regimens#SB3-G31-BC|See link]]<br />
|style="background-color:#eeee01"|[[Complex_multipart_regimens#SB3-G31-BC|See link]]<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycles 2 to 4: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#FEC_.26_H|FEC & H (IV)]]<br />
<br />
===Regimen variant #2, 100 mg/m<sup>2</sup> q3wk docetaxel, weekly trastuzumab {{#subobject:361b97|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.clinical-breast-cancer.com/article/S1526-8209(11)70948-X/pdf Van Pelt et al. 2003]<br />
|style="background-color:#91cf61"|Phase II<br />
|OCR: 77%<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] as follows:<br />
**Cycles 2 to 5: 100 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15<br />
**Cycles 2 to 5: 2 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for 5 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4, then [[#Trastuzumab_monotherapy_2|H]] x 52 wk<br />
<br />
===Regimen variant #3, 100 mg/m<sup>2</sup> q3wk docetaxel, q3wk trastuzumab {{#subobject:a889a0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70397-7/fulltext Untch et al. 2012 (GeparQuinto)]<br />
|2007-2010<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[Complex_multipart_regimens#GeparQuinto|See link]]<br />
| style="background-color:#91cf60" |[[Complex_multipart_regimens#GeparQuinto|See link]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950860/ Alba et al. 2014 (GEICAM 2006-14)]<br />
|2009-2010<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[Stub#TL_.28Taxotere.29|TL (Taxotere)]]<br />
| style="background-color:#1a9850" |Superior pCR rate<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. No loading dose was used for trastuzumab in GeparQuinto because the load occurred during the ECH part of the regimen.''<br />
====Preceding treatment====<br />
*GeparQuinto: [[#ECH|ECH]] x 4<br />
*GEICAM 2006-14: [[Breast_cancer#Cyclophosphamide_.26_Epirubicin_.28EC.29|EC]] x 4<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV once on day 1<br />
**GEICAM 2006-14 used a loading dose of 8 mg/kg in cycle 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
====Subsequent treatment====<br />
*GeparQuinto: [[Surgery#Breast_cancer_surgery|Surgery]], then [[#Trastuzumab_monotherapy_2|adjuvant trastuzumab]] for 1 year total<br />
*GEICAM 2006-14: [[Surgery#Breast_cancer_surgery|Surgery]]<br />
===References===<br />
# Van Pelt AE, Mohsin S, Elledge RM, Hilsenbeck SG, Gutierrez MC, Lucci A Jr, Kalidas M, Granchi T, Scott BG, Allred DC, Chang JC. Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results. Clin Breast Cancer. 2003 Dec;4(5):348-53. [https://www.clinical-breast-cancer.com/article/S1526-8209(11)70948-X/pdf link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/14715110 PubMed]<br />
# '''GeparQuinto:''' Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, Hilfrich J, Strumberg D, Fasching PA, Kreienberg R, Tesch H, Hanusch C, Gerber B, Rezai M, Jackisch C, Huober J, Kühn T, Nekljudova V, von Minckwitz G; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie-Breast Study Group. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 2012 Feb;13(2):135-44. Epub 2012 Jan 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70397-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22257523 PubMed] NCT00567554<br />
## '''Update:''' Untch M, von Minckwitz G, Gerber B, Schem C, Rezai M, Fasching PA, Tesch H, Eggemann H, Hanusch C, Huober J, Solbach C, Jackisch C, Kunz G, Blohmer JU, Hauschild M, Fehm T, Nekljudova V, Loibl S; GBG; AGO-B Study Group. Survival analysis after neoadjuvant chemotherapy with trastuzumab or lapatinib in patients with human epidermal growth factor receptor 2-positive breast cancer in the GeparQuinto (G5) study (GBG 44). J Clin Oncol. 2018 May 1;36(13):1308-1316. Epub 2018 Mar 15. [https://doi.org/10.1200/JCO.2017.75.9175 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29543566 PubMed]<br />
# '''HannaH:''' Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012 Sep;13(9):869-78. Epub 2012 Aug 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70329-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22884505 PubMed] NCT00950300<br />
## '''Update:''' Jackisch C, Kim SB, Semiglazov V, Melichar B, Pivot X, Hillenbach C, Stroyakovskiy D, Lum BL, Elliott R, Weber HA, Ismael G. Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study. Ann Oncol. 2015 Feb;26(2):320-5. Epub 2014 Nov 17. [https://doi.org/10.1093/annonc/mdu524 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25403587 PubMed]<br />
## '''Update:''' Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen SC, Meyenberg C, Al-Sakaff N, Heinzmann D, Hegg R. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol. 2019 May 1;5(5):e190339. Epub 2019 May 9. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2730632 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512301/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30998824 PubMed]<br />
# '''GEICAM 2006-14:''' Alba E, Albanell J, de la Haba J, Barnadas A, Calvo L, Sánchez-Rovira P, Ramos M, Rojo F, Burgués O, Carrasco E, Caballero R, Porras I, Tibau A, Cámara MC, Lluch A. Trastuzumab or lapatinib with standard chemotherapy for HER2-positive breast cancer: results from the GEICAM/2006-14 trial. Br J Cancer. 2014 Mar 4;110(5):1139-47. Epub 2014 Jan 23. [https://www.nature.com/articles/bjc2013831 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950860/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24457911 PubMed] NCT00841828<br />
# '''SB3-G31-BC:''' Pivot X, Bondarenko I, Nowecki Z, Dvorkin M, Trishkina E, Ahn JH, Vinnyk Y, Im SA, Sarosiek T, Chatterjee S, Wojtukiewicz MZ, Moiseyenko V, Shparyk Y, Bello M 3rd, Semiglazov V, Song S, Lim J. Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients treated with neoadjuvant therapy for human epidermal growth factor receptor 2-positive early breast cancer. J Clin Oncol. 2018 Apr 1;36(10):968-974. Epub 2018 Jan 26. [https://doi.org/10.1200/JCO.2017.74.0126 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29373094 PubMed]<br />
<br />
==TH (Taxotere/SC) {{#subobject:ffi9f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TH: '''<u>T</u>'''axotere (Docetaxel) & '''<u>H</u>'''erceptin Hylecta (Trastuzumab and hyaluronidase)<br />
===Regimen {{#subobject:d87acc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70329-7/fulltext Ismael et al. 2012 (HannaH)]<br />
|2009-2010<br />
|style="background-color:#1a9851"|Phase III (E-RT-switch-ic)<br />
|[[Complex_multipart_regimens#HannaH|See link]]<br />
|style="background-color:#eeee01"|[[Complex_multipart_regimens#HannaH|See link]]<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab and hyaluronidase (Herceptin Hylecta)]] 600 mg/10,000 units SC once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[#FEC_.26_H_.28SC.29|FEC & H (SC)]]<br />
<br />
===References===<br />
# '''HannaH:''' Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012 Sep;13(9):869-78. Epub 2012 Aug 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70329-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22884505 PubMed] NCT00950300<br />
## '''Update:''' Jackisch C, Kim SB, Semiglazov V, Melichar B, Pivot X, Hillenbach C, Stroyakovskiy D, Lum BL, Elliott R, Weber HA, Ismael G. Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study. Ann Oncol. 2015 Feb;26(2):320-5. Epub 2014 Nov 17. [https://doi.org/10.1093/annonc/mdu524 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25403587 PubMed]<br />
## '''Update:''' Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen SC, Meyenberg C, Al-Sakaff N, Heinzmann D, Hegg R. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol. 2019 May 1;5(5):e190339. Epub 2019 May 9. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2730632 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512301/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30998824 PubMed]<br />
<br />
==THL (Taxol) {{#subobject:6992f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
THL: '''<u>T</u>'''axol (Paclitaxel), '''<u>H</u>'''erceptin (Trastuzumab), '''<u>L</u>'''apatinib<br />
===Regimen variant #1, weekly paclitaxel x 12 {{#subobject:459c75|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext Baselga et al. 2012 (NeoALTTO)]<br />
|2008-2010<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Complex_multipart_regimens#NeoALTTO|See link]]<br />
|[[Complex_multipart_regimens#NeoALTTO|See link]]<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Lapatinib_.26_Trastuzumab|Lapatinib & Trastuzumab]] x 6 wk<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] 2 mg/kg IV once per day on days 1, 8, 15, 22<br />
*[[Lapatinib (Tykerb)]] 1000 mg PO once per day<br />
<br />
'''28-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#FEC_2|adjuvant FEC]] x 3<br />
<br />
===Regimen variant #2, weekly paclitaxel x 16 {{#subobject:1b4c0a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980567/ Carey et al. 2015 (CALGB 40601)]<br />
|rowspan=2|2008-2012<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-esc)<br />
|1. [[#TH_.28Taxol.29|TH]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of pCR rate<br />
|-<br />
|2. [[#TL_.28Taxol.29|TL]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22<br />
**Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15, 22<br />
*[[Lapatinib (Tykerb)]] 750 mg PO once per day<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]; adjuvant [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]] x 4, then [[#Trastuzumab_monotherapy_2|trastuzumab]] for 36 weeks was recommended but not mandated<br />
<br />
===Regimen variant #3, paclitaxel 3 out of 4 weeks {{#subobject:ca2389|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70411-X/fulltext Robidoux et al. 2013 (NSABP B-41)]<br />
|rowspan=2|2007-2011<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-esc)<br />
|1. [[#TH_.28Taxol.29|TH]]<br />
|style="background-color:#d9ef8b"|Might have superior pCR rate<br />
|-<br />
|2. [[#TL_.28Taxol.29|TL]]<br />
|style="background-color:#d9ef8b"|Might have superior pCR rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]] x 4 <br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22<br />
**Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15, 22<br />
*[[Lapatinib (Tykerb)]] 750 mg PO once per day<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[#Trastuzumab_monotherapy_2|adjuvant trastuzumab]] for a total of 52 weeks of therapy<br />
<br />
===References===<br />
# '''NeoALTTO:''' Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705192/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22257673 PubMed] NCT00553358<br />
## '''Update:''' de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70320-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/25130998 PubMed]<br />
## '''Update:''' Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. [https://doi.org/10.1016/j.ejca.2019.04.038 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31377477 PubMed]<br />
# '''NSABP B-41:''' Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1183-92. Epub 2013 Oct 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70411-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24095300 PubMed] NCT00486668<br />
# '''CALGB 40601:''' Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, Harris LN, Ollila DW, Krop IE, Henry NL, Weckstein DJ, Anders CK, Singh B, Hoadley KA, Iglesia M, Cheang MC, Perou CM, Winer EP, Hudis CA. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol. 2016 Feb 20;34(6):542-9. Epub 2015 Nov 2. [https://doi.org/10.1200/JCO.2015.62.1268 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980567/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26527775 PubMed] NCT00770809<br />
##'''Update:''' Fernandez-Martinez A, Krop IE, Hillman DW, Polley MY, Parker JS, Huebner L, Hoadley KA, Shepherd J, Tolaney S, Henry NL, Dang C, Harris L, Berry D, Hahn O, Hudis C, Winer E, Partridge A, Perou CM, Carey LA. Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer. J Clin Oncol. 2020 Dec 10;38(35):4184-4193. Epub 2020 Oct 23. [https://doi.org/10.1200/jco.20.01276 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723687/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33095682 PubMed]<br />
<br />
==THP (Taxotere) {{#subobject:24b376|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
THP: '''<u>T</u>'''axotere (Docetaxel), '''<u>H</u>'''erceptin (Trastuzumab), '''<u>P</u>'''ertuzumab<br />
===Regimen variant #1, 3 cycles with loading doses {{#subobject:fb33dc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdt182 Schneeweiss et al. 2013 (TRYPHAENA)]<br />
|2009-2011<br />
|style="background-color:#1a9851"|Randomized Phase II (E-RT-switch-ic)<br />
|[[Complex_multipart_regimens#TRYPHAENA|See link]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Breast_cancer#FEC|FEC]] x 3<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] as follows:<br />
**Cycle 1 (4, overall): 75 mg/m<sup>2</sup> IV once on day 1<br />
**Cycles 2 & 3 (5 & 6, overall), if no toxic effects occurred: 100 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycles 2 to 4: 6 mg/kg IV once on day 1<br />
*[[Pertuzumab (Perjeta)]] as follows:<br />
**Cycle 1: 840 mg IV once on day 1<br />
**Cycles 2 to 4: 420 mg IV once on day 1<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then further adjuvant treatment (radiotherapy, chemotherapy, hormonal treatment) according to local guidelines (a total of 1 year of trastuzumab was given)<br />
<br />
===Regimen variant #2, 3 cycles without loading doses {{#subobject:52f6c6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdt182 Schneeweiss et al. 2013 (TRYPHAENA)]<br />
|2009-2011<br />
|style="background-color:#1a9851"|Randomized Phase II (E-RT-switch-ic)<br />
|[[Complex_multipart_regimens#TRYPHAENA|See link]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Stub#FEC_.26_HP|FEC & HP]] x 3<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] as follows:<br />
**Cycle 1 (4, overall): 75 mg/m<sup>2</sup> IV once on day 1<br />
**Cycles 2 & 3 (5 & 6, overall), if no toxic effects occurred: 100 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV once on day 1<br />
*[[Pertuzumab (Perjeta)]] 420 mg IV once on day 1<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then further adjuvant treatment (radiotherapy, chemotherapy, hormonal treatment) according to local guidelines (a total of 1 year of trastuzumab was given)<br />
<br />
===Regimen variant #3, 4 cycles with loading doses {{#subobject:3f1974|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=3|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70336-9/fulltext Gianni et al. 2011 (NeoSphere)]<br />
|rowspan=3|2007-2009<br />
|rowspan=3 style="background-color:#1a9851"|Randomized Phase II (E-RT-esc)<br />
|1. [[Stub#Docetaxel_.26_Pertuzumab|Docetaxel & Pertuzumab]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of pCR rate<br />
|-<br />
|2. Pertuzumab & Trastuzumab<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of pCR rate<br />
|-<br />
|3. TH<br />
|style="background-color:#91cf60"|Seems to have superior pCR rate<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdt182 Schneeweiss et al. 2013 (TRYPHAENA)]<br />
|2009-2011<br />
|style="background-color:#1a9851"|Randomized Phase II (E-RT-switch-ic)<br />
|[[Complex_multipart_regimens#TRYPHAENA|See link]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888999/ Swain et al. 2018 (BERENICE)]<br />
|2014-2015<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*BERENICE: [[Breast_cancer#FEC|FEC]] x 4<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
**Based on tolerability, investigators could increase dose to 100 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycles 2 to 4: 6 mg/kg IV once on day 1<br />
*[[Pertuzumab (Perjeta)]] as follows:<br />
**Cycle 1: 840 mg IV once on day 1<br />
**Cycles 2 to 4: 420 mg IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[#FEC_.26_H_2|adjuvant FEC & H]]<br />
<br />
===References===<br />
# '''NeoSphere:''' Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25-32. Epub 2011 Dec 6. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70336-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22153890 PubMed] NCT00545688<br />
## '''Update:''' Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, Starosławska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi GV, Magazzù D, McNally V, Douthwaite H, Ross G, Valagussa P. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016 Jun;17(6):791-800. Epub 2016 May 11. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00163-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/27179402 PubMed]<br />
# '''TRYPHAENA:''' Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortés J. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013 Sep;24(9):2278-84. Epub 2013 May 22. [https://doi.org/10.1093/annonc/mdt182 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23704196 PubMed] NCT00976989<br />
# '''BERENICE:''' Swain SM, Ewer MS, Viale G, Delaloge S, Ferrero JM, Verrill M, Colomer R, Vieira C, Werner TL, Douthwaite H, Bradley D, Waldron-Lynch M, Kiermaier A, Eng-Wong J, Dang C; BERENICE Study Group. Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol. 2018 Mar 1;29(3):646-653. [https://doi.org/10.1093/annonc/mdx773 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888999/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29253081 PubMed] NCT02132949<br />
<br />
==TL (Taxol) {{#subobject:af5af0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TL: '''<u>T</u>'''axol (Paclitaxel) & '''<u>L</u>'''apatinib<br />
===Regimen variant #1, weekly paclitaxel x 12 {{#subobject:bed34f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext Baselga et al. 2012 (NeoALTTO)]<br />
|2008-2010<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[Complex_multipart_regimens#NeoALTTO|See link]]<br />
|[[Complex_multipart_regimens#NeoALTTO|See link]]<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Lapatinib x 6 wk<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Lapatinib (Tykerb)]] 1500 mg PO once per day<br />
<br />
'''28-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#FEC_2|adjuvant FEC]] x 3<br />
<br />
===Regimen variant #2, weekly paclitaxel x 16 {{#subobject:8aae8f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980567/ Carey et al. 2015 (CALGB 40601)]<br />
|rowspan=2|2008-2012<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|1. [[#TH_.28Taxol.29|TH]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#THL_.28Taxol.29|THL]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: this arm was closed early.''<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Lapatinib (Tykerb)]] 1500 mg PO once per day<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]; adjuvant [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]] x 4, then [[#Trastuzumab_monotherapy_2|trastuzumab]] for 36 weeks was recommended but not mandated<br />
<br />
===Regimen variant #3, paclitaxel 3 out of 4 weeks {{#subobject:6dda48|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70411-X/fulltext Robidoux et al. 2013 (NSABP B-41)]<br />
|rowspan=2|2007-2011<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|1. [[#TH_.28Taxol.29|TH]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of pCR rate<br />
|-<br />
|2. [[#THL_.28Taxol.29|THL]]<br />
|style="background-color:#fee08b"|Might have inferior pCR rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]] x 4 <br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Lapatinib (Tykerb)]] 1250 mg PO once per day<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[#Trastuzumab_monotherapy_2|adjuvant trastuzumab]] for a total of 52 weeks of therapy<br />
===References===<br />
# '''NeoALTTO:''' Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705192/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22257673 PubMed] NCT00553358<br />
## '''Update:''' de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70320-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/25130998 PubMed]<br />
## '''Update:''' Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. [https://doi.org/10.1016/j.ejca.2019.04.038 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31377477 PubMed]<br />
# '''NSABP B-41:''' Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1183-92. Epub 2013 Oct 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70411-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24095300 PubMed] NCT00486668<br />
# '''CALGB 40601:''' Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, Harris LN, Ollila DW, Krop IE, Henry NL, Weckstein DJ, Anders CK, Singh B, Hoadley KA, Iglesia M, Cheang MC, Perou CM, Winer EP, Hudis CA. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol. 2016 Feb 20;34(6):542-9. Epub 2015 Nov 2. [https://doi.org/10.1200/JCO.2015.62.1268 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980567/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26527775 PubMed] NCT00770809<br />
##'''Update:''' Fernandez-Martinez A, Krop IE, Hillman DW, Polley MY, Parker JS, Huebner L, Hoadley KA, Shepherd J, Tolaney S, Henry NL, Dang C, Harris L, Berry D, Hahn O, Hudis C, Winer E, Partridge A, Perou CM, Carey LA. Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer. J Clin Oncol. 2020 Dec 10;38(35):4184-4193. Epub 2020 Oct 23. [https://doi.org/10.1200/jco.20.01276 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723687/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33095682 PubMed]<br />
<br />
==Trastuzumab monotherapy {{#subobject:9cbcb2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===Regimen {{#subobject:9ac66b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext Baselga et al. 2012 (NeoALTTO)]<br />
|2008-2010<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[Complex_multipart_regimens#NeoALTTO|See link]]<br />
|[[Complex_multipart_regimens#NeoALTTO|See link]]<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22, 29, 36<br />
<br />
'''6-week course'''<br />
====Subsequent treatment====<br />
*[[#TH_.28Taxol.29|TH (Taxol)]] x 12 wk, then [[Surgery#Breast_cancer_surgery|surgery]]<br />
<br />
===References===<br />
# '''NeoALTTO:''' Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705192/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22257673 PubMed] NCT00553358<br />
## '''Update:''' de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70320-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/25130998 PubMed]<br />
## '''Update:''' Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. [https://doi.org/10.1016/j.ejca.2019.04.038 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31377477 PubMed]<br />
<br />
=Neoadjuvant response criteria=<br />
<br />
==Clinical response rate (cRR)==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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''Although fairly dated, some trials such as [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107749/ ACOSOG Z1031] make use of the WHO criteria for response to neoadjuvant therapy. Included here primarily for historical purposes.''<br />
===References===<br />
# Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981 Jan 1;47(1):207-14. [https://onlinelibrary.wiley.com/doi/10.1002/1097-0142(19810101)47:1%3C207::AID-CNCR2820470134%3E3.0.CO;2-6/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/7459811 PubMed]<br />
<br />
==Miller-Payne scoring system==<br />
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*Grade 1: No change or some changes to individual malignant cells, but no reduction in overall cellularity<br />
*Grade 2: Minor loss of tumor cells (up to 30%), but overall cellularity still high <br />
*Grade 3: An estimated 30 to 90% reduction in the number of tumor cells<br />
*Grade 4: Marked disappearance of tumor cells such that only small clusters or widely dispersed individual cells remain (loss of greater than 90% of tumor cells) <br />
*Grade 5: No invasive cancer cells identifiable in sections from the site of the tumor (carcinoma ''in situ'' may be present) <br />
===References===<br />
# Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, Schofield A, Heys SD. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast. 2003 Oct;12(5):320-7. [http://www.thebreastonline.com/article/S0960-9776(03)00106-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/14659147 PubMed]<br />
<br />
==Residual cancer burden (RCB)==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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*The RCB is calculated as follows: RCB = 1.4 (''f<sub>inv</sub>*d<sub>prim</sub>'')<sup>0.17</sup> + [4(1 - 0.75<sup>''LN''</sup>)''d<sub>met</sub>'']<sup>0.17</sup><br />
**where ''d<sub>prim</sub>'' is derived from the bidimensional diameters of the primary tumor bed in the resected specimen, ''f<sub>inv</sub>'' is the proportion of the primary tumor bed that contains invasive carcinoma, ''LN'' is the number of axillary lymph nodes containing metastatic carcinoma, and ''d<sub>met</sub>'' is the diameter of the largest metastasis in an axillary lymph node.<br />
**The cut-off points are 1.36 and 3.28.<br />
===References===<br />
# Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007 Oct 1;25(28):4414-22. Epub 2007 Sep 4. [https://doi.org/10.1200/JCO.2007.10.6823 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17785706 PubMed]<br />
<br />
==Residual disease in breast and nodes (RDBN)==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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*Level 1: pCR in breast and nodes with or without ''in situ'' carcinoma<br />
*Levels 2 to 4: Residual disease, calculated as 0.2 (residual breast tumor size in cm) + index of involved nodes (0 for no positive nodes, 1 for 1 to 4 positive nodes, 2 for 5 to 7 positive nodes, and 3 for 8 positive nodes) + the Scarff–Bloom–Richardson grade (1, 2, or 3). The cut-off points are 3 and 4.3.<br />
===References===<br />
# Chollet P, Abrial C, Durando X, Thivat E, Tacca O, Mouret-Reynier MA, Leheurteur M, Kwiatkowski F, Dauplat J, Penault-Llorca F. A new prognostic classification after primary chemotherapy for breast cancer: residual disease in breast and nodes (RDBN). Cancer J. 2008 Mar-Apr;14(2):128-32. [https://insights.ovid.com/pubmed?pmid=18391619 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18391619 PubMed]<br />
<br />
==Sataloff's classification==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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*Breast: <br />
**T-A: Total or nearly total therapeutic effect <br />
**T-B: Greater than 50% therapeutic effect<br />
**T-C: Less than 50% therapeutic effect <br />
**T-D: No therapeutic effect<br />
*Lymph node:<br />
**N-A: Therapeutic effect but no metastasis<br />
**N-B: No metastasis, no therapeutic effect<br />
**N-C: Therapeutic effect but metastasis<br />
**N-D: Metastasis, no therapeutic effect<br />
===References===<br />
# Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z. Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome. J Am Coll Surg. 1995 Mar;180(3):297-306. [https://pubmed.ncbi.nlm.nih.gov/7874340 PubMed]<br />
<br />
==Tumor response ratio==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Calculated as follows: Residual breast disease observed upon pathologic examination divided by the size of the tumor on the pre-neoadjuvant therapy image.<br />
*TRR = 0: pathologic complete response (pCR)<br />
*TRR greater than 0 up to 0.4: strong partial response<br />
*TRR greater than 0.4 up to 1.0: weak partial response (WPR)<br />
*TRR greater than 1.0: tumor growth<br />
===References===<br />
# Miller M, Ottesen RA, Niland JC, Kruper L, Chen SL, Vito C. Tumor response ratio predicts overall survival in breast cancer patients treated with neoadjuvant chemotherapy. Ann Surg Oncol. 2014 Oct;21(10):3317-23. Epub 2014 Jul 25. [https://link.springer.com/article/10.1245%2Fs10434-014-3922-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25059788 PubMed]<br />
<br />
==ypTNM staging==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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This system is proprietary to the AJCC. Please [https://cancerstaging.org/Pages/default.aspx visit their site] or consult the AJCC Manual for further details.<br />
<br />
=Adjuvant chemotherapy=<br />
==Cyclophosphamide & Doxorubicin (AC) {{#subobject:77b0fd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
AC: '''<u>A</u>'''driamycin (Doxorubicin) and '''<u>C</u>'''yclophosphamide<br />
<br>CA: '''<u>C</u>'''yclophosphamide and '''<u>A</u>'''driamycin (Doxorubicin)<br />
===Regimen variant #1, 60/600 x 4 {{#subobject:ac3513|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.clinical-breast-cancer.com/article/S1526-8209(11)70948-X/pdf Van Pelt et al. 2003]<br />
|2000-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa052122 Romond et al. 2005 (NSABP B-31)]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa052122 Romond et al. 2005 (NCCTG N9831)]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268553/ Slamon et al. 2011 (BCIRG 006)]<br />
|2001-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#BCIRG_006|See link]]<br />
|[[Complex_multipart_regimens#BCIRG_006|See link]]<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Van Pelt et al. 2003: [[#TH_.28Taxotere.29|Neoadjuvant TH]], then [[Surgery#Breast_cancer_surgery|surgery]]<br />
*NSABP B-31, NCCTG N9831, BCIRG 006: [[Surgery#Breast_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Van Pelt et al. 2003: [[#Trastuzumab_monotherapy_2|H]] x 12 mo<br />
*NSABP B-31: [[Breast_cancer#Paclitaxel_monotherapy.2C_weekly_2|weekly T (Taxol)]] x 12 versus [[#TH_.28Taxol.29_2|TH (Taxol)]] x 12 mo<br />
*NCCTG N9831: [[Breast_cancer#Paclitaxel_monotherapy.2C_weekly_2|weekly T (Taxol)]] x 12 versus sequential [[Breast_cancer#Paclitaxel_monotherapy.2C_weekly_2|weekly T (Taxol)]] x 12, then [[#Trastuzumab_monotherapy|H]] x 12 mo versus concurrent [[#TH_.28Taxol.29_2|TH (Taxol)]] x 12 mo<br />
*BCIRG 006: [[Breast_cancer#Docetaxel_monotherapy_2|q3wk T (Taxotere)]] x 4 versus [[#TH_.28Taxotere.29_2|TH (Taxotere)]] x 12 mo<br />
<br />
===Regimen variant #2, with range {{#subobject:67eda7|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ von Minckwitz et al. 2017 (APHINITY)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Patients in APHINITY had HER2-positive breast cancer. Note that ranges for AC are given in the protocol, replicated here. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] 500 to 600 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[#TH_.28Taxol.29_2|TH (Taxol)]] versus [[#THP_.28Taxol.29_2|THP (Taxol)]] or [[#TH_.28Taxotere.29_2|TH (Taxotere)]] versus [[#THP_.28Taxotere.29_2|THP (Taxotere)]]<br />
<br />
===References===<br />
# Van Pelt AE, Mohsin S, Elledge RM, Hilsenbeck SG, Gutierrez MC, Lucci A Jr, Kalidas M, Granchi T, Scott BG, Allred DC, Chang JC. Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results. Clin Breast Cancer. 2003 Dec;4(5):348-53. [https://www.clinical-breast-cancer.com/article/S1526-8209(11)70948-X/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/14715110 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# '''NSABP B-31/NCCTG N9831:''' Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. [https://www.nejm.org/doi/full/10.1056/NEJMoa052122 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16236738 PubMed] NCT00004067; NCT00005970<br />
## '''Update:''' Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE Jr, Martino S, Mamounas EP, Kaufman PA, Wolmark N. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011 Sep 1;29(25):3366-73. Epub 2011 Jul 18. [https://doi.org/10.1200/JCO.2011.35.0868 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164242/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21768458 PubMed]<br />
## '''Update:''' Perez EA, Suman VJ, Davidson NE, Gralow JR, Kaufman PA, Visscher DW, Chen B, Ingle JN, Dakhil SR, Zujewski J, Moreno-Aspitia A, Pisansky TM, Jenkins RB. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4491-7. Epub 2011 Oct 31. [https://doi.org/10.1200/JCO.2011.36.7045 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236650/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22042958 PubMed]<br />
## '''Update:''' Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014 Nov 20;32(33):3744-52. [https://doi.org/10.1200/JCO.2014.55.5730 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226805/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25332249 PubMed]<br />
## '''Update and HRQoL analysis:''' Ganz PA, Romond EH, Cecchini RS, Rastogi P, Geyer CE Jr, Swain SM, Jeong JH, Fehrenbacher L, Gross HM, Brufsky AM, Flynn PJ, Wahl TA, Seay TE, Wade JL 3rd, Biggs DD, Atkins JN, Polikoff J, Zapas JL, Mamounas EP, Wolmark N. Long-term follow-up of cardiac function and quality of life for patients in NSABP protocol B-31/NRG Oncology: a randomized trial comparing the safety and efficacy of doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel and trastuzumab in patients with node-positive breast cancer with tumors overexpressing human epidermal growth factor receptor 2. J Clin Oncol. 2017 Dec 10;35(35):3942-3948. Epub 2017 Oct 26. [https://doi.org/10.1200/JCO.2017.74.1165 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721228/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29072977 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# '''BCIRG 006:''' Slamon D, Eiermann W, Robert N, Pienkowski T, Martín M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. [https://www.nejm.org/doi/full/10.1056/NEJMoa0910383 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268553/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21991949 PubMed] NCT00021255<br />
# '''APHINITY:''' von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1703643 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1703643/suppl_file/nejmoa1703643_protocol.pdf link to supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28581356 PubMed] NCT01358877<br />
##'''Update:''' Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. [https://doi.org/10.1200/jco.20.01204 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33539215/ PubMed]<br />
# '''RESPECT:''' Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. [https://doi.org/10.1200/jco.20.00184 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32936713/ PubMed] NCT01104935<br />
<br />
==Dose-dense Cyclophosphamide & Doxorubicin (ddAC) {{#subobject:b52056|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ddAC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>A</u>'''driamycin (Doxorubicin) and '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1, 60/600 x 4 {{#subobject:cdafd0|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2007.12.0733 Dang et al. 2008]<br />
|2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2, given 24 hours after chemotherapy<br />
<br />
'''14-day cycle for 4 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#ddTH_.28Taxol.29|ddTH (Taxol)]]<br />
<br />
===Regimen variant #2, 4 cycles, with range {{#subobject:b6d1ca|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ von Minckwitz et al. 2017 (APHINITY)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note that ranges for ddAC are given in the protocol, replicated here.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] 500 to 600 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] support (drug/dose/schedule not specified)<br />
<br />
'''14-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[#TH_.28Taxol.29_2|TH (Taxol)]] versus [[#THP_.28Taxol.29_2|THP (Taxol)]] or [[#TH_.28Taxotere.29_2|TH (Taxotere)]] versus [[#THP_.28Taxotere.29_2|THP (Taxotere)]]<br />
<br />
===References===<br />
# Dang C, Fornier M, Sugarman S, Troso-Sandoval T, Lake D, D'Andrea G, Seidman A, Sklarin N, Dickler M, Currie V, Gilewski T, Moynahan ME, Drullinsky P, Robson M, Wasserheit-Leiblich C, Mills N, Steingart R, Panageas K, Norton L, Hudis C. The safety of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel with trastuzumab in HER-2/neu overexpressed/amplified breast cancer. J Clin Oncol. 2008 Mar 10;26(8):1216-22. [https://doi.org/10.1200/jco.2007.12.0733 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18323546 PubMed]<br />
# '''APHINITY:''' von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1703643 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1703643/suppl_file/nejmoa1703643_protocol.pdf link to supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28581356 PubMed] NCT01358877<br />
##'''Update:''' Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. [https://doi.org/10.1200/jco.20.01204 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33539215/ PubMed]<br />
<br />
==Cyclophosphamide & Epirubicin (EC) {{#subobject:8d8dbe|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
EC: '''<u>E</u>'''pirubicin and '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen {{#subobject:ef0b86|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ von Minckwitz et al. 2017 (APHINITY)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Patients had HER2-positive breast cancer.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Epirubicin (Ellence)]] 90 to 120 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] 500 to 600 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[#TH_.28Taxol.29_2|TH (Taxol)]] versus [[#THP_.28Taxol.29_2|THP (Taxol)]] or [[#TH_.28Taxotere.29_2|TH (Taxotere)]] versus [[#THP_.28Taxotere.29_2|THP (Taxotere)]]<br />
<br />
===References===<br />
# '''APHINITY:''' von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1703643 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1703643/suppl_file/nejmoa1703643_protocol.pdf link to supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28581356 PubMed] NCT01358877<br />
##'''Update:''' Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. [https://doi.org/10.1200/jco.20.01204 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33539215/ PubMed]<br />
<br />
==ddEC {{#subobject:824585|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ddEC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>E</u>'''pirubicin and '''<u>C</u>'''yclophosphamide<br />
===Regimen {{#subobject:d9d108|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ von Minckwitz et al. 2017 (APHINITY)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note that ranges for ddEC are given in the protocol, replicated here.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Epirubicin (Ellence)]] 90 to 120 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] 500 to 600 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] support (drug/dose/schedule not specified)<br />
<br />
'''14-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[#TH_.28Taxol.29_2|TH (Taxol)]] versus [[#THP_.28Taxol.29_2|THP (Taxol)]] or [[#TH_.28Taxotere.29_2|TH (Taxotere)]] versus [[#THP_.28Taxotere.29_2|THP (Taxotere)]]<br />
<br />
===References===<br />
# '''APHINITY:''' von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1703643 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1703643/suppl_file/nejmoa1703643_protocol.pdf link to supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28581356 PubMed] NCT01358877<br />
##'''Update:''' Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. [https://doi.org/10.1200/jco.20.01204 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33539215/ PubMed]<br />
<br />
==FAC {{#subobject:1e6621|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FAC: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide<br />
<br>CAF: '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:67eda7|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ von Minckwitz et al. 2017 (APHINITY)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Note that ranges for FAC are given in the protocol, replicated here.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 500 to 600 mg/m<sup>2</sup> IV once on day 1<br />
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] 500 to 600 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[#TH_.28Taxol.29_2|TH (Taxol)]] versus [[#THP_.28Taxol.29_2|THP (Taxol)]] or [[#TH_.28Taxotere.29_2|TH (Taxotere)]] versus [[#THP_.28Taxotere.29_2|THP (Taxotere)]]<br />
<br />
===References===<br />
# '''APHINITY:''' von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1703643 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1703643/suppl_file/nejmoa1703643_protocol.pdf link to supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28581356 PubMed] NCT01358877<br />
##'''Update:''' Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. [https://doi.org/10.1200/jco.20.01204 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33539215/ PubMed]<br />
<br />
==FEC {{#subobject:3613b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FEC: '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide<br />
<br>CEF: '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''pirubicin, '''<u>F</u>'''luorouracil<br />
===Regimen variant #1, 500/100/500 x 3 ("FEC 100") {{#subobject:99d167|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext Baselga et al. 2012 (NeoALTTO)]<br />
|2008-2010<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
*[[Epirubicin (Ellence)]] 100 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*Lapatinib or [[#Lapatinib_.26_Trastuzumab_2|Lapatinib & Trastuzumab]] or [[#Trastuzumab_monotherapy_2|Trastuzumab]], according to initial randomization<br />
<br />
===Regimen variant #2, 600/60/600 x 3 {{#subobject:e6b54b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa053028 Joensuu et al. 2006 (FinHer)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[#Docetaxel_monotherapy_2|Docetaxel]] x 3 versus [[#TH_.28Taxotere.29_2|TH]] x 3 versus [[#Vinorelbine_monotherapy|Vinorelbine]] x 3 versus [[#Vinorelbine_.26_Trastuzumab_.28VH.29|VH]] x 3<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1<br />
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===Regimen variant #3, 600/75/600 x 3 {{#subobject:b0f889|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 50%"|Study<br />
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2682589 Joensuu et al. 2018 (SOLD)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[#TH_.28Taxotere.29_2|TH (Taxotere)]] x 3<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1<br />
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[#Trastuzumab_monotherapy_2|Trastuzumab maintenance]] for a total of 1 year versus no further treatment<br />
<br />
===Regimen variant #4, with range {{#subobject:a1c683|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ von Minckwitz et al. 2017 (APHINITY)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Note that ranges for FEC are given in the protocol, replicated here.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 500 to 600 mg/m<sup>2</sup> IV once on day 1<br />
*[[Epirubicin (Ellence)]] 90 to 120 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] 500 to 600 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[#TH_.28Taxol.29_2|TH (Taxol)]] versus [[#THP_.28Taxol.29_2|THP (Taxol)]] or [[#TH_.28Taxotere.29_2|TH (Taxotere)]] versus [[#THP_.28Taxotere.29_2|THP (Taxotere)]]<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# '''FinHer:''' Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa053028 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16495393 PubMed] ISRCTN76560285<br />
## '''Update:''' Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. [https://doi.org/10.1200/JCO.2008.21.4577 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19884557 PubMed]<br />
# '''NeoALTTO:''' Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705192/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22257673 PubMed] NCT00553358<br />
## '''Update:''' de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70320-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/25130998 PubMed]<br />
## '''Update:''' Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. [https://doi.org/10.1016/j.ejca.2019.04.038 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31377477 PubMed]<br />
# '''APHINITY:''' von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1703643 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1703643/suppl_file/nejmoa1703643_protocol.pdf link to supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28581356 PubMed] NCT01358877<br />
##'''Update:''' Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. [https://doi.org/10.1200/jco.20.01204 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33539215/ PubMed]<br />
# '''SOLD:''' Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, Nyandoto P, Villman KK, Halonen P, Granstam-Björneklett H, Lundgren L, Sailas L, Turpeenniemi-Hujanen T, Tanner M, Yachnin J, Ritchie D, Johansson O, Huttunen T, Neven P, Canney P, Harvey VJ, Kellokumpu-Lehtinen PL, Lindman H. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 2018 Sep 1;4(9):1199-1206. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2682589 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29852043 PubMed] NCT00593697<br />
# '''RESPECT:''' Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. [https://doi.org/10.1200/jco.20.00184 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32936713/ PubMed] NCT01104935<br />
<br />
==ddFEC {{#subobject:45dbc1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
ddFEC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide<br />
===Regimen {{#subobject:21ab45|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdv213 Mavroudis et al. 2015 (HORG CT/04.23)]<br />
|2004-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 700 mg/m<sup>2</sup> IV over 5 to 15 minutes once on day 1 <br />
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV over 5 to 15 minutes once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] 700 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 1<br />
<br />
====Supportive medications====<br />
*[[Filgrastim (Neupogen)]] 300 or 480 mcg SC once per day on days 3 to 10<br />
<br />
'''14-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[#ddTH_.28Taxotere.29|ddTH (Taxotere)]] x 4<br />
===References===<br />
# '''HORG CT/04.23:''' Mavroudis D, Saloustros E, Malamos N, Kakolyris S, Boukovinas I, Papakotoulas P, Kentepozidis N, Ziras N, Georgoulias V; Hellenic Oncology Research Group. Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2015 Jul;26(7):1333-40. Epub 2015 May 1. [https://doi.org/10.1093/annonc/mdv213 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25935793 PubMed]<br />
<br />
==FEC & H {{#subobject:bdf58d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:0b4c6d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70336-9/fulltext Gianni et al. 2011 (NeoSphere)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*Neoadjuvant [[Stub#Docetaxel_.26_Pertuzumab|Docetaxel & Pertuzumab]] versus [[#THP_.28Taxotere.29|THP (Taxotere)]] versus pertuzumab & trastuzumab versus [[#TH_.28Taxotere.29|TH (Taxotere)]], then [[Surgery#Breast_cancer_surgery|surgery]]<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] as follows:<br />
**Cycles 1 to 3: 600 mg/m<sup>2</sup> IV once on day 1<br />
*[[Epirubicin (Ellence)]] as follows:<br />
**Cycles 1 to 3: 90 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 3: 600 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 18 cycles'''<br />
====Subsequent treatment====<br />
*Radiotherapy and/or hormone therapy for ER positive patients is given "per local guidelines"<br />
<br />
===References===<br />
# '''NeoSphere:''' Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25-32. Epub 2011 Dec 6. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70336-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22153890 PubMed] NCT00545688<br />
## '''Update:''' Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, Starosławska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi GV, Magazzù D, McNally V, Douthwaite H, Ross G, Valagussa P. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016 Jun;17(6):791-800. Epub 2016 May 11. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00163-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/27179402 PubMed]<br />
<br />
==Lapatinib & Trastuzumab {{#subobject:da072f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ec4131|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872016/ Piccart-Gebhart et al. 2015 (ALTTO)]<br />
|2007-2011<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|1. Lapatinib<br> 2. [[#Trastuzumab_monotherapy_2|Trastuzumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext Baselga et al. 2012 (NeoALTTO)]<br />
|2008-2010<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Complex_multipart_regimens#NeoALTTO|See link]]<br />
|[[Complex_multipart_regimens#NeoALTTO|See link]]<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*NeoALTTO: [[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#FEC_2|adjuvant FEC]] x 3<br />
====Targeted therapy====<br />
*[[Lapatinib (Tykerb)]] 1000 mg PO once per day<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV over 90 minutes once on day 1<br />
**Cycles 2 to 12: 6 mg/kg IV over 30 minutes once on day 1<br />
<br />
'''21-day cycle for 12 cycles (34-week course)'''<br />
<br />
===References===<br />
# '''NeoALTTO:''' Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705192/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22257673 PubMed] NCT00553358<br />
## '''Update:''' de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70320-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/25130998 PubMed]<br />
## '''Update:''' Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. [https://doi.org/10.1016/j.ejca.2019.04.038 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31377477 PubMed]<br />
# '''ALTTO:''' Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, Zujewski JA, Goldhirsch A, Armour A, Pritchard KI, McCullough AE, Dolci S, McFadden E, Holmes AP, Tonghua L, Eidtmann H, Dinh P, Di Cosimo S, Harbeck N, Tjulandin S, Im YH, Huang CS, Diéras V, Hillman DW, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Suter T, Gelber RD, Perez EA. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol. 2016 Apr 1;34(10):1034-42. Epub 2015 Nov 23. [https://doi.org/10.1200/JCO.2015.62.1797 link to original article] [https://ascopubs.org/doi/suppl/10.1200/JCO.2015.62.1797/suppl_file/protocol_2015.621797.pdf link to protocol] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872016/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26598744 PubMed] NCT00490139<br />
<br />
==Neratinib monotherapy {{#subobject:3c1a9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d9f619|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00551-3/fulltext Chan et al. 2016 (ExteNET)]<br />
|2009-2011<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[Breast_cancer_-_null_regimens#Placebo|Placebo]]<br />
|style="background-color:#1a9850"|Superior invasive DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]] and trastuzumab-containing chemotherapy (neoadjuvant or adjuvant)<br />
====Targeted therapy====<br />
*[[Neratinib (Nerlynx)]] 240 mg PO once per day, with food<br />
====Supportive medications====<br />
*(per FDA package insert)<br />
*[[Loperamide (Imodium)]] as follows:<br />
**Weeks 1 & 2: 4 mg PO three times per day<br />
**Weeks 3 to 8: 4 mg PO twice per day<br />
**Weeks 9 to 52: 4 mg PO as needed for diarrhea, not to exceed 16 mg/d<br />
<br />
'''12-month course'''<br />
<br />
===References===<br />
# '''ExteNET:''' Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ, Robert NJ, Silovski T, Gokmen E, von Minckwitz G, Ejlertsen B, Chia SK, Mansi J, Barrios CH, Gnant M, Buyse M, Gore I, Smith J 2nd, Harker G, Masuda N, Petrakova K, Zotano AG, Iannotti N, Rodriguez G, Tassone P, Wong A, Bryce R, Ye Y, Yao B, Martin M; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):367-77. Epub 2016 Feb 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00551-3/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26874901 PubMed] NCT00878709<br />
## '''Update:''' Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, von Minckwitz G, Chia SKL, Mansi J, Barrios CH, Gnant M, Tomašević Z, Denduluri N, Šeparović R, Gokmen E, Bashford A, Ruiz Borrego M, Kim SB, Jakobsen EH, Ciceniene A, Inoue K, Overkamp F, Heijns JB, Armstrong AC, Link JS, Joy AA, Bryce R, Wong A, Moran S, Yao B, Xu F, Auerbach A, Buyse M, Chan A; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1688-1700. Epub 2017 Nov 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30717-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29146401 PubMed]<br />
## '''HRQoL analysis:''' Delaloge S, Cella D, Ye Y, Buyse M, Chan A, Barrios CH, Holmes FA, Mansi J, Iwata H, Ejlertsen B, Moy B, Chia SKL, Gnant M, Smichkoska S, Ciceniene A, Martinez N, Filipović S, Ben-Baruch NE, Joy AA, Langkjer ST, Senecal F, de Boer RH, Moran S, Yao B, Bryce R, Auerbach A, Fallowfield L, Martin M. Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer: longitudinal analyses from the randomized phase III ExteNET trial. Ann Oncol. 2019 Apr 1;30(4):567-574. [https://doi.org/10.1093/annonc/mdz016 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30689703 PubMed]<br />
## '''Subgroup analysis:''' Iwata H, Masuda N, Kim SB, Inoue K, Rai Y, Fujita T, Chiu J, Ohtani S, Takahashi M, Miyaki T, Lu YS, Xu B, Yap YS, Bustam A, Yao B, Zhang B, Bryce R, Chan A. Neratinib after trastuzumab-based adjuvant therapy in patients from Asia with early stage HER2-positive breast cancer. Future Oncol. 2019 Jul;15(21):2489-2501. Epub 2019 May 29. [https://www.futuremedicine.com/doi/abs/10.2217/fon-2019-0143 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31140297 PubMed]<br />
<br />
==TCH (Taxotere, Carboplatin) {{#subobject:1b999b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TCH: '''<u>T</u>'''axotere (Docetaxel), '''<u>C</u>'''arboplatin, '''<u>H</u>'''erceptin (Trastuzumab)<br />
===Regimen variant #1, capped carboplatin {{#subobject:99cbd0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ von Minckwitz et al. 2017 (APHINITY)]<br />
|2011-2013<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#TCHP_.28Taxotere.29_2|TCHP (Taxotere)]] <br />
| style="background-color:#d73027" |Inferior IDFS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2021 update.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] as follows:<br />
**Cycles 1 to 6: 75 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Carboplatin (Paraplatin)]] as follows:<br />
**Cycles 1 to 6: AUC 6 (maximum dose of 900 mg) IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for up to 18 cycles (1 year)'''<br />
<br />
===Regimen variant #2, no cap {{#subobject:7a8d90|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268553/ Slamon et al. 2011 (BCIRG 006)]<br />
|rowspan=2|2001-2004<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|1. [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]], then [[Breast_cancer#Docetaxel_monotherapy_2|T (Taxotere)]]<br />
|style="background-color:#91cf60"|Seems to have superior OS<br />
|-<br />
|2. [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]], then [[#TH_.28Taxotere.29_2|TH (Taxotere)]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of DFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872016/ Piccart-Gebhart et al. 2015 (ALTTO)]<br />
|2007-2011<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|1. [[Stub#TCL_.28Taxotere.29|TCL]]<br> 2. [[#TCH_.28Taxotere.2C_Carboplatin.29|TCH]], then Lapatinib<br> 3. [[Stub#TCHL_.28Taxotere.29|TCHL]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] as follows:<br />
**Cycles 1 to 6: 75 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Carboplatin (Paraplatin)]] as follows:<br />
**Cycles 1 to 6: AUC 6 IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15 <br />
**Cycles 2 to 6: 2 mg/kg IV once per day on days 1, 8, 15<br />
**Cycles 7 to 18: 6 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*ALTTO: [[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] use is mandatory (details not provided)<br />
<br />
'''21-day cycle for 18 cycles (1 year)'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# '''BCIRG 006:''' Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. [https://www.nejm.org/doi/full/10.1056/NEJMoa0910383 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268553/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21991949 PubMed] NCT00021255<br />
# '''APHINITY:''' von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1703643 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1703643/suppl_file/nejmoa1703643_protocol.pdf link to supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28581356 PubMed] NCT01358877<br />
##'''Update:''' Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. [https://doi.org/10.1200/jco.20.01204 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33539215/ PubMed]<br />
# '''ALTTO:''' Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, Zujewski JA, Goldhirsch A, Armour A, Pritchard KI, McCullough AE, Dolci S, McFadden E, Holmes AP, Tonghua L, Eidtmann H, Dinh P, Di Cosimo S, Harbeck N, Tjulandin S, Im YH, Huang CS, Diéras V, Hillman DW, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Suter T, Gelber RD, Perez EA. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol. 2016 Apr 1;34(10):1034-42. Epub 2015 Nov 23. [https://doi.org/10.1200/JCO.2015.62.1797 link to original article] [https://ascopubs.org/doi/suppl/10.1200/JCO.2015.62.1797/suppl_file/protocol_2015.621797.pdf link to protocol] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872016/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26598744 PubMed] NCT00490139<br />
# '''RESPECT:''' Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. [https://doi.org/10.1200/jco.20.00184 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32936713/ PubMed] NCT01104935<br />
<br />
==TCH (Taxotere, Cyclophosphamide) {{#subobject:b0421b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TCH: '''<u>T</u>'''axotere, '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''erceptin<br />
===Regimen {{#subobject:d3aba1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2813%2970384-X/fulltext Jones et al. 2013 (US Oncology 06-038)]<br />
|2007-2009<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], within 84 days<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] as follows:<br />
**Cycles 1 to 4: 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1 <br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 4: 600 mg/m<sup>2</sup> IV over 15 to 30 minutes once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV over 90 minutes once on day 1, then 2 mg/kg IV over 30 to 60 minutes once per day on days 8 & 15<br />
**Cycles 2 to 4: 2 mg/kg IV over 30 to 60 minutes once per day on days 1, 8, 15<br />
**Cycles 6 to 18: 6 mg/kg IV once on day 1<br />
====Supportive medications====<br />
*Use of [[Filgrastim (Neupogen)]] or [[Pegfilgrastim (Neulasta)]] was allowed.<br />
*Prophylactic antibiotics were not recommended.<br />
<br />
'''21-day cycle for 18 cycles'''<br />
<br />
===References===<br />
# '''US Oncology 06-038:''' Jones SE, Collea R, Paul D, Sedlacek S, Favret AM, Gore I Jr, Lindquist DL, Holmes FA, Allison MA, Brooks BD, Portillo RM, Vukelja SJ, Steinberg MS, Stokoe C, Crockett MW, Wang Y, Asmar L, Robert NJ, O'Shaughnessy J. Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol. 2013 Oct;14(11):1121-8. Epub 2013 Sep 2. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2813%2970384-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24007746 PubMed] NCT00493649<br />
# '''RESPECT:''' Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. [https://doi.org/10.1200/jco.20.00184 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32936713/ PubMed] NCT01104935<br />
<br />
==TCHP (Taxotere) {{#subobject:14bd42|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TCHP: '''<u>T</u>'''axotere (Docetaxel), '''<u>C</u>'''arboplatin, '''<u>H</u>'''erceptin (Trastuzumab), '''<u>P</u>'''ertuzumab<br />
===Regimen {{#subobject:34a874|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ von Minckwitz et al. 2017 (APHINITY)]<br />
|2011-2013<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#TCH_.28Taxotere.2C_Carboplatin.29|TCH]] <br />
| style="background-color:#1a9850" |Superior IDFS<sup>1</sup><br>IDFS72: 91% vs 88%<br>(HR 0.76, 95% CI 0.64-0.91)<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2021 update.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] as follows:<br />
**Cycles 1 to 6: 75 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Carboplatin (Paraplatin)]] as follows:<br />
**Cycles 1 to 6: AUC 6 (maximum dose: 900 mg) IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
*[[Pertuzumab (Perjeta)]] as follows:<br />
**Cycle 1: 840 mg IV once on day 1<br />
**Cycle 2 onwards: 420 mg IV once on day 1<br />
<br />
'''21-day cycle for up to 18 cycles (1 year)'''<br />
<br />
===References===<br />
# '''APHINITY:''' von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1703643 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1703643/suppl_file/nejmoa1703643_protocol.pdf link to supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28581356 PubMed] NCT01358877<br />
##'''Update:''' Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. [https://doi.org/10.1200/jco.20.01204 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33539215/ PubMed]<br />
<br />
==TH (Taxol) {{#subobject:dc66e8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TH: '''<u>T</u>'''axol (Paclitaxel) & '''<u>H</u>'''erceptin (Trastuzumab)<br />
<br> PH: '''<u>P</u>'''aclitaxel & '''<u>H</u>'''erceptin (Trastuzumab)<br />
===Regimen variant #1, weekly paclitaxel, weekly trastuzumab {{#subobject:PPV1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313867/ Tolaney et al. 2015 (APT)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] as follows:<br />
**Cycles 1 to 4: 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15<br />
**Cycles 2 to 18: 2 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for 18 cycles (1 year)'''<br />
<br />
===Regimen variant #2, weekly paclitaxel, weekly then q3wk trastuzumab {{#subobject:6e5b6d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313867/ Tolaney et al. 2015 (APT)]<br />
|2007-2010<br />
|style="background-color:#91cf61"|Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872016/ Piccart-Gebhart et al. 2015 (ALTTO)]<br />
|2007-2011<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|1. [[#TH_.28Taxol.29_2|TH (Taxol)]], then Lapatinib<br> 2. THL (Taxol)<br> 3. TL (Taxol)<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*APT: [[Surgery#Breast_cancer_surgery|Surgery]]<br />
*ALTTO: [[Surgery#Breast_cancer_surgery|Surgery]], then [[Regimen_classes#Anthracycline-based_regimen|anthracycline-based chemotherapy]]<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] as follows:<br />
**Cycles 1 to 4: 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15<br />
**Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15<br />
**Cycles 5 to 18: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 18 cycles (1 year)'''<br />
<br />
===Regimen variant #3, weekly paclitaxel, q3wk trastuzumab {{#subobject:a4b465|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.00184 Sawaki et al. 2020 (RESPECT)]<br />
|2009-2014<br />
|style="background-color:#1a9851"|Randomized (C)<br />
|[[#Trastuzumab_monotherapy_2|Trastuzumab]] x 12 mo<br />
|style="background-color:#ffffbf"|Inconclusive whether non-inferior DFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ von Minckwitz et al. 2017 (APHINITY)]<br />
|2011-2013<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#THP_.28Taxol.29_2|THP (Taxol)]]<br />
| style="background-color:#d73027" |Inferior IDFS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for APHINITY is based on the 2021 update.''<br />
====Preceding treatment====<br />
*RESPECT: [[Surgery#Breast_cancer_surgery|Surgery]]<br />
*APHINITY: [[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Epibicin_.28ddEC.29|ddEC]] x 4 or [[Breast_cancer#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]] x 4 or [[Breast_cancer#FAC|FAC]] x 4 or [[Breast_cancer#FEC_2|FEC]] x 4<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] as follows:<br />
**Cycles 1 to 4: 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycles 2 to 18: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 18 cycles (1 year)'''<br />
<br />
===Regimen variant #4, q3wk paclitaxel, weekly trastuzumab {{#subobject:158d3d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa052122 Romond et al. 2005 (NSABP B-31)]<br />
|2000-2005<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|1. [[Breast_cancer#Paclitaxel_monotherapy.2C_weekly_2|weekly T (Taxol)]]<br> 2. [[Breast_cancer_-_historical#Paclitaxel_monotherapy.2C_q3wk|q3wk T (Taxol)]]<br />
|style="background-color:#1a9850"|Superior OS<br />
|style="background-color:#d9ef8b"|Might have superior DASI score<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa052122 Romond et al. 2005 (NCCTG N9831)]<br />
|2000-2005<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[Complex_multipart_regimens#NCCTG_N9831|See link]]<br />
|[[Complex_multipart_regimens#NCCTG_N9831|See link]]<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] as follows:<br />
**Cycles 1 to 4: 175 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15<br />
**Cycles 2 to 18: 2 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for 18 cycles (1 year)'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# '''NSABP B-31/NCCTG N9831:''' Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. [https://www.nejm.org/doi/full/10.1056/NEJMoa052122 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16236738 PubMed] NCT00004067; NCT00005970<br />
## '''Update:''' Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE Jr, Martino S, Mamounas EP, Kaufman PA, Wolmark N. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011 Sep 1;29(25):3366-73. Epub 2011 Jul 18. [https://doi.org/10.1200/JCO.2011.35.0868 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164242/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21768458 PubMed]<br />
## '''Update:''' Perez EA, Suman VJ, Davidson NE, Gralow JR, Kaufman PA, Visscher DW, Chen B, Ingle JN, Dakhil SR, Zujewski J, Moreno-Aspitia A, Pisansky TM, Jenkins RB. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4491-7. Epub 2011 Oct 31. [https://doi.org/10.1200/JCO.2011.36.7045 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236650/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22042958 PubMed]<br />
## '''Update:''' Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014 Nov 20;32(33):3744-52. [https://doi.org/10.1200/JCO.2014.55.5730 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226805/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25332249 PubMed]<br />
## '''Update and HRQoL analysis:''' Ganz PA, Romond EH, Cecchini RS, Rastogi P, Geyer CE Jr, Swain SM, Jeong JH, Fehrenbacher L, Gross HM, Brufsky AM, Flynn PJ, Wahl TA, Seay TE, Wade JL 3rd, Biggs DD, Atkins JN, Polikoff J, Zapas JL, Mamounas EP, Wolmark N. Long-term follow-up of cardiac function and quality of life for patients in NSABP protocol B-31/NRG Oncology: a randomized trial comparing the safety and efficacy of doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel and trastuzumab in patients with node-positive breast cancer with tumors overexpressing human epidermal growth factor receptor 2. J Clin Oncol. 2017 Dec 10;35(35):3942-3948. Epub 2017 Oct 26. [https://doi.org/10.1200/JCO.2017.74.1165 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721228/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29072977 PubMed]<br />
# '''CALGB 40101:''' Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. [https://doi.org/10.1200/jco.2011.40.6405 link to original article] '''does not contain protocol''' [https://ascopubs.org/doi/suppl/10.1200/jco.2011.40.6405/suppl_file/Protocol.pdf link to study protocol PDF] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494835/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22826271 PubMed] NCT00041119<br />
## '''Update:''' Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105484/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24934787 PubMed]<br />
<!-- # '''Abstract:''' Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, Albain KS, Rugo HS, Ellis M, Shapira I, Wolff AC, Carey LA, Overmoyer BA, Partridge AH, Guo H, Hudis CA, Krop IE, Burstein HJ, Winer EP. A phase II study of adjuvant paclitaxel and trastuzumab (APT trial) for node-negative, HER2-positive breast cancer. SABCS 2013, Abstract S1-04. [http://cancerres.aacrjournals.org/content/73/24_Supplement/S1-04.abstract link to abstract] --><br />
# '''APT:''' Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, Albain KS, Rugo HS, Ellis M, Shapira I, Wolff AC, Carey LA, Overmoyer BA, Partridge AH, Guo H, Hudis CA, Krop IE, Burstein HJ, Winer EP. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015 Jan 8;372(2):134-41. Erratum in: N Engl J Med. 2015 Nov 12;373(20):1989. [https://www.nejm.org/doi/full/10.1056/NEJMoa1406281 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313867/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25564897 PubMed] NCT00542451<br />
## '''Update:'''Tolaney SM, Guo H, Pernas S, et al. Seven-Year Follow-Up Analysis of Adjuvant Paclitaxel and Trastuzumab Trial for Node-Negative, Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. J Clin Oncol. 2019;37(22):1868-1875 [https://ascopubs.org/doi/10.1200/JCO.19.00066 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587424/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30939096/ PubMed] NCT00542451<br />
# '''ALTTO:''' Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, Zujewski JA, Goldhirsch A, Armour A, Pritchard KI, McCullough AE, Dolci S, McFadden E, Holmes AP, Tonghua L, Eidtmann H, Dinh P, Di Cosimo S, Harbeck N, Tjulandin S, Im YH, Huang CS, Diéras V, Hillman DW, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Suter T, Gelber RD, Perez EA. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol. 2016 Apr 1;34(10):1034-42. Epub 2015 Nov 23. [https://doi.org/10.1200/JCO.2015.62.1797 link to original article] [https://ascopubs.org/doi/suppl/10.1200/JCO.2015.62.1797/suppl_file/protocol_2015.621797.pdf link to protocol] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872016/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26598744 PubMed] NCT00490139<br />
# '''APHINITY:''' von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1703643 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1703643/suppl_file/nejmoa1703643_protocol.pdf link to supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28581356 PubMed] NCT01358877<br />
##'''Update:''' Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. [https://doi.org/10.1200/jco.20.01204 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33539215/ PubMed]<br />
# '''RESPECT:''' Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. [https://doi.org/10.1200/jco.20.00184 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32936713/ PubMed] NCT01104935<br />
<br />
==ddTH (Taxol) {{#subobject:65c9a8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ddTH: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>T</u>'''axol (Paclitaxel) & '''<u>H</u>'''erceptin (Trastuzumab)<br />
===Regimen {{#subobject:4c0f4a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2007.12.0733 Dang et al. 2008]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]] x 4<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once on day 8<br />
**Cycles 2 to 4: 2 mg/kg IV once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2<br />
<br />
'''14-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[#Trastuzumab_monotherapy_2|Trastuzumab]] for a total of 52 weeks<br />
<br />
===References===<br />
# Dang C, Fornier M, Sugarman S, Troso-Sandoval T, Lake D, D'Andrea G, Seidman A, Sklarin N, Dickler M, Currie V, Gilewski T, Moynahan ME, Drullinsky P, Robson M, Wasserheit-Leiblich C, Mills N, Steingart R, Panageas K, Norton L, Hudis C. The safety of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel with trastuzumab in HER-2/neu overexpressed/amplified breast cancer. J Clin Oncol. 2008 Mar 10;26(8):1216-22. [https://doi.org/10.1200/jco.2007.12.0733 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18323546 PubMed]<br />
<br />
==TH (Taxotere) {{#subobject:a0af2c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TH: '''<u>T</u>'''axotere (Docetaxel) & '''<u>H</u>'''erceptin (Trastuzumab)<br />
===Regimen variant #1, 75 x 4, q3wk trastuzumab {{#subobject:2fb74a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.00184 Sawaki et al. 2020 (RESPECT)]<br />
|2009-2014<br />
|style="background-color:#1a9851"|Randomized (C)<br />
|[[#Trastuzumab_monotherapy_2|Trastuzumab]] x 12 mo<br />
|style="background-color:#ffffbf"|Inconclusive whether non-inferior DFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ von Minckwitz et al. 2017 (APHINITY)]<br />
|2011-2013<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#THP_.28Taxotere.29_2|THP (Taxotere)]]<br />
| style="background-color:#d73027" |Inferior IDFS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for APHINITY is based on the 2021 update.''<br />
====Preceding treatment====<br />
*RESPECT: [[Surgery#Breast_cancer_surgery|Surgery]]<br />
*APHINITY: [[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Epibicin_.28ddEC.29|ddEC]] x 4 or [[Breast_cancer#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]] x 4 or [[Breast_cancer#FAC|FAC]] x 4 or [[Breast_cancer#FEC_2|FEC]] x 4<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycles 2 to 4: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[#Trastuzumab_monotherapy_2|Trastuzumab maintenance (q3wk)]] for a total of 1 year<br />
<br />
===Regimen variant #2, 75 x 4, weekly trastuzumab {{#subobject:5cbacf|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872016/ Piccart-Gebhart et al. 2015 (ALTTO)]<br />
|2007-2011<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|1. [[#TH_.28Taxotere.29_2|TH (Taxotere)]], then Lapatinib<br> 2. THL (Taxotere)<br> 3. [[Stub#TL_.28Taxotere.29|TL (Taxotere)]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Regimen_classes#Anthracycline-based_regimen|anthracycline-based chemotherapy]]<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15<br />
**Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[#Trastuzumab_monotherapy_2|Trastuzumab maintenance (q3wk)]] for a total of 1 year<br />
<br />
===Regimen variant #3, 75-100 x 3, q3wk trastuzumab {{#subobject:b884e0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ von Minckwitz et al. 2017 (APHINITY)]<br />
|2011-2013<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#THP_.28Taxotere.29_2|THP (Taxotere)]]<br />
| style="background-color:#d73027" |Inferior IDFS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2021 update.''<br><br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Epibicin_.28ddEC.29|ddEC]] x 4 or [[Breast_cancer#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]] x 4 or [[Breast_cancer#FAC|FAC]] x 4 or [[Breast_cancer#FEC_2|FEC]] x 4<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] as follows:<br />
**Cycle 1: 75 mg/m<sup>2</sup> IV once on day 1 <br />
**Cycles 2 & 3: 100 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[#Trastuzumab_monotherapy_2|Trastuzumab maintenance (q3wk)]] for a total of 1 year<br />
<br />
===Regimen variant #4, 80 x 3, q3wk trastuzumab {{#subobject:481c04|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2682589 Joensuu et al. 2018 (SOLD)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycles 2 & 3: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[Breast_cancer#FEC_2|FEC]] x 3, then [[#Trastuzumab_monotherapy_2|trastuzumab maintenance]] for a total of 1 year versus no further treatment<br />
<br />
===Regimen variant #5, 80 x 3, weekly trastuzumab {{#subobject:f18df7|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2682589 Joensuu et al. 2018 (SOLD)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15 <br />
**Cycles 2 & 3: 2 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[Breast_cancer#FEC_2|FEC]] x 3, then [[#Trastuzumab_monotherapy_2|trastuzumab maintenance]] for a total of 1 year versus no further treatment<br />
<br />
===Regimen variant #6, 100 x 3, q3wk trastuzumab {{#subobject:bea44d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2682589 Joensuu et al. 2018 (SOLD)]<br />
|2008-2014<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ von Minckwitz et al. 2017 (APHINITY)]<br />
|2011-2013<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#THP_.28Taxotere.29_2|THP (Taxotere)]]<br />
| style="background-color:#d73027" |Inferior IDFS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for APHINITY is based on the 2021 update.''<br><br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Epibicin_.28ddEC.29|ddEC]] x 4 or [[Breast_cancer#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]] x 4 or [[Breast_cancer#FAC|FAC]] x 4 or [[Breast_cancer#FEC_2|FEC]] x 4<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycles 2 & 3: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*APHINITY: [[#Trastuzumab_monotherapy_2|Trastuzumab maintenance]] for a total of 1 year<br />
*SOLD: [[Breast_cancer#FEC_2|FEC]] x 3, then [[#Trastuzumab_monotherapy_2|trastuzumab maintenance]] for a total of 1 year versus no further treatment<br />
<br />
===Regimen variant #7, 100 x 3, weekly trastuzumab {{#subobject:8a1397|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://www.nejm.org/doi/full/10.1056/NEJMoa053028 Joensuu et al. 2006 (FinHer)]<br />
|rowspan=2|2000-2003<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-esc)<br />
|1. [[Breast_cancer#Docetaxel_monotherapy_2|T]]<br> 2. [[Breast_cancer#Vinorelbine_monotherapy|V]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of RFS<br />
|-<br />
|3. [[#Vinorelbine_.26_Trastuzumab_.28VH.29|VH]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2682589 Joensuu et al. 2018 (SOLD)]<br />
|2008-2014<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15 <br />
**Cycles 2 & 3: 2 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*FinHer: [[Breast_cancer#FEC_2|FEC]]<br />
*SOLD: [[Breast_cancer#FEC_2|FEC]] x 3, then [[#Trastuzumab_monotherapy_2|trastuzumab maintenance]] for a total of 1 year versus no further treatment<br />
<br />
===Regimen variant #8, 100 x 4, weekly trastuzumab {{#subobject:87716b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268553/ Slamon et al. 2011 (BCIRG 006)]<br />
|2001-2004<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[Complex_multipart_regimens#BCIRG_006|See link]]<br />
|[[Complex_multipart_regimens#BCIRG_006|See link]]<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15<br />
**Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[#Trastuzumab_monotherapy_2|Trastuzumab maintenance (q3wk)]] for a total of 1 year<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# '''FinHer:''' Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa053028 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16495393 PubMed] ISRCTN76560285<br />
## '''Update:''' Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. [https://doi.org/10.1200/JCO.2008.21.4577 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19884557 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# '''BCIRG 006:''' Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. [https://www.nejm.org/doi/full/10.1056/NEJMoa0910383 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268553/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21991949 PubMed] NCT00021255<br />
# '''ALTTO:''' Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, Zujewski JA, Goldhirsch A, Armour A, Pritchard KI, McCullough AE, Dolci S, McFadden E, Holmes AP, Tonghua L, Eidtmann H, Dinh P, Di Cosimo S, Harbeck N, Tjulandin S, Im YH, Huang CS, Diéras V, Hillman DW, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Suter T, Gelber RD, Perez EA. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol. 2016 Apr 1;34(10):1034-42. Epub 2015 Nov 23. [https://doi.org/10.1200/JCO.2015.62.1797 link to original article] [https://ascopubs.org/doi/suppl/10.1200/JCO.2015.62.1797/suppl_file/protocol_2015.621797.pdf link to protocol] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872016/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26598744 PubMed] NCT00490139<br />
# '''APHINITY:''' von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1703643 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1703643/suppl_file/nejmoa1703643_protocol.pdf link to supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28581356 PubMed] NCT01358877<br />
##'''Update:''' Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. [https://doi.org/10.1200/jco.20.01204 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33539215/ PubMed]<br />
# '''SOLD:''' Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, Nyandoto P, Villman KK, Halonen P, Granstam-Björneklett H, Lundgren L, Sailas L, Turpeenniemi-Hujanen T, Tanner M, Yachnin J, Ritchie D, Johansson O, Huttunen T, Neven P, Canney P, Harvey VJ, Kellokumpu-Lehtinen PL, Lindman H. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 2018 Sep 1;4(9):1199-1206. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2682589 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29852043 PubMed] NCT00593697<br />
# '''RESPECT:''' Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. [https://doi.org/10.1200/jco.20.00184 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32936713/ PubMed] NCT01104935<br />
<br />
==ddTH (Taxotere) {{#subobject:61cda8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ddTH: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>T</u>'''axotere (Docetaxel) & '''<u>H</u>'''erceptin (Trastuzumab)<br />
===Regimen {{#subobject:1b2f4a|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdv213 Mavroudis et al. 2015 (HORG CT/04.23)]<br />
|2004-2012<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Breast_cancer#ddFEC|ddFEC]] x 4<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 6 mg/kg IV once on day 1<br />
**Cycles 2 to 4: 4 mg/kg IV once on day 1<br />
====Supportive medications====<br />
*[[Filgrastim (Neupogen)]] 300 or 480 mcg SC once per day on days 3 to 10<br />
<br />
'''14-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[#Trastuzumab_monotherapy_2|Trastuzumab]] x a total of 26 weeks versus [[#Trastuzumab_monotherapy_2|Trastuzumab]] x a total of 52 weeks<br />
<br />
===References===<br />
# '''HORG CT/04.23:''' Mavroudis D, Saloustros E, Malamos N, Kakolyris S, Boukovinas I, Papakotoulas P, Kentepozidis N, Ziras N, Georgoulias V; Hellenic Oncology Research Group. Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2015 Jul;26(7):1333-40. Epub 2015 May 1. [https://doi.org/10.1093/annonc/mdv213 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25935793 PubMed]<br />
<br />
==TH (Taxotere/SC) {{#subobject:b8bf2c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TH: '''<u>T</u>'''axotere (Docetaxel) & '''<u>H</u>'''erceptin Hylecta (Trastuzumab and hyaluronidase)<br />
===Regimen variant #1, 80 x 3, q3wk trastuzumab {{#subobject:92b8bf|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2682589 Joensuu et al. 2018 (SOLD)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab and hyaluronidase (Herceptin Hylecta)]] 600 mg/10,000 units SC once on day 1<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[Breast_cancer#FEC_2|FEC]] x 3, then [[#Trastuzumab_monotherapy_2|trastuzumab maintenance]] for a total of 1 year versus no further treatment<br />
<br />
===Regimen variant #2, 100 x 3, q3wk trastuzumab {{#subobject:eb48a0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2682589 Joensuu et al. 2018 (SOLD)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab and hyaluronidase (Herceptin Hylecta)]] 600 mg/10,000 units SC once on day 1<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[Breast_cancer#FEC_2|FEC]] x 3, then [[#Trastuzumab_monotherapy_2|trastuzumab maintenance]] for a total of 1 year versus no further treatment<br />
<br />
===References===<br />
# '''SOLD:''' Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, Nyandoto P, Villman KK, Halonen P, Granstam-Björneklett H, Lundgren L, Sailas L, Turpeenniemi-Hujanen T, Tanner M, Yachnin J, Ritchie D, Johansson O, Huttunen T, Neven P, Canney P, Harvey VJ, Kellokumpu-Lehtinen PL, Lindman H. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 2018 Sep 1;4(9):1199-1206. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2682589 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29852043 PubMed] NCT00593697<br />
<br />
==THP (Taxol) {{#subobject:144d6f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
THP: '''<u>T</u>'''axol (Paclitaxel), '''<u>H</u>'''erceptin (Trastuzumab), '''<u>P</u>'''ertuzumab<br />
<br />
===Regimen {{#subobject:fae5d9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ von Minckwitz et al. 2017 (APHINITY)]<br />
|2011-2013<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#TH_.28Taxol.29_2|TH (Taxol)]]<br />
| style="background-color:#1a9850" |Superior IDFS<sup>1</sup><br>IDFS72: 91% vs 88%<br>(HR 0.76, 95% CI 0.64-0.91)<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2021 update.''<br><br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Epibicin_.28ddEC.29|ddEC]] x 4 or [[Breast_cancer#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]] x 4 or [[Breast_cancer#FAC|FAC]] x 4 or [[Breast_cancer#FEC_2|FEC]] x 4<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] as follows:<br />
**Cycles 1 to 4: 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycles 2 to 18: 6 mg/kg IV once on day 1<br />
*[[Pertuzumab (Perjeta)]] as follows:<br />
**Cycle 1: 840 mg IV once on day 1<br />
**Cycles 2 to 18: 420 mg IV once on day 1<br />
<br />
'''21-day cycle for up to 18 cycles (1 year)'''<br />
<br />
===References===<br />
# '''APHINITY:''' von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1703643 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1703643/suppl_file/nejmoa1703643_protocol.pdf link to supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28581356 PubMed] NCT01358877<br />
##'''Update:''' Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. [https://doi.org/10.1200/jco.20.01204 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33539215/ PubMed]<br />
# '''KAITLIN:''' NCT01966471<br />
<br />
==THP (Taxotere) {{#subobject:2e09e0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
THP: '''<u>T</u>'''axotere (Docetaxel), '''<u>H</u>'''erceptin (Trastuzumab), '''<u>P</u>'''ertuzumab<br />
===Regimen variant #1 {{#subobject:04d21a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ von Minckwitz et al. 2017 (APHINITY)]<br />
|2011-2013<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#TH_.28Taxotere.29_2|TH (Taxotere)]]<br />
| style="background-color:#1a9850" |Superior IDFS<sup>1</sup><br>IDFS72: 91% vs 88%<br>(HR 0.76, 95% CI 0.64-0.91)<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2021 update.''<br><br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Epibicin_.28ddEC.29|ddEC]] x 4 or [[Breast_cancer#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]] x 4 or [[Breast_cancer#FAC|FAC]] x 4 or [[Breast_cancer#FEC_2|FEC]] x 4<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] as follows:<br />
**Cycles 1 to 3: 100 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
*[[Pertuzumab (Perjeta)]] as follows:<br />
**Cycle 1: 840 mg IV once on day 1<br />
**Cycle 2 onwards: 420 mg IV once on day 1<br />
<br />
'''21-day cycle for up to 18 cycles (1 year)'''<br />
<br />
===Regimen variant #2 {{#subobject:43cff1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ von Minckwitz et al. 2017 (APHINITY)]<br />
|2011-2013<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#TH_.28Taxotere.29_2|TH (Taxotere)]]<br />
| style="background-color:#1a9850" |Superior IDFS<sup>1</sup><br>IDFS72: 91% vs 88%<br>(HR 0.76, 95% CI 0.64-0.91)<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2021 update.''<br><br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Epibicin_.28ddEC.29|ddEC]] x 4 or [[Breast_cancer#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]] x 4 or [[Breast_cancer#FAC|FAC]] x 4 or [[Breast_cancer#FEC_2|FEC]] x 4<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] as follows:<br />
**Cycle 1: 75 mg/m<sup>2</sup> IV once on day 1 <br />
**Cycles 2 & 3: 100 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
*[[Pertuzumab (Perjeta)]] as follows:<br />
**Cycle 1: 840 mg IV once on day 1<br />
**Cycle 2 onwards: 420 mg IV once on day 1<br />
<br />
'''21-day cycle for up to 18 cycles (1 year)'''<br />
<br />
===Regimen variant #3 {{#subobject:db9cfb|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ von Minckwitz et al. 2017 (APHINITY)]<br />
|2011-2013<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#TH_.28Taxotere.29_2|TH (Taxotere)]]<br />
| style="background-color:#1a9850" |Superior IDFS<sup>1</sup><br>IDFS72: 91% vs 88%<br>(HR 0.76, 95% CI 0.64-0.91)<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy is based on the 2021 update.''<br><br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]] x 4 or [[Breast_cancer#Dose-dense_Cyclophosphamide_.26_Epibicin_.28ddEC.29|ddEC]] x 4 or [[Breast_cancer#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]] x 4 or [[Breast_cancer#FAC|FAC]] x 4 or [[Breast_cancer#FEC_2|FEC]] x 4<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] as follows:<br />
**Cycles 1 to 4: 75 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
*[[Pertuzumab (Perjeta)]] as follows:<br />
**Cycle 1: 840 mg IV once on day 1<br />
**Cycle 2 onwards: 420 mg IV once on day 1<br />
<br />
'''21-day cycle for up to 18 cycles (1 year)'''<br />
<br />
===References===<br />
# '''APHINITY:''' von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1703643 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1703643/suppl_file/nejmoa1703643_protocol.pdf link to supplementary protocol] '''contains verified protocol in supplementary protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538020/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28581356 PubMed] NCT01358877<br />
##'''Update:''' Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. [https://doi.org/10.1200/jco.20.01204 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33539215/ PubMed]<br />
# '''KAITLIN:''' NCT01966471<br />
<br />
==Trastuzumab monotherapy {{#subobject:e585d5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 6 mo course {{#subobject:056v24|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615016/ Earl et al. 2019 (PERSEPHONE)]<br />
|2007-2015<br />
|style="background-color:#1a9851"|Phase III (E-de-esc)<br />
|[[#Trastuzumab_monotherapy_2|Trastuzumab]] x 12 mo<br />
| style="background-color:#eeee01" |Non-inferior DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Not explicitly specified (pragmatic trial)<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV over 90 minutes once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV over 90 minutes once on day 1<br />
<br />
'''21-day cycle for 9 cycles (6 months)'''<br />
<br />
===Regimen variant #2, 30-week course, q3wk {{#subobject:057a24|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2017.74.0126 Pivot et al. 2018 (SB3-G31-BC)]<br />
|2014-2015<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[Complex_multipart_regimens#SB3-G31-BC|See link]]<br />
|style="background-color:#eeee01"|[[Complex_multipart_regimens#SB3-G31-BC|See link]]<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[#TH_.28Taxotere.29|Neoadjuvant TH (Taxotere)]] x 4, then [[#FEC_.26_H|FEC & H]] x 4, then [[Surgery#Breast_cancer_surgery|surgery]]<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV over 30 minutes once on day 1<br />
<br />
'''21-day cycle for 10 cycles (30-week course)'''<br />
<br />
===Regimen variant #3, 34-week course, q3wk {{#subobject:aa250f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext Baselga et al. 2012 (NeoALTTO)]<br />
|2008-2010<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[Complex_multipart_regimens#NeoALTTO|See link]]<br />
|[[Complex_multipart_regimens#NeoALTTO|See link]]<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#FEC_2|adjuvant FEC]] x 3<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV over 90 minutes once on day 1<br />
**Cycles 2 to 12: 6 mg/kg IV over 30 minutes once on day 1<br />
<br />
'''21-day cycle for 12 cycles (34-week course)'''<br />
<br />
===Regimen variant #4, 42-week course, q3wk {{#subobject:ay253f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1814017 von Minckwitz et al. 2018 (KATHERINE)]<br />
|2013-2015<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Ado-trastuzumab_emtansine_monotherapy|T-DM1]]<br />
| style="background-color:#d73027" |Inferior IDFS<br />
|-<br />
|}<br />
''Note: the loading dose in cycle 1 was only used if it had been more than 6 weeks since any preceding dose of trastuzumab.''<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], with residual invasive disease<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycles 2 to 14: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 14 cycles'''<br />
<br />
===Regimen variant #5, 1-year course, weekly {{#subobject:9a3cba|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.clinical-breast-cancer.com/article/S1526-8209(11)70948-X/pdf Van Pelt et al. 2003]<br />
|2000-2002<br />
|style="background-color:#91cf61"|Phase II<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa052122 Romond et al. 2005 (NCCTG N9831)]<br />
|2000-2005<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[Complex_multipart_regimens#NCCTG_N9831|See link]]<br />
| style="background-color:#fee08b" |[[Complex_multipart_regimens#NCCTG_N9831|See link]]<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Van Pelt et al. 2003 does not describe a loading dose (in the abstract).''<br />
====Preceding treatment====<br />
*Van Pelt et al. 2003: [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4<br />
*NCCTG N9831: [[Breast_cancer#Paclitaxel_monotherapy.2C_weekly_2|weekly T]] x 12<br />
<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22<br />
**Cycles 2 to 13: 2 mg/kg IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 13 cycles (1 year)'''<br />
<br />
===Regimen variant #6, 1-year total course, q3wk {{#subobject:857980|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://www.nejm.org/doi/full/10.1056/NEJMoa052306 Piccart-Gebhart et al. 2005 (HERA)]<br />
|rowspan=2|2001-2005<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|1. No trastuzumab after (neo-)adjuvant chemotherapy<br />
|style="background-color:#1a9850"|Superior OS<br />
|-<br />
|2. [[#Trastuzumab_monotherapy_2|Trastuzumab]] x 2 y<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of DFS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61964-4/fulltext Gianni et al. 2010 (NOAH)]<br />
|2002-2005<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Complex_multipart_regimens#NOAH|See link]]<br />
| style="background-color:#91cf60" |[[Complex_multipart_regimens#NOAH|See link]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70225-0/fulltext Pivot et al. 2013 (PHARE)]<br />
|2006-2010<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Trastuzumab_monotherapy_2|Trastuzumab]] x 6 mo<br />
|style="background-color:#ffffbf"|Inconclusive whether non-inferior DFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872016/ Piccart-Gebhart et al. 2015 (ALTTO)]<br />
|2007-2011<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|1. Lapatinib<br> 2. Trastuzumab, then Lapatinib<br> 3. [[#Lapatinib_.26_Trastuzumab_2|Lapatinib & Trastuzumab]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of DFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615016/ Earl et al. 2019 (PERSEPHONE)]<br />
|2007-2015<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Trastuzumab_monotherapy_2|Trastuzumab]] x 6 mo<br />
| style="background-color:#eeee01" |Non-inferior DFS<br />
|-<br />
|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2682589 Joensuu et al. 2018 (SOLD)]<br />
|2008-2014<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|No further treatment<br />
|style="background-color:#ffffbf"|Inconclusive whether non-inferior DFS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdy414 Conte et al. 2018 (Short-HER)]<br />
|NR<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Trastuzumab_monotherapy_2|Trastuzumab]] x 9 wks<br />
|style="background-color:#ffffbf"|Inconclusive whether non-inferior DFS<br />
|-<br />
|[https://doi.org/10.1200/jco.20.00184 Sawaki et al. 2020 (RESPECT)]<br />
|2009-2014<br />
|style="background-color:#1a9851"|Randomized (E-de-esc)<br />
|1. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]], then H<br> 2. [[#CMF_.26_H|CMF & H]]<br> 3. CMF, then H<br> [[#Cyclophosphamide_.26_Epirubicin_.28EC.29|EC]], then H<br> 4. [[#FEC_2|FEC]], then H<br> 5. T (Taxol), then H<br> 6. T (Taxotere), then H<br> 7. [[#TCH_.28Taxotere.2C_Cyclophosphamide.29|TC, then H]]<br> 8. [[#TCH_.28Taxotere.2C_Carboplatin.29|TCH]]<br> 9. [[#TH_.28Taxol.29_2|TH (Taxol)]]<br> 10. [[#TH_.28Taxotere.29_2|TH (Taxotere)]]<br />
|style="background-color:#ffffbf"|Inconclusive whether non-inferior DFS<br />
|-<br />
|}<br />
''Note: for patients already receiving trastuzumab prior to transitioning to monotherapy, re-loading is not necessary.''<br />
====Preceding treatment====<br />
*HERA: Participants had already received at least four courses of an approved (neo-)adjuvant chemotherapy regimen and [[Surgery#Breast_cancer_surgery|surgery]] (see individual trials)<br />
*PERSEPHONE: Not explicitly specified (pragmatic trial)<br />
*SOLD: [[Surgery#Breast_cancer_surgery|Surgery]], then [[#TH_.28Taxotere.29_2|TH (Taxotere)]] x 3, then [[Breast_cancer#FEC_2|FEC]] x 3<br />
*Short-HER: [[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] or [[Breast_cancer#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]] x 4, then [[#TH_.28Taxol.29_2|TH (Taxol)]] or [[#TH_.28Taxotere.29_2|TH (Taxotere)]]<br />
*RESPECT: [[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows (see note):<br />
**Cycle 1: 8 mg/kg IV over 90 minutes once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV over 90 minutes once on day 1<br />
<br />
'''21-day cycle for 18 cycles (1 year)'''<br />
<br />
===Regimen variant #7, 2-year course {{#subobject:2e0aa2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://www.nejm.org/doi/full/10.1056/NEJMoa052306 Piccart-Gebhart et al. 2005 (HERA)]<br />
|rowspan=2|2001-2005<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|1. No trastuzumab after (neo-)adjuvant chemotherapy<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|2. [[#Trastuzumab_monotherapy_2|Trastuzumab]] x 1 y<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*HERA: Participants had already received at least four courses of an approved (neo-)adjuvant chemotherapy regimen and [[Surgery#Breast_cancer_surgery|surgery]]<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV over 90 minutes once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV over 90 minutes once on day 1<br />
<br />
'''21-day cycle for 35 cycles (2 years)'''<br />
<br />
===References===<br />
# Van Pelt AE, Mohsin S, Elledge RM, Hilsenbeck SG, Gutierrez MC, Lucci A Jr, Kalidas M, Granchi T, Scott BG, Allred DC, Chang JC. Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results. Clin Breast Cancer. 2003 Dec;4(5):348-53. [https://www.clinical-breast-cancer.com/article/S1526-8209(11)70948-X/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/14715110 PubMed]<br />
# '''HERA:''' Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Láng I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1659-72. [https://www.nejm.org/doi/full/10.1056/NEJMoa052306 link to original article] '''contains verified protocol''' [https://www.nejm.org/doi/suppl/10.1056/NEJMoa052306/suppl_file/nejm_piccart_1659sa1-2.pdf link to data supplement]] [https://pubmed.ncbi.nlm.nih.gov/16236737 PubMed] NCT00045032<br />
## '''Update:''' Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, Kaufmann M, Cameron D, Bell R, Bergh J, Coleman R, Wardley A, Harbeck N, Lopez RI, Mallmann P, Gelmon K, Wilcken N, Wist E, Sánchez Rovira P, Piccart-Gebhart MJ; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007 Jan 6;369(9555):29-36. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)60028-2/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17208639 PubMed]<br />
## '''Update:''' Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, Untch M, Smith I, Baselga J, Jackisch C, Cameron D, Mano M, Pedrini JL, Veronesi A, Mendiola C, Pluzanska A, Semiglazov V, Vrdoljak E, Eckart MJ, Shen Z, Skiadopoulos G, Procter M, Pritchard KI, Piccart-Gebhart MJ, Bell R; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol. 2011 Mar;12(3):236-44. Epub 2011 Feb 25. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70033-X/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21354370 PubMed]<br />
## '''Update:''' Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, de Azambuja E, Procter M, Suter TM, Jackisch C, Cameron D, Weber HA, Heinzmann D, Dal Lago L, McFadden E, Dowsett M, Untch M, Gianni L, Bell R, Köhne CH, Vindevoghel A, Andersson M, Brunt AM, Otero-Reyes D, Song S, Smith I, Leyland-Jones B, Baselga J; Herceptin Adjuvant (HERA) Trial Study Team. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013 Sep 21;382(9897):1021-8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61094-6/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/23871490 PubMed]<br />
## '''Update:''' Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, Castro G Jr, Untch M, Smith I, Gianni L, Baselga J, Al-Sakaff N, Lauer S, McFadden E, Leyland-Jones B, Bell R, Dowsett M, Jackisch C; Herceptin Adjuvant (HERA) Trial Study Team. 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017 Mar 25;389(10075):1195-1205. Epub 2017 Feb 17. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32616-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465633/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28215665 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# '''NCCTG N9831:''' Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. [https://www.nejm.org/doi/full/10.1056/NEJMoa052122 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16236738 PubMed] NCT00005970<br />
## '''Update:''' Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE Jr, Martino S, Mamounas EP, Kaufman PA, Wolmark N. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011 Sep 1;29(25):3366-73. Epub 2011 Jul 18. [https://doi.org/10.1200/JCO.2011.35.0868 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164242/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21768458 PubMed]<br />
## '''Update:''' Perez EA, Suman VJ, Davidson NE, Gralow JR, Kaufman PA, Visscher DW, Chen B, Ingle JN, Dakhil SR, Zujewski J, Moreno-Aspitia A, Pisansky TM, Jenkins RB. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4491-7. Epub 2011 Oct 31. [https://doi.org/10.1200/JCO.2011.36.7045 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236650/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22042958 PubMed]<br />
## '''Update:''' Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014 Nov 20;32(33):3744-52. [https://doi.org/10.1200/JCO.2014.55.5730 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226805/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25332249 PubMed]<br />
# '''NOAH:''' Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, Zambetti M, Vazquez F, Byakhow M, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Baronio R, Feyereislova A, Barton C, Valagussa P, Baselga J. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010 Jan 30;375(9712):377-84. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61964-4/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20113825 PubMed] ISRCTN86043495<br />
## '''Update:''' Gianni L, Eiermann W, Semiglazov V, Lluch A, Tjulandin S, Zambetti M, Moliterni A, Vazquez F, Byakhov MJ, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Magazzù D, Heinzmann D, Steinseifer J, Valagussa P, Baselga J. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 2014 May;15(6):640-7. Epub 2014 Mar 20. Erratum in: Lancet Oncol. 2018 Dec;19(12):e667. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70080-4/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/24657003 PubMed]<br />
# '''NeoALTTO:''' Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705192/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22257673 PubMed] NCT00553358<br />
## '''Update:''' de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70320-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/25130998 PubMed]<br />
## '''Update:''' Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. [https://doi.org/10.1016/j.ejca.2019.04.038 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31377477 PubMed]<br />
# '''CALGB 40101:''' Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. [https://doi.org/10.1200/JCO.2011.40.6405 link to original article] '''contains verified protocol''' [https://ascopubs.org/doi/suppl/10.1200/jco.2011.40.6405/suppl_file/Protocol.pdf link to study protocol PDF] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494835/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22826271 PubMed] NCT00041119<br />
## '''Update:''' Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105484/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24934787 PubMed]<br />
# '''PHARE:''' Pivot X, Romieu G, Debled M, Pierga JY, Kerbrat P, Bachelot T, Lortholary A, Espié M, Fumoleau P, Serin D, Jacquin JP, Jouannaud C, Rios M, Abadie-Lacourtoisie S, Tubiana-Mathieu N, Cany L, Catala S, Khayat D, Pauporté I, Kramar A; PHARE trial investigators. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 2013 Jul;14(8):741-8. Epub 2013 Jun 11. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70225-0/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/23764181 PubMed] NCT00381901<br />
## '''Update:''' Pivot X, Romieu G, Debled M, Pierga JY, Kerbrat P, Bachelot T, Lortholary A, Espié M, Fumoleau P, Serin D, Jacquin JP, Jouannaud C, Rios M, Abadie-Lacourtoisie S, Venat-Bouvet L, Cany L, Catala S, Khayat D, Gambotti L, Pauporté I, Faure-Mercier C, Paget-Bailly S, Henriques J, Grouin JM; PHARE trial investigators. 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial. Lancet. 2019 Jun 29;393(10191):2591-2598. Epub 2019 Jun 6. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30653-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/31178155 PubMed]<br />
# '''NSABP B-41:''' Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1183-92. Epub 2013 Oct 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70411-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/24095300 PubMed] NCT00486668<br />
# '''HORG CT/04.23:''' Mavroudis D, Saloustros E, Malamos N, Kakolyris S, Boukovinas I, Papakotoulas P, Kentepozidis N, Ziras N, Georgoulias V; Hellenic Oncology Research Group. Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2015 Jul;26(7):1333-40. Epub 2015 May 1. [https://doi.org/10.1093/annonc/mdv213 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25935793 PubMed]<br />
# '''ALTTO:''' Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, Zujewski JA, Goldhirsch A, Armour A, Pritchard KI, McCullough AE, Dolci S, McFadden E, Holmes AP, Tonghua L, Eidtmann H, Dinh P, Di Cosimo S, Harbeck N, Tjulandin S, Im YH, Huang CS, Diéras V, Hillman DW, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Suter T, Gelber RD, Perez EA. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol. 2016 Apr 1;34(10):1034-42. Epub 2015 Nov 23. [https://doi.org/10.1200/JCO.2015.62.1797 link to original article] [https://ascopubs.org/doi/suppl/10.1200/JCO.2015.62.1797/suppl_file/protocol_2015.621797.pdf link to protocol] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872016/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26598744 PubMed] NCT00490139<br />
# '''SB3-G31-BC:''' Pivot X, Bondarenko I, Nowecki Z, Dvorkin M, Trishkina E, Ahn JH, Vinnyk Y, Im SA, Sarosiek T, Chatterjee S, Wojtukiewicz MZ, Moiseyenko V, Shparyk Y, Bello M 3rd, Semiglazov V, Song S, Lim J. Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients treated with neoadjuvant therapy for human epidermal growth factor receptor 2-positive early breast cancer. J Clin Oncol. 2018 Apr 1;36(10):968-974. Epub 2018 Jan 26. [https://doi.org/10.1200/JCO.2017.74.0126 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29373094 PubMed]<br />
# '''SOLD:''' Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, Nyandoto P, Villman KK, Halonen P, Granstam-Björneklett H, Lundgren L, Sailas L, Turpeenniemi-Hujanen T, Tanner M, Yachnin J, Ritchie D, Johansson O, Huttunen T, Neven P, Canney P, Harvey VJ, Kellokumpu-Lehtinen PL, Lindman H. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 2018 Sep 1;4(9):1199-1206. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2682589 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29852043 PubMed] NCT00593697<br />
# '''Short-HER:''' Conte P, Frassoldati A, Bisagni G, Brandes AA, Donadio M, Garrone O, Piacentini F, Cavanna L, Giotta F, Aieta M, Gebbia V, Molino A, Musolino A, Ferro A, Maltoni R, Danese S, Zamagni C, Rimanti A, Cagossi K, Russo A, Pronzato P, Giovanardi F, Moretti G, Lombardo L, Schirone A, Beano A, Amaducci L, Bajardi EA, Vicini R, Balduzzi S, D'Amico R, Guarneri V; Reader study level-I and level-II Groups. Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study. Ann Oncol. 2018 Dec 1;29(12):2328-2333. [https://doi.org/10.1093/annonc/mdy414 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30219886 PubMed] NCT00629278<br />
# '''KATHERINE:''' von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schneeweiss A, Redondo A, Fischer HH, Jacot W, Conlin AK, Arce-Salinas C, Wapnir IL, Jackisch C, DiGiovanna MP, Fasching PA, Crown JP, Wülfing P, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, Geyer CE Jr; KATHERINE Investigators. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019 Feb 14;380(7):617-628. Epub 2018 Dec 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1814017 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30516102 PubMed] NCT01772472<br />
# '''PERSEPHONE:''' Earl HM, Hiller L, Vallier AL, Loi S, McAdam K, Hughes-Davies L, Harnett AN, Ah-See ML, Simcock R, Rea D, Raj S, Woodings P, Harries M, Howe D, Raynes K, Higgins HB, Wilcox M, Plummer C, Mansi J, Gounaris I, Mahler-Araujo B, Provenzano E, Chhabra A, Abraham JE, Caldas C, Hall PS, McCabe C, Hulme C, Miles D, Wardley AM, Cameron DA, Dunn JA; PERSEPHONE Steering Committee and Trial Investigators. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial. Lancet. 2019 Jun 29;393(10191):2599-2612. Epub 2019 Jun 6. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30650-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615016/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31178152 PubMed] NCT00712140<br />
# '''RESPECT:''' Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. [https://doi.org/10.1200/jco.20.00184 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32936713/ PubMed] NCT01104935<br />
<br />
==Trastuzumab and hyaluronidase monotherapy {{#subobject:e972d5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 6 mos {{#subobject:0dd6c6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615016/ Earl et al. 2019 (PERSEPHONE)]<br />
|2007-2015<br />
|style="background-color:#1a9851"|Phase III (E-de-esc)<br />
|[[#Trastuzumab_monotherapy_2|Trastuzumab]] x 12 mo<br />
| style="background-color:#eeee01" |Non-inferior DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Not explicitly specified (pragmatic trial)<br />
====Targeted therapy====<br />
*[[Trastuzumab and hyaluronidase (Herceptin Hylecta)]] 600 mg/10,000 units SC once on day 1<br />
<br />
'''21-day cycle for 9 cycles (6 months)'''<br />
<br />
===Regimen variant #2, 12 mos {{#subobject:0cc6c6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615016/ Earl et al. 2019 (PERSEPHONE)]<br />
|2007-2015<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Trastuzumab_monotherapy_2|Trastuzumab]] x 6 mo<br />
| style="background-color:#eeee01" |Non-inferior DFS<br />
|-<br />
|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2682589 Joensuu et al. 2018 (SOLD)]<br />
|2008-2014<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|No further treatment<br />
|style="background-color:#ffffbf"|Inconclusive whether non-inferior DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*SOLD: [[Surgery#Breast_cancer_surgery|Surgery]], then [[#TH_.28Taxotere.29_2|TH (Taxotere)]] x 3, then [[Breast_cancer#FEC_2|FEC]] x 3<br />
*PERSEPHONE: Not explicitly specified (pragmatic trial)<br />
====Targeted therapy====<br />
*[[Trastuzumab and hyaluronidase (Herceptin Hylecta)]] 600 mg/10,000 units SC once on day 1<br />
<br />
'''21-day cycle for 18 cycles (1 year)'''<br />
===References===<br />
# '''SOLD:''' Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, Nyandoto P, Villman KK, Halonen P, Granstam-Björneklett H, Lundgren L, Sailas L, Turpeenniemi-Hujanen T, Tanner M, Yachnin J, Ritchie D, Johansson O, Huttunen T, Neven P, Canney P, Harvey VJ, Kellokumpu-Lehtinen PL, Lindman H. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 2018 Sep 1;4(9):1199-1206. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2682589 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29852043 PubMed] NCT00593697<br />
# '''PERSEPHONE:''' Earl HM, Hiller L, Vallier AL, Loi S, McAdam K, Hughes-Davies L, Harnett AN, Ah-See ML, Simcock R, Rea D, Raj S, Woodings P, Harries M, Howe D, Raynes K, Higgins HB, Wilcox M, Plummer C, Mansi J, Gounaris I, Mahler-Araujo B, Provenzano E, Chhabra A, Abraham JE, Caldas C, Hall PS, McCabe C, Hulme C, Miles D, Wardley AM, Cameron DA, Dunn JA; PERSEPHONE Steering Committee and Trial Investigators. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial. Lancet. 2019 Jun 29;393(10191):2599-2612. Epub 2019 Jun 6. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30650-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615016/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31178152 PubMed] NCT00712140<br />
<br />
==Ado-trastuzumab emtansine monotherapy {{#subobject:d150e0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
T-DM1: '''<u>T</u>'''rastuzumab-'''<u>DM1</u>''' (Ado-trastuzumab emtansine)<br />
===Example orders===<br />
*[[Example orders for Ado-trastuzumab emtansine (Kadcyla) in breast cancer]]<br />
<br />
===Regimen {{#subobject:d31a82|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1814017 von Minckwitz et al. 2018 (KATHERINE)]<br />
|2013-2015<br />
|style="background-color:#1a9851"|Phase III (E-RT-switch-ic)<br />
|[[#Trastuzumab_monotherapy_2|Trastuzumab]]<br />
|style="background-color:#1a9850"|Superior IDFS<br>IDFS36: 88% vs 77%<br>(HR 0.50, 95% CI 0.39-0.64)<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]], with residual invasive disease<br />
====Antibody-drug conjugate therapy====<br />
*[[Ado-trastuzumab emtansine (Kadcyla)]] 3.6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 14 cycles'''<br />
<br />
===References===<br />
# '''KATHERINE:''' von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schneeweiss A, Redondo A, Fischer HH, Jacot W, Conlin AK, Arce-Salinas C, Wapnir IL, Jackisch C, DiGiovanna MP, Fasching PA, Crown JP, Wülfing P, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, Geyer CE Jr; KATHERINE Investigators. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019 Feb 14;380(7):617-628. Epub 2018 Dec 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1814017 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30516102 PubMed] NCT01772472<br />
<br />
==Vinorelbine & Trastuzumab (VH) {{#subobject:ca8dff|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
VH: '''<u>V</u>'''inorelbine & '''<u>H</u>'''erceptin (Trastuzumab)<br />
<br />
===Regimen {{#subobject:f78da8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://www.nejm.org/doi/full/10.1056/NEJMoa053028 Joensuu et al. 2006 (FinHer)]<br />
|rowspan=2|2000-2003<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-esc)<br />
|1. [[Breast_cancer#Docetaxel_monotherapy_2|T]]<br> 2. [[Breast_cancer#Vinorelbine_monotherapy|V]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of RFS<br />
|-<br />
|3. [[#TH_.28Taxotere.29_2|TH (Taxotere)]] <br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Surgery#Breast_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Vinorelbine (Navelbine)]] 24 mg/m<sup>2</sup> IV over 5 to 10 minutes once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15<br />
**Cycles 2 & 3: 2 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[Breast_cancer#FEC_2|FEC]]<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# '''FinHer:''' Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa053028 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16495393 PubMed] ISRCTN76560285<br />
## '''Update:''' Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. [https://doi.org/10.1200/JCO.2008.21.4577 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19884557 PubMed]<br />
<br />
=Metastatic or unresectable disease, first-line=<br />
''Note: some patients in these trials were pre-treated with non-HER2-targeted therapies.''<br />
==ACH {{#subobject:92e436|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ACH: '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''erceptin (Trastuzumab)<br />
<br />
===Regimen {{#subobject:67e482|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM200103153441101 Slamon et al. 2001]<br />
|1995-1997<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[Breast_cancer,_HER2-positive_-_historical#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]]<br />
|style="background-color:#91cf60"|Seems to have superior OS<br />
|-<br />
|}<br />
''Note: patients had not previously received adjuvant (postoperative) therapy with an anthracycline. Not commonly used; here for reference purposes only.''<br />
====Chemotherapy====<br />
*[[Doxorubicin (Adriamycin)]] <br />
*[[Cyclophosphamide (Cytoxan)]] <br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]]<br />
<br />
===References===<br />
# Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. [https://www.nejm.org/doi/full/10.1056/NEJM200103153441101 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11248153 PubMed]<br />
<br />
==Capecitabine, Bevacizumab, Trastuzumab {{#subobject:b68b8e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d76d98|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3336828/ Martín et al. 2012 (MO21926)]<br />
|style="background-color:#91cf61"|Phase II<br />
|style="background-color:#bababa"|ORR: 73% (95% CI 62-82)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
====Targeted therapy====<br />
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''MO21926:''' Martín M, Makhson A, Gligorov J, Lichinitser M, Lluch A, Semiglazov V, Scotto N, Mitchell L, Tjulandin S. Phase II study of bevacizumab in combination with trastuzumab and capecitabine as first-line treatment for HER-2-positive locally recurrent or metastatic breast cancer. Oncologist. 2012;17(4):469-75. Epub 2012 Mar 30. [http://theoncologist.alphamedpress.org/content/17/4/469.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3336828/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22467666 PubMed]<br />
<br />
==Capecitabine & Lapatinib {{#subobject:800fde|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:653bef|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2014.57.1794 Pivot et al. 2015 (CEREBEL)]<br />
|2009-2012<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[#Capecitabine_.26_Trastuzumab_.28XH.29|Capecitabine & Trastuzumab]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of CNS site of first relapse<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
====Targeted therapy====<br />
*[[Lapatinib (Tykerb)]] 1250 mg PO once per day<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''CEREBEL:''' Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. [https://doi.org/10.1200/JCO.2014.57.1794 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25605838 PubMed] NCT00820222<br />
<br />
==Capecitabine & Trastuzumab (XH) {{#subobject:677608|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
XH: '''<u>X</u>'''eloda (Capecitabine) & '''<u>H</u>'''erceptin<br />
===Regimen {{#subobject:e14cab|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2014.57.1794 Pivot et al. 2015 (CEREBEL)]<br />
|2009-2012<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Capecitabine_.26_Lapatinib|Capecitabine & Lapatanib]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of CNS site of first relapse<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''CEREBEL:''' Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. [https://doi.org/10.1200/JCO.2014.57.1794 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/25605838 PubMed] NCT00820222<br />
<br />
==ECH {{#subobject:fd17f7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECH: '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''erceptin (Trastuzumab)<br />
<br />
===Regimen {{#subobject:959eb9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM200103153441101 Slamon et al. 2001]<br />
|1995-1997<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[Breast_cancer,_HER2-positive_-_historical#Cyclophosphamide_.26_Epirubicin_.28EC.29|EC]]<br />
|style="background-color:#91cf60"|Seems to have superior OS<br />
|-<br />
|}<br />
''Not commonly used; here for reference purposes only.''<br />
====Chemotherapy====<br />
*[[Epirubicin (Ellence)]] <br />
*[[Cyclophosphamide (Cytoxan)]]<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]]<br />
<br />
===References===<br />
# Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. [https://www.nejm.org/doi/full/10.1056/NEJM200103153441101 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11248153 PubMed]<br />
<br />
==nab-Paclitaxel & Trastuzumab {{#subobject:fgh1bc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c8cg38|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 50%"|Study<br />
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.clinical-breast-cancer.com/article/S1526-8209(11)00008-5/fulltext Mirtsching et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 125 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV over 90 minutes once on day 1, then 2 mg/kg IV over 30 minutes once per day on days 8, 15, 22<br />
**Cycle 2 onwards: 2 mg/kg IV over 30 minutes once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Mirtsching B, Cosgriff T, Harker G, Keaton M, Chidiac T, Min M. A phase II study of weekly nanoparticle albumin-bound paclitaxel with or without trastuzumab in metastatic breast cancer. Clin Breast Cancer. 2011 Apr;11(2):121-8. Epub 2011 Apr 11. [https://www.clinical-breast-cancer.com/article/S1526-8209(11)00008-5/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21569998 PubMed]<br />
<br />
==Pertuzumab & T-DM1 {{#subobject:ffffbc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Pertuzumab & T-DM1: Pertuzumab & '''<u>T</u>'''rastuzumab-'''<u>DM1</u>''' (Ado-trastuzumab emtansine)<br />
===Regimen {{#subobject:c8ce38|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455677/ Perez et al. 2016 (MARIANNE)]<br />
|rowspan=2|2010-2012<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-esc)<br />
|1. [[#Ado-trastuzumab_emtansine_monotherapy_3|T-DM1]]<br />
|style="background-color:#eeee01"|Non-inferior PFS<br />
|-<br />
|2. [[#TH_.28Taxotere.29_3|TH (Taxotere)]]<br> 3. [[#TH_.28Taxol.29_3|TH (Taxol)]]<br />
|style="background-color:#eeee01"|Non-inferior PFS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pertuzumab (Perjeta)]] as follows:<br />
**Cycle 1: 840 mg IV once on day 1<br />
**Cycle 2 onwards: 420 mg IV once on day 1<br />
====Antibody-drug conjugate therapy====<br />
*[[Ado-trastuzumab emtansine (Kadcyla)]] 3.6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''MARIANNE:''' Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot X, Burris H 3rd, Petersen JA, Stanzel S, Strasak A, Patre M, Ellis P. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol. 2017 Jan 10;35(2):141-148. Epub 2016 Nov 7. [https://doi.org/10.1200/JCO.2016.67.4887 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455677/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28056202 PubMed] NCT01120184<br />
## '''Update:''' Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot XB, Burris HA 3rd, Petersen JA, De Haas S, Hoersch S, Patre M, Ellis PA. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: final results from MARIANNE. Cancer. 2019 Nov 15;125(22):3974-3984. Epub 2019 Jul 18. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.32392 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31318460 PubMed]<br />
<br />
==TCH (Taxotere, Carboplatin) {{#subobject:cb6592|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TCH: '''<u>T</u>'''axotere (Docetaxel), '''<u>C</u>'''arboplatin, '''<u>H</u>'''erceptin (Trastuzumab)<br />
<br />
===Regimen {{#subobject:570bd5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2010.28.6450 Valero et al. 2011 (BCIRG 007)]<br />
|2001-2004<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[#TH_.28Taxotere.29_3|TH]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of TTP<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15<br />
**Cycles 2 to 8: 2 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for 8 cycles'''<br />
====Subsequent treatment====<br />
*[[#Trastuzumab_monotherapy_4|Trastuzumab maintenance]]<br />
<br />
===References===<br />
# '''BCIRG 007:''' Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, von Minckwitz G, Roche H, Martin M, Crown J, Mackey JR, Fumoleau P, Rolski J, Mrsic-Krmpotic Z, Jagiello-Gruszfeld A, Riva A, Buyse M, Taupin H, Sauter G, Press MF, Slamon DJ. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol. 2011 Jan 10;29(2):149-56. Epub 2010 Nov 29. [https://doi.org/10.1200/jco.2010.28.6450 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21115860 PubMed] NCT00047255<br />
<br />
==TH (Taxotere) {{#subobject:c99645|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TH: '''<u>T</u>'''axotere (Docetaxel) & '''<u>H</u>'''erceptin (Trastuzumab)<br />
<br>HT: '''<u>H</u>'''erceptin (Trastuzumab) & '''<u>T</u>'''axotere (Docetaxel)<br />
<br>H+D: '''<u>H</u>'''erceptin (Trastuzumab) & '''<u>D</u>'''ocetaxel<br />
===Regimen variant #1, 35 mg/m<sup>2</sup> docetaxel, 3 out of 4 weeks {{#subobject:f2e79b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2002.07.058 Esteva et al. 2002]<br />
|NR<br />
|style="background-color:#91cf61"|Phase II<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.22885/full Burstein et al. 2007 (TRAVIOTA)]<br />
|2001-2003<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[#Vinorelbine_.26_Trastuzumab_.28VH.29_2|VH]]<br />
|style="background-color:#fee08b"|Might have inferior TTP<br />
|-<br />
|}<br />
''Esteva et al. 2002 described the day before the start of a cycle as "day 0," which is not the typical convention, so day -1 is being used instead.''<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, '''given first'''<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] '''given second''' as follows:<br />
**Cycle 1: 4 mg/kg IV over 90 minutes once on day -1, then 2 mg/kg IV over 30 minutes once per day on days 8 & 15<br />
**Cycle 2 onwards: 2 mg/kg IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
*[[Dexamethasone (Decadron)]] 4 mg PO every 12 hours x 3 doses on cycles 1 & 2, starting the night before [[Docetaxel (Taxotere)]]. Patients who did not have "hypersensitivity reactions and no significant fluid retention during the first 8 weeks" received 4 mg PO twice per day on day 1 for at least the next two cycles. Patients who "remained free of fluid retention after 8 additional weeks" then received 4 mg PO once on day 1 prior to [[Docetaxel (Taxotere)]] in subsequent cycles.<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, 60 mg/m<sup>2</sup> q3wk docetaxel, weekly trastuzumab {{#subobject:8c2fd1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs10549-009-0498-7 Inoue et al. 2009 (JO17360)]<br />
|2004-2008<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|H --> H + D<br />
|style="background-color:#91cf60"|Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15<br />
**Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #3, 75 mg/m<sup>2</sup> q3wk docetaxel, q3wk trastuzumab {{#subobject:d6d8da|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2012.44.9694 Hurvitz et al. 2013 (TDM4450g)]<br />
|2008-2009<br />
|style="background-color:#1a9851"|Randomized Phase II (C)<br />
|[[#Ado-trastuzumab_emtansine_monotherapy_3|T-DM1]]<br />
|style="background-color:#fc8d59"|Seems to have inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705202/ Baselga et al. 2011 (CLEOPATRA)]<br />
|2008-2010<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#THP_.28Taxotere.29_3|THP]]<br />
|style="background-color:#d73027"|Inferior OS<sup>1</sup><br />
|-<br />
|[https://doi.org/10.1200/JCO.2014.56.9590 Gelmon et al. 2015 (NCIC-CTG MA.31)]<br />
|2008-2011<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|Docetaxel & Lapatinib<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|rowspan=3|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455677/ Perez et al. 2016 (MARIANNE)]<br />
|rowspan=3|2010-2012<br />
|rowspan=3 style="background-color:#1a9851"|Phase III (C)<br />
|1. [[#Ado-trastuzumab_emtansine_monotherapy_3|T-DM1]]<br />
|style="background-color:#eeee01"|Non-inferior PFS<br />
|-<br />
|2. [[#Pertuzumab_.26_T-DM1|Pertuzumab & T-DM1]]<br />
|style="background-color:#eeee01"|Non-inferior PFS<br />
|-<br />
|3. [[#TH_.28Taxol.29_3|TH (Taxol)]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for CLEOPATRA is based on the 2020 update.''<br><br />
''Note: Dose of docetaxel in TDM4450g and MARIANNE was per investigator's discretion. CLEOPATRA has an unusual schedule with both medications being given on day 2 of cycle 1, due to this regimen being the control arm, in which patients in one arm received a placebo instead of pertuzumab on day 1. It is reasonable to assume that in practice, drugs in this regimen will be given on day 1 from the beginning.''<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 2<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for at least 6 cycles'''<br />
====Subsequent treatment====<br />
*CLEOPATRA: If it is decided to no longer administer docetaxel with this regimen, then patients could continue to receive [[#Trastuzumab_monotherapy_4|trastuzumab]] maintenance<br />
*NCIC-CTG MA.31: [[#Trastuzumab_monotherapy_4|Trastuzumab]] maintenance, after 8 cycles<br />
<br />
===Regimen variant #4, 100 mg/m<sup>2</sup> q3wk docetaxel, weekly trastuzumab {{#subobject:31786c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.04.173 Marty et al. 2005 (M77001)]<br />
|2000-2002<br />
|style="background-color:#1a9851"|Randomized Phase II (E-esc)<br />
|[[Breast_cancer,_HER2-positive_-_historical#Docetaxel_monotherapy|Docetaxel]]<br />
|style="background-color:#91cf60"|Seems to have superior OS<br />
|-<br />
|[https://doi.org/10.1200/jco.2010.28.6450 Valero et al. 2010 (BCIRG 007)]<br />
|2001-2004<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#TCH_.28Taxotere.2C_Carboplatin.29_2|TCH]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of TTP<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV over 90 minutes once on day 1, then 2 mg/kg IV over 30 minutes once per day on days 8 & 15<br />
**Cycles 2 to 8: 2 mg/kg IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
*[[Dexamethasone (Decadron)]] 8 mg (or equivalent) PO twice per day x 6 doses, starting the night before [[Docetaxel (Taxotere)]]<br />
*"Antiemetic premedication was mandatory" (no additional details given).<br />
<br />
'''21-day cycle for 6 cycles (M77001; see note) or 8 cycles (BCIRG 007)''' <br />
====Subsequent treatment====<br />
*M77001: Patients could receive docetaxel beyond six cycles at the discretion of the investigator. Otherwise, patients proceeded to [[#Trastuzumab_monotherapy_4|trastuzumab maintenance]].<br />
*BCIRG 007: [[#Trastuzumab_monotherapy_4|Trastuzumab maintenance]]<br />
<br />
===Regimen variant #5, 100 mg/m<sup>2</sup> q3wk docetaxel, q3wk trastuzumab {{#subobject:a951ac|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2010.30.8213 Andersson et al. 2010 (HERNATA)]<br />
|2004-2008<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Vinorelbine_.26_Trastuzumab_.28VH.29_2|VH]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of TTP<br />
|-<br />
|[https://doi.org/10.1200/jco.2012.44.7912 Gianni et al. 2013 (AVAREL)]<br />
|2006-2010<br />
|style="background-color:#1a9851"|Randomized Phase II (C)<br />
|[[Stub#BTH_.28Taxotere.29|BTH]]<br />
|style="background-color:#fee08b"|Might have inferior PFS<br />
|-<br />
|[https://doi.org/10.1200/jco.2012.44.9694 Hurvitz et al. 2013 (TDM4450g)]<br />
|2008-2009<br />
|style="background-color:#1a9851"|Randomized Phase II (C)<br />
|[[#Ado-trastuzumab_emtansine_monotherapy_3|T-DM1]]<br />
|style="background-color:#fc8d59"|Seems to have inferior PFS<br />
|-<br />
|rowspan=3|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455677/ Perez et al. 2016 (MARIANNE)]<br />
|rowspan=3|2010-2012<br />
|rowspan=3 style="background-color:#1a9851"|Phase III (E-esc)<br />
|1. [[#Ado-trastuzumab_emtansine_monotherapy_3|T-DM1]]<br />
|style="background-color:#eeee01"|Non-inferior PFS<br />
|-<br />
|2. [[#Pertuzumab_.26_T-DM1|Pertuzumab & T-DM1]]<br />
|style="background-color:#eeee01"|Non-inferior PFS<br />
|-<br />
|3. [[#TH_.28Taxol.29_3|TH (Taxol)]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|}<br />
''Note: In HERNATA, the day of docetaxel and trastuzumab were reversed in cycle 1. Dose of docetaxel in TDM4450g and MARIANNE was per investigator's discretion.''<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1 (see note)<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV over 90 minutes once on day 2 (see note)<br />
**Cycle 2 onwards: 6 mg/kg IV over 30 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Esteva FJ, Valero V, Booser D, Guerra LT, Murray JL, Pusztai L, Cristofanilli M, Arun B, Esmaeli B, Fritsche HA, Sneige N, Smith TL, Hortobagyi GN. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2002 Apr 1;20(7):1800-8. [https://doi.org/10.1200/jco.2002.07.058 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11919237 PubMed]<br />
# '''M77001:''' Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Antón A, Lluch A, Kennedy J, O'Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005 Jul 1;23(19):4265-74. Epub 2005 May 23. [https://doi.org/10.1200/jco.2005.04.173 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15911866 PubMed]<br />
# '''TRAVIOTA:''' Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.22885/full link to original article] [https://pubmed.ncbi.nlm.nih.gov/17614302 PubMed]<br />
# '''JO17360:''' Inoue K, Nakagami K, Mizutani M, Hozumi Y, Fujiwara Y, Masuda N, Tsukamoto F, Saito M, Miura S, Eguchi K, Shinkai T, Ando M, Watanabe T, Masuda N, Ohashi Y, Sano M, Noguchi S. Randomized phase III trial of trastuzumab monotherapy followed by trastuzumab plus docetaxel versus trastuzumab plus docetaxel as first-line therapy in patients with HER2-positive metastatic breast cancer: the JO17360 Trial Group. Breast Cancer Res Treat. 2010 Jan;119(1):127-36. Epub 2009 Aug 19. [https://link.springer.com/article/10.1007%2Fs10549-009-0498-7 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19690954 PubMed]<br />
# '''BCIRG 007:''' Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, von Minckwitz G, Roche H, Martin M, Crown J, Mackey JR, Fumoleau P, Rolski J, Mrsic-Krmpotic Z, Jagiello-Gruszfeld A, Riva A, Buyse M, Taupin H, Sauter G, Press MF, Slamon DJ. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol. 2011 Jan 10;29(2):149-56. Epub 2010 Nov 29. [https://doi.org/10.1200/jco.2010.28.6450 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21115860 PubMed] NCT00047255<br />
# '''HERNATA:''' Andersson M, Lidbrink E, Bjerre K, Wist E, Enevoldsen K, Jensen AB, Karlsson P, Tange UB, Sørensen PG, Møller S, Bergh J, Langkjer ST. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011 Jan 20;29(3):264-71. Epub 2010 Dec 13. [https://doi.org/10.1200/JCO.2010.30.8213 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21149659 PubMed]<br />
# '''CLEOPATRA:''' Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. Epub 2011 Dec 7. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113216 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705202/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22149875 PubMed] NCT00567190<br />
## '''Update:''' Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. Epub 2013 Apr 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70130-X/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076842/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23602601 PubMed]<br />
## '''Update:''' Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. [https://www.nejm.org/doi/full/10.1056/NEJMoa1413513 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25693012 PubMed]<br />
## '''Update:''' Swain SM, Miles D, Kim SB, Im YH, Im SA, Semiglazov V, Ciruelos E, Schneeweiss A, Loi S, Monturus E, Clark E, Knott A, Restuccia E, Benyunes MC, Cortés J; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Apr;21(4):519-530. Epub 2020 Mar 12. [https://doi.org/10.1016/s1470-2045(19)30863-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32171426 PubMed]<br />
<!-- Presented at the European Multidisciplinary Cancer Congress, Stockholm, Sweden, September 23-27, 2011, and the European Society of Medical Oncology Congress, Milan, Italy, October 8–12, 2010. --><br />
# '''TDM4450g:''' Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes J, Guardino E, Song C, Tong B, Ng V, Chu YW, Perez EA. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2013 Mar 20;31(9):1157-63. Epub 2013 Feb 4. Erratum in: J Clin Oncol. 2013 Aug 10;31(23):2977. [https://doi.org/10.1200/jco.2012.44.9694 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23382472 PubMed] NCT00679341<br />
<!-- Presented in part at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 6-11, 2011. --><br />
# '''AVAREL:''' Gianni L, Romieu GH, Lichinitser M, Serrano SV, Mansutti M, Pivot X, Mariani P, Andre F, Chan A, Lipatov O, Chan S, Wardley A, Greil R, Moore N, Prot S, Pallaud C, Semiglazov V. AVEREL: a randomized phase III trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol. 2013 May 10;31(14):1719-25. Epub 2013 Apr 8. [https://doi.org/10.1200/jco.2012.44.7912 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23569311 PubMed] NCT00391092<br />
# '''NCIC-CTG MA.31:''' Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, Di Leo A, Martin M, Schwartzberg LS, Lemieux J, Aparicio S, Shepherd LE, Dent S, Ellard SL, Tonkin K, Pritchard KI, Whelan TJ, Nomikos D, Nusch A, Coleman RE, Mukai H, Tjulandin S, Khasanov R, Rizel S, Connor AP, Santillana SL, Chapman JA, Parulekar WR. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC-CTG MA.31. J Clin Oncol. 2015 May 10;33(14):1574-83. Epub 2015 Mar 16. [https://doi.org/10.1200/JCO.2014.56.9590 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25779558 PubMed] NCT00667251<br />
# '''MARIANNE:''' Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot X, Burris H 3rd, Petersen JA, Stanzel S, Strasak A, Patre M, Ellis P. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol. 2017 Jan 10;35(2):141-148. Epub 2016 Nov 7. [https://doi.org/10.1200/JCO.2016.67.4887 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455677/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28056202 PubMed] NCT01120184<br />
## '''Update:''' Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot XB, Burris HA 3rd, Petersen JA, De Haas S, Hoersch S, Patre M, Ellis PA. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: final results from MARIANNE. Cancer. 2019 Nov 15;125(22):3974-3984. Epub 2019 Jul 18. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.32392 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31318460 PubMed]<br />
<br />
==TH (Taxol) {{#subobject:aa22dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TH: '''<u>T</u>'''axol (Paclitaxel), '''<u>H</u>'''erceptin (Trastuzumab)<br />
<br>TP: '''<u>T</u>'''rastuzumab, '''<u>P</u>'''aclitaxel<br />
<br />
===Regimen variant #1, weekly paclitaxel (80 mg/m<sup>2</sup>) {{#subobject:2628d8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2007.11.6699 Seidman et al. 2008 (CALGB 9840)]<br />
|1998-NR<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[#TH_.28Taxol.29_3|TH]]; q3wk paclitaxel<br />
|style="background-color:#1a9850"|Superior OS<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.22885/full Burstein et al. 2007 (TRAVIOTA)]<br />
|2001-2003<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[#Vinorelbine_.26_Trastuzumab_.28VH.29_2|VH]]<br />
|style="background-color:#fee08b"|Might have inferior TTP<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433508/ Baselga et al. 2014 (STM01-102)]<br />
|2006-2009<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[Stub#MTP|MTP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|rowspan=3|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455677/ Perez et al. 2016 (MARIANNE)]<br />
|rowspan=3|2010-2012<br />
|rowspan=3 style="background-color:#1a9851"|Phase III (C)<br />
|1. [[#Ado-trastuzumab_emtansine_monotherapy_3|T-DM1]]<br />
|style="background-color:#eeee01"|Non-inferior PFS<br />
|-<br />
|2. [[#Pertuzumab_.26_T-DM1|Pertuzumab & T-DM1]]<br />
|style="background-color:#eeee01"|Non-inferior PFS<br />
|-<br />
|3. [[#TH_.28Taxotere.29_3|TH (Taxotere)]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22<br />
**Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, weekly paclitaxel (90 mg/m<sup>2</sup>) {{#subobject:2628d8|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2001.19.10.2587 Seidman et al. 2001]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 90 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 0, then 2 mg/kg IV once per day on days 8, 15, 22<br />
**Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3, paclitaxel 3 weeks out of 4, 6 cycles {{#subobject:812115|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2014.56.9590 Gelmon et al. 2015 (NCIC-CTG MA.31)]<br />
|2008-2011<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|Lapatinib & Paclitaxel<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22 <br />
**Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
*[[#Trastuzumab_monotherapy_4|Trastuzumab]] maintenance<br />
<br />
===Regimen variant #4, paclitaxel 3 weeks out of 4, indefinite {{#subobject:bf7990|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00051-0/abstract Hurvitz et al. 2015 (BOLERO-1)]<br />
|2009-2012<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[Stub#TH_.28Taxol.29_.26_Everolimus|TH & Everolimus]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|[http://jamanetwork.com/journals/jamaoncology/fullarticle/2513249 Awada et al. 2016 (NEfERT-T)]<br />
|2009-2014<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|Neratinib & Paclitaxel<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22 <br />
**Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #5, q3wk paclitaxel {{#subobject:31e4b6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM200103153441101 Slamon et al. 2001]<br />
|1995-1997<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[Breast_cancer,_HER2-positive_-_historical#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel]]<br />
|style="background-color:#91cf60"|Seems to have superior OS<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.04.1764 Robert et al. 2006]<br />
|1998-2002<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#TPC|TPC]]<br />
|style="background-color:#fc8d59"|Seems to have inferior PFS<br />
|-<br />
|[https://doi.org/10.1200/jco.2007.11.6699 Seidman et al. 2008 (CALGB 9840)]<br />
|1998-NR<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|TH, weekly paclitaxel (80 mg/m<sup>2</sup>)<br />
|style="background-color:#d73027"|Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] as follows:<br />
**Cycles 1 to 6: 175 mg/m<sup>2</sup> IV once on day 2 <br />
**Cycle 7 onwards: continued at investigator's discretion<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15 <br />
**Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for at least 6 cycles'''<br />
<br />
===References===<br />
# Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. [https://www.nejm.org/doi/full/10.1056/NEJM200103153441101 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11248153 PubMed]<br />
# Seidman AD, Fornier MN, Esteva FJ, Tan L, Kaptain S, Bach A, Panageas KS, Arroyo C, Valero V, Currie V, Gilewski T, Theodoulou M, Moynahan ME, Moasser M, Sklarin N, Dickler M, D'Andrea G, Cristofanilli M, Rivera E, Hortobagyi GN, Norton L, Hudis CA. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol. 2001 May 15;19(10):2587-95. [https://doi.org/10.1200/jco.2001.19.10.2587 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11352950 PubMed]<br />
# Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R, Cobleigh M, Albain K, McCullough C, Fuchs L, Slamon D. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006 Jun 20;24(18):2786-92. [https://doi.org/10.1200/jco.2005.04.1764 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16782917 PubMed]<br />
# '''TRAVIOTA:''' Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.22885/full link to original article] [https://pubmed.ncbi.nlm.nih.gov/17614302 PubMed]<br />
<!-- Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA. --><br />
# '''CALGB 9840:''' Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. [https://doi.org/10.1200/jco.2007.11.6699 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18375893 PubMed]<br />
# '''STM01-102:''' Baselga J, Manikhas A, Cortés J, Llombart A, Roman L, Semiglazov VF, Byakhov M, Lokanatha D, Forenza S, Goldfarb RH, Matera J, Azarnia N, Hudis CA, Rozencweig M. Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer. Ann Oncol. 2014 Mar;25(3):592-8. Epub 2014 Jan 8. [https://doi.org/10.1093/annonc/mdt543 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433508/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24401928 PubMed] NCT00294996<br />
# '''NCIC-CTG MA.31:''' Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, Di Leo A, Martin M, Schwartzberg LS, Lemieux J, Aparicio S, Shepherd LE, Dent S, Ellard SL, Tonkin K, Pritchard KI, Whelan TJ, Nomikos D, Nusch A, Coleman RE, Mukai H, Tjulandin S, Khasanov R, Rizel S, Connor AP, Santillana SL, Chapman JA, Parulekar WR. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC-CTG MA.31. J Clin Oncol. 2015 May 10;33(14):1574-83. Epub 2015 Mar 16. [https://doi.org/10.1200/JCO.2014.56.9590 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25779558 PubMed] NCT00667251<br />
# '''BOLERO-1:''' Hurvitz SA, Andre F, Jiang Z, Shao Z, Mano MS, Neciosup SP, Tseng LM, Zhang Q, Shen K, Liu D, Dreosti LM, Burris HA, Toi M, Buyse ME, Cabaribere D, Lindsay MA, Rao S, Pacaud LB, Taran T, Slamon D. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 2015 Jul;16(7):816-29. Epub 2015 Jun 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00051-0/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/26092818 PubMed] NCT00876395<br />
# '''MARIANNE:''' Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot X, Burris H 3rd, Petersen JA, Stanzel S, Strasak A, Patre M, Ellis P. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol. 2017 Jan 10;35(2):141-148. Epub 2016 Nov 7. [https://doi.org/10.1200/JCO.2016.67.4887 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455677/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28056202 PubMed] NCT01120184<br />
## '''Update:''' Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot XB, Burris HA 3rd, Petersen JA, De Haas S, Hoersch S, Patre M, Ellis PA. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: final results from MARIANNE. Cancer. 2019 Nov 15;125(22):3974-3984. Epub 2019 Jul 18. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.32392 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31318460 PubMed]<br />
# '''NEfERT-T:''' Awada A, Colomer R, Inoue K, Bondarenko I, Badwe RA, Demetriou G, Lee SC, Mehta AO, Kim SB, Bachelot T, Goswami C, Deo S, Bose R, Wong A, Xu F, Yao B, Bryce R, Carey LA. neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: The NEfERT-T randomized clinical trial. JAMA Oncol. 2016 Dec 1;2(12):1557-1564. [http://jamanetwork.com/journals/jamaoncology/fullarticle/2513249 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27078022 PubMed] NCT00915018<br />
<br />
==THP (Taxotere) {{#subobject:938b69|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
THP: '''<u>T</u>'''axotere (Docetaxel), '''<u>H</u>'''erceptin (Trastuzumab), '''<u>P</u>'''ertuzumab<br />
===Regimen {{#subobject:37f3dc|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705202/ Baselga et al. 2011 (CLEOPATRA)]<br />
|2008-2010<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#TH_.28Taxotere.29_3|Docetaxel & Trastuzumab]]<br />
|style="background-color:#1a9850"|Superior OS<sup>1</sup><br>Median OS: 57.1 vs 40.8 mo<br>(HR 0.69, 95% CI 0.58-0.82)<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7320929/ Xu et al. 2020 (PUFFIN)]<br />
|2016-2017<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[#TH_.28Taxotere.29_3|Docetaxel & Trastuzumab]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br>Median PFS: 14.5 vs 12.4 mo<br>(HR 0.69, 95% CI 0.49-0.99)<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for CLEOPATRA is based on the 2020 update.''<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] '''given third''' as follows:<br />
**Cycle 1: 75 mg/m<sup>2</sup> IV once on day 2<br />
**Cycle 2 onwards: 75 mg/m<sup>2</sup> IV once on day 1<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV over 90 minutes once on day 2<br />
**Cycle 2 onwards: 6 mg/kg IV over 30 to 90 minutes once on day 1<br />
*[[Pertuzumab (Perjeta)]] as follows:<br />
**Cycle 1: 840 mg IV over 60 minutes once on day 1<br />
**Cycle 2 onwards: 420 mg IV over 30 to 60 minutes once on day 1<br />
<br />
'''21-day cycle for at least 6 cycles'''<br />
====Subsequent treatment====<br />
*If it is decided to no longer administer docetaxel, then patients could continue to receive [[#Pertuzumab_.26_Trastuzumab_2|pertuzumab & trastuzumab]] maintenance.<br />
<br />
===References===<br />
# '''CLEOPATRA:''' Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. Epub 2011 Dec 7. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113216 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705202/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22149875 PubMed] NCT00567190<br />
## '''Update:''' Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. Epub 2013 Apr 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70130-X/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076842/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23602601 PubMed]<br />
## '''Update:''' Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. [https://www.nejm.org/doi/full/10.1056/NEJMoa1413513 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25693012 PubMed]<br />
## '''Update:''' Swain SM, Miles D, Kim SB, Im YH, Im SA, Semiglazov V, Ciruelos E, Schneeweiss A, Loi S, Monturus E, Clark E, Knott A, Restuccia E, Benyunes MC, Cortés J; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Apr;21(4):519-530. Epub 2020 Mar 12. [https://doi.org/10.1016/s1470-2045(19)30863-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32171426 PubMed]<br />
# '''PUFFIN:''' Xu B, Li W, Zhang Q, Shao Z, Li Q, Wang X, Li H, Sun T, Yin Y, Zheng H, Feng J, Zhang H, Lei G, Restuccia E. Pertuzumab, trastuzumab, and docetaxel for Chinese patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer (PUFFIN): a phase III, randomized, double-blind, placebo-controlled study. Breast Cancer Res Treat. 2020 Aug;182(3):689-697. Epub 2020 Jun 20. [https://doi.org/10.1007/s10549-020-05728-w link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7320929/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32564260/ PubMed] NCT02896855<br />
<br />
==TL (Taxol) {{#subobject:af5af0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
TL: '''<u>T</u>'''axol (Paclitaxel) & '''<u>L</u>'''apatinib<br />
===Regimen {{#subobject:6dda48|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2011.40.5241 Guan et al. 2013 (EGF104535)]<br />
|2006-2009<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Breast_cancer,_HER2-positive_-_historical#Paclitaxel_monotherapy.2C_weekly_3|Paclitaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Lapatinib (Tykerb)]] 1500 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<!-- Presented in part at the 33rd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-12, 2010, and at the 36th Annual European Society of Medical Oncology Congress, Stockholm, Sweden, September 23-27, 2011. --><br />
# '''EGF104535:''' Guan Z, Xu B, DeSilvio ML, Shen Z, Arpornwirat W, Tong Z, Lorvidhaya V, Jiang Z, Yang J, Makhson A, Leung WL, Russo MW, Newstat B, Wang L, Chen G, Oliva C, Gomez H. Randomized trial of lapatinib versus placebo added to paclitaxel in the treatment of human epidermal growth factor receptor 2-overexpressing metastatic breast cancer. J Clin Oncol. 2013 Jun 1;31(16):1947-53. Epub 2013 Mar 18. [https://doi.org/10.1200/JCO.2011.40.5241 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23509322 PubMed] NCT00281658<br />
# '''NCIC-CTG MA.31:''' Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, Di Leo A, Martin M, Schwartzberg LS, Lemieux J, Aparicio S, Shepherd LE, Dent S, Ellard SL, Tonkin K, Pritchard KI, Whelan TJ, Nomikos D, Nusch A, Coleman RE, Mukai H, Tjulandin S, Khasanov R, Rizel S, Connor AP, Santillana SL, Chapman JA, Parulekar WR. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC-CTG MA.31. J Clin Oncol. 2015 May 10;33(14):1574-83. Epub 2015 Mar 16. [https://doi.org/10.1200/JCO.2014.56.9590 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25779558 PubMed] NCT00667251<br />
<br />
==TPC {{#subobject:dc581d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
TPC: '''<u>T</u>'''rastuzumab, '''<u>P</u>'''aclitaxel, '''<u>C</u>'''arboplatin<br />
<br>TCH: '''<u>T</u>'''axol (Paclitaxel), '''<u>C</u>'''arboplatin, '''<u>H</u>'''erceptin (Trastuzumab) <br />
===Regimen variant #1, weekly {{#subobject:deacc5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.clinical-breast-cancer.com/article/S1526-8209(11)70461-X/abstract Perez et al. 2005 (NCCTG 983252)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22<br />
**Cycles 2 to 6: 2 mg/kg IV once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
*[[#Trastuzumab_monotherapy_4|Trastuzumab maintenance (weekly)]]<br />
<br />
===Regimen variant #2, weekly T, q3wk PC {{#subobject:573aed|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.04.1764 Robert et al. 2006]<br />
|1998-2002<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[#TH_.28Taxol.29_3|TP]]<br />
|style="background-color:#91cf60"|Seems to have superior PFS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15 <br />
**Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 2 <br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 2<br />
<br />
'''21-day cycle for at least 6 cycles'''<br />
====Subsequent treatment====<br />
*[[#Trastuzumab_monotherapy_4|Trastuzumab maintenance (weekly)]]<br />
<br />
===Regimen variant #3, q3wk {{#subobject:582fae|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.clinical-breast-cancer.com/article/S1526-8209(11)70461-X/abstract Perez et al. 2005 (NCCTG 983252)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1 <br />
**Cycles 2 to 8: 6 mg/kg IV once on day 1<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV once on day 1 <br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
<br />
'''21-day cycle for 8 cycles'''<br />
====Subsequent treatment====<br />
*[[#Trastuzumab_monotherapy_4|Trastuzumab maintenance (q3wk)]]<br />
===References===<br />
# '''NCCTG 983252:''' Perez EA, Suman VJ, Rowland KM, Ingle JN, Salim M, Loprinzi CL, Flynn PJ, Mailliard JA, Kardinal CG, Krook JE, Thrower AR, Visscher DW, Jenkins RB. Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer. 2005 Dec;6(5):425-32. [http://www.clinical-breast-cancer.com/article/S1526-8209(11)70461-X/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/16381626 PubMed]<br />
# Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R, Cobleigh M, Albain K, McCullough C, Fuchs L, Slamon D. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006 Jun 20;24(18):2786-92. [https://doi.org/10.1200/jco.2005.04.1764 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16782917 PubMed]<br />
<br />
==Ado-trastuzumab emtansine monotherapy {{#subobject:d320be|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
T-DM1: '''<u>T</u>'''rastuzumab-'''<u>DM1</u>''' (Ado-trastuzumab emtansine)<br />
===Example orders===<br />
*[[Example orders for Ado-trastuzumab emtansine (Kadcyla) in breast cancer]]<br />
<br />
===Regimen {{#subobject:63b7de|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2012.44.9694 Hurvitz et al. 2013 (TDM4450g)]<br />
|2008-2009<br />
|style="background-color:#1a9851"|Randomized Phase II (E-de-esc)<br />
|[[#TH_.28Taxotere.29_3|TH]]<br />
|style="background-color:#91cf60"|Seems to have superior PFS<br />
|-<br />
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455677/ Perez et al. 2016 (MARIANNE)]<br />
|rowspan=2|2010-2012<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-de-esc)<br />
|1. T-DM1 & Pertuzumab<br />
|style="background-color:#eeee01"|Non-inferior PFS<br />
|-<br />
|2. [[#TH_.28Taxotere.29_3|TH (Taxotere)]]<br> 3. [[#TH_.28Taxol.29_3|TH (Taxol)]]<br />
|style="background-color:#eeee01"|Non-inferior PFS<br />
|-<br />
|}<br />
====Antibody-drug conjugate therapy====<br />
*[[Ado-trastuzumab emtansine (Kadcyla)]] 3.6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<!-- Presented at the European Multidisciplinary Cancer Congress, Stockholm, Sweden, September 23-27, 2011, and the European Society of Medical Oncology Congress, Milan, Italy, October 8–12, 2010. --><br />
# '''TDM4450g:''' Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes J, Guardino E, Song C, Tong B, Ng V, Chu YW, Perez EA. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2013 Mar 20;31(9):1157-63. Epub 2013 Feb 4. Erratum in: J Clin Oncol. 2013 Aug 10;31(23):2977. [https://doi.org/10.1200/jco.2012.44.9694 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23382472 PubMed] NCT00679341<br />
# '''MARIANNE:''' Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot X, Burris H 3rd, Petersen JA, Stanzel S, Strasak A, Patre M, Ellis P. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol. 2017 Jan 10;35(2):141-148. Epub 2016 Nov 7. [https://doi.org/10.1200/JCO.2016.67.4887 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455677/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28056202 PubMed] NCT01120184<br />
## '''Update:''' Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot XB, Burris HA 3rd, Petersen JA, De Haas S, Hoersch S, Patre M, Ellis PA. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: final results from MARIANNE. Cancer. 2019 Nov 15;125(22):3974-3984. Epub 2019 Jul 18. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.32392 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31318460 PubMed]<br />
<br />
==Trastuzumab monotherapy {{#subobject:9dedb2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1 {{#subobject:9be86b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdw622 Pagani et al. 2017 (SAKK 22/99)]<br />
|1999-2013<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|Chemotherapy & Trastuzumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 2 mg/kg IV once on day 1<br />
<br />
'''7-day cycles'''<br />
<br />
===Regimen variant #2, flat dose {{#subobject:1ac22c|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1996.14.3.737 Baselga et al. 1996]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: this is of historical interest, only.''<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 250 mg IV once on day 1<br />
**Cycles 2 to 11: 100 mg IV once on day 1<br />
<br />
'''7-day cycle for 11 cycles'''<br />
===References===<br />
# Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklarin NT, Seidman AD, Hudis CA, Moore J, Rosen PP, Twaddell T, Henderson IC, Norton L. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol. 1996 Mar;14(3):737-44. [https://doi.org/10.1200/JCO.1996.14.3.737 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8622019 PubMed]<br />
# '''SAKK 22/99:''' Pagani O, Klingbiel D, Ruhstaller T, Nolè F, Eppenberger S, Oehlschlegel C, Bernhard J, Brauchli P, Hess D, Mamot C, Munzone E, Pestalozzi B, Rabaglio M, Aebi S, Ribi K, Rochlitz C, Rothgiesser K, Thürlimann B, von Moos R, Zaman K, Goldhirsch A; Swiss Group for Clinical Cancer Research. Do all patients with advanced HER2 positive breast cancer need upfront-chemo when receiving trastuzumab? Randomized phase III trial SAKK 22/99. Ann Oncol. 2017 Feb 1;28(2):305-312. [https://doi.org/10.1093/annonc/mdw622 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27998961 PubMed] NCT00004935<br />
<br />
==Vinorelbine & Trastuzumab (VH) {{#subobject:59edc1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
VH: '''<u>V</u>'''inorelbine & '''<u>H</u>'''erceptin (Trastuzumab)<br />
===Regimen variant #1, vinorelbine 25 mg/m<sup>2</sup> {{#subobject:947c3a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.22885/full Burstein et al. 2007 (TRAVIOTA)]<br />
|2001-2003<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|1. [[#TH_.28Taxotere.29_3|TH (Taxotere)]]<br> 2. [[#TH_.28Taxol.29_3|TH (Taxol)]]<br />
|style="background-color:#d9ef8b"|Might have superior TTP<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22<br />
**Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, vinorelbine 30 mg/m<sup>2</sup>, 2 out of 3 weeks {{#subobject:fac964|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2010.30.8213 Andersson et al. 2010 (HERNATA)]<br />
|2004-2008<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[#TH_.28Taxotere.29_3|TH (Taxotere)]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of TTP<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV over 90 minutes once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV over 30 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #3, vinorelbine 35 mg/m<sup>2</sup>, 2 out of 3 weeks {{#subobject:a6dae9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2010.30.8213 Andersson et al. 2010 (HERNATA)]<br />
|2004-2008<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[#TH_.28Taxotere.29_3|TH (Taxotere)]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of TTP<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Vinorelbine (Navelbine)]] 35 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV over 90 minutes once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV over 30 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''TRAVIOTA:''' Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.22885/full link to original article] [https://pubmed.ncbi.nlm.nih.gov/17614302 PubMed]<br />
# '''HERNATA:''' Andersson M, Lidbrink E, Bjerre K, Wist E, Enevoldsen K, Jensen AB, Karlsson P, Tange UB, Sørensen PG, Møller S, Bergh J, Langkjer ST. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011 Jan 20;29(3):264-71. Epub 2010 Dec 13. [https://doi.org/10.1200/JCO.2010.30.8213 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21149659 PubMed]<br />
<br />
=Metastatic or unresectable disease, subsequent lines=<br />
==Capecitabine & Lapatinib {{#subobject:5474dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:6d0733|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa064320 Geyer et al. 2006 (EGF100151)]<br />
|2004-2005<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[Breast_cancer,_HER2-positive_-_historical#Capecitabine_monotherapy_3|Capecitabine]]<br />
|style="background-color:#1a9850"|Superior TTP<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125250/ Verma et al. 2012 (EMILIA)]<br />
|2009-2011<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Ado-trastuzumab_emtansine_monotherapy_4|T-DM1]]<br />
|style="background-color:#d73027"|Inferior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2014.57.1794 Pivot et al. 2015 (CEREBEL)]<br />
|2009-2012<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Capecitabine_.26_Trastuzumab_.28XH.29_2|Capecitabine & Trastuzumab]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of CNS site of first relapse<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7499616/ Saura et al. 2020 (NALA)]<br />
|2013-2017<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Capecitabine_.26_Neratinib|Capecitabine & Neratinib]]<br />
|style="background-color:#d73027"|Inferior PFS<br />
|-<br />
|[https://doi.org/10.1016/s1470-2045(20)30702-6 Xu et al. 2021 (PHOEBE)]<br />
|2017-2018<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|Capecitabine & Pyrotinib<br />
|style="background-color:#d73027"|Inferior PFS<br />
|-<br />
|}<br />
''Note: the primary endpoint of CEREBEL was incidence of CNS as site of first relapse; this was very low in both arms, with no statistically significant difference.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
====Targeted therapy====<br />
*[[Lapatinib (Tykerb)]] 1250 mg PO once per day<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''EGF100151:''' Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28;355(26):2733-43. [https://www.nejm.org/doi/full/10.1056/NEJMoa064320 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17192538 PubMed] NCT00078572<br />
## '''Update:''' Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, Chan S, Jagiello-Gruszfeld A, Kaufman B, Crown J, Chan A, Campone M, Viens P, Davidson N, Gorbounova V, Raats JI, Skarlos D, Newstat B, Roychowdhury D, Paoletti P, Oliva C, Rubin S, Stein S, Geyer CE. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat. 2008 Dec;112(3):533-43. [http://link.springer.com/article/10.1007%2Fs10549-007-9885-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18188694 PubMed]<br />
## '''Update:''' Cameron D, Casey M, Oliva C, Newstat B, Imwalle B, Geyer CE. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist. 2010;15(9):924-34. [http://theoncologist.alphamedpress.org/content/15/9/924.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228041/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20736298 PubMed]<br />
# '''EMILIA:''' Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012 Nov 8;367(19):1783-91. Epub 2012 Oct 1. Erratum in: N Engl J Med. 2013 Jun 20;368(25):2442. [https://www.nejm.org/doi/full/10.1056/NEJMoa1209124 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125250/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23020162 PubMed] NCT00829166<br />
## '''Update:''' Diéras V, Miles D, Verma S, Pegram M, Welslau M, Baselga J, Krop IE, Blackwell K, Hoersch S, Xu J, Green M, Gianni L. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Jun;18(6):732-742. Epub 2017 May 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30312-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531181/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28526536 PubMed]<br />
# '''CEREBEL:''' Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. [https://doi.org/10.1200/JCO.2014.57.1794 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25605838 PubMed] NCT00820222<br />
<!-- # '''Abstract:''' Cristina Saura, Mafalda Oliveira, Yin-Hsun Feng, Ming-Shen Dai, Sara A. Hurvitz, Sung-Bae Kim, Beverly Moy, Suzette Delaloge, William John Gradishar, Norikazu Masuda, Marketa Palacova, Maureen E. Trudeau, Johanna Mattson, Yoon Sim Yap, Richard Bryce, Bin Yao, Judith D. Bebchuk, Kiana Keyvanjah, Adam Brufsky, and NALA Investigators. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial. Journal of Clinical Oncology 2019 37:15_suppl, 1002-1002 [https://doi.org/10.1200/JCO.2019.37.15_suppl.1002 link to abstract] --><br />
#'''NALA:''' Saura C, Oliveira M, Feng YH, Dai MS, Chen SW, Hurvitz SA, Kim SB, Moy B, Delaloge S, Gradishar W, Masuda N, Palacova M, Trudeau ME, Mattson J, Yap YS, Hou MF, De Laurentiis M, Yeh YM, Chang HT, Yau T, Wildiers H, Haley B, Fagnani D, Lu YS, Crown J, Lin J, Takahashi M, Takano T, Yamaguchi M, Fujii T, Yao B, Bebchuk J, Keyvanjah K, Bryce R, Brufsky A; NALA Investigators. Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial. J Clin Oncol. 2020 Sep 20;38(27):3138-3149. Epub 2020 Jul 17. [https://doi.org/10.1200/jco.20.00147 link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7499616/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32678716/ PubMed] NCT01808573<br />
#'''PHOEBE:''' Xu B, Yan M, Ma F, Hu X, Feng J, Ouyang Q, Tong Z, Li H, Zhang Q, Sun T, Wang X, Yin Y, Cheng Y, Li W, Gu Y, Chen Q, Liu J, Cheng J, Geng C, Qin S, Wang S, Lu J, Shen K, Liu Q, Wang X, Wang H, Luo T, Yang J, Wu Y, Yu Z, Zhu X, Chen C, Zou J; PHOEBE Investigators. Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Feb 11:S1470-2045(20)30702-6. Epub ahead of print. [https://doi.org/10.1016/s1470-2045(20)30702-6 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/33581774/ PubMed] NCT03080805<br />
<br />
==Capecitabine & Margetuximab {{#subobject:7mz1hq|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1de6ad|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ Rugo et al. 2021 (SOPHIA)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Capecitabine_.26_Trastuzumab_.28XH.29_2|XH]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS <br>Median PFS: 6 mo vs 5 mo <br>(HR 0.76, 95% CI 0.59-0.98)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
====Targeted therapy====<br />
*[[Margetuximab (Margenza)]] 15 mg/kg IV over 120 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
# '''SOPHIA:''' Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. [https://doi.org/10.1001/jamaoncol.2020.7932 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33480963/ PubMed] NCT02492711<br />
<br />
==Capecitabine & Neratinib {{#subobject:01baec|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3a0475|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2014.56.3809 Saura et al. 2014 (3144A1-2206)]<br />
|2008-NR<br />
|style="background-color:#91cf61"|Phase I/II<br />
|style="background-color:#d3d3d3"|<br />
| style="background-color:#bfd3e6" |ORR: 64%<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7499616/ Saura et al. 2020 (NALA)]<br />
|2013-2017<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Capecitabine_.26_Lapatinib_2|Capecitabine & Lapatinib]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
====Targeted therapy====<br />
*[[Neratinib (Nerlynx)]] 240 mg PO once per day<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''3144A1-2206:''' Saura C, Garcia-Saenz JA, Xu B, Harb W, Moroose R, Pluard T, Cortés J, Kiger C, Germa C, Wang K, Martin M, Baselga J, Kim SB. Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2014 Nov 10;32(32):3626-33. Epub 2014 Oct 6. [https://doi.org/10.1200/JCO.2014.56.3809 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25287822 PubMed] NCT00741260<br />
<!-- # '''Abstract:''' Cristina Saura, Mafalda Oliveira, Yin-Hsun Feng, Ming-Shen Dai, Sara A. Hurvitz, Sung-Bae Kim, Beverly Moy, Suzette Delaloge, William John Gradishar, Norikazu Masuda, Marketa Palacova, Maureen E. Trudeau, Johanna Mattson, Yoon Sim Yap, Richard Bryce, Bin Yao, Judith D. Bebchuk, Kiana Keyvanjah, Adam Brufsky, and NALA Investigators. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial. Journal of Clinical Oncology 2019 37:15_suppl, 1002-1002 [https://doi.org/10.1200/JCO.2019.37.15_suppl.1002 link to abstract] --><br />
#'''NALA:''' Saura C, Oliveira M, Feng YH, Dai MS, Chen SW, Hurvitz SA, Kim SB, Moy B, Delaloge S, Gradishar W, Masuda N, Palacova M, Trudeau ME, Mattson J, Yap YS, Hou MF, De Laurentiis M, Yeh YM, Chang HT, Yau T, Wildiers H, Haley B, Fagnani D, Lu YS, Crown J, Lin J, Takahashi M, Takano T, Yamaguchi M, Fujii T, Yao B, Bebchuk J, Keyvanjah K, Bryce R, Brufsky A; NALA Investigators. Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial. J Clin Oncol. 2020 Sep 20;38(27):3138-3149. Epub 2020 Jul 17. [https://doi.org/10.1200/jco.20.00147 link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7499616/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32678716/ PubMed] NCT01808573<br />
<br />
==Capecitabine, Pertuzumab, Trastuzumab {{#subobject:fa074d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b7d240|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2016.70.6267 Urruticoechea et al. 2017 (PHEREXA)]<br />
|2010-2013<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[#Capecitabine_.26_Trastuzumab_.28XH.29_2|Capecitabine & Trastuzumab]]<br />
|style="background-color:#d9ef8b"|Might have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
====Targeted therapy====<br />
*[[Pertuzumab (Perjeta)]] as follows:<br />
**Cycle 1: 840 mg IV once on day 1<br />
**Cycle 2 onwards: 420 mg IV once on day 1<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''PHEREXA:''' Urruticoechea A, Rizwanullah M, Im SA, Ruiz ACS, Láng I, Tomasello G, Douthwaite H, Badovinac Crnjevic T, Heeson S, Eng-Wong J, Muñoz M. Randomized phase III trial of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who experienced disease progression during or after trastuzumab-based therapy. J Clin Oncol. 2017 Sep 10;35(26):3030-3038. Epub 2017 Apr 24. [https://doi.org/10.1200/JCO.2016.70.6267 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28437161 PubMed] NCT01026142<br />
<br />
==Capecitabine & Trastuzumab (XH) {{#subobject:8d0dd5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
XH: '''<u>X</u>'''eloda (Capecitabine) & '''<u>H</u>'''erceptin<br />
===Regimen variant #1, 2000/6, with loading dose {{#subobject:776bcc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ Rugo et al. 2021 (SOPHIA)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Margetuximab|Capecitabine & Margetuximab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://doi.org/10.1056/nejmoa1914609 Murthy et al. 2019 (HER2CLIMB)]<br />
|2016-2019<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Capecitabine.2C_Tucatinib.2C_Trastuzumab|Capecitabine, Tucatinib, Trastuzumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 2500/6, with loading dose {{#subobject:663bcc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2007.11.9776 Bartsch et al. 2007]<br />
|2004-2006<br />
|style="background-color:#91cf61"|Phase II<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[https://doi.org/10.1200/JCO.2014.57.1794 Pivot et al. 2015 (CEREBEL)]<br />
|2009-2012<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Capecitabine_.26_Lapatinib_2|Capecitabine & Lapatanib]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of CNS site of first relapse<br />
|-<br />
|[https://doi.org/10.1200/JCO.2016.70.6267 Urruticoechea et al. 2017 (PHEREXA)]<br />
|2010-2013<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Capecitabine.2C_Pertuzumab.2C_Trastuzumab|Capecitabine, Pertuzumab, Trastuzumab]]<br />
|style="background-color:#fee08b"|Might have inferior PFS<br />
|-<br />
|}<br />
''Note: the only difference between this and variant #2 is the use of a loading dose of trastuzumab. The primary endpoint of CEREBEL was incidence of CNS as site of first relapse; this was very low in both arms, with no statistically significant difference.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #3, 2500/6, no loading dose {{#subobject:e38ff|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2008.19.6618 von Minckwitz et al. 2009 (GBG 26/BIG 3-05)]<br />
|2003-NR<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Breast_cancer,_HER2-positive_-_historical#Capecitabine_monotherapy_3|Capecitabine]]<br />
|style="background-color:#91cf60"|Seems to have superior TTP<br />
|-<br />
|}<br />
''This is a continuation of trastuzumab so there is no loading dose.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Bartsch R, Wenzel C, Altorjai G, Pluschnig U, Rudas M, Mader RM, Gnant M, Zielinski CC, Steger GG. Capecitabine and trastuzumab in heavily pretreated metastatic breast cancer. J Clin Oncol. 2007 Sep 1;25(25):3853-8. Epub 2007 Aug 6. [https://doi.org/10.1200/jco.2007.11.9776 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17679724 PubMed]<br />
# '''GBG 26/BIG 3-05:''' von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Loibl S. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol. 2009 Apr 20;27(12):1999-2006. Epub 2009 Mar 16. [https://doi.org/10.1200/jco.2008.19.6618 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19289619 PubMed]<br />
## '''Update:''' von Minckwitz G, Schwedler K, Schmidt M, Barinoff J, Mundhenke C, Cufer T, Maartense E, de Jongh FE, Baumann KH, Bischoff J, Harbeck N, Lück HJ, Maass N, Zielinski C, Andersson M, Stein RC, Nekljudova V, Loibl S; GBG 26/BIG 03-05 study group and participating investigators. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur J Cancer. 2011 Oct;47(15):2273-81. Epub 2011 Jul 7. [https://www.ejcancer.com/article/S0959-8049(11)00425-4/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/21741829 PubMed]<br />
# '''CEREBEL:''' Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. [https://doi.org/10.1200/JCO.2014.57.1794 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/25605838 PubMed] NCT00820222<br />
# '''PHEREXA:''' Urruticoechea A, Rizwanullah M, Im SA, Ruiz ACS, Láng I, Tomasello G, Douthwaite H, Badovinac Crnjevic T, Heeson S, Eng-Wong J, Muñoz M. Randomized phase III trial of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who experienced disease progression during or after trastuzumab-based therapy. J Clin Oncol. 2017 Sep 10;35(26):3030-3038. Epub 2017 Apr 24. [https://doi.org/10.1200/JCO.2016.70.6267 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28437161 PubMed] NCT01026142<br />
# '''HER2CLIMB:''' Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, Lin NU, Borges V, Abramson V, Anders C, Bedard PL, Oliveira M, Jakobsen E, Bachelot T, Shachar SS, Müller V, Braga S, Duhoux FP, Greil R, Cameron D, Carey LA, Curigliano G, Gelmon K, Hortobagyi G, Krop I, Loibl S, Pegram M, Slamon D, Palanca-Wessels MC, Walker L, Feng W, Winer EP. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):597-609. Epub 2019 Dec 11. Erratum in: N Engl J Med. 2020 Feb 6;382(6):586. [https://doi.org/10.1056/nejmoa1914609 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/31825569 PubMed] NCT02614794<br />
## '''Subgroup analysis:''' Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, Hurvitz S, Loi S, Okines A, Abramson V, Bedard PL, Oliveira M, Mueller V, Zelnak A, DiGiovanna MP, Bachelot T, Chien AJ, O'Regan R, Wardley A, Conlin A, Cameron D, Carey L, Curigliano G, Gelmon K, Loibl S, Mayor J, McGoldrick S, An X, Winer EP. Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial. J Clin Oncol. 2020 Aug 10;38(23):2610-2619. Epub 2020 May 29. [https://doi.org/10.1200/jco.20.00775 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403000/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32468955 PubMed]<br />
# '''SOPHIA:''' Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. [https://doi.org/10.1001/jamaoncol.2020.7932 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33480963/ PubMed] NCT02492711<br />
<br />
==Capecitabine, Tucatinib, Trastuzumab {{#subobject:8d0gg5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:771gcc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1056/nejmoa1914609 Murthy et al. 2019 (HER2CLIMB)]<br />
|2016-2019<br />
|style="background-color:#1a9851"|Phase III (E-RT)<br />
|[[#Capecitabine_.26_Trastuzumab_.28XH.29_2|XH]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
====Targeted therapy====<br />
*[[Tucatinib (Tukysa)]] 300 mg PO twice per day<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''HER2CLIMB:''' Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, Lin NU, Borges V, Abramson V, Anders C, Bedard PL, Oliveira M, Jakobsen E, Bachelot T, Shachar SS, Müller V, Braga S, Duhoux FP, Greil R, Cameron D, Carey LA, Curigliano G, Gelmon K, Hortobagyi G, Krop I, Loibl S, Pegram M, Slamon D, Palanca-Wessels MC, Walker L, Feng W, Winer EP. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):597-609. Epub 2019 Dec 11. Erratum in: N Engl J Med. 2020 Feb 6;382(6):586. [https://doi.org/10.1056/nejmoa1914609 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/31825569 PubMed] NCT02614794<br />
## '''Subgroup analysis:''' Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, Hurvitz S, Loi S, Okines A, Abramson V, Bedard PL, Oliveira M, Mueller V, Zelnak A, DiGiovanna MP, Bachelot T, Chien AJ, O'Regan R, Wardley A, Conlin A, Cameron D, Carey L, Curigliano G, Gelmon K, Loibl S, Mayor J, McGoldrick S, An X, Winer EP. Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial. J Clin Oncol. 2020 Aug 10;38(23):2610-2619. Epub 2020 May 29. [https://doi.org/10.1200/jco.20.00775 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403000/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32468955 PubMed]<br />
<br />
==Eribulin & Margetuximab {{#subobject:7mz1b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:18op1d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ Rugo et al. 2021 (SOPHIA)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Eribulin_.26_Trastuzumab|Eribulin & Trastuzumab]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS <br>Median PFS: 6 mo vs 5 mo <br>(HR 0.76, 95% CI 0.59-0.98)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Eribulin (Halaven)]] 1.4 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
====Targeted therapy====<br />
*[[Margetuximab (Margenza)]] 15 mg/kg IV over 120 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
# '''SOPHIA:''' Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. [https://doi.org/10.1001/jamaoncol.2020.7932 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33480963/ PubMed] NCT02492711<br />
<br />
==Eribulin & Trastuzumab {{#subobject:98ug71|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:gh10bb|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ Rugo et al. 2021 (SOPHIA)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Eribulin_.26_Margetuximab|Eribulin & Margetuximab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Eribulin (Halaven)]] 1.4 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
# '''SOPHIA:''' Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. [https://doi.org/10.1001/jamaoncol.2020.7932 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33480963/ PubMed] NCT02492711<br />
<br />
==Gemcitabine & Margetuximab {{#subobject:ugn1b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:158gua|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ Rugo et al. 2021 (SOPHIA)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Gemcitabine_.26_Trastuzumab|Gemcitabine & Trastuzumab]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS <br>Median PFS: 6 mo vs 5 mo <br>(HR 0.76, 95% CI 0.59-0.98)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
====Targeted therapy====<br />
*[[Margetuximab (Margenza)]] 15 mg/kg IV over 120 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
# '''SOPHIA:''' Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. [https://doi.org/10.1001/jamaoncol.2020.7932 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33480963/ PubMed] NCT02492711<br />
<br />
==Gemcitabine & Trastuzumab {{#subobject:981yy2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, q3wk {{#subobject:ehgy1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ Rugo et al. 2021 (SOPHIA)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_Margetuximab|Gemcitabine & Margetuximab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, weekly {{#subobject:e320bb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 50%"|Study<br />
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.3816/cbc.2004.n.019 O'Shaughnessy et al. 2004]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1200 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15<br />
**Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# O'Shaughnessy JA, Vukelja S, Marsland T, Kimmel G, Ratnam S, Pippen JE. Phase II study of trastuzumab plus gemcitabine in chemotherapy-pretreated patients with metastatic breast cancer. Clin Breast Cancer. 2004 Jun;5(2):142-7. [https://doi.org/10.3816/cbc.2004.n.019 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15245619 PubMed]<br />
# '''SOPHIA:''' Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. [https://doi.org/10.1001/jamaoncol.2020.7932 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33480963/ PubMed] NCT02492711<br />
<br />
==Lapatinib & Trastuzumab {{#subobject:9be4d2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e892bb|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2008.21.4437 Blackwell et al. 2010 (EGF104900)]<br />
|2005-2006<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|Lapatinib<br />
|style="background-color:#91cf60"|Seems to have superior OS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lapatinib (Tykerb)]] 1000 mg PO once per day<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22<br />
**Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<!-- Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL, and the 33rd Annual Meeting of the European Society for Medical Oncology, September 12-16, 2008, Stockholm, Sweden. --><br />
# '''EGF104900:''' Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010 Mar 1;28(7):1124-30. Epub 2010 Feb 1. [https://doi.org/10.1200/jco.2008.21.4437 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20124187 PubMed] NCT00320385<br />
## '''Update:''' Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, Ellis C, Florance A, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012 Jul 20;30(21):2585-92. Epub 2012 Jun 11. [https://doi.org/10.1200/jco.2011.35.6725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22689807 PubMed]<br />
<br />
==Paclitaxel, Pertuzumab, Ado-trastuzumab emtansine {{#subobject:bjc7e1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, q3wk T-DM1 {{#subobject:18ba4d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791863/ Krop et al. 2016 (TDM4652g)]<br />
|style="background-color:#91cf61"|Phase 1b/2a<br />
|-<br />
|}<br />
''Note: this is the MTD.''<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Pertuzumab (Perjeta)]] as follows:<br />
**Cycle 1: 840 mg IV once on day 1<br />
**Cycle 2 onwards: 420 mg IV once on day 1<br />
====Antibody-drug conjugate therapy====<br />
*[[Ado-trastuzumab emtansine (Kadcyla)]] 3.6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, weekly T-DM1 {{#subobject:18hb4d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791863/ Krop et al. 2016 (TDM4652g)]<br />
|style="background-color:#91cf61"|Phase 1b/2a<br />
|-<br />
|}<br />
''Note: this is the MTD.''<br />
====Chemotherapy====<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Pertuzumab (Perjeta)]] as follows:<br />
**Cycle 1: 840 mg IV once on day 1<br />
**Cycle 2 onwards: 420 mg IV once on day 1<br />
====Antibody-drug conjugate therapy====<br />
*[[Ado-trastuzumab emtansine (Kadcyla)]] 2.4 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''TDM4652g:''' Krop IE, Modi S, LoRusso PM, Pegram M, Guardino E, Althaus B, Lu D, Strasak A, Elias A. Phase 1b/2a study of trastuzumab emtansine (T-DM1), paclitaxel, and pertuzumab in HER2-positive metastatic breast cancer. Breast Cancer Res. 2016 Mar 15;18(1):34. [https://breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-016-0691-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791863/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/26979312 PubMed]<br />
<br />
==Pertuzumab & Trastuzumab {{#subobject:b1d7b1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, q3wk trastuzumab {{#subobject:4f5a4d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979216/ Baselga et al. 2010]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pertuzumab (Perjeta)]] as follows, '''given second''':<br />
**Cycle 1: 840 mg IV once on day 2<br />
**Cycle 2 onwards: 420 mg IV once on day 1<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Loading dose: 8 mg/kg IV once on day -28 (that is, 28 days before the start of cycle 1)<br />
**Cycle 1 onwards: 6 mg/kg IV once on day 1, '''given first'''<br />
<br />
'''21-day cycle for 8 cycles'''<br />
<br />
''Treatment can be continued if there is no progressive disease.''<br />
<br />
===Regimen variant #2, weekly trastuzumab {{#subobject:ecb953|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979216/ Baselga et al. 2010 (NCI-P6660)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pertuzumab (Perjeta)]] '''given second''' as follows:<br />
**Cycle 1: 840 mg IV once on day 2<br />
**Cycles 2 to 8: 420 mg IV once on day 1<br />
*[[Trastuzumab (Herceptin)]] '''given first''' as follows:<br />
**Cycle 0: 4 mg/kg IV once on day -28 (that is, 28 days before the start of cycle 1)<br />
**Cycles 1 to 8: 2 mg/kg IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for 8 cycles'''; treatment can be continued if there is no progressive disease<br />
<br />
===References===<br />
# '''NCI-P6660:''' Baselga J, Gelmon KA, Verma S, Wardley A, Conte P, Miles D, Bianchi G, Cortes J, McNally VA, Ross GA, Fumoleau P, Gianni L. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 2010 Mar 1;28(7):1138-44. Epub 2010 Feb 1. [https://doi.org/10.1200/jco.2009.24.2024 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979216/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20124182 PubMed] NCT00301899<br />
<br />
==Ado-trastuzumab emtansine monotherapy {{#subobject:d260e0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
T-DM1: '''<u>T</u>'''rastuzumab-'''<u>DM1</u>''' (Ado-trastuzumab emtansine)<br />
===Example orders===<br />
*[[Example orders for Ado-trastuzumab emtansine (Kadcyla) in breast cancer]]<br />
<br />
===Regimen {{#subobject:d42e82|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125250/ Verma et al. 2012 (EMILIA)]<br />
|2009-2011<br />
|style="background-color:#1a9851"|Phase III (E-RT-switch-ooc)<br />
|[[#Capecitabine_.26_Lapatinib_2|Capecitabine & Lapatinib]]<br />
|style="background-color:#1a9850"|Superior OS<sup>1</sup> <br>(HR 0.75, 95% CI 0.64-0.88)<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70178-0/fulltext Krop et al. 2014 (TH3RESA)]<br />
|2011-2012<br />
|style="background-color:#1a9851"|Phase III (E-switch-ooc)<br />
|Physician's choice<br />
|style="background-color:#1a9850"|Superior OS<sup>2</sup> <br>(HR 0.68, 95% CI 0.54-0.85)<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for EMILIA is based on the 2017 update.''<br><br />
''<sup>2</sup>Reported efficacy for TH3RESA is based on the 2017 update.''<br />
====Antibody-drug conjugate therapy====<br />
*[[Ado-trastuzumab emtansine (Kadcyla)]] 3.6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''EMILIA:''' Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012 Nov 8;367(19):1783-91. Epub 2012 Oct 1. Erratum in: N Engl J Med. 2013 Jun 20;368(25):2442. [https://www.nejm.org/doi/full/10.1056/NEJMoa1209124 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125250/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23020162 PubMed] NCT00829166<br />
## '''Update:''' Diéras V, Miles D, Verma S, Pegram M, Welslau M, Baselga J, Krop IE, Blackwell K, Hoersch S, Xu J, Green M, Gianni L. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Jun;18(6):732-742. Epub 2017 May 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30312-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531181/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28526536 PubMed]<br />
# '''TH3RESA:''' Krop IE, Kim SB, González-Martín A, LoRusso PM, Ferrero JM, Smitt M, Yu R, Leung AC, Wildiers H; TH3RESA study collaborators. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Jun;15(7):689-99. Epub 2014 May 2. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70178-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24793816 PubMed] NCT01419197<br />
## '''Update:''' Krop IE, Kim SB, Martin AG, LoRusso PM, Ferrero JM, Badovinac-Crnjevic T, Hoersch S, Smitt M, Wildiers H. Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 2017 Jun;18(6):743-754. Epub 2017 May 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30313-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28526538 PubMed]<br />
<br />
==Fam-trastuzumab deruxtecan monotherapy {{#subobject:d2616v|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d4fac1|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1914510 Modi et al. 2019 (DESTINY-Breast01)]<br />
|2017-2018<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
====Antibody-drug conjugate therapy====<br />
*[[Fam-trastuzumab deruxtecan (Enhertu)]] 5.4 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''DESTINY-Breast01:''' Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, Andre F, Iwata H, Ito Y, Tsurutani J, Sohn J, Denduluri N, Perrin C, Aogi K, Tokunaga E, Im SA, Lee KS, Hurvitz SA, Cortes J, Lee C, Chen S, Zhang L, Shahidi J, Yver A, Krop I; DESTINY-Breast01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):610-621. Epub 2019 Dec 11. [https://www.nejm.org/doi/full/10.1056/NEJMoa1914510 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/31825192 PubMed] NCT03248492<br />
<br />
==Trastuzumab monotherapy {{#subobject:9ugha2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1ac44u|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1999.17.9.2639 Cobleigh et al. 1999]<br />
|1995-1996<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]]<br />
<br />
===References===<br />
# Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999 Sep;17(9):2639-48. [https://doi.org/10.1200/JCO.1999.17.9.2639 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10561337 PubMed]<br />
<br />
==Vinorelbine & Margetuximab {{#subobject:96tyn7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 25 mg/m<sup>2</sup> {{#subobject:15dbhj|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ Rugo et al. 2021 (SOPHIA)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Vinorelbine_.26_Trastuzumab_.28VH.29|VH]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS <br>Median PFS: 6 mo vs 5 mo <br>(HR 0.76, 95% CI 0.59-0.98)<br />
|-<br />
|}<br />
''Note: this is the lower bound of dosing described in SOPHIA.''<br />
====Chemotherapy====<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
====Targeted therapy====<br />
*[[Margetuximab (Margenza)]] 15 mg/kg IV over 120 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 30 mg/m<sup>2</sup> {{#subobject:ghuzb1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ Rugo et al. 2021 (SOPHIA)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Vinorelbine_.26_Trastuzumab_.28VH.29|VH]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS <br>Median PFS: 6 mo vs 5 mo <br>(HR 0.76, 95% CI 0.59-0.98)<br />
|-<br />
|}<br />
''Note: this is the upper bound of dosing described in SOPHIA.''<br />
====Chemotherapy====<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
====Targeted therapy====<br />
*[[Margetuximab (Margenza)]] 15 mg/kg IV over 120 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
# '''SOPHIA:''' Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. [https://doi.org/10.1001/jamaoncol.2020.7932 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33480963/ PubMed] NCT02492711<br />
<br />
==Vinorelbine & Trastuzumab (VH) {{#subobject:932de7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VH: '''<u>V</u>'''inorelbine & '''<u>H</u>'''erceptin (Trastuzumab)<br />
===Regimen variant #1, 25 mg/m<sup>2</sup> {{#subobject:gh10hj|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ Rugo et al. 2021 (SOPHIA)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Vinorelbine_.26_Margetuximab|Vinorelbine & Margetuximab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|}<br />
''Note: this is the lower bound of dosing described in SOPHIA.''<br />
====Chemotherapy====<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 30 mg/m<sup>2</sup> {{#subobject:gh10yq|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ Rugo et al. 2021 (SOPHIA)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Vinorelbine_.26_Margetuximab|Vinorelbine & Margetuximab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|}<br />
''Note: this is the upper bound of dosing described in SOPHIA.''<br />
====Chemotherapy====<br />
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Cycle 2 onwards: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #3, weekly {{#subobject:55cd14|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70138-X/abstract André et al. 2014 (BOLERO-3)]<br />
|2009-2012<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Vinorelbine_.26_Trastuzumab_.28VH.29_.26_Everolimus|VH & Everolimus]]<br />
|style="background-color:#d73027"|Inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00540-9/fulltext Harbeck et al. 2016 (LUX-Breast 1)]<br />
|2010-2013<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[Stub#Afatinib_.26_Vinorelbine|Afatinib & Vinorelbine]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22<br />
**Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''BOLERO-3:''' André F, O'Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, Masuda N, Wilks S, Arena F, Isaacs C, Yap YS, Papai Z, Lang I, Armstrong A, Lerzo G, White M, Shen K, Litton J, Chen D, Zhang Y, Ali S, Taran T, Gianni L. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014 May;15(6):580-91. Epub 2014 Apr 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70138-X/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/24742739 PubMed] NCT01007942<br />
# '''LUX-Breast 1:''' Harbeck N, Huang CS, Hurvitz S, Yeh DC, Shao Z, Im SA, Jung KH, Shen K, Ro J, Jassem J, Zhang Q, Im YH, Wojtukiewicz M, Sun Q, Chen SC, Goeldner RG, Uttenreuther-Fischer M, Xu B, Piccart-Gebhart M; LUX-Breast 1 study group. Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): an open-label, randomised, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):357-66. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00540-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26822398 PubMed] NCT01125566<br />
# '''SOPHIA:''' Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. [https://doi.org/10.1001/jamaoncol.2020.7932 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7823434/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33480963/ PubMed] NCT02492711<br />
<br />
==Vinorelbine & Trastuzumab (VH) & Everolimus {{#subobject:8hude7|Regimen=1}}==<br />
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VH & Everolimus: '''<u>V</u>'''inorelbine, '''<u>H</u>'''erceptin (Trastuzumab), Everolimus<br />
===Regimen {{#subobject:5jha14|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70138-X/abstract André et al. 2014 (BOLERO-3)]<br />
|2009-2012<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[#Vinorelbine_.26_Trastuzumab_.28VH.29_3|VH]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22<br />
**Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22<br />
*[[Everolimus (Afinitor)]] 5 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''BOLERO-3:''' André F, O'Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, Masuda N, Wilks S, Arena F, Isaacs C, Yap YS, Papai Z, Lang I, Armstrong A, Lerzo G, White M, Shen K, Litton J, Chen D, Zhang Y, Ali S, Taran T, Gianni L. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014 May;15(6):580-91. Epub 2014 Apr 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70138-X/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/24742739 PubMed] NCT01007942<br />
<br />
=Maintenance for metastatic or unresectable disease=<br />
==Pertuzumab & Trastuzumab {{#subobject:75e894|Regimen=1}}==<br />
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===Regimen {{#subobject:ecd17f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705202/ Baselga et al. 2011 (CLEOPATRA)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#THP_.28Taxotere.29_3|THP (Taxotere)]] for at least 6 cycles<br />
<br />
====Targeted therapy====<br />
*[[Pertuzumab (Perjeta)]] 420 mg IV once on day 1<br />
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''CLEOPATRA:''' Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. Epub 2011 Dec 7. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113216 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705202/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22149875 PubMed] NCT00567190<br />
## '''Update:''' Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. Epub 2013 Apr 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70130-X/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076842/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23602601 PubMed]<br />
## '''Update:''' Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. [https://www.nejm.org/doi/full/10.1056/NEJMoa1413513 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25693012 PubMed]<br />
<br />
==Trastuzumab monotherapy {{#subobject:c88145|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===Regimen variant #1, q3wk dosing {{#subobject:da43ac|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.clinical-breast-cancer.com/article/S1526-8209(11)70461-X/abstract Perez et al. 2005 (NCCTG 983252)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://doi.org/10.1200/jco.2010.28.6450 Valero et al. 2010 (BCIRG 007)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705202/ Baselga et al. 2011 (CLEOPATRA)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|[https://doi.org/10.1200/JCO.2014.56.9590 Gelmon et al. 2015 (NCIC-CTG MA.31)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*NCCTG 983252: [[#TPC|TPC (q3wk)]] x 8<br />
*BCIRG 0007: [[#TH_.28Taxotere.29_3|TH (Taxotere)]] x 8 versus [[#TCH_.28Taxotere.2C_Carboplatin.29_2|TCH (Taxotere)]] x 8<br />
*CLEOPATRA: [[#TH_.28Taxotere.29_3|TH (Taxotere)]]<br />
*NCIC-CTG MA.31: [[#TH_.28Taxol.29_3|TH (Taxol)]] x 6 or [[#TH_.28Taxotere.29_3|TH (Taxotere)]] x 8<br />
<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, weekly dosing {{#subobject:1ac92c|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.04.173 Marty et al. 2005 (M77001)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|[http://www.clinical-breast-cancer.com/article/S1526-8209(11)70461-X/abstract Perez et al. 2005 (NCCTG 983252)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.04.1764 Robert et al. 2006]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*M77001: [[#TH_.28Taxotere.29_3|TH (Taxotere)]] for at least 6 cycles<br />
*NCCTG 983252: [[#TPC|TPC (weekly)]] x 6<br />
*Robert et al. 2006: [[#TH_.28Taxol.29_3|TP]] x 6 versus [[#TPC|TPC]] x 6<br />
====Targeted therapy====<br />
*[[Trastuzumab (Herceptin)]] 2 mg/kg IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''M77001:''' Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Antón A, Lluch A, Kennedy J, O'Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005 Jul 1;23(19):4265-74. Epub 2005 May 23. [https://doi.org/10.1200/jco.2005.04.173 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15911866 PubMed]<br />
# '''NCCTG 983252:''' Perez EA, Suman VJ, Rowland KM, Ingle JN, Salim M, Loprinzi CL, Flynn PJ, Mailliard JA, Kardinal CG, Krook JE, Thrower AR, Visscher DW, Jenkins RB. Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer. 2005 Dec;6(5):425-32. [http://www.clinical-breast-cancer.com/article/S1526-8209(11)70461-X/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/16381626 PubMed]<br />
# Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R, Cobleigh M, Albain K, McCullough C, Fuchs L, Slamon D. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006 Jun 20;24(18):2786-92. [https://doi.org/10.1200/jco.2005.04.1764 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16782917 PubMed]<br />
# '''BCIRG 007:''' Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, von Minckwitz G, Roche H, Martin M, Crown J, Mackey JR, Fumoleau P, Rolski J, Mrsic-Krmpotic Z, Jagiello-Gruszfeld A, Riva A, Buyse M, Taupin H, Sauter G, Press MF, Slamon DJ. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol. 2011 Jan 10;29(2):149-56. Epub 2010 Nov 29. [https://doi.org/10.1200/jco.2010.28.6450 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21115860 PubMed] NCT00047255<br />
# '''CLEOPATRA:''' Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. Epub 2011 Dec 7. [https://www.nejm.org/doi/full/10.1056/NEJMoa1113216 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705202/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22149875 PubMed] NCT00567190<br />
## '''Update:''' Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. Epub 2013 Apr 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70130-X/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076842/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23602601 PubMed]<br />
## '''Update:''' Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. [https://www.nejm.org/doi/full/10.1056/NEJMoa1413513 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25693012 PubMed]<br />
# '''NCIC-CTG MA.31:''' Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, Di Leo A, Martin M, Schwartzberg LS, Lemieux J, Aparicio S, Shepherd LE, Dent S, Ellard SL, Tonkin K, Pritchard KI, Whelan TJ, Nomikos D, Nusch A, Coleman RE, Mukai H, Tjulandin S, Khasanov R, Rizel S, Connor AP, Santillana SL, Chapman JA, Parulekar WR. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC-CTG MA.31. J Clin Oncol. 2015 May 10;33(14):1574-83. Epub 2015 Mar 16. [https://doi.org/10.1200/JCO.2014.56.9590 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25779558 PubMed] NCT00667251<br />
<br />
=Additional resources=<br />
*[http://www.cancer.gov/bcrisktool/ Gail model Breast Cancer Risk Assessment Tool]<br />
**[[Gail model breast cancer risk factors]]<br />
*[[Breast cancer BRCA1 & BRCA2 genetic testing]]<br />
*[http://www.adjuvantonline.com/index.jsp/ Adjuvant! Online (requires login)]<br />
*[http://www.mycancergenome.org/content/disease/breast-cancer/ My Cancer Genome]<br />
<br />
=Patient information=<br />
*[http://www.lakeviewhealth.com/alcohol-increase-breast-cancer-risk-factors-infographic.php Alcohol and risk of breast cancer infographic]<br />
<br />
[[Category:Breast cancer regimens]]<br />
[[Category:Biomarker-specific pages]]<br />
[[Category:Malignant breast neoplasm]]</div>Karinehttps://hemonc.org/w/index.php?title=Urothelial_carcinoma&diff=49604Urothelial carcinoma2021-05-12T20:16:38Z<p>Karine: reference for RTOG 0524</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" style="color:white; font-size:125%; background-color:#08519c" align="center" |'''Page editor'''<br />
! colspan="2" style="color:white; font-size:125%; background-color:#08519c" align="center" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:RisaWong.jpg|frameless|upright=0.3|center]]<br />
|<big>Risa L. Wong, MD<br>University of Washington<br>Fred Hutchinson Cancer Research Center<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/RisaWongMD RisaWongMD]<br />
| style="background-color:#F0F0F0" |[[File:Alikhaki.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Alikhaki|Ali Raza Khaki, MD]]<br>Stanford University<br>Palo Alto, CA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/arkhaki arkhaki]<br />
|-<br />
|}<br />
''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Bladder_cancer_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Bladder cancer - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''.<br />
<br><big>Note: the page has adjuvant and perioperative regimens specific to bladder cancer as well as systemic regimens for the more general category of urothelial cancer. <br />
<br />
*See the [[Upper tract urothelial carcinoma|'''upper tract urothelial carcinoma page''']] for regimens specific to UTUC.</big><br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==AUA, ASCO, ASTRO, SUO==<br />
<br />
*'''2017:''' Chang et al. [http://www.auanet.org/guidelines/muscle-invasive-bladder-cancer-new-(2017) Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO Guideline] [https://pubmed.ncbi.nlm.nih.gov/28456635 PubMed]<br />
<br />
==EAU-ESMO==<br />
<br />
*'''2019:''' Horwich et al. [https://academic.oup.com/annonc/article/30/11/1697/5629133 EAU–ESMO consensus statements on the management of advanced and variant bladder cancer—an international collaborative multi-stakeholder effort: under the auspices of the EAU and ESMO Guidelines Committees]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2019:''' [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer/eUpdate-Bladder-Cancer-Treatment-Recommendations1 eUpdate – Bladder Cancer Treatment Recommendations]<br />
*'''2019:''' [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer/eUpdate-Bladder-Cancer-Treatment-Recommendations2 eUpdate – Bladder Cancer Treatment Recommendations - Subsequent treatments post-chemotherapy or immunotherapy]<br />
*'''2014:''' Bellmunt et al. [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer Bladder cancer: ESMO Clinical Practice Guidelines] [https://pubmed.ncbi.nlm.nih.gov/25096609 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf NCCN Guidelines - Bladder Cancer]<br />
<br />
=Nonmuscle invasive bladder cancer/Intravesical chemotherapy=<br />
==Bacillus Calmette-Guérin (BCG) monotherapy {{#subobject:eojb2c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, low-dose (27 mg) {{#subobject:52ca75|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/j.eururo.2007.04.062 Ojea et al. 2007 (CUETO study 95011)]<br />
| rowspan="2" |1995-1998<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[Bladder_cancer#Mitomycin_monotherapy|Mitomycin]]<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|2. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]; very-low-dose<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#TURBT|TURBT]], within 14 to 21 days<br />
<br />
====Immunotherapy, induction====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 27 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
'''6-week course, then proceed to additional therapy'''<br />
<br />
====Immunotherapy, continuation====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 27 mg intravesicularly once on day 1<br />
<br />
'''14-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, intravesical (81 mg) & percutaneous, with maintenance therapy {{#subobject:221dfe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.auajournals.org/article/S0022-5347(05)67707-5/fulltext Lamm et al. 2000 (SWOG 8507)]<br />
|1985-1988<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|Intravesical & percutaneous BCG, without maintenance therapy<br />
| style="background-color:#1a9850" |Superior RFS<br />
|-<br />
|}<br />
====Immunotherapy, induction====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 81 mg in 50.5 mL saline suspension is created and administered as follows:<br />
**50 mL (~80.2 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15, 22, 29, 36. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.<br />
**0.5 mL (~0.8 mg) applied once per day on days 1, 8, 15, 22, 29, 36 to the inner thigh, which is first cleaned with alcohol. For percutaneous administration, the skin is punctured 3 times with a sterile 28 gauge needle. Each subsequent administration alternates between thighs (i.e. left thigh on one week, right thigh the next week, left thigh the week after, etc.).<br />
<br />
'''6-week course, then proceed to maintenance therapy'''<br />
<br />
====Immunotherapy, maintenance====<br />
''The authors were a bit unclear about the schedule of maintenance therapy. This is our best interpretation of how the schedule was described.''<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 81 mg in 50.5 mL saline suspension is created and administered as follows:<br />
**50 mL (~80.2 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.<br />
**0.5 mL (~0.8 mg) applied once per day on days 1, 8, 15 to the inner thigh, which is first cleaned with alcohol. For percutaneous administration, the skin is punctured 3 times with a sterile 28 gauge needle. Each subsequent administration alternates between thighs (i.e. left thigh on one week, right thigh the next week, left thigh the week after, etc.).<br />
<br />
'''3-week courses; each course is given at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, and 36 months after the start of induction therapy'''<br />
<br />
===Regimen variant #3, intravesical (81 mg) & percutaneous, without maintenance therapy {{#subobject:f5c250|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.auajournals.org/article/S0022-5347(05)67707-5/fulltext Lamm et al. 2000 (SWOG 8507)]<br />
|1985-1988<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Intravesical & percutaneous BCG, with maintenance therapy<br />
| style="background-color:#d73027" |Inferior RFS<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 81 mg in 50.5 mL saline suspension is created and administered as follows:<br />
**50 mL (~80.2 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15, 22, 29, 36. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.<br />
**0.5 mL (~0.8 mg) applied once per day on days 1, 8, 15, 22, 29, 36 to the inner thigh, which is first cleaned with alcohol. For percutaneous administration, the skin is punctured 3 times with a sterile 28 gauge needle. Each subsequent administration alternates between thighs (i.e. left thigh on one week, right thigh the next week, left thigh the week after, etc.).<br />
<br />
'''6-week course'''<br />
<br />
===Regimen variant #4, intravesical (120 mg) & percutaneous, with maintenance therapy {{#subobject:8e5276|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJM199110243251703 Lamm et al. 1991 (SWOG 8216)]<br />
|1983-1985<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|[[#Doxorubicin_monotherapy|Doxorubicin]]<br />
| style="background-color:#91cf60" |Seems to have superior DFS<br />
|-<br />
|}<br />
====Immunotherapy, induction====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 120 mg (3 vials) in 50.5 mL saline suspension is created and administered as follows:<br />
**50 mL (~120 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15, 22, 29, 36. Patients retain the BCG suspension for up to 2 hours if possible.<br />
**0.5 mL (~1.2 mg) applied once per day on days 1, 8, 15, 22, 29, 36 to the upper part of the inner thigh<br />
<br />
'''6-week course, then proceed to maintenance therapy'''<br />
<br />
====Immunotherapy, maintenance====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 120 mg (3 vials) in 50.5 mL saline suspension is created and administered as follows:<br />
**50 mL (~120 mg) intravesicularly once on day 1. Patients retain the BCG suspension for up to 2 hours if possible.<br />
**0.5 mL (~1.2 mg) applied once on day 1 to the upper part of the inner thigh<br />
<br />
'''Given at 3 months, 6 months, 12 months, 18 months, and 24 months'''<br />
<br />
===Regimen variant #5, 150 mg {{#subobject:d04712|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/s0022-5347(17)40002-4 Martínez-Piñeiro et al. 1990]<br />
| rowspan="2" |1980-1988<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|1. [[#Doxorubicin_monotherapy|Doxorubicin]]<br> 2. [[#Thiotepa_monotherapy|Thiotepa]]<br />
| style="background-color:#1a9850" |Superior RFS<br />
|-<br />
|}<br />
''Note: details are very sparse in the abstract and this is probably only of historic interest.''<br />
====Immunotherapy====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)]] 150 mg intravesicularly x 15 treatments<br />
<br />
===References===<br />
<br />
#Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. [https://doi.org/10.1016/s0022-5347(17)40002-4 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/2106041 PubMed]<br />
#'''SWOG 8216:''' Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA Jr, Sullivan J, Sarosdy MF, Crissman JD, Coltman CA. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med. 1991 Oct 24;325(17):1205-9. [https://www.nejm.org/doi/10.1056/NEJM199110243251703 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1922207 PubMed]<br />
#'''SWOG 8507:''' Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, Sarosdy MF, Bohl RD, Grossman HB, Beck TM, Leimert JT, Crawford ED. Maintenance bacillus Calmette-Guérin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000 Apr;163(4):1124-9. [http://www.auajournals.org/article/S0022-5347(05)67707-5/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10737480 PubMed]<br />
#'''Meta-analysis:''' Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guérin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol. 2002 Nov;168(5):1964-70. [http://www.auajournals.org/article/S0022-5347(05)64273-5/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/12394686 PubMed]<br />
#'''CUETO study 95011:''' Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, Chantada V, Camacho JE, Piñeiro LM, Rodríguez RH, Isorna S, Blas M, Martínez-Piñeiro JA, Madero R; CUETO. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guérin (27 mg) versus very low-dose bacillus Calmette-Guérin (13.5 mg) versus mitomycin C. Eur Urol. 2007 Nov;52(5):1398-406. Epub 2007 Apr 27. [https://doi.org/10.1016/j.eururo.2007.04.062 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17485161 PubMed]<br />
<br />
==Doxorubicin monotherapy {{#subobject:8034b6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:49ccdb|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0022-5347(17)40002-4 Martínez-Piñeiro et al. 1990]<br />
| rowspan="2" |1980-1988<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]<br />
| style="background-color:#d73027" |Inferior RFS<br />
|-<br />
|2. [[#Thiotepa_monotherapy|Thiotepa]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJM199110243251703 Lamm et al. 1991 (SWOG 8216)]<br />
|1983-1985<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]<br />
| style="background-color:#fc8d59" |Seems to have inferior DFS<br />
|-<br />
|}<br />
''Inferior to BCG, included for reference purposes only.''<br />
====Chemotherapy====<br />
<br />
*[[Doxorubicin (Adriamycin)]]<br />
<br />
'''15 or more treatments'''<br />
<br />
===References===<br />
<br />
#Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. [https://doi.org/10.1016/s0022-5347(17)40002-4 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/2106041 PubMed]<br />
#'''SWOG 8216:''' Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA Jr, Sullivan J, Sarosdy MF, Crissman JD, Coltman CA. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med. 1991 Oct 24;325(17):1205-9. [https://www.nejm.org/doi/10.1056/NEJM199110243251703 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1922207 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:343fc9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 1 treatment {{#subobject:170d3b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/2680547 Messing et al. 2018 (SWOG S0337)]<br />
|2008-2012<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Placebo (saline)<br />
| style="background-color:#1a9850" |Superior TTR<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#TURBT|TURBT]], up to 3 hours prior<br />
<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 2000 mg in 100 mL of saline instilled intravesicularly for up to 60 minutes<br />
<br />
'''One treatment'''<br />
<br />
===Regimen variant #2, 6 treatments {{#subobject:fa5bb2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2008.20.8199 Addeo et al. 2009]<br />
|2003-2005<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Mitomycin_monotherapy|Mitomycin]]<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 2000 mg in 50 mL of saline instilled intravesicularly for up to 60 minutes once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
<br />
#Addeo R, Caraglia M, Bellini S, Abbruzzese A, Vincenzi B, Montella L, Miragliuolo A, Guarrasi R, Lanna M, Cennamo G, Faiola V, Del Prete S. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. J Clin Oncol. 2010 Feb 1;28(4):543-8. Epub 2009 Oct 19. [https://doi.org/10.1200/JCO.2008.20.8199 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19841330 PubMed]<br />
#'''SWOG S0337:''' Messing EM, Tangen CM, Lerner SP, Sahasrabudhe DM, Koppie TM, Wood DP Jr, Mack PC, Svatek RS, Evans CP, Hafez KS, Culkin DJ, Brand TC, Karsh LI, Holzbeierlein JM, Wilson SS, Wu G, Plets M, Vogelzang NJ, Thompson IM Jr. Effect of intravesical instillation of gemcitabine vs saline immediately following resection of suspected low-grade non-muscle-invasive bladder cancer on tumor recurrence: SWOG S0337 randomized clinical trial. JAMA. 2018 May 8;319(18):1880-1888. [https://jamanetwork.com/journals/jama/fullarticle/2680547 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29801011 PubMed] NCT00445601<br />
<br />
==Mitomycin monotherapy {{#subobject:2e5944|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 30 mg x 12 {{#subobject:347e3e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/j.eururo.2007.04.062 Ojea et al. 2007 (CUETO study 95011)]<br />
| rowspan="2" |1995-1998<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]; low-dose<br />
| style="background-color:#d73027" |Inferior DFS<br />
|-<br />
|2. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]; very-low-dose<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#TURBT|TURBT]], 14 to 21 days prior<br />
<br />
====Chemotherapy====<br />
<br />
*[[Mitomycin (Mutamycin)]] as follows:<br />
**Cycles 1 to 3: 30 mg intravesicularly once per day on days 1 & 8<br />
**Cycles 4 to 9: 30 mg intravesicularly once on day 1<br />
<br />
'''14-day cycle for 9 cycles'''<br />
<br />
===Regimen variant #2, 40 mg x 11 {{#subobject:531377|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2011.39.2936 Lammers et al. 2012]<br />
|2003-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Keyhole limpet hemocyanin<br />
| style="background-color:#1a9850" |Superior RFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#TURBT|TURBT]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Mitomycin (Mutamycin)]] 40 mg intravesicularly once on day 1<br />
<br />
'''7-day cycle for 4 cycles, then monthly cycle for 4 cycles, then 3-month cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''CUETO study 95011:''' Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, Chantada V, Camacho JE, Piñeiro LM, Rodríguez RH, Isorna S, Blas M, Martínez-Piñeiro JA, Madero R; CUETO. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guérin (27 mg) versus very low-dose bacillus Calmette-Guérin (13.5 mg) versus mitomycin C. Eur Urol. 2007 Nov;52(5):1398-406. Epub 2007 Apr 27. [https://doi.org/10.1016/j.eururo.2007.04.062 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17485161 PubMed]<br />
#Lammers RJ, Witjes WP, Janzing-Pastors MH, Caris CT, Witjes JA. Intracutaneous and intravesical immunotherapy with keyhole limpet hemocyanin compared with intravesical mitomycin in patients with non-muscle-invasive bladder cancer: results from a prospective randomized phase III trial. J Clin Oncol. 2012 Jun 20;30(18):2273-9. Epub 2012 May 14. [https://doi.org/10.1200/JCO.2011.39.2936 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22585689 PubMed]<br />
<br />
==Pembrolizumab monotherapy {{#subobject:3cb963|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7ae9e3|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2019.37.7_suppl.350 Balar et al. (KEYNOTE-057)]<br />
|NR in abstract<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycle for 35 cycles (2 years)'''<br />
====References====<br />
<br />
#'''Abstract:''' Keynote-057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guerin (BCG). Arjun Vasant Balar, Girish S. Kulkarni, Edward M. Uchio, Joost Boormans, Loic Mourey, Laurence Eliot Miles Krieger, Eric A. Singer, Dean F. Bajorin, Ashish M. Kamat, Petros Grivas, Ho Kyung Seo, Hiroyuki Nishiyama, Badrinath R. Konety, Kijoeng Nam, Ekta Kapadia, Tara L. Frenkl, Ronald De Wit. Journal of Clinical Oncology 2019 37:7_suppl, 350-350. [https://doi.org/10.1200/JCO.2019.37.7_suppl.350 link to abstract] NCT02625961<br />
<br />
==Thiotepa monotherapy {{#subobject:5b9d6c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:97d2e7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0022-5347(17)40002-4 Martínez-Piñeiro et al. 1990]<br />
| rowspan="2" |1980-1988<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]<br />
| style="background-color:#d73027" |Inferior RFS<br />
|-<br />
|2. [[#Doxorubicin_monotherapy|Doxorubicin]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Inferior to BCG, included for reference purposes only.''<br />
====Chemotherapy====<br />
<br />
*[[Thiotepa (Thioplex)]] 50 mg intravesicularly x 15 treatments<br />
<br />
===References===<br />
<br />
#Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. [https://doi.org/10.1016/s0022-5347(17)40002-4 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/2106041 PubMed]<br />
<br />
==Valrubicin monotherapy {{#subobject:58jgac|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:74j2e7|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2967799-3 Steinberg et al. 2000]<br />
|1993-1996<br />
| style="background-color:#91cf61" |Non-randomized (RT)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Valrubicin (Valstar)]] 800 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
<br />
#Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M; Valrubicin Study Group. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guérin refractory carcinoma in situ of the bladder. J Urol. 2000 Mar;163(3):761-7. Erratum in: J Urol. 2008 Jan;179(1):386. [https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2967799-3 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10687972 PubMed]<br />
<br />
=Neoadjuvant chemotherapy=<br />
==Atezolizumab monotherapy {{#subobject:3cb963|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7ae9e3|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/s41591-019-0628-7 Powles et al. 2019 (ABACUS)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)|Atezolizumab]] 1200 mg IV over 60 minutes once on day 1<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Cystectomy|Radical cystectomy]] to be performed 4 to 8 weeks after completion of chemotherapy<br />
<br />
===References===<br />
<br />
#'''ABACUS:''' Powles T, Kockx M, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, Szabados B, Pous AF, Gravis G, Herranz UA, Protheroe A, Ravaud A, Maillet D, Mendez MJ, Suarez C, Linch M, Prendergast A, van Dam PJ, Stanoeva D, Daelemans S, Mariathasan S, Tea JS, Mousa K, Banchereau R, Castellano D. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med. 2019 Nov 4. [https://www.nature.com/articles/s41591-019-0628-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31686036 PubMed] NCT02662309<br />
<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:d08e11|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GC: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin<br />
===Regimen variant #1, single-dose cisplatin {{#subobject:dc99d5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585515/ Dash et al. 2008]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Bladder_cancer_surgery|Surgery]]<br />
<br />
===Regimen variant #2, split-dose cisplatin {{#subobject:be43aa|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585515/ Dash et al. 2008]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Bladder_cancer_surgery|Surgery]]<br />
<br />
===References===<br />
<br />
#'''Retrospective:''' Dash A, Pettus JA 4th, Herr HW, Bochner BH, Dalbagni G, Donat SM, Russo P, Boyle MG, Milowsky MI, Bajorin DF. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer. 2008 Nov 1;113(9):2471-7. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585515/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18823036 PubMed]<br />
<br />
==MCV {{#subobject:553fe2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MCV: '''<u>M</u>'''ethotrexate, '''<u>C</u>'''isplatin, '''<u>V</u>'''inblastine<br />
<br>CMV: '''<u>C</u>'''isplatin, '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine<br />
===Regimen variant #1, 2 cycles {{#subobject:450c9f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJM199311043291903 Kaufman et al. 1993]<br />
|NR<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.1996.14.1.119 Tester et al. 1996 (RTOG 88-02)]<br />
|1988-1990<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.1998.16.11.3576 Shipley et al. 1998 (RTOG 89-03)]<br />
|1990-1993<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant chemotherapy]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*Kaufman et al. 1993, CR: [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]<br />
*RTOG 88-02 & 89-03: [[#Cisplatin_.26_RT|Cisplatin & RT induction]]<br />
<br />
===Regimen variant #2, 3 cycles {{#subobject:3d008f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02292-8/abstract Griffiths et al. 1999 (BA06 30894)]<br />
|1989-1995<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 Zapatero et al. 2000]<br />
|1989-1997<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for BA06 30894 is based on the 2011 update.''<br><br />
''Patients in Zapatero et al. 2000 had T2 to T4 Nx M0 disease.''<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 2, before hydration<br />
*[[Vinblastine (Velban)]] 4 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*'''BA06 30894:''' [[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> IV or PO every 6 hours on days 2 & 9, given after hydration, with the first dose 24 hours after the previous day's dose of [[Methotrexate (MTX)]] (total dose per cycle: 120 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
====Subsequent treatment====<br />
<br />
*Zapatero et al. 2000: after 3 cycles of chemotherapy, patients underwent cystoscopy, biopsy, and abdominal CT<br />
**Patients with CR or who were not surgical candidates: [[#Radiation_therapy|RT consolidation]] which begins 4 to 6 weeks after completion of chemotherapy<br />
**Otherwise, patients proceeded to [[Surgery#Cystectomy|cystectomy]]<br />
<br />
===References===<br />
<br />
#Kaufman DS, Shipley WU, Griffin PP, Heney NM, Althausen AF, Efird JT. Selective bladder preservation by combination treatment of invasive bladder cancer. N Engl J Med. 1993 Nov 4;329(19):1377-82. [https://www.nejm.org/doi/10.1056/NEJM199311043291903 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8413433 PubMed]<br />
#'''RTOG 88-02:''' Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. [https://doi.org/10.1200/jco.1996.14.1.119 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8558186 PubMed]<br />
#'''RTOG 89-03:''' Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. [https://doi.org/10.1200/jco.1998.16.11.3576 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9817278 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''BA06 30894:''' Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; CUETO; International Collaboration of Trialists. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. Lancet. 1999 Aug 14;354(9178):533-40. Erratum in: Lancet 1999 Nov 6;354(9190):1650. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02292-8/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/10470696 PubMed]<br />
##'''Update:''' Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group); [[Study_Groups#EORTC|EORTC]] Genito-Urinary Tract Cancer Group; Australian Bladder Cancer Study Group; National Cancer Institute of Canada Clinical Trials Group; Finnbladder; Norwegian Bladder Cancer Study Group; Club Urologico Espanol de Tratamiento Oncologico Group. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011 Jun 1;29(16):2171-7. Epub 2011 Apr 18. [https://doi.org/10.1200/jco.2010.32.3139 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107740/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21502557 PubMed]<br />
#Zapatero A, Martín de Vidales C, Marín A, Cerezo L, Arellano R, Rabadán M, Pérez-Torrubia A. Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Int J Cancer. 2000 Oct 20;90(5):287-94. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11091353 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439%2809%2900029-5/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19362865 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
<br />
==MVAC {{#subobject:701fbe|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''isplatin<br />
===Regimen variant #1, 2 cycles {{#subobject:0f1661|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdu126 Kitamura et al. 2014 (JCOG0209)]<br />
|2003-2009<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Radical_cystectomy|Radical cystectomy]]<br />
<br />
===Regimen variant #2, 3 cycles {{#subobject:dc2c80|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa022148 Grossman et al. 2003 (SWOG S8710)]<br />
|1987-1998<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
<br />
'''28-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Radical_cystectomy|Radical cystectomy]]<br />
<br />
===References===<br />
<br />
#'''SWOG S8710:''' Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003 Aug 28;349(9):859-66. [https://www.nejm.org/doi/full/10.1056/NEJMoa022148 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12944571 PubMed]<br />
#'''JCOG0209:''' Kitamura H, Tsukamoto T, Shibata T, Masumori N, Fujimoto H, Hirao Y, Fujimoto K, Kitamura Y, Tomita Y, Tobisu K, Niwakawa M, Naito S, Eto M, Kakehi Y; Urologic Oncology Study Group of the Japan Clinical Oncology Group. Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209. Ann Oncol. 2014 Jun;25(6):1192-8. [https://doi.org/10.1093/annonc/mdu126 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24669010 PubMed] UMIN C000000093<br />
##'''HRQoL analysis:''' Kitamura H, Hinotsu S, Tsukamoto T, Shibata T, Mizusawa J, Kobayashi T, Miyake M, Nishiyama N, Kojima T, Nishiyama H; Urologic Oncology Study Group of the Japan Clinical Oncology Group. Effect of neoadjuvant chemotherapy on health-related quality of life in patients with muscle-invasive bladder cancer: results from JCOG0209, a randomized phase III study. Jpn J Clin Oncol. 2020 Dec 16;50(12):1464-1469. [https://doi.org/10.1093/jjco/hyaa123 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32699909 PubMed]<br />
<br />
==MVAC, dose-dense {{#subobject:3cb963|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ddMVAC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''isplatin<br />
<br>AMVAC: '''<u>A</u>'''ccelerated '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''isplatin<br />
===Regimen variant #1, 3 cycles {{#subobject:c4bf38|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050203/ Plimack et al. 2014 (FER-GU-026)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV over 30 minutes once on day 1<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV push once on day 2<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV push once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV in 1 liter normal saline once on day 2<br />
**Split dose could be used at physician discretion for patients with CrCl less than 60 mL/min/1.73m<sup>2</sup>: 35 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
<br />
====Supportive medications====<br />
<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once, 24 to 48 hours after completion of chemotherapy<br />
*Antiemetics used often included [[Aprepitant (Emend)]], [[Ondansetron (Zofran)]], and [[Dexamethasone (Decadron)]] but were not specified by the trial.<br />
<br />
'''14-day cycle for 3 cycles'''<br />
<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Radical_cystectomy|Radical cystectomy]] with bilateral [[Surgery#Lymphadenectomy|lymphadenectomy]], within 4 to 8 weeks after the last cycle of chemotherapy<br />
<br />
===Regimen variant #2, 4 cycles {{#subobject:7ae9e3|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7057274/ Choueiri et al. 2014 (DFCI 08-208)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV over 30 minutes once on day 1<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV push once on day 2<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV push once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV in 1 liter normal saline once on day 2<br />
<br />
====Supportive medications====<br />
<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 3 (approximately 24 hours after day 2 chemotherapy)<br />
<br />
'''14-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Cystectomy|Cystectomy]] to be performed 4 to 10 weeks after completion of chemotherapy<br />
<br />
===References===<br />
<!-- # Angela Q. Qu, Susanna J. Jacobus, Sabina Signoretti, Edward C. Stack, Katherine Maragaret Krajewski, Jonathan E. Rosenberg, Toni K. Choueiri. Phase II study of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) chemotherapy in patients with muscle-invasive urothelial cancer (MI-UC): Pathologic and radiologic response, serum tumor markers, and DNA excision repair pathway biomarkers in relation to disease-free survival (DFS). 2013 ASCO Annual Meeting abstract 4530. [http://meetinglibrary.asco.org/content/117233-132 link to abstract] --><br />
<br />
#'''DFCI 08-208:''' Choueiri TK, Jacobus S, Bellmunt J, Qu A, Appleman LJ, Tretter C, Bubley GJ, Stack EC, Signoretti S, Walsh M, Steele G, Hirsch M, Sweeney CJ, Taplin ME, Kibel AS, Krajewski KM, Kantoff PW, Ross RW, Rosenberg JE. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol. 2014 Jun 20;32(18):1889-94. Epub 2014 May 12. [https://doi.org/10.1200/jco.2013.52.4785 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7057274/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24821883 PubMed] NCT00808639<br />
#'''FER-GU-026:''' Plimack ER, Hoffman-Censits JH, Viterbo R, Trabulsi EJ, Ross EA, Greenberg RE, Chen DY, Lallas CD, Wong YN, Lin J, Kutikov A, Dotan E, Brennan TA, Palma N, Dulaimi E, Mehrazin R, Boorjian SA, Kelly WK, Uzzo RG, Hudes GR. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol. 2014 Jun 20;32(18):1895-901. Epub 2014 May 12. [https://doi.org/10.1200/jco.2013.53.2465 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050203/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24821881 PubMed] NCT01031420<br />
<br />
==Pembrolizumab monotherapy {{#subobject:3cfac3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c4bf38|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://pubmed.ncbi.nlm.nih.gov/30343614 Necchi et al. 2018 (PURE-01)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)|Pembrolizumab]] 200 mg IV over 30 minutes once on day 1<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Radical_cystectomy|Radical cystectomy]], within 1 to 3 weeks after the last cycle of chemotherapy<br />
<br />
===References===<br />
<br />
#'''PURE-01:''' Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Lucianò R, Colecchia M, Giannatempo P, Mortarini R, Bianchi M, Farè E, Monopoli F, Colombo R, Gallina A, Salonia A, Messina A, Ali SM, Madison R, Ross JS, Chung JH, Salvioni R, Mariani L, Montorsi F. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol. 2018 Oct 20. [https://doi.org/10.1200/jco.18.01148 Link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30343614 PubMed] NCT02736266<br />
##'''Update:''' Necchi A, Raggi D, Gallina A, Madison R, Colecchia M, Lucianò R, Montironi R, Giannatempo P, Farè E, Pederzoli F, Bandini M, Bianchi M, Colombo R, Gandaglia G, Fossati N, Marandino L, Capitanio U, Dehò F, Ali SM, Chung JH, Ross JS, Salonia A, Briganti A, Montorsi F. Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies. Eur Urol. 2019 Nov 7. [https://doi.org/10.1016/j.eururo.2019.10.026 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31708296 PubMed]<br />
<br />
=Induction chemoradiotherapy=<br />
<br />
==Cisplatin & RT {{#subobject:ebb6e9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Cisplatin & RT: Cisplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
<br />
===Regimen variant #1, cisplatin 40 mg/m<sup>2</sup> qwk x 3 {{#subobject:f782c3|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract Hagan et al. 2003 (RTOG 97-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|[http://www.urologiconcology.org/article/S1078-1439(09)00029-5/fulltext Zapatero et al. 2009]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
''Patients in '''Zapatero et al. 2000''' had T2 to T4 N0 M0 disease. Patients in RTOG 97-06 had T2 to T4a N0 M0 disease without hydronephrosis.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2 (per Figure 1 of Zapatero, et al. 2010), '''given first'''<br />
<br />
'''7-day cycle for 3 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:<br />
**'''Both trials:''' Accelerated hyperfractionated RT (AHFRT) with twice per day radiation, consisting of 1.8 Gy fractions x 12 fractions to the bladder and regional lymph nodes; 6 hours later, a 1.6 Gy fraction x 12 fractions is given to the "bladder tumor plus wide margin." Radiation therapy given 5 days per week. Total induction dose to bladder tumor: 40.8 Gy; total induction dose to regional lymph nodes: 21.6 Gy.<br />
**'''Zapatero et al. 2000 only:''' Normo-fractionated concurrent radiation therapy, 1.8 to 2 Gy fractions, given 5 times per week. Total induction and consolidation bladder dose of 64 to 66 Gy; total induction and consolidation pelvic lymph node dose of 44 to 46 Gy. Zapatero, et al. 2010 & Zapatero, et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy, nor what adjustments, if any, were made to chemotherapy for this radiation schedule.<br />
<br />
====Subsequent treatment====<br />
<br />
*3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT<br />
**Patients with complete regression (R0): [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]<br />
**Nonresponders: [[Surgery#Cystectomy|Cystectomy]]<br />
<br />
===Regimen variant #2, cisplatin 70 mg/m<sup>2</sup> q3wk x 2 {{#subobject:2443a6|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.1996.14.1.119 Tester et al. 1996 (RTOG 88-02)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#MCV|MCV]] x 2<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 22 fractions (total dose: 39.6 Gy)<br />
<br />
'''4.5-week course'''<br />
====Subsequent treatment====<br />
''Patient is restaged 2 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, urinary cytology, and computed tomographic scan of pelvis."''<br />
<br />
*Patients with CR: [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]<br />
*Patients without CR proceeded immediately to: [[Surgery#Cystectomy|cystectomy]]<br />
<br />
===Regimen variant #3, cisplatin 100 mg/m<sup>2</sup> q3wk x 2 {{#subobject:9a3fd0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/article-abstract/367764 Shipley et al. 1988]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|[https://doi.org/10.1200/jco.1998.16.11.3576 Shipley et al. 1998 (RTOG 89-03)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*RTOG 89-03: [[#MCV|MCV]] versus [[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|no neoadjuvant therapy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 2 cycles''' <br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 22 fractions (total dose: 39.6 Gy)<br />
<br />
'''4.5-week course'''<br />
====Subsequent treatment====<br />
''RTOG 89-03: Patient is restaged 4 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, and urinary cytology." ''<br />
<br />
*RTOG 89-03; Patients not in CR usually proceeded to: [[Surgery#Cystectomy|cystectomy]]<br />
*RTOG 89-03; Patients in complete remission usually proceeded to: [[#Cisplatin_.26_RT_2|cisplatin & RT consolidation]]<br />
<br />
===References===<br />
<br />
#Shipley WU, Prout GR Jr, Einstein AB, Coombs LJ, Wajsman Z, Soloway MS, Englander L, Barton BA, Hafermann MD. Treatment of invasive bladder cancer by cisplatin and radiation in patients unsuited for surgery. JAMA. 1987 Aug 21;258(7):931-5. [https://jamanetwork.com/journals/jama/article-abstract/367764 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3613023 PubMed]<br />
#'''RTOG 88-02:''' Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. [https://doi.org/10.1200/jco.1996.14.1.119 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8558186 PubMed]<br />
#'''RTOG 89-03:''' Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. [https://doi.org/10.1200/jco.1998.16.11.3576 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9817278 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 97-06:''' Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. [http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14529770 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439(09)00029-5/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19362865 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
<br />
==Cisplatin & Fluorouracil (CF) & RT {{#subobject:b5e26|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 90/2400/24 {{#subobject:598234|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://theoncologist.alphamedpress.org/content/5/6/471.long Kaufman et al. 2000 (RTOG 95-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Patients in RTOG 95-06 had clinical T2 to T4a Nx M0 disease without hydronephrosis and CrCl of at least 60 mL/min/1.73m<sup>2</sup>.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3, '''given second, before radiation'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*IV hydration at 500 mL/H (no total volume specified) prior to [[Fluorouracil (5-FU)]]<br />
<br />
'''14-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 3 Gy fractions twice per day, with the first fraction of each day given 1 to 2 hours after completion of chemotherapy and at least 4 hours between fractions, x 8 fractions, given on days 1, 3, 15, 17 (total induction dose: 24 Gy), administered to the whole bladder, bladder tumor volume, and pelvic lymph nodes<br />
<br />
'''17-day course'''<br />
====Dose modifications====<br />
<br />
*Patients with grade III hematologic toxicity, defined as platelets less than 50 x 10<sup>9</sup>/L or ANC less than 1800/uL, had chemotherapy and radiation therapy held for at least one week, with therapy resuming when platelets were at least 100 x 10<sup>9</sup>/L and ANC at least 1800/uL.<br />
<br />
====Subsequent treatment====<br />
<br />
*Treatment followed by repeat cystoscopy, biopsy, and urine cytology in week 7 or 8<br />
**Patients with complete response: [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT consolidation]] in week 9<br />
**Incomplete responders were recommended to undergo [[Surgery#Radical_cystectomy|radical cystectomy]]<br />
<br />
===Regimen variant #2, 135/2400/40.3 {{#subobject:6be392|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ Coen et al. 2018 (RTOG 0712)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Gemcitabine_.26_RT|Gemcitabine & RT]]<br />
|-<br />
|}<br />
''Note: this trial was not statistically powered to compare regimens.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3, 8 to 10, 15 to 17<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, 15 to 17<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:<br />
**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17<br />
**1.5 Gy fractions to the bladder every evening on days 1 to 5<br />
**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17<br />
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.<br />
<br />
'''17-day course'''<br />
====Subsequent treatment====<br />
<br />
*Treatment followed by repeat cystoscopy & biopsy<br />
**Patients with complete response: [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT consolidation]]<br />
**Incomplete responders: [[Surgery#Radical_cystectomy|Radical cystectomy]]<br />
<br />
===Regimen variant #3, 135/3600/40.3 {{#subobject:6be39|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day cycle for 3 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:<br />
**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17<br />
**1.5 Gy fractions to the bladder every evening on days 1 to 5<br />
**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17<br />
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.<br />
<br />
'''3-week course'''<br />
====Subsequent treatment====<br />
<br />
*On week 7, patients under reevaluation for response. <br />
**Patients with less than stage T1 disease: [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT consolidation]]<br />
**Patients with at least stage T1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]] on week 9, then [[#PGC|adjuvant PGC]]<br />
<br />
===References===<br />
<br />
#'''RTOG 95-06:''' Kaufman DS, Winter KA, Shipley WU, Heney NM, Chetner MP, Souhami L, Zlotecki RA, Sause WT, True LD. The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response. Oncologist. 2000;5(6):471-6. [http://theoncologist.alphamedpress.org/content/5/6/471.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11110598 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 0712:''' Coen JJ, Zhang P, Saylor PJ, Lee CT, Wu CL, Parker W, Lautenschlaeger T, Zietman AL, Efstathiou JA, Jani AB, Kucuk O, Souhami L, Rodgers JP, Sandler HM, Shipley WU. Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712-a randomized phase II trial. J Clin Oncol. 2019 Jan 1;37(1):44-51. Epub 2018 Nov 15. [https://doi.org/10.1200/JCO.18.00537 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30433852 PubMed] NCT00777491<br />
<br />
==Cisplatin, Paclitaxel, RT {{#subobject:803f28|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 40/50 x 3 + 40.3 Gy {{#subobject:b7ec20|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract Kaufman et al. 2009 (RTOG 99-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Note: the abstract of Kaufman et al. 2009 said that patients with "greater than Stage T1 disease" were recommended for cystectomy, but Figure 1 clarified that it was greater than or equal to ypT1 disease.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#TURBT|TURBT]], within 4 to 6 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycle for 3 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT on days 1 to 5, 8 to 12, 15 to 17; 4 to 6 hours between radiation sessions. Kaufman et al. 2009 (RTOG 99-06) was unclear about exact radiation treatment plan, but it appears to have been the same as described in Mitin et al. 2013 (RTOG 02-33), which used radiation as follows:<br />
**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17<br />
**1.5 Gy fractions to the bladder every evening on days 1 to 5<br />
**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17<br />
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.<br />
<br />
'''3-week course'''<br />
====Subsequent treatment====<br />
<br />
*On week 7, over 3 weeks after induction therapy, patients under reevaluation with exam under anesthesia, cystoscopy with tumor site biopsy, and urine cytology<br />
**Patients with less than stage ypT1 disease: [[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, paclitaxel, RT consolidation]]<br />
**Patients with at least stage ypT1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]], then [[#Cisplatin_.26_Gemcitabine_.28GC.29_2|adjuvant cisplatin & gemcitabine]]<br />
<br />
===Regimen variant #2, 45/50 x 3 + 40.3 Gy {{#subobject:6ecd8b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|Cisplatin, Fluorouracil, RT]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycle for 3 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:<br />
**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17<br />
**1.5 Gy fractions to the bladder every evening on days 1 to 5<br />
**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17<br />
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.<br />
<br />
'''3-week course''' <br />
====Subsequent treatment====<br />
<br />
*On week 7, patients under reevaluation for response<br />
**Patients with less than stage ypT1 disease: [[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, paclitaxel, RT consolidation]]<br />
**Patients with at least stage ypT1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]] on week 9, then [[#PGC|adjuvant PGC]]<br />
<br />
===References===<br />
<br />
#Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. [http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19100600 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==Fluorouracil, Mitomycin, RT {{#subobject:5e89d1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Fluorouracil, Mitomycin, RT: Fluorouracil, Mitomycin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:6a18dc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 James et al. 2012 (BC2001)]<br />
|2001-2008<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Radiation_therapy_2|Radiation therapy]]<br />
| style="background-color:#91cf60" |Seems to have superior locoregional DFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup>/day IV continuous infusion for 10 total days (total dose: 5000 mg/m<sup>2</sup>) during radiation fractions 1 to 5, 16 to 20<br />
*[[Mitomycin (Mutamycin)]] 12 mg/m<sup>2</sup> IV bolus once on day 1<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] given according to one of the following plans:<br />
**Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.75 Gy fractions x 20 fractions (total dose: 55 Gy)<br />
**Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 32 fractions (total dose: 64 Gy)<br />
<br />
'''4- to 6.5-week course'''<br />
===References===<br />
<br />
#'''BC2001:''' James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-88. [https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1106106/suppl_file/nejmoa1106106_appendix.pdf link to supplementary index] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22512481 PubMed] ISRCTN68324339<br />
<br />
==Gemcitabine & RT {{#subobject:91c0ea|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:6333a7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ Coen et al. 2018 (RTOG 0712)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-de-esc)<br />
|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|CF & RT]]<br />
|-<br />
|}<br />
''Note: this trial was not statistically powered to compare regimens.''<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 27 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
<br />
'''14-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 2 Gy per day to the pelvis on days 1 to 10, then 2 Gy per day to the bladder on days 11 to 14, then 2 Gy per day to the bladder tumor on days 15 to 20<br />
**Total doses: pelvis: 20 Gy; whole bladder: 28 Gy; bladder tumor volume 40 Gy<br />
<br />
'''3-week course'''<br />
====Subsequent treatment====<br />
<br />
*Treatment followed by repeat cystoscopy & biopsy<br />
**Patients with complete response: Gemcitabine & RT consolidation<br />
**Incomplete responders: [[Surgery#Radical_cystectomy|Radical cystectomy]]<br />
<br />
===References===<br />
<br />
#'''RTOG 0712:''' Coen JJ, Zhang P, Saylor PJ, Lee CT, Wu CL, Parker W, Lautenschlaeger T, Zietman AL, Efstathiou JA, Jani AB, Kucuk O, Souhami L, Rodgers JP, Sandler HM, Shipley WU. Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712-a randomized phase II trial. J Clin Oncol. 2019 Jan 1;37(1):44-51. Epub 2018 Nov 15. [https://doi.org/10.1200/JCO.18.00537 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30433852 PubMed] NCT00777491<br />
<br />
==Paclitaxel & RT {{#subobject:89c0ea|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:6222a7|Variant=#1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract Zapatero et al. 2012]<br />
| style="background-color:#ffffbe" |Non-randomized, <20 pts<br />
|-<br />
|}<br />
''Patients who had "mild renal insufficiency" received paclitaxel instead of cisplatin and had T2 to T4 N0 M0 disease.''<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per week, '''given 6 hours before radiation therapy'''<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:<br />
**Accelerated hyperfractionated RT (AHFRT) with twice per day radiation, consisting of 1.8 Gy fractions x 12 fractions to the bladder and regional lymph nodes; 6 hours later, a 1.6 Gy fraction x 12 fractions is given to the "bladder tumor plus wide margin." Total induction dose to bladder tumor: 40.8 Gy; total induction dose to regional lymph nodes: 21.6 Gy. Zapatero et al. 2012 did not specify the precise schedule of radiation therapy.<br />
**Normo-fractionated concurrent radiation therapy, total induction and consolidation dose of 64 to 66 Gy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*3 weeks after finishing radiation and chemotherapy, patients underwent restaging [[Surgery#TURBT|TURBT]]<br />
**Patients with complete regression (R0): [[#Paclitaxel_.26_RT_2|Paclitaxel & RT consolidation]]<br />
**Nonresponders: [[Surgery#Cystectomy|Cystectomy]]<br />
<br />
===References===<br />
<br />
#Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
<br />
===Regimen {{#subobject:6222a7|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.redjournal.org/article/S0360-3016(14)01232-2/fulltext#secsectitle0015 Pham et al. 2014 (RTOG 0524)]<br />
| style="background-color:#ffffbe" |Non-randomized, 47 pts<br />
|-<br />
|}<br />
<br />
==== Chemotherapy ====<br />
<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per week for 7 weeks <br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent daily [[External_beam_radiotherapy|radiation therapy]] 64.8 Gy total in 36 fractions<br />
<br />
===References===<br />
<br />
#Michaelson MD, Hu C, Pham HT, et al. A Phase 1/2 Trial of a Combination of Paclitaxel and Trastuzumab With Daily Irradiation or Paclitaxel Alone With Daily Irradiation After Transurethral Surgery for Noncystectomy Candidates With Muscle-Invasive Bladder Cancer (Trial NRG Oncology RTOG 0524). Int J Radiat Oncol Biol Phys. 2017;97(5):995-1001. <br />
<br />
==Radiation therapy {{#subobject:1103c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:e0ed54|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 Zapatero et al. 2000]<br />
|1989-1997<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 James et al. 2012 (BC2001)]<br />
|2001-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil.2C_Mitomycin.2C_RT|Fluorouracil, Mitomycin, RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior locoregional DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response, treatment in Zapatero et al. 2000 preceded by [[#MCV|MCV]] x 3 or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] as follows:<br />
**CR: 2 Gy fractions given 5 days per week, with total bladder dose of 60 Gy. Total dose to regional lymph nodes: 50 Gy.<br />
**Less than CR: total dose to the bladder of 64 to 66 Gy. No further details given about fractionation, schedule, or dose to lymph nodes.<br />
<br />
===References===<br />
<br />
#Zapatero A, Martín de Vidales C, Marín A, Cerezo L, Arellano R, Rabadán M, Pérez-Torrubia A. Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Int J Cancer. 2000 Oct 20;90(5):287-94. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11091353 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439%2809%2900029-5/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19362865 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
#'''BC2001:''' James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-88. [https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22512481 PubMed] ISRCTN68324339<br />
<br />
=Consolidation chemoradiotherapy=<br />
==Cisplatin & RT {{#subobject:308d11|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Cisplatin & RT: Cisplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen variant #1, cisplatin 40 mg/m<sup>2</sup>/wk x 2 {{#subobject:dc2b84|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 Zapatero et al. 2000]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|[http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract Hagan et al. 2003 (RTOG 97-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response: [[#Cisplatin_.26_RT|Cisplatin & RT induction]] or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2 (per Figure 1 of Zapatero et al. 2010), '''given first'''<br />
<br />
'''7-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:<br />
**'''Both trials:''' Accelerated hyperfractionated RT (AHFRT), 1.5 Gy fractions twice per day x 16 fractions (total consolidation dose: 24 Gy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 64.8 Gy; total dose to lymph nodes is 45.6 Gy.<br />
**'''Zapatero et al. 2000 only:''' Normo-fractionated concurrent radiation therapy, 1.8 to 2 Gy fractions, given 5 times per week. Total induction and consolidation bladder dose of 64 to 66 Gy; total induction and consolidation pelvic lymph node dose of 44 to 46 Gy. Zapatero, et al. 2010 & Zapatero, et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy, nor what adjustments, if any, were made to chemotherapy for this radiation schedule.<br />
<br />
====Subsequent treatment====<br />
<br />
*RTOG 97-06: [[#MCV_2|Adjuvant MCV]]<br />
<br />
===Regimen variant #2, cisplatin 70 mg/m<sup>2</sup> x 1 {{#subobject:314189|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.1996.14.1.119 Tester et al. 1996 (RTOG 88-02)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response, treatment preceded by [[#Cisplatin_.26_RT|cisplatin & RT induction]] or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy==== <br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 14 fractions (total dose in consolidation phase: 25.2 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)<br />
<br />
'''3-week course'''<br />
<br />
===Regimen variant #3, cisplatin 100 mg/m<sup>2</sup> x 1 {{#subobject:7afeca|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.1998.16.11.3576 Shipley et al. 1998 (RTOG 89-03)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response, treatment preceded by [[#Cisplatin_.26_RT|cisplatin & RT induction]] or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy==== <br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 14 fractions (total dose in consolidation phase: 39.6 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)<br />
<br />
'''3-week course'''<br />
<br />
===References===<br />
<br />
#'''RTOG 88-02:''' Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. [https://doi.org/10.1200/jco.1996.14.1.119 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8558186 PubMed]<br />
#'''RTOG 89-03:''' Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. [https://doi.org/10.1200/jco.1998.16.11.3576 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9817278 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#Zapatero A, Martín de Vidales C, Marín A, Cerezo L, Arellano R, Rabadán M, Pérez-Torrubia A. Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Int J Cancer. 2000 Oct 20;90(5):287-94. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11091353 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439%2809%2900029-5/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19362865 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
#'''RTOG 97-06:''' Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. [http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14529770 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==Cisplatin & Fluorouracil (CF) & RT {{#subobject:fe2538|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 30/1200 x 2 + 64.3 Gy {{#subobject:a18497|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, Paclitaxel, RT]]<br />
|-<br />
|}<br />
''Consolidation starts starts on week 8.''<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|Cisplatin, 5-FU, RT induction]]<br />
<br />
====Chemotherapy==== <br />
''Starts on week 8.''<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions x 16 fractions, given twice per day x 8 days. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.<br />
<br />
'''2-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[#PGC|Adjuvant PGC]]<br />
<br />
===Regimen variant #2, 45/1200 x 2 + 44 Gy {{#subobject:904a96|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://theoncologist.alphamedpress.org/content/5/6/471.long Kaufman et al. 2000 (RTOG 95-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Treatment starts on week 9.''<br />
====Preceding treatment====<br />
<br />
*Depending on response, treatment preceded by [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|cisplatin, fluorouracil, RT induction]] or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy==== <br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, '''given first'''<br />
<br />
'''14-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.5 Gy fractions twice per day, with at least 4 hours between fractions, x 8 fractions, given on days 1, 3, 15, 17 (total consolidation dose: 20 Gy), administered to the whole bladder and bladder tumor volume. The total dose to the whole bladder and bladder tumor volume was 44 Gy in 16 fractions; the total dose to the pelvic lymph nodes was 24 Gy in 8 fractions.<br />
<br />
====Dose modifications====<br />
<br />
*Patients with grade III hematologic toxicity, defined as platelets less than 50 x 10<sup>9</sup>/L or ANC less than 1800/uL, had chemotherapy and radiation therapy held for at least one week, with therapy resuming when platelets were at least 100 x 10<sup>9</sup>/L and ANC at least 1800/uL.<br />
<br />
====Supportive medications====<br />
<br />
*IV hydration at 500 mL/H (no total volume specified) prior to [[Fluorouracil (5-FU)]]<br />
<br />
'''17-day course'''<br />
<br />
===References===<br />
<br />
#'''RTOG 95-06:''' Kaufman DS, Winter KA, Shipley WU, Heney NM, Chetner MP, Souhami L, Zlotecki RA, Sause WT, True LD. The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response. Oncologist. 2000;5(6):471-6. [http://theoncologist.alphamedpress.org/content/5/6/471.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11110598 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==Cisplatin, Paclitaxel, RT {{#subobject:4bc0dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 30/50 x 2 + 64.3 Gy {{#subobject:9fefbd|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|Cisplatin, 5-FU, RT]]<br />
|-<br />
|}<br />
''Consolidation starts starts on week 8.''<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT induction]]<br />
<br />
====Chemotherapy==== <br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions x 16 fractions, given twice per day x 8 days. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.<br />
<br />
'''2-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[#PGC|Adjuvant PGC]]<br />
<br />
===Regimen variant #2, 40/50 x 2 + 64.3 Gy {{#subobject:6bec62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract Kaufman et al. 2009 (RTOG 99-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Consolidation starts starts on week 8.''<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT induction]]<br />
<br />
====Chemotherapy==== <br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions x 16 fractions, given twice per day (4 to 6 hour interval between treatments) on days 1 to 5, 8 to 10. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.<br />
<br />
'''2-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[#Cisplatin_.26_Gemcitabine_.28GC.29_2|Adjuvant cisplatin & gemcitabine]]<br />
<br />
===References===<br />
<br />
#'''RTOG 99-06:''' Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. [http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19100600 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==Paclitaxel & RT {{#subobject:039b5c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:de252a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract Zapatero et al. 2012]<br />
| style="background-color:#ffffbe" |Non-randomized, <20 pts<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response, treatment preceded by [[#Paclitaxel_.26_RT|paclitaxel & RT induction]] or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per week, given 6 hours before radiation therapy<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:<br />
**Accelerated hyperfractionated RT (AHFRT), 1.5 Gy fractions twice per day x 16 fractions (total consolidation dose: 24 Gy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 64.8 Gy; total dose to lymph nodes is 45.6 Gy.<br />
**Normo-fractionated concurrent radiation therapy, total induction and consolidation dose of 64 to 66 Gy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.<br />
<br />
'''One course'''<br />
===References===<br />
<br />
#Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
<br />
=Adjuvant chemotherapy=<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:684e48|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:72a413|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract Kaufman et al. 2009 (RTOG 99-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response to induction, treatment starts 12 weeks after [[#Cisplatin.2C_Paclitaxel.2C_RT_2|cisplatin, paclitaxel, RT consolidation]], or 8 weeks after [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. [http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19100600 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==Cisplatin & Methotrexate {{#subobject:684e48|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:72a413|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.11.094 Lehmann et al. 2005 (AUO-AB 05/95)]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|M-VEC x 3<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS<br />
| style="background-color:#1a9850" |Less toxic<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Cystectomy|Radical cystectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]]<br />
*[[Methotrexate (MTX)]]<br />
<br />
===References===<br />
<br />
#'''AUO-AB 05/95:''' Lehmann J, Retz M, Wiemers C, Beck J, Thüroff J, Weining C, Albers P, Frohneberg D, Becker T, Funke PJ, Walz P, Langbein S, Reiher F, Schiller M, Miller K, Roth S, Kälble T, Sternberg D, Wellek S, Stöckle M; AUO. Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter, phase III trial (AUO-AB 05/95). J Clin Oncol. 2005 Aug 1;23(22):4963-74. Epub 2005 Jun 6. [https://doi.org/10.1200/JCO.2005.11.094 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15939920 PubMed]<br />
<br />
==MCV {{#subobject:8e6bb8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MCV: '''<u>M</u>'''ethotrexate, '''<u>C</u>'''isplatin, '''<u>V</u>'''inblastine<br />
<br />
===Regimen {{#subobject:ca6708|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract Hagan et al. 2003 (RTOG 97-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Begins 8 weeks after consolidation. Note that only 45% of patients in RTOG 97-06 were able to complete all 3 cycles of MCV.''<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 2 to 4<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. [http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14529770 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==PGC {{#subobject:22e1d2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PGC: '''<u>P</u>'''aclitaxel, '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin<br />
<br>PCG: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''isplatin, '''<u>G</u>'''emcitabine<br />
===Regimen variant #1 {{#subobject:ad1bc8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2010.28.18_suppl.lba4518 Paz-Ares et al 2010 (SOGUG 99/01)]<br />
|2000-2007<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#Observation_2|Observation]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Patients in SOGUG 99/01 had pT3-4 and/or pN positive disease with adequate renal function (CrCl greater than 50 mL/min/1.73m<sup>2</sup>). The study prematurely closed due to poor recruitment and lacks adequate power to make firm conclusions, and has never been published in manuscript format.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Cystectomy|Cystectomy]]; the median time treatment started post-cystectomy was 48 days<br />
<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 80 mg mg/2 IV once per day on days 1 & 8<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:29bee9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response, adjuvant chemotherapy began 12 weeks after [[#Cisplatin.2C_Paclitaxel.2C_RT_2|cisplatin, paclitaxel, RT]] versus [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|cisplatin, 5-FU, RT]] or 8 weeks after [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#'''Abstract:''' L. G. Paz-Ares, E. Solsona, E. Esteban, A. Saez, J. Gonzalez-Larriba, A. Anton, M. Hevia, F. de la Rosa, V. Guillem, and J. Bellmunt. Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study. ASCO MEETING ABSTRACTS Jun 22, 2010:LBA4518. [https://doi.org/10.1200/jco.2010.28.18_suppl.lba4518 link to abstract] '''contains verified protocol'''<br />
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
=Locally advanced or metastatic disease, first-line, platinum-ineligible=<br />
==Atezolizumab monotherapy {{#subobject:1d9e29|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:764948|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |Years of enrollment<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568632/ Balar et al. 2016 (IMvigor210)]<br />
|2014-2015<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#88419d; color:white " |ORR: 23% (95% CI 16-31)<br />
|-<br />
|}<br />
<big>'''On 8/16/2018 the FDA updated the prescribing information for atezolizumab to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are cisplatin-ineligible.'''</big><br />
<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''IMvigor210:''' Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, Dawson NA, van der Heijden MS, Dreicer R, Srinivas S, Retz MM, Joseph RW, Drakaki A, Vaishampayan UN, Sridhar SS, Quinn DI, Durán I, Shaffer DR, Eigl BJ, Grivas PD, Yu EY, Li S, Kadel EE 3rd, Boyd Z, Bourgon R, Hegde PS, Mariathasan S, Thåström A, Abidoye OO, Fine GD, Bajorin DF; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017 Jan 7;389(10064):67-76. Epub 2016 Dec 8. [http://thelancet.com/journals/lancet/article/PIIS0140-6736(16)32455-2/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568632/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27939400 PubMed] NCT02951767<br />
<br />
<br /><br />
<br />
==Pembrolizumab monotherapy {{#subobject:7fc2f6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:946aec|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |Years of enrollment<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30616-2/fulltext Balar et al. 2017 (KEYNOTE-052)]<br />
|2015-2016<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#88419d; color:white " |ORR: 24% (95% CI 20-29)<br />
|-<br />
|} <br />
<big>'''On 5/18/2018 the FDA released a warning that patients in the monotherapy arms of the ongoing KEYNOTE-361 trial with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy.'''</big><br />
<br />
<big>'''On 8/16/2018 the FDA updated the prescribing information for pembrolizumab to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are cisplatin-ineligible.'''</big><br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''KEYNOTE-052:''' Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, Savage MJ, Perini RF, Keefe SM, Bajorin D, Bellmunt J. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Nov;18(11):1483-1492. Epub 2017 Sep 26. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30616-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28967485 PubMed] NCT02335424<br />
<br />
=Locally advanced or metastatic disease, first-line, platinum-eligible=<br />
<br />
==Atezolizumab monotherapy {{#subobject:1d9e29|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===Regimen {{#subobject:764948|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]<br />
| rowspan="2" |2016-2018<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|1. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]<br> 2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|3. [[#GCb_.26_Atezolizumab|GCb & Atezolizumab]]<br> 4. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Atezolizumab|GC & Atezolizumab]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''IMvigor130:''' Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636<br />
<br />
==Carboplatin & Gemcitabine (GCb) {{#subobject:8855e5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
GCb: '''<u>G</u>'''emcitabine & '''<u>C</u>'''ar'''<u>b</u>'''oplatin<br />
===Regimen variant #1, AUC 4.5/1000 {{#subobject:5f00b7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792956 De Santis et al. 2009 (EORTC 30986)]<br />
|2001-2005<br />
| style="background-color:#1a9851" |Randomized Phase II/III (E-de-esc)<br />
|M-CAVI<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#1a9851" |Lower toxicity than M-CAVI<br />
|Intention to treat: <br>38% (2009)<br>41.2% (2012)<br />
|Intention to treat: <br>20% (2009)<br>30.3% (2012)<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]<br />
| rowspan="2" |2015-2017<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Durvalumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]])<br />
| style="background-color:#d73027" |(Grouped with [[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]]) More toxic<br />
|Intention to treat (Cisplatin-ineligible): 46%<br />
|Intention to treat (Cisplatin-ineligible): 24%<br />
|-<br />
|2. Durvalumab & Tremelimumab, then Durvalumab maintenance<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
| style="background-color:#ffffbf" |(Grouped with [[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]]) Not more toxic<br />
|Intention to treat (Cisplatin-ineligible): 46%<br />
|Intention to treat (Cisplatin-ineligible): 36%<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]<br />
| rowspan="2" |2016-2018<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|<br />
|<br />
|-<br />
|2. [[#GCb_.26_Atezolizumab|GCb & Atezolizumab]]<br> 3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Atezolizumab|GC & Atezolizumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|<br />
|<br />
|<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 4.5 IV over 60 minutes once on day 1, '''given second'''<br />
**''In DANUBE trial, AUC was 4.5-5.0 IV.''<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given first'''<br />
<br />
'''21-day cycles''' <br />
<br />
''Patients who achieved complete response were given two additional cycles of treatment.''<br />
<br>''Patients on the DANUBE trial received up to 6 cycles.''<br />
<br />
===Regimen variant #2, AUC 5/1250 {{#subobject:4f0596|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext Dogliotti et al. 2006]<br />
|2000-2002<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|Intention to treat: 40% (95% CI NR)<br>Evaluable patients only: 56%<br>(95% CI: 40–72)<br />
|Intention to treat: 49% (95% CI NR)<br>Evaluable patients only: 66%<br>(95% CI: 49–80)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 30 to 60 minutes once on day 2<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. [https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17207911 PubMed]<br />
#'''EORTC 30986:''' De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Skoneczna I, Marreaud S, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol. 2009 Nov 20;27(33):5634-9. [https://doi.org/10.1200/JCO.2008.21.4924 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792956/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19786668 PubMed] NCT00111787<br />
##'''Update:''' De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Gil T, Marreaud S, Daugaard G, Skoneczna I, Collette S, Lorent J, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012 Jan 10;30(2):191-9. [https://doi.org/10.1200/JCO.2011.37.3571 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255563/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22162575 PubMed]<br />
#'''IMvigor130:''' Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636<br />
#'''DANUBE:''' Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Sep 21:S1470-2045(20)30541-6. Epub ahead of print. [https://doi.org/10.1016/s1470-2045(20)30541-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32971005 PubMed] NCT02516241<br />
<br />
==Carboplatin & Paclitaxel (CP) {{#subobject:b33fe7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===Regimen {{#subobject:5d481c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.10782/full Vaughn et al. 2002 (ECOG E2896)]<br />
|1996-1999<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#3d3d3d; color:white" |ORR: 24% (95% CI 12-42)<br />
|-<br />
|[https://doi.org/10.1002/cncr.20123 Dreicer et al. 2004]<br />
|1998-2001<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: Dreicer et al. 2004 was closed early due to poor accrual.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''ECOG E2896:''' Vaughn DJ, Manola J, Dreicer R, See W, Levitt R, Wilding G. Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a trial of the Eastern Cooperative Oncology Group. Cancer. 2002 Sep 1;95(5):1022-7. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.10782/full link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12209686 PubMed]<br />
#Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. [https://doi.org/10.1002/cncr.20123 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15073851/ PubMed]<br />
<br />
==CISCA {{#subobject:b60f2a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CISCA: '''<u>CIS</u>'''platin, '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''driamycin (Doxorubicin)<br />
===Regimen {{#subobject:2d0b5e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/article-abstract/356753 Sternberg et al. 1977]<br />
|1976-1977<br />
| style="background-color:#ffffbe" |Non-randomized, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|<br />
|<br />
|-<br />
|[https://doi.org/10.1200/jco.1990.8.6.1050 Logothetis et al. 1990]<br />
|1985-1989<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|46% (95% CI 32-62)<br />
|65% (95% CI 52-77)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 2<br />
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 2<br />
<br />
====Supportive medications====<br />
<br />
*Forced mannitol diuresis with [[Cisplatin (Platinol)]]<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Sternberg JJ, Bracken RB, Handel PB, Johnson DE. Combination chemotherapy (CISCA) for advanced urinary tract carcinoma: a preliminary report. JAMA. 1977 Nov 21;238(21):2282-7. [https://jamanetwork.com/journals/jama/article-abstract/356753 link to original article] [https://pubmed.ncbi.nlm.nih.gov/578848 PubMed]<br />
#Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. [https://doi.org/10.1200/jco.1990.8.6.1050 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2189954 PubMed]<br />
<br />
==Cisplatin monotherapy {{#subobject:1af7a9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:71bd05|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19830901)52:5%3C767::AID-CNCR2820520502%3E3.0.CO;2-P Soloway et al. 1983]<br />
|1978-NR<br />
| style="background-color:#1a9851" |Randomized (C)<br />
|Cisplatin & Cyclophosphamide<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[https://doi.org/10.1200/JCO.1985.3.4.539 Khandekar et al. 1985]<br />
|1978-1981<br />
| style="background-color:#1a9851" |Randomized (C)<br />
|[[Stub#CAD|CAD]]<br />
| style="background-color:#fee08b" |Might have inferior ORR<br />
|-<br />
|[https://doi.org/10.1016/s0022-5347(17)44167-x Troner et al. 1987]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#CAD|CAD]]<br />
| style="background-color:#ffffbf" |Did not meet endpoint of ORR<br />
|-<br />
|[https://doi.org/10.1200/JCO.1989.7.6.706 Hillcoat et al. 1989]<br />
|1982-1986<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Cisplatin_.26_Methotrexate|Cisplatin & Methotrexate]]<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
|-<br />
|[https://doi.org/10.1200/JCO.1992.10.7.1066 Loehrer et al. 1992]<br />
|1984-1989<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''For historic reference. To our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]]<br />
<br />
===References===<br />
<br />
#Soloway MS, Einstein A, Corder MP, Bonney W, Prout GR Jr, Coombs J; National Bladder Cancer Collaborative Group A. A comparison of cisplatin and the combination of cisplatin and cyclophosphamide in advanced urothelial cancer: a National Bladder Cancer Collaborative Group A study. Cancer. 1983 Sep 1;52(5):767-72. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19830901)52:5%3C767::AID-CNCR2820520502%3E3.0.CO;2-P link to original article] [https://pubmed.ncbi.nlm.nih.gov/6347356 PubMed]<br />
#Khandekar JD, Elson PJ, DeWys WD, Slayton RE, Harris DT. Comparative activity and toxicity of cis-diamminedichloroplatinum (DDP) and a combination of doxorubicin, cyclophosphamide, and DDP in disseminated transitional cell carcinomas of the urinary tract. J Clin Oncol. 1985 Apr;3(4):539-45. [https://doi.org/10.1200/JCO.1985.3.4.539 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3884746 PubMed]<br />
#Troner M, Birch R, Omura GA, Williams S; Southeastern Cancer Study Group. Phase III comparison of cisplatin alone versus cisplatin, doxorubicin and cyclophosphamide in the treatment of bladder (urothelial) cancer: a Southeastern Cancer Study Group trial. J Urol. 1987 Apr;137(4):660-2. [https://doi.org/10.1016/s0022-5347(17)44167-x link to original article] [https://pubmed.ncbi.nlm.nih.gov/3550148 PubMed]<br />
#Hillcoat BL, Raghavan D, Matthews J, Kefford R, Yuen K, Woods R, Olver I, Bishop J, Pearson B, Coorey G, Levi J, Abbott RL, Aroney R, Gill PG, McLennan R. A randomized trial of cisplatin versus cisplatin plus methotrexate in advanced cancer of the urothelial tract. J Clin Oncol. 1989 Jun;7(6):706-9. [https://doi.org/10.1200/JCO.1989.7.6.706 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2654329 PubMed]<br />
#Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, Blumenstein B, Trump D. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. [https://doi.org/10.1200/JCO.1992.10.7.1066 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/1607913 PubMed]<br />
##'''Update:''' Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, Loehrer PJ Sr, Trump D. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997 Jul;15(7):2564-9. [https://doi.org/10.1200/JCO.1997.15.7.2564 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9215826 PubMed]<br />
<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:5cbd83|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GC: '''<u>G</u>'''emcitabine & '''<u>C</u>'''isplatin<br />
<br>GP: '''<u>G</u>'''emcitabine & '''<u>P</u>'''latinol (Cisplatin)<br />
===Regimen variant #1, 70/1000, q3wk {{#subobject:69fea8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdf186 Soto Parra et al. 2002]<br />
|1998-2000<br />
| style="background-color:#ffffbe" |Randomized Phase II, <20 pts in this subgroup (E-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]; q4wk<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]<br />
| rowspan="2" |2015-2017<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Durvalumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
|-<br />
|2. Durvalumab & Tremelimumab, then Durvalumab maintenance<br />
| style="background-color:#fee08b" |Might have inferior OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]<br />
| rowspan="2" |2016-2018<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#GCb_.26_Atezolizumab|GCb & Atezolizumab]]<br> 3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Atezolizumab|GC & Atezolizumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 1 or 2<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*2 liters of fluid and "appropriate antiemetic therapy" given with [[Cisplatin (Platinol)]]<br />
*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"<br />
<br />
'''21-day cycles (up to 6 cycles in DANUBE)'''<br />
<br />
===Regimen variant #2, 70/1000, q4wk {{#subobject:53ad73|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2000.18.17.3068 von der Maase et al. 2000]<br />
|1996-1998<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdf186 Soto Parra et al. 2002]<br />
|1998-2000<br />
| style="background-color:#ffffbe" |Randomized Phase II, <20 pts in this subgroup (E-de-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]; q3wk<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ Bellmunt et al. 2012 (EORTC 30987)]<br />
|2001-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#PGC_2|PCG]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.karger.com/Article/Abstract/354085 Sternberg et al. 2013 (CILAB)]<br />
|2008-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Larotaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]<br />
| rowspan="2" |2015-2017<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Durvalumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
|-<br />
|2. Durvalumab & Tremelimumab, then Durvalumab maintenance<br />
| style="background-color:#fee08b" |Might have inferior OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
|-<br />
|}<br />
''Only a minority of patients in Soto Parra et al. 2002 had bladder cancer. The majority of patients had [[non-small cell lung cancer]].''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 2<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
<br />
*Per Soto Parra et al. 2002:<br />
*2 liters of fluid and "appropriate antiemetic therapy" given with [[Cisplatin (Platinol)]]<br />
*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #3, 70/1250, q3wk {{#subobject:44c03b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext Dogliotti et al. 2006]<br />
|2000-2002<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Carboplatin_.26_Gemcitabine_.28GCb.29|Carboplatin & Gemcitabine]]<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of reduced toxicity<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]<br />
| rowspan="2" |2015-2017<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Durvalumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
| style="background-color:#d73027" |(Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]]) More toxic<br />
|-<br />
|2. Durvalumab & Tremelimumab, then Durvalumab maintenance<br />
| style="background-color:#fee08b" |Might have inferior OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
| style="background-color:#ffffbf" |(Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]]) Not more toxic<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
**''In DANUBE, Cisplatin given on day 1.''<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. [https://doi.org/10.1200/jco.2000.18.17.3068 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11001674 PubMed]<br />
##'''Update:''' von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. [https://doi.org/10.1200/JCO.2005.07.757 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16034041 PubMed]<br />
#Soto Parra H, Cavina R, Latteri F, Sala A, Dambrosio M, Antonelli G, Morenghi E, Alloisio M, Ravasi G, Santoro A. Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study. Ann Oncol. 2002 Jul;13(7):1080-6. [https://doi.org/10.1093/annonc/mdf186 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12176787 PubMed]<br />
#Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. [https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17207911 PubMed]<br />
#'''EORTC 30987:''' Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. [https://doi.org/10.1200/JCO.2011.38.6979 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22370319 PubMed] NCT00022191<br />
#'''CILAB:''' Sternberg CN, Skoneczna IA, Castellano D, Theodore C, Blais N, Voog E, Bellmunt J, Peters F, Le-Guennec S, Cerbone L, Risse ML, Machiels JP. Larotaxel with cisplatin in the first-line treatment of locally advanced/metastatic urothelial tract or bladder cancer: a randomized, active-controlled, phase III trial (CILAB). Oncology. 2013;85(4):208-15. Epub 2013 Sep 24. [https://www.karger.com/Article/Abstract/354085 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24080920 PubMed] NCT00625664<br />
#'''IMvigor130:''' Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636<br />
#'''DANUBE:''' Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Sep 21:S1470-2045(20)30541-6. Epub ahead of print. [https://doi.org/10.1016/s1470-2045(20)30541-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32971005 PubMed] NCT02516241<br />
<br />
==Cisplatin & Gemcitabine (GC) & Atezolizumab {{#subobject:8gajcz|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GC & Atezolizumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin, Atezolizumab<br />
===Regimen {{#subobject:80ihjx8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]<br />
| rowspan="2" |2016-2018<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]<br> 3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''IMvigor130:''' Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636<br />
<br />
==GCb & Atezolizumab {{#subobject:8tqccz|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GCb & Atezolizumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''ar'''<u>b</u>'''oplatin, Atezolizumab<br />
===Regimen {{#subobject:8q1jx8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]<br />
| rowspan="2" |2016-2018<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]<br> 3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 4.5 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''IMvigor130:''' Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636<br />
<br />
==Gemcitabine & Paclitaxel {{#subobject:385447|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1 {{#subobject:af7c37|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.24313/full Calabrò et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#5e5e5e; color:white" |ORR: 37%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 2500 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 150 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycle for 6 to 12 cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:b840fe|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2001.19.12.3018 Meluch et al. 2001]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#8a8a8a" |ORR: 54% (95% CI 40-67)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. [https://doi.org/10.1200/jco.2001.19.12.3018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11408496 PubMed]<br />
#Calabrò F, Lorusso V, Rosati G, Manzione L, Frassineti L, Sava T, Di Paula ED, Alonso S, Sternberg CN. Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer. 2009 Jun 15;115(12):2652-9. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.24313/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19396817 PubMed]<br />
<br />
==MVAC {{#subobject:d2ea09|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin<br />
===Regimen variant #1, standard {{#subobject:33db41|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1992.10.7.1066 Loehrer et al. 1992]<br />
|1984-1989<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_monotherapy|Cisplatin]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://doi.org/10.1200/jco.1990.8.6.1050 Logothetis et al. 1990]<br />
|1985-1989<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#CISCA|CISCA]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2002.20.5.1361 Siefker-Radtke et al. 2002]<br />
|1992-1999<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#FAP|FAP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%<br />
|-<br />
|[https://doi.org/10.1200/jco.2001.19.10.2638 Sternberg et al. 2001 (EORTC 30924)]<br />
|1993-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MVAC.2C_dose-dense_2|Dose-dense MVAC]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup><br />
|-<br />
|[https://doi.org/10.1200/jco.2000.18.17.3068 von der Maase et al. 2000]<br />
|1996-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1002/cncr.20123 Dreicer et al. 2004]<br />
|1998-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29|CP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for EORTC 30924 is based on the 2005 update.''<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once over 120 minutes on day 1 or 2<br />
<br />
'''28-day cycles''' (number of cycles and criteria to continue therapy varies depending on reference)<br />
<br />
===Regimen variant #2, with G-CSF support {{#subobject:72266e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2004.02.152 Bamias et al. 2003]<br />
|1997-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Docetaxel<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[Filgrastim (Neupogen)]] (dose not specified) SC once per day on days 7, 8, 9, 25, 26<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. [https://doi.org/10.1200/jco.1990.8.6.1050 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2189954 PubMed]<br />
#Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, Blumenstein B, Trump D. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. [https://doi.org/10.1200/JCO.1992.10.7.1066 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/1607913 PubMed]<br />
##'''Update:''' Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, Loehrer PJ Sr, Trump D. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997 Jul;15(7):2564-9. [https://doi.org/10.1200/JCO.1997.15.7.2564 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9215826 PubMed]<br />
#von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. [https://doi.org/10.1200/jco.2000.18.17.3068 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11001674 PubMed]<br />
##'''Update:''' von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. [https://doi.org/10.1200/JCO.2005.07.757 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16034041 PubMed]<br />
#'''EORTC 30924:''' Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [https://doi.org/10.1200/jco.2001.19.10.2638 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11352955 PubMed]<br />
##'''Update:''' Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. [https://www.ejcancer.com/article/S0959-8049(05)00874-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16330205 PubMed]<br />
#Siefker-Radtke AO, Millikan RE, Tu SM, Moore DF Jr, Smith TL, Williams D, Logothetis CJ. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol. 2002 Mar 1;20(5):1361-7. [https://doi.org/10.1200/JCO.2002.20.5.1361 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11870180 PubMed]<br />
#Bamias A, Aravantinos G, Deliveliotis C, Bafaloukos D, Kalofonos C, Xiros N, Zervas A, Mitropoulos D, Samantas E, Pectasides D, Papakostas P, Gika D, Kourousis C, Koutras A, Papadimitriou C, Bamias C, Kosmidis P, Dimopoulos MA; Hellenic Cooperative Oncology Group. Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. J Clin Oncol. 2004 Jan 15;22(2):220-8. Epub 2003 Dec 9. Erratum in: J Clin Oncol. 2004 May 1;22(9):1771. [https://doi.org/10.1200/JCO.2004.02.152 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14665607 PubMed]<br />
#Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. [https://doi.org/10.1002/cncr.20123 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15073851/ PubMed]<br />
<br />
==MVAC, dose-dense {{#subobject:c9beb1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ddMVAC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin<br />
===Regimen {{#subobject:daeb1c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://doi.org/10.1200/jco.2001.19.10.2638 Sternberg et al. 2001 (EORTC 30924)]<br />
|1993-1998<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br />
|62% (95% CI 54-70)<br />
|50% (95% CI 42-59)<br />
|-<br />
|[https://doi.org/10.1093/annonc/mds583 Bamias et al. 2012 (HE 16/03)]<br />
|2003-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|DD-GC<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for EORTC 30924 is based on the 2005 update.''<br><br />
''Note: In contrast to Sternberg et al. 2001, Sternberg et al. 2006 specified 15-day cycles.''<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once on day 2<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Granulocyte colony-stimulating factors|G-CSF]] (type not specified) 240 mcg/m<sup>2</sup> SC once per day on days 4 to 10 (additional use up to a total of 14 consecutive days if needed), injected at alternating sites, discontinued if ANC greater than 30,000/uL. <br />
**''In contrast to Sternberg et al. 2001, Sternberg et al. 2006 said G-CSF was given on days 3 to 7.''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''EORTC 30924:''' Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [https://doi.org/10.1200/jco.2001.19.10.2638 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11352955 PubMed]<br />
##'''Update:''' Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. [https://www.ejcancer.com/article/S0959-8049(05)00874-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16330205 PubMed]<br />
#'''HE 16/03:''' Bamias A, Dafni U, Karadimou A, Timotheadou E, Aravantinos G, Psyrri A, Xanthakis I, Tsiatas M, Koutoulidis V, Constantinidis C, Hatzimouratidis C, Samantas E, Visvikis A, Chrisophos M, Stravodimos K, Deliveliotis C, Eleftheraki A, Pectasides D, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol. 2013 Apr;24(4):1011-7. Epub 2012 Nov 7. [https://doi.org/10.1093/annonc/mds583 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23136231 PubMed] ACTRN12610000845033<br />
<br />
==PGC {{#subobject:393eb6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PGC: '''<u>P</u>'''aclitaxel, '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin<br />
<br>PCG: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''isplatin, '''<u>G</u>'''emcitabine<br />
===Regimen {{#subobject:837446|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ Bellmunt et al. 2012 (EORTC 30987)]<br />
|2001-2004<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|56% (95% CI NR)<br />
|44% (95% CI NR)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1 & 8, '''given first'''<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''EORTC 30987:''' Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. [https://doi.org/10.1200/JCO.2011.38.6979 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22370319 PubMed] NCT00022191<br />
<br />
=Locally advanced or metastatic disease, maintenance after platinum chemotherapy=<br />
<br />
==Avelumab monotherapy {{#subobject:efub4c|Regimen=1}}==<br />
{| class="wikitable sortable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:913o9g|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa2002788 Powles et al. 2020 (JAVELIN Bladder 100)]<br />
|2016-2019<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Best supportive care<br />
| style="background-color:#1a9851" |Superior OS<br />
| style="background-color:#d73027" |More toxic<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]] x 4 to 6 or [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]] x 4 to 6 cycles<br />
<br />
====Immunotherapy====<br />
<br />
*[[Avelumab (Bavencio)]] 10 mg/kg IV over 60 minutes once per day on days 1 & 15<br />
<br />
====Supportive Medications====<br />
Premedication with a histamine H1 receptor (H1) blocker and acetaminophen approximately 30 to 60 minutes prior to each dose of avelumab for the first 4 doses; for example:<br />
<br />
*[[Diphenhydramine (Benadryl)]] 25 to 50 mg IV or oral equivalent<br />
*[[Acetaminophen (Tylenol)]] 500 to 650 mg IV or oral equivalent<br />
<br />
'''28-day cycles'''<br />
===References===<br />
<br />
#'''JAVELIN Bladder 100:''' Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Kalofonos H, Radulović S, Demey W, Ullén A, Loriot Y, Sridhar SS, Tsuchiya N, Kopyltsov E, Sternberg CN, Bellmunt J, Aragon-Ching JB, Petrylak DP, Laliberte R, Wang J, Huang B, Davis C, Fowst C, Costa N, Blake-Haskins JA, di Pietro A, Grivas P. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020 Sep 24;383(13):1218-1230. Epub 2020 Sep 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa2002788 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32945632 PubMed] NCT02603432<br />
<br />
==Pembrolizumab monotherapy {{#subobject:gbzb4c|Regimen=1}}==<br />
{| class="wikitable sortable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9gia9g|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255983/ Galsky et al. 2020 (HCRN GU14-182)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
| style="background-color:#d73027" |More toxic<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*First-line platinum-based combination chemotherapy for up to 8 cycles without progression of disease<br />
<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
<!-- # Joaquim Bellmunt, Guru Sonpavde, Ronald De Wit, Toni K. Choueiri, Arlene O. Siefker-Radtke, Elizabeth R. Plimack, Nicole M. Lewis, Holly Brown, Yabing Mai, Christine K. Gause, David Ross Kaufman, Dean F. Bajorin. KEYNOTE-045: Randomized phase 3 trial of pembrolizumab (MK-3475) versus paclitaxel, docetaxel, or vinflunine for previously treated metastatic urothelial cancer. 2015 ASCO Annual Meeting abstract TPS4571. [http://meetinglibrary.asco.org/content/145993-156 link to abstract] --><br />
#'''HCRN GU14-182:''' Galsky MD, Mortazavi A, Milowsky MI, George S, Gupta S, Fleming MT, Dang LH, Geynisman DM, Walling R, Alter RS, Kassar M, Wang J, Gupta S, Davis N, Picus J, Philips G, Quinn DI, Haines GK 3rd, Hahn NM, Zhao Q, Yu M, Pal SK. Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer. J Clin Oncol. 2020 Jun 1;38(16):1797-1806. Epub 2020 Apr 9. [https://doi.org/10.1200/jco.19.03091 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255983/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32271672 PubMed] NCT02500121<br />
<br />
=Locally advanced or metastatic disease, after platinum chemotherapy=<br />
==Avelumab monotherapy {{#subobject:6C1497|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:D9FB6C|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |Years of enrollment<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493051/ Apolo et al. 2017 (JAVELIN)]<br />
|2014<br />
| style="background-color:#ffffbe" |Phase Ib (RT)<br />
|18% (95% CI 8-33)<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Avelumab (Bavencio)]] 10 mg/kg IV over 60 minutes once on day 1<br />
<br />
====Supportive medications====<br />
''Per Apolo et al. 2017 (JAVELIN):''<br />
<br />
*"All patients were premedicated with [[:Category:Antihistamines|an antihistamine]] and [[Acetaminophen (Tylenol)|acetaminophen]] (doses and routes not given)<br />
*The avelumab package insert suggests "Premedicate with acetaminophen and an antihistamine for the first 4 infusions and subsequently as needed."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Phase 1:''' Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, Mega AE, Britten CD, Ravaud A, Mita AC, Safran H, Stinchcombe TE, Srdanov M, Gelb AB, Schlichting M, Chin K, Gulley JL. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: Results from a multicenter, phase Ib study. J Clin Oncol. 2017 Jul 1;35(19):2117-2124. Epub 2017 Apr 4. [https://doi.org/10.1200/JCO.2016.71.6795 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493051/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28375787 PubMed] NCT01772004<br />
<br />
==Docetaxel monotherapy {{#subobject:385447|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b840fe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1997.15.5.1853 McCaffrey et al. 1997]<br />
|1993-1995<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ Choueiri et al. 2012 (DFCI 06-116)]<br />
|2007-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel & Vandetanib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2015.65.0218 Petrylak et al. 2016 (JCDC)]<br />
| rowspan="2" |2011-2014<br />
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (C)<br />
|1. Docetaxel & Icrucumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|2. [[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy_5|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<br />
|2015-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext Petrylak et al. 2017 (RANGE)]<br />
|2015-2017<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]<br />
| style="background-color:#d73027" |Inferior PFS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for RANGE is based on the 2019 update.''<br><br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7. [https://doi.org/10.1200/JCO.1997.15.5.1853 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9164195 PubMed]<br />
#'''DFCI 06-116:''' Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, Hahn NM, Hutson TE, Sonpavde G, Morrissey SC, Buckle GC, Kim WY, Petrylak DP, Ryan CW, Eisenberger MA, Mortazavi A, Bubley GJ, Taplin ME, Rosenberg JE, Kantoff PW. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012 Feb 10;30(5):507-12. [https://doi.org/10.1200/jco.2011.37.7002 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22184381 PubMed] NCT00880334<br />
#'''JCDC:''' Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. [https://doi.org/10.1200/JCO.2015.65.0218 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26926681 PubMed] NCT01282463<br />
<!-- # Joaquim Bellmunt, Guru Sonpavde, Ronald De Wit, Toni K. Choueiri, Arlene O. Siefker-Radtke, Elizabeth R. Plimack, Nicole M. Lewis, Holly Brown, Yabing Mai, Christine K. Gause, David Ross Kaufman, Dean F. Bajorin. KEYNOTE-045: Randomized phase 3 trial of pembrolizumab (MK-3475) versus paclitaxel, docetaxel, or vinflunine for previously treated metastatic urothelial cancer. 2015 ASCO Annual Meeting abstract TPS4571. [http://meetinglibrary.asco.org/content/145993-156 link to abstract] --><br />
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28212060 PubMed] NCT02256436<br />
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707 PubMed]<br />
#'''RANGE:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28916371 PubMed] NCT02426125<br />
##'''Update:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30668-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946880/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31753727 PubMed]<br />
#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29268948 PubMed] NCT02302807<br />
#'''TROPiCS-04:''' NCT04527991<br />
<br />
==Docetaxel & Ramucirumab {{#subobject:385447|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b840fe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2015.65.0218 Petrylak et al. 2016 (JCDC)]<br />
|2011-2014<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext Petrylak et al. 2017 (RANGE)]<br />
|2015-2017<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior PFS<sup>1</sup> <br>(HR 0.70, 95% CI 0.57-0.85)<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for RANGE is based on the 2019 update.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Targeted therapy====<br />
<br />
*[[Ramucirumab (Cyramza)]] 10 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''JCDC:''' Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. [https://doi.org/10.1200/JCO.2015.65.0218 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26926681 PubMed] NCT01282463<br />
#'''RANGE:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28916371 PubMed] NCT02426125<br />
##'''Update:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30668-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946880/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31753727 PubMed]<br />
<br />
==Erdafitinib monotherapy {{#subobject:dbc30d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:473057|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |Years of enrollment<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1817323 Loriot et al. 2019 (BLC2001)]<br />
|2015-2018<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#8c96c6" |ORR 40% (95% CI 31-50)<br />
|-<br />
|}<br />
====Biomarker eligibility criteria====<br />
<br />
*Alterations: FGFR3 mutation, FGFR2 fusion, or FGFR3 fusion<br />
<br />
====Targeted therapy====<br />
<br />
*[[Erdafitinib (Balversa)]] 8 mg PO once per day<br />
**If serum phosphorus level and tolerability are acceptable at days 14 to 21, increase to 9 mg PO once per day<br />
**Additional dose adjustments per package insert<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Arlene O. Siefker-Radtke, Andrea Necchi, Se Hoon Park, Jesus Garcia-Donas, Robert A Huddart, Earle Frederick Burgess, Mark T. Fleming, Arash Rezazadeh, Begona Mellado, Sergei Varlamov, Monika Joshi, Ignacio Duran, Scott T. Tagawa, Anne OHagan, Anjali Narayan Avadhani, Bob Zhong, Peter De Porre, Yohann Loriot, on behalf of the BLC2001 Study Group. First results from the primary analysis population of the phase 2 study of erdafitinib (ERDA; JNJ-42756493) in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt). 2018 ASCO Annual Meeting abstract 4503 [https://meetinglibrary.asco.org/record/160559/abstract link to abstract] '''contains verified protocol'''<br />
# '''BLC2001:''' [https://clinicaltrials.gov/ct2/show/NCT02365597 CT.gov] --><br />
<br />
#'''BLC2001:''' Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, Fleming M, Rezazadeh A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Zhong B, Stuyckens K, Santiago-Walker A, De Porre P, O'Hagan A, Avadhani A, Siefker-Radtke AO; BLC2001 Study Group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348. [https://www.nejm.org/doi/full/10.1056/NEJMoa1817323 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31340094 PubMed] NCT02365597<br />
<br />
==Gemcitabine & Paclitaxel {{#subobject:ecfc0d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GP: '''<u>G</u>'''emcitabine & '''<u>P</u>'''aclitaxel<br />
===Regimen variant #1, gemcitabine 2 out of 3 weeks {{#subobject:384057|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdq398 Albers et al. 2010 (AUO AB 20/99)]<br />
|2001-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_Paclitaxel_2|GP]]; prolonged<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #2, weekly gemcitabine {{#subobject:9aa3e0|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2001.19.12.3018 Meluch et al. 2001]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts in this subgroup<br />
| style="background-color:#8c96c6" |ORR: 47%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. [https://doi.org/10.1200/jco.2001.19.12.3018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11408496 PubMed]<br />
#'''AUO AB 20/99:''' Albers P, Park SI, Niegisch G, Fechner G, Steiner U, Lehmann J, Heimbach D, Heidenreich A, Fimmers R, Siener R; AUO Bladder Cancer Group. Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99]. Ann Oncol. 2011 Feb;22(2):288-94. Epub 2010 Aug 2. [https://doi.org/10.1093/annonc/mdq398 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20682548 PubMed]<br />
<br />
==MVAC {{#subobject:373ed3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin<br />
<br />
===Regimen {{#subobject:af2e64|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359702/ Han et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#8c6bb1" |ORR: 30%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
<br />
'''28-day cycles''' (number of cycles and criteria to continue therapy varies depending on reference)<br />
<br />
===References===<br />
<br />
#Han KS, Joung JY, Kim TS, Jeong IG, Seo HK, Chung J, Lee KH. Methotrexate, vinblastine, doxorubicin and cisplatin combination regimen as salvage chemotherapy for patients with advanced or metastatic transitional cell carcinoma after failure of gemcitabine and cisplatin chemotherapy. Br J Cancer. 2008 Jan 15;98(1):86-90. Epub 2007 Dec 18. [https://doi.org/10.1038/sj.bjc.6604113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359702/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18087289 PubMed]<br />
<br />
==Nivolumab monotherapy {{#subobject:86b89c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:beb7fa|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |Years of enrollment<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30065-7/fulltext Sharma et al. 2017 (CheckMate 275)]<br />
|2015<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|19.6% overall<br>PD-L1 expression ≥5%: 28.4%<br>PD-L1 expression ≥1%: 23.8%<br>PD-L1 expression <1%: 16.1%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*At least one [[Regimen_classes#Platinum-based_regimen|platinum-based therapy]], with progression<br />
<br />
====Immunotherapy====<br />
<br />
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1<br />
**''The FDA-approved dose which is listed in the package insert is 240 mg IV over 60 minutes once on day 1''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''CheckMate 275:''' Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S, Arranz JÁ, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017 Mar;18(3):312-322. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30065-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/28131785 PubMed] NCT02387996<br />
##'''Update:''' Galsky MD, Saci A, Szabo PM, Han GC, Grossfeld G, Collette S, Siefker-Radtke A, Necchi A, Sharma P. Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275. Clin Cancer Res. 2020 Jun 12. Epub ahead of print. [https://doi.org/10.1158/1078-0432.ccr-19-4162 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32532789 PubMed]<br />
<br />
==nab-Paclitaxel monotherapy {{#subobject:fec6dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7dc525|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70162-1/fulltext Ko et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#8c6bb1" |ORR: 28% (95% CI 17-44)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 260 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
====Dose modifications====<br />
<br />
*"Two dose reductions were permitted, to 240 mg/m<sup>2</sup> and then to 180 mg/m<sup>2</sup>. When further dose reductions were required, study treatment was discontinued. Patients with febrile neutropenia, or delay of cycle because of persistent neutropenia, ANC of less than 500/uL for 1 week, or grade 3 or 4 thrombocytopenia required dose reductions. When sensory neuropathy of grade 2 or higher occurred, study drug was withheld until resolution to grade 2 or better, then reinstituted at the next lower dose. When mucositis or diarrhea of grade 3 or higher occurred, study drug was withheld until resolution to grade 1 or better, then reinstituted at the next lower dose. Patients with mucositis or diarrhea of grade 4 were removed from the trial."<br />
<br />
===References===<br />
<br />
#Ko YJ, Canil CM, Mukherjee SD, Winquist E, Elser C, Eisen A, Reaume MN, Zhang L, Sridhar SS. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study. Lancet Oncol. 2013 Jul;14(8):769-76. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70162-1/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23706985 PubMed] NCT00683059<br />
<br />
==Paclitaxel monotherapy {{#subobject:fec6dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, q3wks {{#subobject:9fddc0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy_5|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<br />
|2015-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm. IMvigor211 allowed up to 2 prior lines of platinum-containing chemotherapy.''<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 3 out of 4 weeks {{#subobject:524ebf|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2002.20.4.937 Vaughn et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#6e016b; color:white" |ORR: 10% (95% CI 0-20)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. [https://doi.org/10.1200/jco.2002.20.4.937 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11844814 PubMed]<br />
#'''Retrospective:''' Sideris S, Aoun F, Zanaty M, Martinez NC, Latifyan S, Awada A, Gil T. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol Clin Oncol. 2016 Jun;4(6):1063-1067. Epub 2016 Mar 17. [https://doi.org/10.3892/mco.2016.821 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887921/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27284445 PubMed]<br />
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28212060 PubMed] NCT02256436<br />
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707 PubMed]<br />
#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29268948 PubMed] NCT02302807<br />
#'''TROPiCS-04:''' NCT04527991<br />
<br />
==Pembrolizumab monotherapy {{#subobject:b0cd2a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8aec07|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|Investigator's choice of:<br> 1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. [[#Paclitaxel_monotherapy|Paclitaxel]]<br> 3. [[#Vinflunine_monotherapy|Vinflunine]]<br />
| style="background-color:#1a9850" |Superior OS <br>Median OS: 10 mo vs 7 mo <br>(HR 0.73, 95% CI 0.59-0.91)<br />
|-<br />
|}<br />
====Biomarker eligibility criteria====<br />
<br />
For the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.<br />
<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28212060 PubMed] NCT02256436<br />
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707 PubMed]<br />
<br />
==Pemetrexed monotherapy {{#subobject:fec6dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7dc525|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.03.6699 Sweeney et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#8c6bb1" |ORR: 28% (95% CI 16-43)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, Nicol SJ, Kaufman DS. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006 Jul 20;24(21):3451-7. [https://doi.org/10.1200/jco.2005.03.6699 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16849761 PubMed]<br />
<br />
==Vinflunine monotherapy {{#subobject:e40f4c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b5b9b9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2008.20.5534 Bellmunt et al. 2009 (CA183004)]<br />
|2003-2006<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<sup>1</sup> <br>(HR 0.72, 95% CI 0.57-0.91)<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy_5|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<br />
|2015-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''<sup>1<sup>Reported efficacy for CA183004 is based on the 2013 update.''<br />
====Chemotherapy====<br />
<br />
*[[Vinflunine (Javlor)]] 320 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#'''CA183004:''' Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, Caty A, Carles J, Jagiello-Gruszfeld A, Karyakin O, Delgado FM, Hurteloup P, Winquist E, Morsli N, Salhi Y, Culine S, von der Maase H. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009 Sep 20;27(27):4454-61. Epub 2009 Aug 17. Erratum in: J Clin Oncol. 2010 Jan 1;28(1):182. Winquist, Eric [added]. [https://doi.org/10.1200/JCO.2008.20.5534 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19687335 PubMed] NCT00315237<br />
##'''Update:''' Bellmunt J, Fougeray R, Rosenberg JE, von der Maase H, Schutz FA, Salhi Y, Culine S, Choueiri TK. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. Ann Oncol. 2013 Jun;24(6):1466-72. Epub 2013 Feb 17. [https://doi.org/10.1093/annonc/mdt007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23419284 PubMed]<br />
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28212060 PubMed] NCT02256436<br />
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707 PubMed]<br />
#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29268948 PubMed] NCT02302807<br />
#'''TROPiCS-04:''' NCT04527991<br />
<br />
=Locally advanced or metastatic disease, after platinum chemotherapy and immune checkpoint inhibitor=<br />
==Enfortumab vedotin monotherapy {{#subobject:dbdcad|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:415bc7|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 15%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 15%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784850/ Rosenberg et al. 2018 (EV-201)]<br />
|2017-2018<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|None<br />
|N/A<br />
| style="background-color:#8c96c6" |44% (95% CI 35.2-53.2)<br />
|N/A<br />
|-<br />
|[https://doi.org/10.1056/NEJMoa2035807 Powles et al. 2021 (EV-301)]<br />
|2018-2020<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Investigator-chosen chemotherapy (standard [[Bladder_cancer#Docetaxel_monotherapy | Docetaxel]], [[Bladder_cancer#Paclitaxel_monotherapy | Paclitaxel]], or [[Bladder_cancer#Vinflunine_monotherapy | Vinflunine]])<br />
| style="background-color:#1a9851" |Superior OS<br />
|Intention to treat: 40.6%<br />
|Intention to treat: 17.9%<br />
|}<br />
====Antibody-drug conjugate therapy====<br />
<br />
*[[Enfortumab vedotin (Padcev)]] 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''EV-201:''' Rosenberg JE, O'Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, Galsky MD, Hahn NM, Gartner EM, Pinelli JM, Liang SY, Melhem-Bertrandt A, Petrylak DP. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Oct 10;37(29): 2592-2600. Epub 2019 Jul 29. [https://doi.org/10.1200/JCO.19.01140 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784850/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31356140 Pubmed] NCT03219333<br />
#'''EV-301:''' Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. [https://doi.org/10.1056/NEJMoa2035807 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33577729 Pubmed] NCT03474107<br />
<br />
==Sacituzumab govitecan monotherapy {{#subobject:d9gacd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:417gu7|Variant=1}}===<br />
{| class="wikitable sortable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|No publication yet<br />
|2018-NR<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
''Note: dosing information is from ClinicalTrials.gov.''<br />
====Antibody-drug conjugate therapy====<br />
<br />
*[[Sacituzumab govitecan (Trodelvy)]] 10 mg/kg IV once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''TROPHY:''' NCT03547973<br />
<br />
=Links=<br />
<br />
*[http://www.eortc.be/tools/bladdercalculator/ EORTC Risk Tables for Predicting Recurrence and Progression in Individual Patients with Stage Ta T1 Bladder Cancer] - predicts probability of recurrence and progression in 1 to 5 years<br />
<br />
=Urine assays=<br />
''These are assays intended/being investigated as adjuncts to urine cytology and cystoscopy.''<br />
<br />
*[https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=347921 Cxbladder (uRNA-2)], a "urine based bladder cancer test (uRNA-2) which detects RNA markers in urine."<br />
*[http://www.scimedx.com/products/bladder_cancer/bladder_cancer.php ImmunoCyt™/uCyt+™], a cell-based detection assay which "uses fluorescent-labeled antibodies to 3 markers that are commonly found on malignant exfoliated urothelial cells."<ref>Greene KL, Berry A, Konety BR. Diagnostic Utility of the ImmunoCyt/uCyt+ Test in Bladder Cancer. Rev Urol. 2006 Fall;8(4):190-7. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751037/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17192798 PubMed]</ref><br />
*[http://www.abbottmolecular.com/us/products/oncology/fish/bladder-cancer-urovysion.html UroVysion] (Abbott Molecular) "designed to detect aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus via fluorescence in situ hybridization (FISH) in urine specimens from persons with hematuria suspected of having bladder cancer."<br />
<br />
=References=<br />
<references /><br />
<br />
[[Category:Bladder cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Genitourinary cancers]]</div>Karinehttps://hemonc.org/w/index.php?title=Urothelial_carcinoma&diff=49603Urothelial carcinoma2021-05-12T20:06:20Z<p>Karine: paclitaxel RT Pham 2014</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" style="color:white; font-size:125%; background-color:#08519c" align="center" |'''Page editor'''<br />
! colspan="2" style="color:white; font-size:125%; background-color:#08519c" align="center" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:RisaWong.jpg|frameless|upright=0.3|center]]<br />
|<big>Risa L. Wong, MD<br>University of Washington<br>Fred Hutchinson Cancer Research Center<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/RisaWongMD RisaWongMD]<br />
| style="background-color:#F0F0F0" |[[File:Alikhaki.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Alikhaki|Ali Raza Khaki, MD]]<br>Stanford University<br>Palo Alto, CA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/arkhaki arkhaki]<br />
|-<br />
|}<br />
''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Bladder_cancer_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Bladder cancer - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''.<br />
<br><big>Note: the page has adjuvant and perioperative regimens specific to bladder cancer as well as systemic regimens for the more general category of urothelial cancer. <br />
<br />
*See the [[Upper tract urothelial carcinoma|'''upper tract urothelial carcinoma page''']] for regimens specific to UTUC.</big><br />
<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==AUA, ASCO, ASTRO, SUO==<br />
<br />
*'''2017:''' Chang et al. [http://www.auanet.org/guidelines/muscle-invasive-bladder-cancer-new-(2017) Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO Guideline] [https://pubmed.ncbi.nlm.nih.gov/28456635 PubMed]<br />
<br />
==EAU-ESMO==<br />
<br />
*'''2019:''' Horwich et al. [https://academic.oup.com/annonc/article/30/11/1697/5629133 EAU–ESMO consensus statements on the management of advanced and variant bladder cancer—an international collaborative multi-stakeholder effort: under the auspices of the EAU and ESMO Guidelines Committees]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2019:''' [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer/eUpdate-Bladder-Cancer-Treatment-Recommendations1 eUpdate – Bladder Cancer Treatment Recommendations]<br />
*'''2019:''' [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer/eUpdate-Bladder-Cancer-Treatment-Recommendations2 eUpdate – Bladder Cancer Treatment Recommendations - Subsequent treatments post-chemotherapy or immunotherapy]<br />
*'''2014:''' Bellmunt et al. [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer Bladder cancer: ESMO Clinical Practice Guidelines] [https://pubmed.ncbi.nlm.nih.gov/25096609 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf NCCN Guidelines - Bladder Cancer]<br />
<br />
=Nonmuscle invasive bladder cancer/Intravesical chemotherapy=<br />
==Bacillus Calmette-Guérin (BCG) monotherapy {{#subobject:eojb2c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, low-dose (27 mg) {{#subobject:52ca75|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/j.eururo.2007.04.062 Ojea et al. 2007 (CUETO study 95011)]<br />
| rowspan="2" |1995-1998<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[Bladder_cancer#Mitomycin_monotherapy|Mitomycin]]<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|2. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]; very-low-dose<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#TURBT|TURBT]], within 14 to 21 days<br />
<br />
====Immunotherapy, induction====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 27 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
'''6-week course, then proceed to additional therapy'''<br />
<br />
====Immunotherapy, continuation====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 27 mg intravesicularly once on day 1<br />
<br />
'''14-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, intravesical (81 mg) & percutaneous, with maintenance therapy {{#subobject:221dfe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.auajournals.org/article/S0022-5347(05)67707-5/fulltext Lamm et al. 2000 (SWOG 8507)]<br />
|1985-1988<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|Intravesical & percutaneous BCG, without maintenance therapy<br />
| style="background-color:#1a9850" |Superior RFS<br />
|-<br />
|}<br />
====Immunotherapy, induction====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 81 mg in 50.5 mL saline suspension is created and administered as follows:<br />
**50 mL (~80.2 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15, 22, 29, 36. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.<br />
**0.5 mL (~0.8 mg) applied once per day on days 1, 8, 15, 22, 29, 36 to the inner thigh, which is first cleaned with alcohol. For percutaneous administration, the skin is punctured 3 times with a sterile 28 gauge needle. Each subsequent administration alternates between thighs (i.e. left thigh on one week, right thigh the next week, left thigh the week after, etc.).<br />
<br />
'''6-week course, then proceed to maintenance therapy'''<br />
<br />
====Immunotherapy, maintenance====<br />
''The authors were a bit unclear about the schedule of maintenance therapy. This is our best interpretation of how the schedule was described.''<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 81 mg in 50.5 mL saline suspension is created and administered as follows:<br />
**50 mL (~80.2 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.<br />
**0.5 mL (~0.8 mg) applied once per day on days 1, 8, 15 to the inner thigh, which is first cleaned with alcohol. For percutaneous administration, the skin is punctured 3 times with a sterile 28 gauge needle. Each subsequent administration alternates between thighs (i.e. left thigh on one week, right thigh the next week, left thigh the week after, etc.).<br />
<br />
'''3-week courses; each course is given at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, and 36 months after the start of induction therapy'''<br />
<br />
===Regimen variant #3, intravesical (81 mg) & percutaneous, without maintenance therapy {{#subobject:f5c250|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.auajournals.org/article/S0022-5347(05)67707-5/fulltext Lamm et al. 2000 (SWOG 8507)]<br />
|1985-1988<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Intravesical & percutaneous BCG, with maintenance therapy<br />
| style="background-color:#d73027" |Inferior RFS<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 81 mg in 50.5 mL saline suspension is created and administered as follows:<br />
**50 mL (~80.2 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15, 22, 29, 36. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.<br />
**0.5 mL (~0.8 mg) applied once per day on days 1, 8, 15, 22, 29, 36 to the inner thigh, which is first cleaned with alcohol. For percutaneous administration, the skin is punctured 3 times with a sterile 28 gauge needle. Each subsequent administration alternates between thighs (i.e. left thigh on one week, right thigh the next week, left thigh the week after, etc.).<br />
<br />
'''6-week course'''<br />
<br />
===Regimen variant #4, intravesical (120 mg) & percutaneous, with maintenance therapy {{#subobject:8e5276|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJM199110243251703 Lamm et al. 1991 (SWOG 8216)]<br />
|1983-1985<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|[[#Doxorubicin_monotherapy|Doxorubicin]]<br />
| style="background-color:#91cf60" |Seems to have superior DFS<br />
|-<br />
|}<br />
====Immunotherapy, induction====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 120 mg (3 vials) in 50.5 mL saline suspension is created and administered as follows:<br />
**50 mL (~120 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15, 22, 29, 36. Patients retain the BCG suspension for up to 2 hours if possible.<br />
**0.5 mL (~1.2 mg) applied once per day on days 1, 8, 15, 22, 29, 36 to the upper part of the inner thigh<br />
<br />
'''6-week course, then proceed to maintenance therapy'''<br />
<br />
====Immunotherapy, maintenance====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 120 mg (3 vials) in 50.5 mL saline suspension is created and administered as follows:<br />
**50 mL (~120 mg) intravesicularly once on day 1. Patients retain the BCG suspension for up to 2 hours if possible.<br />
**0.5 mL (~1.2 mg) applied once on day 1 to the upper part of the inner thigh<br />
<br />
'''Given at 3 months, 6 months, 12 months, 18 months, and 24 months'''<br />
<br />
===Regimen variant #5, 150 mg {{#subobject:d04712|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/s0022-5347(17)40002-4 Martínez-Piñeiro et al. 1990]<br />
| rowspan="2" |1980-1988<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|1. [[#Doxorubicin_monotherapy|Doxorubicin]]<br> 2. [[#Thiotepa_monotherapy|Thiotepa]]<br />
| style="background-color:#1a9850" |Superior RFS<br />
|-<br />
|}<br />
''Note: details are very sparse in the abstract and this is probably only of historic interest.''<br />
====Immunotherapy====<br />
<br />
*[[Bacillus Calmette-Guérin (BCG)]] 150 mg intravesicularly x 15 treatments<br />
<br />
===References===<br />
<br />
#Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. [https://doi.org/10.1016/s0022-5347(17)40002-4 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/2106041 PubMed]<br />
#'''SWOG 8216:''' Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA Jr, Sullivan J, Sarosdy MF, Crissman JD, Coltman CA. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med. 1991 Oct 24;325(17):1205-9. [https://www.nejm.org/doi/10.1056/NEJM199110243251703 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1922207 PubMed]<br />
#'''SWOG 8507:''' Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, Sarosdy MF, Bohl RD, Grossman HB, Beck TM, Leimert JT, Crawford ED. Maintenance bacillus Calmette-Guérin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000 Apr;163(4):1124-9. [http://www.auajournals.org/article/S0022-5347(05)67707-5/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10737480 PubMed]<br />
#'''Meta-analysis:''' Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guérin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol. 2002 Nov;168(5):1964-70. [http://www.auajournals.org/article/S0022-5347(05)64273-5/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/12394686 PubMed]<br />
#'''CUETO study 95011:''' Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, Chantada V, Camacho JE, Piñeiro LM, Rodríguez RH, Isorna S, Blas M, Martínez-Piñeiro JA, Madero R; CUETO. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guérin (27 mg) versus very low-dose bacillus Calmette-Guérin (13.5 mg) versus mitomycin C. Eur Urol. 2007 Nov;52(5):1398-406. Epub 2007 Apr 27. [https://doi.org/10.1016/j.eururo.2007.04.062 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17485161 PubMed]<br />
<br />
==Doxorubicin monotherapy {{#subobject:8034b6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:49ccdb|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0022-5347(17)40002-4 Martínez-Piñeiro et al. 1990]<br />
| rowspan="2" |1980-1988<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]<br />
| style="background-color:#d73027" |Inferior RFS<br />
|-<br />
|2. [[#Thiotepa_monotherapy|Thiotepa]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJM199110243251703 Lamm et al. 1991 (SWOG 8216)]<br />
|1983-1985<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]<br />
| style="background-color:#fc8d59" |Seems to have inferior DFS<br />
|-<br />
|}<br />
''Inferior to BCG, included for reference purposes only.''<br />
====Chemotherapy====<br />
<br />
*[[Doxorubicin (Adriamycin)]]<br />
<br />
'''15 or more treatments'''<br />
<br />
===References===<br />
<br />
#Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. [https://doi.org/10.1016/s0022-5347(17)40002-4 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/2106041 PubMed]<br />
#'''SWOG 8216:''' Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA Jr, Sullivan J, Sarosdy MF, Crissman JD, Coltman CA. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med. 1991 Oct 24;325(17):1205-9. [https://www.nejm.org/doi/10.1056/NEJM199110243251703 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1922207 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:343fc9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 1 treatment {{#subobject:170d3b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/2680547 Messing et al. 2018 (SWOG S0337)]<br />
|2008-2012<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Placebo (saline)<br />
| style="background-color:#1a9850" |Superior TTR<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#TURBT|TURBT]], up to 3 hours prior<br />
<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 2000 mg in 100 mL of saline instilled intravesicularly for up to 60 minutes<br />
<br />
'''One treatment'''<br />
<br />
===Regimen variant #2, 6 treatments {{#subobject:fa5bb2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2008.20.8199 Addeo et al. 2009]<br />
|2003-2005<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Mitomycin_monotherapy|Mitomycin]]<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 2000 mg in 50 mL of saline instilled intravesicularly for up to 60 minutes once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
<br />
#Addeo R, Caraglia M, Bellini S, Abbruzzese A, Vincenzi B, Montella L, Miragliuolo A, Guarrasi R, Lanna M, Cennamo G, Faiola V, Del Prete S. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. J Clin Oncol. 2010 Feb 1;28(4):543-8. Epub 2009 Oct 19. [https://doi.org/10.1200/JCO.2008.20.8199 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19841330 PubMed]<br />
#'''SWOG S0337:''' Messing EM, Tangen CM, Lerner SP, Sahasrabudhe DM, Koppie TM, Wood DP Jr, Mack PC, Svatek RS, Evans CP, Hafez KS, Culkin DJ, Brand TC, Karsh LI, Holzbeierlein JM, Wilson SS, Wu G, Plets M, Vogelzang NJ, Thompson IM Jr. Effect of intravesical instillation of gemcitabine vs saline immediately following resection of suspected low-grade non-muscle-invasive bladder cancer on tumor recurrence: SWOG S0337 randomized clinical trial. JAMA. 2018 May 8;319(18):1880-1888. [https://jamanetwork.com/journals/jama/fullarticle/2680547 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29801011 PubMed] NCT00445601<br />
<br />
==Mitomycin monotherapy {{#subobject:2e5944|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 30 mg x 12 {{#subobject:347e3e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/j.eururo.2007.04.062 Ojea et al. 2007 (CUETO study 95011)]<br />
| rowspan="2" |1995-1998<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]; low-dose<br />
| style="background-color:#d73027" |Inferior DFS<br />
|-<br />
|2. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]; very-low-dose<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#TURBT|TURBT]], 14 to 21 days prior<br />
<br />
====Chemotherapy====<br />
<br />
*[[Mitomycin (Mutamycin)]] as follows:<br />
**Cycles 1 to 3: 30 mg intravesicularly once per day on days 1 & 8<br />
**Cycles 4 to 9: 30 mg intravesicularly once on day 1<br />
<br />
'''14-day cycle for 9 cycles'''<br />
<br />
===Regimen variant #2, 40 mg x 11 {{#subobject:531377|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2011.39.2936 Lammers et al. 2012]<br />
|2003-2007<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Keyhole limpet hemocyanin<br />
| style="background-color:#1a9850" |Superior RFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#TURBT|TURBT]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Mitomycin (Mutamycin)]] 40 mg intravesicularly once on day 1<br />
<br />
'''7-day cycle for 4 cycles, then monthly cycle for 4 cycles, then 3-month cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''CUETO study 95011:''' Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, Chantada V, Camacho JE, Piñeiro LM, Rodríguez RH, Isorna S, Blas M, Martínez-Piñeiro JA, Madero R; CUETO. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guérin (27 mg) versus very low-dose bacillus Calmette-Guérin (13.5 mg) versus mitomycin C. Eur Urol. 2007 Nov;52(5):1398-406. Epub 2007 Apr 27. [https://doi.org/10.1016/j.eururo.2007.04.062 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17485161 PubMed]<br />
#Lammers RJ, Witjes WP, Janzing-Pastors MH, Caris CT, Witjes JA. Intracutaneous and intravesical immunotherapy with keyhole limpet hemocyanin compared with intravesical mitomycin in patients with non-muscle-invasive bladder cancer: results from a prospective randomized phase III trial. J Clin Oncol. 2012 Jun 20;30(18):2273-9. Epub 2012 May 14. [https://doi.org/10.1200/JCO.2011.39.2936 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22585689 PubMed]<br />
<br />
==Pembrolizumab monotherapy {{#subobject:3cb963|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7ae9e3|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2019.37.7_suppl.350 Balar et al. (KEYNOTE-057)]<br />
|NR in abstract<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycle for 35 cycles (2 years)'''<br />
====References====<br />
<br />
#'''Abstract:''' Keynote-057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guerin (BCG). Arjun Vasant Balar, Girish S. Kulkarni, Edward M. Uchio, Joost Boormans, Loic Mourey, Laurence Eliot Miles Krieger, Eric A. Singer, Dean F. Bajorin, Ashish M. Kamat, Petros Grivas, Ho Kyung Seo, Hiroyuki Nishiyama, Badrinath R. Konety, Kijoeng Nam, Ekta Kapadia, Tara L. Frenkl, Ronald De Wit. Journal of Clinical Oncology 2019 37:7_suppl, 350-350. [https://doi.org/10.1200/JCO.2019.37.7_suppl.350 link to abstract] NCT02625961<br />
<br />
==Thiotepa monotherapy {{#subobject:5b9d6c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:97d2e7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0022-5347(17)40002-4 Martínez-Piñeiro et al. 1990]<br />
| rowspan="2" |1980-1988<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]<br />
| style="background-color:#d73027" |Inferior RFS<br />
|-<br />
|2. [[#Doxorubicin_monotherapy|Doxorubicin]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Inferior to BCG, included for reference purposes only.''<br />
====Chemotherapy====<br />
<br />
*[[Thiotepa (Thioplex)]] 50 mg intravesicularly x 15 treatments<br />
<br />
===References===<br />
<br />
#Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. [https://doi.org/10.1016/s0022-5347(17)40002-4 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/2106041 PubMed]<br />
<br />
==Valrubicin monotherapy {{#subobject:58jgac|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:74j2e7|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |Years of enrollment<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2967799-3 Steinberg et al. 2000]<br />
|1993-1996<br />
| style="background-color:#91cf61" |Non-randomized (RT)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Valrubicin (Valstar)]] 800 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
<br />
#Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M; Valrubicin Study Group. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guérin refractory carcinoma in situ of the bladder. J Urol. 2000 Mar;163(3):761-7. Erratum in: J Urol. 2008 Jan;179(1):386. [https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2967799-3 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10687972 PubMed]<br />
<br />
=Neoadjuvant chemotherapy=<br />
==Atezolizumab monotherapy {{#subobject:3cb963|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7ae9e3|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/s41591-019-0628-7 Powles et al. 2019 (ABACUS)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)|Atezolizumab]] 1200 mg IV over 60 minutes once on day 1<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Cystectomy|Radical cystectomy]] to be performed 4 to 8 weeks after completion of chemotherapy<br />
<br />
===References===<br />
<br />
#'''ABACUS:''' Powles T, Kockx M, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, Szabados B, Pous AF, Gravis G, Herranz UA, Protheroe A, Ravaud A, Maillet D, Mendez MJ, Suarez C, Linch M, Prendergast A, van Dam PJ, Stanoeva D, Daelemans S, Mariathasan S, Tea JS, Mousa K, Banchereau R, Castellano D. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med. 2019 Nov 4. [https://www.nature.com/articles/s41591-019-0628-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31686036 PubMed] NCT02662309<br />
<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:d08e11|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GC: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin<br />
===Regimen variant #1, single-dose cisplatin {{#subobject:dc99d5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585515/ Dash et al. 2008]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Bladder_cancer_surgery|Surgery]]<br />
<br />
===Regimen variant #2, split-dose cisplatin {{#subobject:be43aa|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585515/ Dash et al. 2008]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Bladder_cancer_surgery|Surgery]]<br />
<br />
===References===<br />
<br />
#'''Retrospective:''' Dash A, Pettus JA 4th, Herr HW, Bochner BH, Dalbagni G, Donat SM, Russo P, Boyle MG, Milowsky MI, Bajorin DF. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer. 2008 Nov 1;113(9):2471-7. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585515/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18823036 PubMed]<br />
<br />
==MCV {{#subobject:553fe2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MCV: '''<u>M</u>'''ethotrexate, '''<u>C</u>'''isplatin, '''<u>V</u>'''inblastine<br />
<br>CMV: '''<u>C</u>'''isplatin, '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine<br />
===Regimen variant #1, 2 cycles {{#subobject:450c9f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJM199311043291903 Kaufman et al. 1993]<br />
|NR<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.1996.14.1.119 Tester et al. 1996 (RTOG 88-02)]<br />
|1988-1990<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.1998.16.11.3576 Shipley et al. 1998 (RTOG 89-03)]<br />
|1990-1993<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant chemotherapy]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*Kaufman et al. 1993, CR: [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]<br />
*RTOG 88-02 & 89-03: [[#Cisplatin_.26_RT|Cisplatin & RT induction]]<br />
<br />
===Regimen variant #2, 3 cycles {{#subobject:3d008f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02292-8/abstract Griffiths et al. 1999 (BA06 30894)]<br />
|1989-1995<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 Zapatero et al. 2000]<br />
|1989-1997<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for BA06 30894 is based on the 2011 update.''<br><br />
''Patients in Zapatero et al. 2000 had T2 to T4 Nx M0 disease.''<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 2, before hydration<br />
*[[Vinblastine (Velban)]] 4 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*'''BA06 30894:''' [[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> IV or PO every 6 hours on days 2 & 9, given after hydration, with the first dose 24 hours after the previous day's dose of [[Methotrexate (MTX)]] (total dose per cycle: 120 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
====Subsequent treatment====<br />
<br />
*Zapatero et al. 2000: after 3 cycles of chemotherapy, patients underwent cystoscopy, biopsy, and abdominal CT<br />
**Patients with CR or who were not surgical candidates: [[#Radiation_therapy|RT consolidation]] which begins 4 to 6 weeks after completion of chemotherapy<br />
**Otherwise, patients proceeded to [[Surgery#Cystectomy|cystectomy]]<br />
<br />
===References===<br />
<br />
#Kaufman DS, Shipley WU, Griffin PP, Heney NM, Althausen AF, Efird JT. Selective bladder preservation by combination treatment of invasive bladder cancer. N Engl J Med. 1993 Nov 4;329(19):1377-82. [https://www.nejm.org/doi/10.1056/NEJM199311043291903 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8413433 PubMed]<br />
#'''RTOG 88-02:''' Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. [https://doi.org/10.1200/jco.1996.14.1.119 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8558186 PubMed]<br />
#'''RTOG 89-03:''' Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. [https://doi.org/10.1200/jco.1998.16.11.3576 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9817278 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''BA06 30894:''' Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; CUETO; International Collaboration of Trialists. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. Lancet. 1999 Aug 14;354(9178):533-40. Erratum in: Lancet 1999 Nov 6;354(9190):1650. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02292-8/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/10470696 PubMed]<br />
##'''Update:''' Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group); [[Study_Groups#EORTC|EORTC]] Genito-Urinary Tract Cancer Group; Australian Bladder Cancer Study Group; National Cancer Institute of Canada Clinical Trials Group; Finnbladder; Norwegian Bladder Cancer Study Group; Club Urologico Espanol de Tratamiento Oncologico Group. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011 Jun 1;29(16):2171-7. Epub 2011 Apr 18. [https://doi.org/10.1200/jco.2010.32.3139 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107740/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21502557 PubMed]<br />
#Zapatero A, Martín de Vidales C, Marín A, Cerezo L, Arellano R, Rabadán M, Pérez-Torrubia A. Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Int J Cancer. 2000 Oct 20;90(5):287-94. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11091353 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439%2809%2900029-5/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19362865 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
<br />
==MVAC {{#subobject:701fbe|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''isplatin<br />
===Regimen variant #1, 2 cycles {{#subobject:0f1661|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdu126 Kitamura et al. 2014 (JCOG0209)]<br />
|2003-2009<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Radical_cystectomy|Radical cystectomy]]<br />
<br />
===Regimen variant #2, 3 cycles {{#subobject:dc2c80|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa022148 Grossman et al. 2003 (SWOG S8710)]<br />
|1987-1998<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
<br />
'''28-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Radical_cystectomy|Radical cystectomy]]<br />
<br />
===References===<br />
<br />
#'''SWOG S8710:''' Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003 Aug 28;349(9):859-66. [https://www.nejm.org/doi/full/10.1056/NEJMoa022148 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12944571 PubMed]<br />
#'''JCOG0209:''' Kitamura H, Tsukamoto T, Shibata T, Masumori N, Fujimoto H, Hirao Y, Fujimoto K, Kitamura Y, Tomita Y, Tobisu K, Niwakawa M, Naito S, Eto M, Kakehi Y; Urologic Oncology Study Group of the Japan Clinical Oncology Group. Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209. Ann Oncol. 2014 Jun;25(6):1192-8. [https://doi.org/10.1093/annonc/mdu126 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24669010 PubMed] UMIN C000000093<br />
##'''HRQoL analysis:''' Kitamura H, Hinotsu S, Tsukamoto T, Shibata T, Mizusawa J, Kobayashi T, Miyake M, Nishiyama N, Kojima T, Nishiyama H; Urologic Oncology Study Group of the Japan Clinical Oncology Group. Effect of neoadjuvant chemotherapy on health-related quality of life in patients with muscle-invasive bladder cancer: results from JCOG0209, a randomized phase III study. Jpn J Clin Oncol. 2020 Dec 16;50(12):1464-1469. [https://doi.org/10.1093/jjco/hyaa123 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32699909 PubMed]<br />
<br />
==MVAC, dose-dense {{#subobject:3cb963|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ddMVAC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''isplatin<br />
<br>AMVAC: '''<u>A</u>'''ccelerated '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''isplatin<br />
===Regimen variant #1, 3 cycles {{#subobject:c4bf38|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050203/ Plimack et al. 2014 (FER-GU-026)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV over 30 minutes once on day 1<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV push once on day 2<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV push once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV in 1 liter normal saline once on day 2<br />
**Split dose could be used at physician discretion for patients with CrCl less than 60 mL/min/1.73m<sup>2</sup>: 35 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
<br />
====Supportive medications====<br />
<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once, 24 to 48 hours after completion of chemotherapy<br />
*Antiemetics used often included [[Aprepitant (Emend)]], [[Ondansetron (Zofran)]], and [[Dexamethasone (Decadron)]] but were not specified by the trial.<br />
<br />
'''14-day cycle for 3 cycles'''<br />
<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Radical_cystectomy|Radical cystectomy]] with bilateral [[Surgery#Lymphadenectomy|lymphadenectomy]], within 4 to 8 weeks after the last cycle of chemotherapy<br />
<br />
===Regimen variant #2, 4 cycles {{#subobject:7ae9e3|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7057274/ Choueiri et al. 2014 (DFCI 08-208)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV over 30 minutes once on day 1<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV push once on day 2<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV push once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV in 1 liter normal saline once on day 2<br />
<br />
====Supportive medications====<br />
<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 3 (approximately 24 hours after day 2 chemotherapy)<br />
<br />
'''14-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Cystectomy|Cystectomy]] to be performed 4 to 10 weeks after completion of chemotherapy<br />
<br />
===References===<br />
<!-- # Angela Q. Qu, Susanna J. Jacobus, Sabina Signoretti, Edward C. Stack, Katherine Maragaret Krajewski, Jonathan E. Rosenberg, Toni K. Choueiri. Phase II study of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) chemotherapy in patients with muscle-invasive urothelial cancer (MI-UC): Pathologic and radiologic response, serum tumor markers, and DNA excision repair pathway biomarkers in relation to disease-free survival (DFS). 2013 ASCO Annual Meeting abstract 4530. [http://meetinglibrary.asco.org/content/117233-132 link to abstract] --><br />
<br />
#'''DFCI 08-208:''' Choueiri TK, Jacobus S, Bellmunt J, Qu A, Appleman LJ, Tretter C, Bubley GJ, Stack EC, Signoretti S, Walsh M, Steele G, Hirsch M, Sweeney CJ, Taplin ME, Kibel AS, Krajewski KM, Kantoff PW, Ross RW, Rosenberg JE. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol. 2014 Jun 20;32(18):1889-94. Epub 2014 May 12. [https://doi.org/10.1200/jco.2013.52.4785 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7057274/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24821883 PubMed] NCT00808639<br />
#'''FER-GU-026:''' Plimack ER, Hoffman-Censits JH, Viterbo R, Trabulsi EJ, Ross EA, Greenberg RE, Chen DY, Lallas CD, Wong YN, Lin J, Kutikov A, Dotan E, Brennan TA, Palma N, Dulaimi E, Mehrazin R, Boorjian SA, Kelly WK, Uzzo RG, Hudes GR. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol. 2014 Jun 20;32(18):1895-901. Epub 2014 May 12. [https://doi.org/10.1200/jco.2013.53.2465 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050203/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24821881 PubMed] NCT01031420<br />
<br />
==Pembrolizumab monotherapy {{#subobject:3cfac3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c4bf38|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://pubmed.ncbi.nlm.nih.gov/30343614 Necchi et al. 2018 (PURE-01)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)|Pembrolizumab]] 200 mg IV over 30 minutes once on day 1<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Radical_cystectomy|Radical cystectomy]], within 1 to 3 weeks after the last cycle of chemotherapy<br />
<br />
===References===<br />
<br />
#'''PURE-01:''' Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Lucianò R, Colecchia M, Giannatempo P, Mortarini R, Bianchi M, Farè E, Monopoli F, Colombo R, Gallina A, Salonia A, Messina A, Ali SM, Madison R, Ross JS, Chung JH, Salvioni R, Mariani L, Montorsi F. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol. 2018 Oct 20. [https://doi.org/10.1200/jco.18.01148 Link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30343614 PubMed] NCT02736266<br />
##'''Update:''' Necchi A, Raggi D, Gallina A, Madison R, Colecchia M, Lucianò R, Montironi R, Giannatempo P, Farè E, Pederzoli F, Bandini M, Bianchi M, Colombo R, Gandaglia G, Fossati N, Marandino L, Capitanio U, Dehò F, Ali SM, Chung JH, Ross JS, Salonia A, Briganti A, Montorsi F. Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies. Eur Urol. 2019 Nov 7. [https://doi.org/10.1016/j.eururo.2019.10.026 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31708296 PubMed]<br />
<br />
=Induction chemoradiotherapy=<br />
<br />
==Cisplatin & RT {{#subobject:ebb6e9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Cisplatin & RT: Cisplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
<br />
===Regimen variant #1, cisplatin 40 mg/m<sup>2</sup> qwk x 3 {{#subobject:f782c3|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract Hagan et al. 2003 (RTOG 97-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|[http://www.urologiconcology.org/article/S1078-1439(09)00029-5/fulltext Zapatero et al. 2009]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
''Patients in '''Zapatero et al. 2000''' had T2 to T4 N0 M0 disease. Patients in RTOG 97-06 had T2 to T4a N0 M0 disease without hydronephrosis.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2 (per Figure 1 of Zapatero, et al. 2010), '''given first'''<br />
<br />
'''7-day cycle for 3 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:<br />
**'''Both trials:''' Accelerated hyperfractionated RT (AHFRT) with twice per day radiation, consisting of 1.8 Gy fractions x 12 fractions to the bladder and regional lymph nodes; 6 hours later, a 1.6 Gy fraction x 12 fractions is given to the "bladder tumor plus wide margin." Radiation therapy given 5 days per week. Total induction dose to bladder tumor: 40.8 Gy; total induction dose to regional lymph nodes: 21.6 Gy.<br />
**'''Zapatero et al. 2000 only:''' Normo-fractionated concurrent radiation therapy, 1.8 to 2 Gy fractions, given 5 times per week. Total induction and consolidation bladder dose of 64 to 66 Gy; total induction and consolidation pelvic lymph node dose of 44 to 46 Gy. Zapatero, et al. 2010 & Zapatero, et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy, nor what adjustments, if any, were made to chemotherapy for this radiation schedule.<br />
<br />
====Subsequent treatment====<br />
<br />
*3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT<br />
**Patients with complete regression (R0): [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]<br />
**Nonresponders: [[Surgery#Cystectomy|Cystectomy]]<br />
<br />
===Regimen variant #2, cisplatin 70 mg/m<sup>2</sup> q3wk x 2 {{#subobject:2443a6|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.1996.14.1.119 Tester et al. 1996 (RTOG 88-02)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#MCV|MCV]] x 2<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 22 fractions (total dose: 39.6 Gy)<br />
<br />
'''4.5-week course'''<br />
====Subsequent treatment====<br />
''Patient is restaged 2 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, urinary cytology, and computed tomographic scan of pelvis."''<br />
<br />
*Patients with CR: [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]<br />
*Patients without CR proceeded immediately to: [[Surgery#Cystectomy|cystectomy]]<br />
<br />
===Regimen variant #3, cisplatin 100 mg/m<sup>2</sup> q3wk x 2 {{#subobject:9a3fd0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/article-abstract/367764 Shipley et al. 1988]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|[https://doi.org/10.1200/jco.1998.16.11.3576 Shipley et al. 1998 (RTOG 89-03)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*RTOG 89-03: [[#MCV|MCV]] versus [[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|no neoadjuvant therapy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 2 cycles''' <br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 22 fractions (total dose: 39.6 Gy)<br />
<br />
'''4.5-week course'''<br />
====Subsequent treatment====<br />
''RTOG 89-03: Patient is restaged 4 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, and urinary cytology." ''<br />
<br />
*RTOG 89-03; Patients not in CR usually proceeded to: [[Surgery#Cystectomy|cystectomy]]<br />
*RTOG 89-03; Patients in complete remission usually proceeded to: [[#Cisplatin_.26_RT_2|cisplatin & RT consolidation]]<br />
<br />
===References===<br />
<br />
#Shipley WU, Prout GR Jr, Einstein AB, Coombs LJ, Wajsman Z, Soloway MS, Englander L, Barton BA, Hafermann MD. Treatment of invasive bladder cancer by cisplatin and radiation in patients unsuited for surgery. JAMA. 1987 Aug 21;258(7):931-5. [https://jamanetwork.com/journals/jama/article-abstract/367764 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3613023 PubMed]<br />
#'''RTOG 88-02:''' Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. [https://doi.org/10.1200/jco.1996.14.1.119 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8558186 PubMed]<br />
#'''RTOG 89-03:''' Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. [https://doi.org/10.1200/jco.1998.16.11.3576 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9817278 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 97-06:''' Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. [http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14529770 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439(09)00029-5/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19362865 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
<br />
==Cisplatin & Fluorouracil (CF) & RT {{#subobject:b5e26|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 90/2400/24 {{#subobject:598234|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://theoncologist.alphamedpress.org/content/5/6/471.long Kaufman et al. 2000 (RTOG 95-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Patients in RTOG 95-06 had clinical T2 to T4a Nx M0 disease without hydronephrosis and CrCl of at least 60 mL/min/1.73m<sup>2</sup>.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3, '''given second, before radiation'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*IV hydration at 500 mL/H (no total volume specified) prior to [[Fluorouracil (5-FU)]]<br />
<br />
'''14-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 3 Gy fractions twice per day, with the first fraction of each day given 1 to 2 hours after completion of chemotherapy and at least 4 hours between fractions, x 8 fractions, given on days 1, 3, 15, 17 (total induction dose: 24 Gy), administered to the whole bladder, bladder tumor volume, and pelvic lymph nodes<br />
<br />
'''17-day course'''<br />
====Dose modifications====<br />
<br />
*Patients with grade III hematologic toxicity, defined as platelets less than 50 x 10<sup>9</sup>/L or ANC less than 1800/uL, had chemotherapy and radiation therapy held for at least one week, with therapy resuming when platelets were at least 100 x 10<sup>9</sup>/L and ANC at least 1800/uL.<br />
<br />
====Subsequent treatment====<br />
<br />
*Treatment followed by repeat cystoscopy, biopsy, and urine cytology in week 7 or 8<br />
**Patients with complete response: [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT consolidation]] in week 9<br />
**Incomplete responders were recommended to undergo [[Surgery#Radical_cystectomy|radical cystectomy]]<br />
<br />
===Regimen variant #2, 135/2400/40.3 {{#subobject:6be392|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ Coen et al. 2018 (RTOG 0712)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Gemcitabine_.26_RT|Gemcitabine & RT]]<br />
|-<br />
|}<br />
''Note: this trial was not statistically powered to compare regimens.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3, 8 to 10, 15 to 17<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, 15 to 17<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:<br />
**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17<br />
**1.5 Gy fractions to the bladder every evening on days 1 to 5<br />
**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17<br />
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.<br />
<br />
'''17-day course'''<br />
====Subsequent treatment====<br />
<br />
*Treatment followed by repeat cystoscopy & biopsy<br />
**Patients with complete response: [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT consolidation]]<br />
**Incomplete responders: [[Surgery#Radical_cystectomy|Radical cystectomy]]<br />
<br />
===Regimen variant #3, 135/3600/40.3 {{#subobject:6be39|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day cycle for 3 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:<br />
**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17<br />
**1.5 Gy fractions to the bladder every evening on days 1 to 5<br />
**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17<br />
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.<br />
<br />
'''3-week course'''<br />
====Subsequent treatment====<br />
<br />
*On week 7, patients under reevaluation for response. <br />
**Patients with less than stage T1 disease: [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT consolidation]]<br />
**Patients with at least stage T1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]] on week 9, then [[#PGC|adjuvant PGC]]<br />
<br />
===References===<br />
<br />
#'''RTOG 95-06:''' Kaufman DS, Winter KA, Shipley WU, Heney NM, Chetner MP, Souhami L, Zlotecki RA, Sause WT, True LD. The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response. Oncologist. 2000;5(6):471-6. [http://theoncologist.alphamedpress.org/content/5/6/471.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11110598 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 0712:''' Coen JJ, Zhang P, Saylor PJ, Lee CT, Wu CL, Parker W, Lautenschlaeger T, Zietman AL, Efstathiou JA, Jani AB, Kucuk O, Souhami L, Rodgers JP, Sandler HM, Shipley WU. Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712-a randomized phase II trial. J Clin Oncol. 2019 Jan 1;37(1):44-51. Epub 2018 Nov 15. [https://doi.org/10.1200/JCO.18.00537 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30433852 PubMed] NCT00777491<br />
<br />
==Cisplatin, Paclitaxel, RT {{#subobject:803f28|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 40/50 x 3 + 40.3 Gy {{#subobject:b7ec20|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract Kaufman et al. 2009 (RTOG 99-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Note: the abstract of Kaufman et al. 2009 said that patients with "greater than Stage T1 disease" were recommended for cystectomy, but Figure 1 clarified that it was greater than or equal to ypT1 disease.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#TURBT|TURBT]], within 4 to 6 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycle for 3 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT on days 1 to 5, 8 to 12, 15 to 17; 4 to 6 hours between radiation sessions. Kaufman et al. 2009 (RTOG 99-06) was unclear about exact radiation treatment plan, but it appears to have been the same as described in Mitin et al. 2013 (RTOG 02-33), which used radiation as follows:<br />
**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17<br />
**1.5 Gy fractions to the bladder every evening on days 1 to 5<br />
**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17<br />
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.<br />
<br />
'''3-week course'''<br />
====Subsequent treatment====<br />
<br />
*On week 7, over 3 weeks after induction therapy, patients under reevaluation with exam under anesthesia, cystoscopy with tumor site biopsy, and urine cytology<br />
**Patients with less than stage ypT1 disease: [[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, paclitaxel, RT consolidation]]<br />
**Patients with at least stage ypT1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]], then [[#Cisplatin_.26_Gemcitabine_.28GC.29_2|adjuvant cisplatin & gemcitabine]]<br />
<br />
===Regimen variant #2, 45/50 x 3 + 40.3 Gy {{#subobject:6ecd8b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|Cisplatin, Fluorouracil, RT]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycle for 3 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:<br />
**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17<br />
**1.5 Gy fractions to the bladder every evening on days 1 to 5<br />
**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17<br />
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.<br />
<br />
'''3-week course''' <br />
====Subsequent treatment====<br />
<br />
*On week 7, patients under reevaluation for response<br />
**Patients with less than stage ypT1 disease: [[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, paclitaxel, RT consolidation]]<br />
**Patients with at least stage ypT1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]] on week 9, then [[#PGC|adjuvant PGC]]<br />
<br />
===References===<br />
<br />
#Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. [http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19100600 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==Fluorouracil, Mitomycin, RT {{#subobject:5e89d1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Fluorouracil, Mitomycin, RT: Fluorouracil, Mitomycin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:6a18dc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 James et al. 2012 (BC2001)]<br />
|2001-2008<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Radiation_therapy_2|Radiation therapy]]<br />
| style="background-color:#91cf60" |Seems to have superior locoregional DFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup>/day IV continuous infusion for 10 total days (total dose: 5000 mg/m<sup>2</sup>) during radiation fractions 1 to 5, 16 to 20<br />
*[[Mitomycin (Mutamycin)]] 12 mg/m<sup>2</sup> IV bolus once on day 1<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] given according to one of the following plans:<br />
**Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.75 Gy fractions x 20 fractions (total dose: 55 Gy)<br />
**Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 32 fractions (total dose: 64 Gy)<br />
<br />
'''4- to 6.5-week course'''<br />
===References===<br />
<br />
#'''BC2001:''' James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-88. [https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1106106/suppl_file/nejmoa1106106_appendix.pdf link to supplementary index] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22512481 PubMed] ISRCTN68324339<br />
<br />
==Gemcitabine & RT {{#subobject:91c0ea|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:6333a7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ Coen et al. 2018 (RTOG 0712)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-de-esc)<br />
|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|CF & RT]]<br />
|-<br />
|}<br />
''Note: this trial was not statistically powered to compare regimens.''<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 27 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
<br />
'''14-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 2 Gy per day to the pelvis on days 1 to 10, then 2 Gy per day to the bladder on days 11 to 14, then 2 Gy per day to the bladder tumor on days 15 to 20<br />
**Total doses: pelvis: 20 Gy; whole bladder: 28 Gy; bladder tumor volume 40 Gy<br />
<br />
'''3-week course'''<br />
====Subsequent treatment====<br />
<br />
*Treatment followed by repeat cystoscopy & biopsy<br />
**Patients with complete response: Gemcitabine & RT consolidation<br />
**Incomplete responders: [[Surgery#Radical_cystectomy|Radical cystectomy]]<br />
<br />
===References===<br />
<br />
#'''RTOG 0712:''' Coen JJ, Zhang P, Saylor PJ, Lee CT, Wu CL, Parker W, Lautenschlaeger T, Zietman AL, Efstathiou JA, Jani AB, Kucuk O, Souhami L, Rodgers JP, Sandler HM, Shipley WU. Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712-a randomized phase II trial. J Clin Oncol. 2019 Jan 1;37(1):44-51. Epub 2018 Nov 15. [https://doi.org/10.1200/JCO.18.00537 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30433852 PubMed] NCT00777491<br />
<br />
==Paclitaxel & RT {{#subobject:89c0ea|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:6222a7|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract Zapatero et al. 2012]<br />
| style="background-color:#ffffbe" |Non-randomized, <20 pts<br />
|-<br />
|}<br />
''Patients who had "mild renal insufficiency" received paclitaxel instead of cisplatin and had T2 to T4 N0 M0 disease.''<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per week, '''given 6 hours before radiation therapy'''<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:<br />
**Accelerated hyperfractionated RT (AHFRT) with twice per day radiation, consisting of 1.8 Gy fractions x 12 fractions to the bladder and regional lymph nodes; 6 hours later, a 1.6 Gy fraction x 12 fractions is given to the "bladder tumor plus wide margin." Total induction dose to bladder tumor: 40.8 Gy; total induction dose to regional lymph nodes: 21.6 Gy. Zapatero et al. 2012 did not specify the precise schedule of radiation therapy.<br />
**Normo-fractionated concurrent radiation therapy, total induction and consolidation dose of 64 to 66 Gy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*3 weeks after finishing radiation and chemotherapy, patients underwent restaging [[Surgery#TURBT|TURBT]]<br />
**Patients with complete regression (R0): [[#Paclitaxel_.26_RT_2|Paclitaxel & RT consolidation]]<br />
**Nonresponders: [[Surgery#Cystectomy|Cystectomy]]<br />
<br />
===References===<br />
<br />
#Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
<br />
===Regimen {{#subobject:6222a7|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.redjournal.org/article/S0360-3016(14)01232-2/fulltext#secsectitle0015 Pham et al. 2014 (RTOG 0524)]<br />
| style="background-color:#ffffbe" |Non-randomized, 47 pts<br />
|-<br />
|}<br />
<br />
<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per week<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent daily [[External_beam_radiotherapy|radiation therapy]] 64.8 Gy total in 36 fractions<br />
<br />
===References===<br />
<br />
#Pham<br />
<br />
==Radiation therapy {{#subobject:1103c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:e0ed54|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 Zapatero et al. 2000]<br />
|1989-1997<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 James et al. 2012 (BC2001)]<br />
|2001-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil.2C_Mitomycin.2C_RT|Fluorouracil, Mitomycin, RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior locoregional DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response, treatment in Zapatero et al. 2000 preceded by [[#MCV|MCV]] x 3 or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] as follows:<br />
**CR: 2 Gy fractions given 5 days per week, with total bladder dose of 60 Gy. Total dose to regional lymph nodes: 50 Gy.<br />
**Less than CR: total dose to the bladder of 64 to 66 Gy. No further details given about fractionation, schedule, or dose to lymph nodes.<br />
<br />
===References===<br />
<br />
#Zapatero A, Martín de Vidales C, Marín A, Cerezo L, Arellano R, Rabadán M, Pérez-Torrubia A. Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Int J Cancer. 2000 Oct 20;90(5):287-94. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11091353 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439%2809%2900029-5/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19362865 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
#'''BC2001:''' James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-88. [https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22512481 PubMed] ISRCTN68324339<br />
<br />
=Consolidation chemoradiotherapy=<br />
==Cisplatin & RT {{#subobject:308d11|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Cisplatin & RT: Cisplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen variant #1, cisplatin 40 mg/m<sup>2</sup>/wk x 2 {{#subobject:dc2b84|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 Zapatero et al. 2000]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|[http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract Hagan et al. 2003 (RTOG 97-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response: [[#Cisplatin_.26_RT|Cisplatin & RT induction]] or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2 (per Figure 1 of Zapatero et al. 2010), '''given first'''<br />
<br />
'''7-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:<br />
**'''Both trials:''' Accelerated hyperfractionated RT (AHFRT), 1.5 Gy fractions twice per day x 16 fractions (total consolidation dose: 24 Gy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 64.8 Gy; total dose to lymph nodes is 45.6 Gy.<br />
**'''Zapatero et al. 2000 only:''' Normo-fractionated concurrent radiation therapy, 1.8 to 2 Gy fractions, given 5 times per week. Total induction and consolidation bladder dose of 64 to 66 Gy; total induction and consolidation pelvic lymph node dose of 44 to 46 Gy. Zapatero, et al. 2010 & Zapatero, et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy, nor what adjustments, if any, were made to chemotherapy for this radiation schedule.<br />
<br />
====Subsequent treatment====<br />
<br />
*RTOG 97-06: [[#MCV_2|Adjuvant MCV]]<br />
<br />
===Regimen variant #2, cisplatin 70 mg/m<sup>2</sup> x 1 {{#subobject:314189|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.1996.14.1.119 Tester et al. 1996 (RTOG 88-02)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response, treatment preceded by [[#Cisplatin_.26_RT|cisplatin & RT induction]] or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy==== <br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 14 fractions (total dose in consolidation phase: 25.2 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)<br />
<br />
'''3-week course'''<br />
<br />
===Regimen variant #3, cisplatin 100 mg/m<sup>2</sup> x 1 {{#subobject:7afeca|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/jco.1998.16.11.3576 Shipley et al. 1998 (RTOG 89-03)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response, treatment preceded by [[#Cisplatin_.26_RT|cisplatin & RT induction]] or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy==== <br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 14 fractions (total dose in consolidation phase: 39.6 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)<br />
<br />
'''3-week course'''<br />
<br />
===References===<br />
<br />
#'''RTOG 88-02:''' Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. [https://doi.org/10.1200/jco.1996.14.1.119 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8558186 PubMed]<br />
#'''RTOG 89-03:''' Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. [https://doi.org/10.1200/jco.1998.16.11.3576 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9817278 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#Zapatero A, Martín de Vidales C, Marín A, Cerezo L, Arellano R, Rabadán M, Pérez-Torrubia A. Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Int J Cancer. 2000 Oct 20;90(5):287-94. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11091353 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439%2809%2900029-5/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19362865 PubMed]<br />
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
#'''RTOG 97-06:''' Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. [http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14529770 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==Cisplatin & Fluorouracil (CF) & RT {{#subobject:fe2538|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 30/1200 x 2 + 64.3 Gy {{#subobject:a18497|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, Paclitaxel, RT]]<br />
|-<br />
|}<br />
''Consolidation starts starts on week 8.''<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|Cisplatin, 5-FU, RT induction]]<br />
<br />
====Chemotherapy==== <br />
''Starts on week 8.''<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions x 16 fractions, given twice per day x 8 days. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.<br />
<br />
'''2-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[#PGC|Adjuvant PGC]]<br />
<br />
===Regimen variant #2, 45/1200 x 2 + 44 Gy {{#subobject:904a96|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://theoncologist.alphamedpress.org/content/5/6/471.long Kaufman et al. 2000 (RTOG 95-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Treatment starts on week 9.''<br />
====Preceding treatment====<br />
<br />
*Depending on response, treatment preceded by [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|cisplatin, fluorouracil, RT induction]] or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy==== <br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, '''given first'''<br />
<br />
'''14-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.5 Gy fractions twice per day, with at least 4 hours between fractions, x 8 fractions, given on days 1, 3, 15, 17 (total consolidation dose: 20 Gy), administered to the whole bladder and bladder tumor volume. The total dose to the whole bladder and bladder tumor volume was 44 Gy in 16 fractions; the total dose to the pelvic lymph nodes was 24 Gy in 8 fractions.<br />
<br />
====Dose modifications====<br />
<br />
*Patients with grade III hematologic toxicity, defined as platelets less than 50 x 10<sup>9</sup>/L or ANC less than 1800/uL, had chemotherapy and radiation therapy held for at least one week, with therapy resuming when platelets were at least 100 x 10<sup>9</sup>/L and ANC at least 1800/uL.<br />
<br />
====Supportive medications====<br />
<br />
*IV hydration at 500 mL/H (no total volume specified) prior to [[Fluorouracil (5-FU)]]<br />
<br />
'''17-day course'''<br />
<br />
===References===<br />
<br />
#'''RTOG 95-06:''' Kaufman DS, Winter KA, Shipley WU, Heney NM, Chetner MP, Souhami L, Zlotecki RA, Sause WT, True LD. The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response. Oncologist. 2000;5(6):471-6. [http://theoncologist.alphamedpress.org/content/5/6/471.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11110598 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==Cisplatin, Paclitaxel, RT {{#subobject:4bc0dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 30/50 x 2 + 64.3 Gy {{#subobject:9fefbd|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|Cisplatin, 5-FU, RT]]<br />
|-<br />
|}<br />
''Consolidation starts starts on week 8.''<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT induction]]<br />
<br />
====Chemotherapy==== <br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions x 16 fractions, given twice per day x 8 days. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.<br />
<br />
'''2-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[#PGC|Adjuvant PGC]]<br />
<br />
===Regimen variant #2, 40/50 x 2 + 64.3 Gy {{#subobject:6bec62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract Kaufman et al. 2009 (RTOG 99-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Consolidation starts starts on week 8.''<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT induction]]<br />
<br />
====Chemotherapy==== <br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions x 16 fractions, given twice per day (4 to 6 hour interval between treatments) on days 1 to 5, 8 to 10. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.<br />
<br />
'''2-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[#Cisplatin_.26_Gemcitabine_.28GC.29_2|Adjuvant cisplatin & gemcitabine]]<br />
<br />
===References===<br />
<br />
#'''RTOG 99-06:''' Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. [http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19100600 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==Paclitaxel & RT {{#subobject:039b5c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:de252a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract Zapatero et al. 2012]<br />
| style="background-color:#ffffbe" |Non-randomized, <20 pts<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response, treatment preceded by [[#Paclitaxel_.26_RT|paclitaxel & RT induction]] or [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per week, given 6 hours before radiation therapy<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:<br />
**Accelerated hyperfractionated RT (AHFRT), 1.5 Gy fractions twice per day x 16 fractions (total consolidation dose: 24 Gy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 64.8 Gy; total dose to lymph nodes is 45.6 Gy.<br />
**Normo-fractionated concurrent radiation therapy, total induction and consolidation dose of 64 to 66 Gy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.<br />
<br />
'''One course'''<br />
===References===<br />
<br />
#Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]<br />
<br />
=Adjuvant chemotherapy=<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:684e48|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:72a413|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract Kaufman et al. 2009 (RTOG 99-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response to induction, treatment starts 12 weeks after [[#Cisplatin.2C_Paclitaxel.2C_RT_2|cisplatin, paclitaxel, RT consolidation]], or 8 weeks after [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. [http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19100600 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==Cisplatin & Methotrexate {{#subobject:684e48|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:72a413|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2005.11.094 Lehmann et al. 2005 (AUO-AB 05/95)]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|M-VEC x 3<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS<br />
| style="background-color:#1a9850" |Less toxic<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Cystectomy|Radical cystectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]]<br />
*[[Methotrexate (MTX)]]<br />
<br />
===References===<br />
<br />
#'''AUO-AB 05/95:''' Lehmann J, Retz M, Wiemers C, Beck J, Thüroff J, Weining C, Albers P, Frohneberg D, Becker T, Funke PJ, Walz P, Langbein S, Reiher F, Schiller M, Miller K, Roth S, Kälble T, Sternberg D, Wellek S, Stöckle M; AUO. Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter, phase III trial (AUO-AB 05/95). J Clin Oncol. 2005 Aug 1;23(22):4963-74. Epub 2005 Jun 6. [https://doi.org/10.1200/JCO.2005.11.094 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15939920 PubMed]<br />
<br />
==MCV {{#subobject:8e6bb8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MCV: '''<u>M</u>'''ethotrexate, '''<u>C</u>'''isplatin, '''<u>V</u>'''inblastine<br />
<br />
===Regimen {{#subobject:ca6708|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract Hagan et al. 2003 (RTOG 97-06)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Begins 8 weeks after consolidation. Note that only 45% of patients in RTOG 97-06 were able to complete all 3 cycles of MCV.''<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 2 to 4<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. [http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14529770 PubMed]<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
==PGC {{#subobject:22e1d2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PGC: '''<u>P</u>'''aclitaxel, '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin<br />
<br>PCG: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''isplatin, '''<u>G</u>'''emcitabine<br />
===Regimen variant #1 {{#subobject:ad1bc8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2010.28.18_suppl.lba4518 Paz-Ares et al 2010 (SOGUG 99/01)]<br />
|2000-2007<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#Observation_2|Observation]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Patients in SOGUG 99/01 had pT3-4 and/or pN positive disease with adequate renal function (CrCl greater than 50 mL/min/1.73m<sup>2</sup>). The study prematurely closed due to poor recruitment and lacks adequate power to make firm conclusions, and has never been published in manuscript format.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Cystectomy|Cystectomy]]; the median time treatment started post-cystectomy was 48 days<br />
<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 80 mg mg/2 IV once per day on days 1 & 8<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:29bee9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Depending on response, adjuvant chemotherapy began 12 weeks after [[#Cisplatin.2C_Paclitaxel.2C_RT_2|cisplatin, paclitaxel, RT]] versus [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|cisplatin, 5-FU, RT]] or 8 weeks after [[Surgery#Cystectomy|cystectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#'''Abstract:''' L. G. Paz-Ares, E. Solsona, E. Esteban, A. Saez, J. Gonzalez-Larriba, A. Anton, M. Hevia, F. de la Rosa, V. Guillem, and J. Bellmunt. Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study. ASCO MEETING ABSTRACTS Jun 22, 2010:LBA4518. [https://doi.org/10.1200/jco.2010.28.18_suppl.lba4518 link to abstract] '''contains verified protocol'''<br />
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601<br />
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]<br />
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]<br />
<br />
=Locally advanced or metastatic disease, first-line, platinum-ineligible=<br />
==Atezolizumab monotherapy {{#subobject:1d9e29|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:764948|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568632/ Balar et al. 2016 (IMvigor210)]<br />
|2014-2015<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#88419d; color:white " |ORR: 23% (95% CI 16-31)<br />
|-<br />
|}<br />
<big>'''On 8/16/2018 the FDA updated the prescribing information for atezolizumab to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are cisplatin-ineligible.'''</big><br />
<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''IMvigor210:''' Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, Dawson NA, van der Heijden MS, Dreicer R, Srinivas S, Retz MM, Joseph RW, Drakaki A, Vaishampayan UN, Sridhar SS, Quinn DI, Durán I, Shaffer DR, Eigl BJ, Grivas PD, Yu EY, Li S, Kadel EE 3rd, Boyd Z, Bourgon R, Hegde PS, Mariathasan S, Thåström A, Abidoye OO, Fine GD, Bajorin DF; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017 Jan 7;389(10064):67-76. Epub 2016 Dec 8. [http://thelancet.com/journals/lancet/article/PIIS0140-6736(16)32455-2/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568632/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27939400 PubMed] NCT02951767<br />
<br />
<br /><br />
<br />
==Pembrolizumab monotherapy {{#subobject:7fc2f6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:946aec|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |Years of enrollment<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30616-2/fulltext Balar et al. 2017 (KEYNOTE-052)]<br />
|2015-2016<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#88419d; color:white " |ORR: 24% (95% CI 20-29)<br />
|-<br />
|} <br />
<big>'''On 5/18/2018 the FDA released a warning that patients in the monotherapy arms of the ongoing KEYNOTE-361 trial with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy.'''</big><br />
<br />
<big>'''On 8/16/2018 the FDA updated the prescribing information for pembrolizumab to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are cisplatin-ineligible.'''</big><br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''KEYNOTE-052:''' Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, Savage MJ, Perini RF, Keefe SM, Bajorin D, Bellmunt J. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Nov;18(11):1483-1492. Epub 2017 Sep 26. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30616-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28967485 PubMed] NCT02335424<br />
<br />
=Locally advanced or metastatic disease, first-line, platinum-eligible=<br />
<br />
==Atezolizumab monotherapy {{#subobject:1d9e29|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:764948|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]<br />
| rowspan="2" |2016-2018<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|1. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]<br> 2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|3. [[#GCb_.26_Atezolizumab|GCb & Atezolizumab]]<br> 4. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Atezolizumab|GC & Atezolizumab]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''IMvigor130:''' Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636<br />
<br />
==Carboplatin & Gemcitabine (GCb) {{#subobject:8855e5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GCb: '''<u>G</u>'''emcitabine & '''<u>C</u>'''ar'''<u>b</u>'''oplatin<br />
===Regimen variant #1, AUC 4.5/1000 {{#subobject:5f00b7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792956 De Santis et al. 2009 (EORTC 30986)]<br />
|2001-2005<br />
| style="background-color:#1a9851" |Randomized Phase II/III (E-de-esc)<br />
|M-CAVI<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#1a9851" |Lower toxicity than M-CAVI<br />
|Intention to treat: <br>38% (2009)<br>41.2% (2012)<br />
|Intention to treat: <br>20% (2009)<br>30.3% (2012)<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]<br />
| rowspan="2" |2015-2017<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Durvalumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]])<br />
| style="background-color:#d73027" |(Grouped with [[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]]) More toxic<br />
|Intention to treat (Cisplatin-ineligible): 46%<br />
|Intention to treat (Cisplatin-ineligible): 24%<br />
|-<br />
|2. Durvalumab & Tremelimumab, then Durvalumab maintenance<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
| style="background-color:#ffffbf" |(Grouped with [[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]]) Not more toxic<br />
|Intention to treat (Cisplatin-ineligible): 46%<br />
|Intention to treat (Cisplatin-ineligible): 36%<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]<br />
| rowspan="2" |2016-2018<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|<br />
|<br />
|-<br />
|2. [[#GCb_.26_Atezolizumab|GCb & Atezolizumab]]<br> 3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Atezolizumab|GC & Atezolizumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|<br />
|<br />
|<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 4.5 IV over 60 minutes once on day 1, '''given second'''<br />
**''In DANUBE trial, AUC was 4.5-5.0 IV.''<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given first'''<br />
<br />
'''21-day cycles''' <br />
<br />
''Patients who achieved complete response were given two additional cycles of treatment.''<br />
<br>''Patients on the DANUBE trial received up to 6 cycles.''<br />
<br />
===Regimen variant #2, AUC 5/1250 {{#subobject:4f0596|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext Dogliotti et al. 2006]<br />
|2000-2002<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|Intention to treat: 40% (95% CI NR)<br>Evaluable patients only: 56%<br>(95% CI: 40–72)<br />
|Intention to treat: 49% (95% CI NR)<br>Evaluable patients only: 66%<br>(95% CI: 49–80)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 30 to 60 minutes once on day 2<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. [https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17207911 PubMed]<br />
#'''EORTC 30986:''' De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Skoneczna I, Marreaud S, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol. 2009 Nov 20;27(33):5634-9. [https://doi.org/10.1200/JCO.2008.21.4924 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792956/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19786668 PubMed] NCT00111787<br />
##'''Update:''' De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Gil T, Marreaud S, Daugaard G, Skoneczna I, Collette S, Lorent J, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012 Jan 10;30(2):191-9. [https://doi.org/10.1200/JCO.2011.37.3571 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255563/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22162575 PubMed]<br />
#'''IMvigor130:''' Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636<br />
#'''DANUBE:''' Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Sep 21:S1470-2045(20)30541-6. Epub ahead of print. [https://doi.org/10.1016/s1470-2045(20)30541-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32971005 PubMed] NCT02516241<br />
<br />
==Carboplatin & Paclitaxel (CP) {{#subobject:b33fe7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5d481c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.10782/full Vaughn et al. 2002 (ECOG E2896)]<br />
|1996-1999<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#3d3d3d; color:white" |ORR: 24% (95% CI 12-42)<br />
|-<br />
|[https://doi.org/10.1002/cncr.20123 Dreicer et al. 2004]<br />
|1998-2001<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: Dreicer et al. 2004 was closed early due to poor accrual.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''ECOG E2896:''' Vaughn DJ, Manola J, Dreicer R, See W, Levitt R, Wilding G. Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a trial of the Eastern Cooperative Oncology Group. Cancer. 2002 Sep 1;95(5):1022-7. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.10782/full link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12209686 PubMed]<br />
#Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. [https://doi.org/10.1002/cncr.20123 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15073851/ PubMed]<br />
<br />
==CISCA {{#subobject:b60f2a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CISCA: '''<u>CIS</u>'''platin, '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''driamycin (Doxorubicin)<br />
===Regimen {{#subobject:2d0b5e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/article-abstract/356753 Sternberg et al. 1977]<br />
|1976-1977<br />
| style="background-color:#ffffbe" |Non-randomized, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|<br />
|<br />
|-<br />
|[https://doi.org/10.1200/jco.1990.8.6.1050 Logothetis et al. 1990]<br />
|1985-1989<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|46% (95% CI 32-62)<br />
|65% (95% CI 52-77)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 2<br />
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 2<br />
<br />
====Supportive medications====<br />
<br />
*Forced mannitol diuresis with [[Cisplatin (Platinol)]]<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Sternberg JJ, Bracken RB, Handel PB, Johnson DE. Combination chemotherapy (CISCA) for advanced urinary tract carcinoma: a preliminary report. JAMA. 1977 Nov 21;238(21):2282-7. [https://jamanetwork.com/journals/jama/article-abstract/356753 link to original article] [https://pubmed.ncbi.nlm.nih.gov/578848 PubMed]<br />
#Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. [https://doi.org/10.1200/jco.1990.8.6.1050 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2189954 PubMed]<br />
<br />
==Cisplatin monotherapy {{#subobject:1af7a9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:71bd05|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19830901)52:5%3C767::AID-CNCR2820520502%3E3.0.CO;2-P Soloway et al. 1983]<br />
|1978-NR<br />
| style="background-color:#1a9851" |Randomized (C)<br />
|Cisplatin & Cyclophosphamide<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[https://doi.org/10.1200/JCO.1985.3.4.539 Khandekar et al. 1985]<br />
|1978-1981<br />
| style="background-color:#1a9851" |Randomized (C)<br />
|[[Stub#CAD|CAD]]<br />
| style="background-color:#fee08b" |Might have inferior ORR<br />
|-<br />
|[https://doi.org/10.1016/s0022-5347(17)44167-x Troner et al. 1987]<br />
|NR<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#CAD|CAD]]<br />
| style="background-color:#ffffbf" |Did not meet endpoint of ORR<br />
|-<br />
|[https://doi.org/10.1200/JCO.1989.7.6.706 Hillcoat et al. 1989]<br />
|1982-1986<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#Cisplatin_.26_Methotrexate|Cisplatin & Methotrexate]]<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
|-<br />
|[https://doi.org/10.1200/JCO.1992.10.7.1066 Loehrer et al. 1992]<br />
|1984-1989<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''For historic reference. To our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]]<br />
<br />
===References===<br />
<br />
#Soloway MS, Einstein A, Corder MP, Bonney W, Prout GR Jr, Coombs J; National Bladder Cancer Collaborative Group A. A comparison of cisplatin and the combination of cisplatin and cyclophosphamide in advanced urothelial cancer: a National Bladder Cancer Collaborative Group A study. Cancer. 1983 Sep 1;52(5):767-72. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19830901)52:5%3C767::AID-CNCR2820520502%3E3.0.CO;2-P link to original article] [https://pubmed.ncbi.nlm.nih.gov/6347356 PubMed]<br />
#Khandekar JD, Elson PJ, DeWys WD, Slayton RE, Harris DT. Comparative activity and toxicity of cis-diamminedichloroplatinum (DDP) and a combination of doxorubicin, cyclophosphamide, and DDP in disseminated transitional cell carcinomas of the urinary tract. J Clin Oncol. 1985 Apr;3(4):539-45. [https://doi.org/10.1200/JCO.1985.3.4.539 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3884746 PubMed]<br />
#Troner M, Birch R, Omura GA, Williams S; Southeastern Cancer Study Group. Phase III comparison of cisplatin alone versus cisplatin, doxorubicin and cyclophosphamide in the treatment of bladder (urothelial) cancer: a Southeastern Cancer Study Group trial. J Urol. 1987 Apr;137(4):660-2. [https://doi.org/10.1016/s0022-5347(17)44167-x link to original article] [https://pubmed.ncbi.nlm.nih.gov/3550148 PubMed]<br />
#Hillcoat BL, Raghavan D, Matthews J, Kefford R, Yuen K, Woods R, Olver I, Bishop J, Pearson B, Coorey G, Levi J, Abbott RL, Aroney R, Gill PG, McLennan R. A randomized trial of cisplatin versus cisplatin plus methotrexate in advanced cancer of the urothelial tract. J Clin Oncol. 1989 Jun;7(6):706-9. [https://doi.org/10.1200/JCO.1989.7.6.706 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2654329 PubMed]<br />
#Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, Blumenstein B, Trump D. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. [https://doi.org/10.1200/JCO.1992.10.7.1066 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/1607913 PubMed]<br />
##'''Update:''' Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, Loehrer PJ Sr, Trump D. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997 Jul;15(7):2564-9. [https://doi.org/10.1200/JCO.1997.15.7.2564 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9215826 PubMed]<br />
<br />
==Cisplatin & Gemcitabine (GC) {{#subobject:5cbd83|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
GC: '''<u>G</u>'''emcitabine & '''<u>C</u>'''isplatin<br />
<br>GP: '''<u>G</u>'''emcitabine & '''<u>P</u>'''latinol (Cisplatin)<br />
===Regimen variant #1, 70/1000, q3wk {{#subobject:69fea8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdf186 Soto Parra et al. 2002]<br />
|1998-2000<br />
| style="background-color:#ffffbe" |Randomized Phase II, <20 pts in this subgroup (E-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]; q4wk<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]<br />
| rowspan="2" |2015-2017<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Durvalumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
|-<br />
|2. Durvalumab & Tremelimumab, then Durvalumab maintenance<br />
| style="background-color:#fee08b" |Might have inferior OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]<br />
| rowspan="2" |2016-2018<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#GCb_.26_Atezolizumab|GCb & Atezolizumab]]<br> 3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Atezolizumab|GC & Atezolizumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 1 or 2<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
<br />
*2 liters of fluid and "appropriate antiemetic therapy" given with [[Cisplatin (Platinol)]]<br />
*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"<br />
<br />
'''21-day cycles (up to 6 cycles in DANUBE)'''<br />
<br />
===Regimen variant #2, 70/1000, q4wk {{#subobject:53ad73|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2000.18.17.3068 von der Maase et al. 2000]<br />
|1996-1998<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdf186 Soto Parra et al. 2002]<br />
|1998-2000<br />
| style="background-color:#ffffbe" |Randomized Phase II, <20 pts in this subgroup (E-de-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]; q3wk<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ Bellmunt et al. 2012 (EORTC 30987)]<br />
|2001-2004<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#PGC_2|PCG]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.karger.com/Article/Abstract/354085 Sternberg et al. 2013 (CILAB)]<br />
|2008-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Larotaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]<br />
| rowspan="2" |2015-2017<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Durvalumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
|-<br />
|2. Durvalumab & Tremelimumab, then Durvalumab maintenance<br />
| style="background-color:#fee08b" |Might have inferior OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
|-<br />
|}<br />
''Only a minority of patients in Soto Parra et al. 2002 had bladder cancer. The majority of patients had [[non-small cell lung cancer]].''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 2<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
<br />
*Per Soto Parra et al. 2002:<br />
*2 liters of fluid and "appropriate antiemetic therapy" given with [[Cisplatin (Platinol)]]<br />
*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #3, 70/1250, q3wk {{#subobject:44c03b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext Dogliotti et al. 2006]<br />
|2000-2002<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Carboplatin_.26_Gemcitabine_.28GCb.29|Carboplatin & Gemcitabine]]<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of reduced toxicity<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]<br />
| rowspan="2" |2015-2017<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Durvalumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
| style="background-color:#d73027" |(Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]]) More toxic<br />
|-<br />
|2. Durvalumab & Tremelimumab, then Durvalumab maintenance<br />
| style="background-color:#fee08b" |Might have inferior OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])<br />
| style="background-color:#ffffbf" |(Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]]) Not more toxic<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
**''In DANUBE, Cisplatin given on day 1.''<br />
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. [https://doi.org/10.1200/jco.2000.18.17.3068 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11001674 PubMed]<br />
##'''Update:''' von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. [https://doi.org/10.1200/JCO.2005.07.757 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16034041 PubMed]<br />
#Soto Parra H, Cavina R, Latteri F, Sala A, Dambrosio M, Antonelli G, Morenghi E, Alloisio M, Ravasi G, Santoro A. Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study. Ann Oncol. 2002 Jul;13(7):1080-6. [https://doi.org/10.1093/annonc/mdf186 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12176787 PubMed]<br />
#Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. [https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17207911 PubMed]<br />
#'''EORTC 30987:''' Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. [https://doi.org/10.1200/JCO.2011.38.6979 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22370319 PubMed] NCT00022191<br />
#'''CILAB:''' Sternberg CN, Skoneczna IA, Castellano D, Theodore C, Blais N, Voog E, Bellmunt J, Peters F, Le-Guennec S, Cerbone L, Risse ML, Machiels JP. Larotaxel with cisplatin in the first-line treatment of locally advanced/metastatic urothelial tract or bladder cancer: a randomized, active-controlled, phase III trial (CILAB). Oncology. 2013;85(4):208-15. Epub 2013 Sep 24. [https://www.karger.com/Article/Abstract/354085 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24080920 PubMed] NCT00625664<br />
#'''IMvigor130:''' Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636<br />
#'''DANUBE:''' Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Sep 21:S1470-2045(20)30541-6. Epub ahead of print. [https://doi.org/10.1016/s1470-2045(20)30541-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32971005 PubMed] NCT02516241<br />
<br />
==Cisplatin & Gemcitabine (GC) & Atezolizumab {{#subobject:8gajcz|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GC & Atezolizumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin, Atezolizumab<br />
===Regimen {{#subobject:80ihjx8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]<br />
| rowspan="2" |2016-2018<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]<br> 3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''IMvigor130:''' Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636<br />
<br />
==GCb & Atezolizumab {{#subobject:8tqccz|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GCb & Atezolizumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''ar'''<u>b</u>'''oplatin, Atezolizumab<br />
===Regimen {{#subobject:8q1jx8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]<br />
| rowspan="2" |2016-2018<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]<br> 3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 4.5 IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''IMvigor130:''' Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636<br />
<br />
==Gemcitabine & Paclitaxel {{#subobject:385447|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1 {{#subobject:af7c37|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.24313/full Calabrò et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#5e5e5e; color:white" |ORR: 37%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 2500 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 150 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycle for 6 to 12 cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:b840fe|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2001.19.12.3018 Meluch et al. 2001]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#8a8a8a" |ORR: 54% (95% CI 40-67)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. [https://doi.org/10.1200/jco.2001.19.12.3018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11408496 PubMed]<br />
#Calabrò F, Lorusso V, Rosati G, Manzione L, Frassineti L, Sava T, Di Paula ED, Alonso S, Sternberg CN. Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer. 2009 Jun 15;115(12):2652-9. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.24313/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19396817 PubMed]<br />
<br />
==MVAC {{#subobject:d2ea09|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin<br />
===Regimen variant #1, standard {{#subobject:33db41|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1992.10.7.1066 Loehrer et al. 1992]<br />
|1984-1989<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_monotherapy|Cisplatin]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://doi.org/10.1200/jco.1990.8.6.1050 Logothetis et al. 1990]<br />
|1985-1989<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#CISCA|CISCA]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://doi.org/10.1200/JCO.2002.20.5.1361 Siefker-Radtke et al. 2002]<br />
|1992-1999<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Stub#FAP|FAP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%<br />
|-<br />
|[https://doi.org/10.1200/jco.2001.19.10.2638 Sternberg et al. 2001 (EORTC 30924)]<br />
|1993-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MVAC.2C_dose-dense_2|Dose-dense MVAC]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup><br />
|-<br />
|[https://doi.org/10.1200/jco.2000.18.17.3068 von der Maase et al. 2000]<br />
|1996-1998<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://doi.org/10.1002/cncr.20123 Dreicer et al. 2004]<br />
|1998-2001<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin_.26_Paclitaxel_.28CP.29|CP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for EORTC 30924 is based on the 2005 update.''<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once over 120 minutes on day 1 or 2<br />
<br />
'''28-day cycles''' (number of cycles and criteria to continue therapy varies depending on reference)<br />
<br />
===Regimen variant #2, with G-CSF support {{#subobject:72266e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2004.02.152 Bamias et al. 2003]<br />
|1997-2002<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Docetaxel<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[Filgrastim (Neupogen)]] (dose not specified) SC once per day on days 7, 8, 9, 25, 26<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. [https://doi.org/10.1200/jco.1990.8.6.1050 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2189954 PubMed]<br />
#Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, Blumenstein B, Trump D. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. [https://doi.org/10.1200/JCO.1992.10.7.1066 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/1607913 PubMed]<br />
##'''Update:''' Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, Loehrer PJ Sr, Trump D. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997 Jul;15(7):2564-9. [https://doi.org/10.1200/JCO.1997.15.7.2564 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9215826 PubMed]<br />
#von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. [https://doi.org/10.1200/jco.2000.18.17.3068 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11001674 PubMed]<br />
##'''Update:''' von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. [https://doi.org/10.1200/JCO.2005.07.757 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16034041 PubMed]<br />
#'''EORTC 30924:''' Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [https://doi.org/10.1200/jco.2001.19.10.2638 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11352955 PubMed]<br />
##'''Update:''' Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. [https://www.ejcancer.com/article/S0959-8049(05)00874-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16330205 PubMed]<br />
#Siefker-Radtke AO, Millikan RE, Tu SM, Moore DF Jr, Smith TL, Williams D, Logothetis CJ. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol. 2002 Mar 1;20(5):1361-7. [https://doi.org/10.1200/JCO.2002.20.5.1361 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11870180 PubMed]<br />
#Bamias A, Aravantinos G, Deliveliotis C, Bafaloukos D, Kalofonos C, Xiros N, Zervas A, Mitropoulos D, Samantas E, Pectasides D, Papakostas P, Gika D, Kourousis C, Koutras A, Papadimitriou C, Bamias C, Kosmidis P, Dimopoulos MA; Hellenic Cooperative Oncology Group. Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. J Clin Oncol. 2004 Jan 15;22(2):220-8. Epub 2003 Dec 9. Erratum in: J Clin Oncol. 2004 May 1;22(9):1771. [https://doi.org/10.1200/JCO.2004.02.152 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14665607 PubMed]<br />
#Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. [https://doi.org/10.1002/cncr.20123 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15073851/ PubMed]<br />
<br />
==MVAC, dose-dense {{#subobject:c9beb1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ddMVAC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin<br />
===Regimen {{#subobject:daeb1c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://doi.org/10.1200/jco.2001.19.10.2638 Sternberg et al. 2001 (EORTC 30924)]<br />
|1993-1998<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br />
|62% (95% CI 54-70)<br />
|50% (95% CI 42-59)<br />
|-<br />
|[https://doi.org/10.1093/annonc/mds583 Bamias et al. 2012 (HE 16/03)]<br />
|2003-2008<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|DD-GC<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|<br />
|<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for EORTC 30924 is based on the 2005 update.''<br><br />
''Note: In contrast to Sternberg et al. 2001, Sternberg et al. 2006 specified 15-day cycles.''<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once on day 2<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Granulocyte colony-stimulating factors|G-CSF]] (type not specified) 240 mcg/m<sup>2</sup> SC once per day on days 4 to 10 (additional use up to a total of 14 consecutive days if needed), injected at alternating sites, discontinued if ANC greater than 30,000/uL. <br />
**''In contrast to Sternberg et al. 2001, Sternberg et al. 2006 said G-CSF was given on days 3 to 7.''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''EORTC 30924:''' Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [https://doi.org/10.1200/jco.2001.19.10.2638 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11352955 PubMed]<br />
##'''Update:''' Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. [https://www.ejcancer.com/article/S0959-8049(05)00874-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16330205 PubMed]<br />
#'''HE 16/03:''' Bamias A, Dafni U, Karadimou A, Timotheadou E, Aravantinos G, Psyrri A, Xanthakis I, Tsiatas M, Koutoulidis V, Constantinidis C, Hatzimouratidis C, Samantas E, Visvikis A, Chrisophos M, Stravodimos K, Deliveliotis C, Eleftheraki A, Pectasides D, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol. 2013 Apr;24(4):1011-7. Epub 2012 Nov 7. [https://doi.org/10.1093/annonc/mds583 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23136231 PubMed] ACTRN12610000845033<br />
<br />
==PGC {{#subobject:393eb6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PGC: '''<u>P</u>'''aclitaxel, '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin<br />
<br>PCG: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''isplatin, '''<u>G</u>'''emcitabine<br />
===Regimen {{#subobject:837446|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ Bellmunt et al. 2012 (EORTC 30987)]<br />
|2001-2004<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|56% (95% CI NR)<br />
|44% (95% CI NR)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1 & 8, '''given first'''<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''EORTC 30987:''' Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. [https://doi.org/10.1200/JCO.2011.38.6979 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22370319 PubMed] NCT00022191<br />
<br />
=Locally advanced or metastatic disease, maintenance after platinum chemotherapy=<br />
<br />
==Avelumab monotherapy {{#subobject:efub4c|Regimen=1}}==<br />
{| class="wikitable sortable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:913o9g|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa2002788 Powles et al. 2020 (JAVELIN Bladder 100)]<br />
|2016-2019<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Best supportive care<br />
| style="background-color:#1a9851" |Superior OS<br />
| style="background-color:#d73027" |More toxic<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]] x 4 to 6 or [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]] x 4 to 6 cycles<br />
<br />
====Immunotherapy====<br />
<br />
*[[Avelumab (Bavencio)]] 10 mg/kg IV over 60 minutes once per day on days 1 & 15<br />
<br />
====Supportive Medications====<br />
Premedication with a histamine H1 receptor (H1) blocker and acetaminophen approximately 30 to 60 minutes prior to each dose of avelumab for the first 4 doses; for example:<br />
<br />
*[[Diphenhydramine (Benadryl)]] 25 to 50 mg IV or oral equivalent<br />
*[[Acetaminophen (Tylenol)]] 500 to 650 mg IV or oral equivalent<br />
<br />
'''28-day cycles'''<br />
===References===<br />
<br />
#'''JAVELIN Bladder 100:''' Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Kalofonos H, Radulović S, Demey W, Ullén A, Loriot Y, Sridhar SS, Tsuchiya N, Kopyltsov E, Sternberg CN, Bellmunt J, Aragon-Ching JB, Petrylak DP, Laliberte R, Wang J, Huang B, Davis C, Fowst C, Costa N, Blake-Haskins JA, di Pietro A, Grivas P. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020 Sep 24;383(13):1218-1230. Epub 2020 Sep 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa2002788 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32945632 PubMed] NCT02603432<br />
<br />
==Pembrolizumab monotherapy {{#subobject:gbzb4c|Regimen=1}}==<br />
{| class="wikitable sortable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9gia9g|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 17%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255983/ Galsky et al. 2020 (HCRN GU14-182)]<br />
|2015-2018<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
| style="background-color:#d73027" |More toxic<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*First-line platinum-based combination chemotherapy for up to 8 cycles without progression of disease<br />
<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
<!-- # Joaquim Bellmunt, Guru Sonpavde, Ronald De Wit, Toni K. Choueiri, Arlene O. Siefker-Radtke, Elizabeth R. Plimack, Nicole M. Lewis, Holly Brown, Yabing Mai, Christine K. Gause, David Ross Kaufman, Dean F. Bajorin. KEYNOTE-045: Randomized phase 3 trial of pembrolizumab (MK-3475) versus paclitaxel, docetaxel, or vinflunine for previously treated metastatic urothelial cancer. 2015 ASCO Annual Meeting abstract TPS4571. [http://meetinglibrary.asco.org/content/145993-156 link to abstract] --><br />
#'''HCRN GU14-182:''' Galsky MD, Mortazavi A, Milowsky MI, George S, Gupta S, Fleming MT, Dang LH, Geynisman DM, Walling R, Alter RS, Kassar M, Wang J, Gupta S, Davis N, Picus J, Philips G, Quinn DI, Haines GK 3rd, Hahn NM, Zhao Q, Yu M, Pal SK. Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer. J Clin Oncol. 2020 Jun 1;38(16):1797-1806. Epub 2020 Apr 9. [https://doi.org/10.1200/jco.19.03091 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255983/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32271672 PubMed] NCT02500121<br />
<br />
=Locally advanced or metastatic disease, after platinum chemotherapy=<br />
==Avelumab monotherapy {{#subobject:6C1497|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:D9FB6C|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |Years of enrollment<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493051/ Apolo et al. 2017 (JAVELIN)]<br />
|2014<br />
| style="background-color:#ffffbe" |Phase Ib (RT)<br />
|18% (95% CI 8-33)<br />
|-<br />
|}<br />
====Immunotherapy====<br />
<br />
*[[Avelumab (Bavencio)]] 10 mg/kg IV over 60 minutes once on day 1<br />
<br />
====Supportive medications====<br />
''Per Apolo et al. 2017 (JAVELIN):''<br />
<br />
*"All patients were premedicated with [[:Category:Antihistamines|an antihistamine]] and [[Acetaminophen (Tylenol)|acetaminophen]] (doses and routes not given)<br />
*The avelumab package insert suggests "Premedicate with acetaminophen and an antihistamine for the first 4 infusions and subsequently as needed."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Phase 1:''' Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, Mega AE, Britten CD, Ravaud A, Mita AC, Safran H, Stinchcombe TE, Srdanov M, Gelb AB, Schlichting M, Chin K, Gulley JL. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: Results from a multicenter, phase Ib study. J Clin Oncol. 2017 Jul 1;35(19):2117-2124. Epub 2017 Apr 4. [https://doi.org/10.1200/JCO.2016.71.6795 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493051/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28375787 PubMed] NCT01772004<br />
<br />
==Docetaxel monotherapy {{#subobject:385447|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b840fe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.1997.15.5.1853 McCaffrey et al. 1997]<br />
|1993-1995<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ Choueiri et al. 2012 (DFCI 06-116)]<br />
|2007-2010<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel & Vandetanib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
| rowspan="2" |[https://doi.org/10.1200/JCO.2015.65.0218 Petrylak et al. 2016 (JCDC)]<br />
| rowspan="2" |2011-2014<br />
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (C)<br />
|1. Docetaxel & Icrucumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|2. [[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy_5|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<br />
|2015-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext Petrylak et al. 2017 (RANGE)]<br />
|2015-2017<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]<br />
| style="background-color:#d73027" |Inferior PFS<sup>1</sup><br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for RANGE is based on the 2019 update.''<br><br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7. [https://doi.org/10.1200/JCO.1997.15.5.1853 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9164195 PubMed]<br />
#'''DFCI 06-116:''' Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, Hahn NM, Hutson TE, Sonpavde G, Morrissey SC, Buckle GC, Kim WY, Petrylak DP, Ryan CW, Eisenberger MA, Mortazavi A, Bubley GJ, Taplin ME, Rosenberg JE, Kantoff PW. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012 Feb 10;30(5):507-12. [https://doi.org/10.1200/jco.2011.37.7002 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22184381 PubMed] NCT00880334<br />
#'''JCDC:''' Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. [https://doi.org/10.1200/JCO.2015.65.0218 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26926681 PubMed] NCT01282463<br />
<!-- # Joaquim Bellmunt, Guru Sonpavde, Ronald De Wit, Toni K. Choueiri, Arlene O. Siefker-Radtke, Elizabeth R. Plimack, Nicole M. Lewis, Holly Brown, Yabing Mai, Christine K. Gause, David Ross Kaufman, Dean F. Bajorin. KEYNOTE-045: Randomized phase 3 trial of pembrolizumab (MK-3475) versus paclitaxel, docetaxel, or vinflunine for previously treated metastatic urothelial cancer. 2015 ASCO Annual Meeting abstract TPS4571. [http://meetinglibrary.asco.org/content/145993-156 link to abstract] --><br />
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28212060 PubMed] NCT02256436<br />
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707 PubMed]<br />
#'''RANGE:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28916371 PubMed] NCT02426125<br />
##'''Update:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30668-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946880/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31753727 PubMed]<br />
#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29268948 PubMed] NCT02302807<br />
#'''TROPiCS-04:''' NCT04527991<br />
<br />
==Docetaxel & Ramucirumab {{#subobject:385447|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b840fe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2015.65.0218 Petrylak et al. 2016 (JCDC)]<br />
|2011-2014<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext Petrylak et al. 2017 (RANGE)]<br />
|2015-2017<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior PFS<sup>1</sup> <br>(HR 0.70, 95% CI 0.57-0.85)<br />
|-<br />
|}<br />
''<sup>1</sup>Reported efficacy for RANGE is based on the 2019 update.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Targeted therapy====<br />
<br />
*[[Ramucirumab (Cyramza)]] 10 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''JCDC:''' Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. [https://doi.org/10.1200/JCO.2015.65.0218 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26926681 PubMed] NCT01282463<br />
#'''RANGE:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28916371 PubMed] NCT02426125<br />
##'''Update:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30668-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946880/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31753727 PubMed]<br />
<br />
==Erdafitinib monotherapy {{#subobject:dbc30d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:473057|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |Years of enrollment<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1817323 Loriot et al. 2019 (BLC2001)]<br />
|2015-2018<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#8c96c6" |ORR 40% (95% CI 31-50)<br />
|-<br />
|}<br />
====Biomarker eligibility criteria====<br />
<br />
*Alterations: FGFR3 mutation, FGFR2 fusion, or FGFR3 fusion<br />
<br />
====Targeted therapy====<br />
<br />
*[[Erdafitinib (Balversa)]] 8 mg PO once per day<br />
**If serum phosphorus level and tolerability are acceptable at days 14 to 21, increase to 9 mg PO once per day<br />
**Additional dose adjustments per package insert<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Arlene O. Siefker-Radtke, Andrea Necchi, Se Hoon Park, Jesus Garcia-Donas, Robert A Huddart, Earle Frederick Burgess, Mark T. Fleming, Arash Rezazadeh, Begona Mellado, Sergei Varlamov, Monika Joshi, Ignacio Duran, Scott T. Tagawa, Anne OHagan, Anjali Narayan Avadhani, Bob Zhong, Peter De Porre, Yohann Loriot, on behalf of the BLC2001 Study Group. First results from the primary analysis population of the phase 2 study of erdafitinib (ERDA; JNJ-42756493) in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt). 2018 ASCO Annual Meeting abstract 4503 [https://meetinglibrary.asco.org/record/160559/abstract link to abstract] '''contains verified protocol'''<br />
# '''BLC2001:''' [https://clinicaltrials.gov/ct2/show/NCT02365597 CT.gov] --><br />
<br />
#'''BLC2001:''' Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, Fleming M, Rezazadeh A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Zhong B, Stuyckens K, Santiago-Walker A, De Porre P, O'Hagan A, Avadhani A, Siefker-Radtke AO; BLC2001 Study Group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348. [https://www.nejm.org/doi/full/10.1056/NEJMoa1817323 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31340094 PubMed] NCT02365597<br />
<br />
==Gemcitabine & Paclitaxel {{#subobject:ecfc0d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GP: '''<u>G</u>'''emcitabine & '''<u>P</u>'''aclitaxel<br />
===Regimen variant #1, gemcitabine 2 out of 3 weeks {{#subobject:384057|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdq398 Albers et al. 2010 (AUO AB 20/99)]<br />
|2001-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_Paclitaxel_2|GP]]; prolonged<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Regimen variant #2, weekly gemcitabine {{#subobject:9aa3e0|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2001.19.12.3018 Meluch et al. 2001]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts in this subgroup<br />
| style="background-color:#8c96c6" |ORR: 47%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. [https://doi.org/10.1200/jco.2001.19.12.3018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11408496 PubMed]<br />
#'''AUO AB 20/99:''' Albers P, Park SI, Niegisch G, Fechner G, Steiner U, Lehmann J, Heimbach D, Heidenreich A, Fimmers R, Siener R; AUO Bladder Cancer Group. Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99]. Ann Oncol. 2011 Feb;22(2):288-94. Epub 2010 Aug 2. [https://doi.org/10.1093/annonc/mdq398 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20682548 PubMed]<br />
<br />
==MVAC {{#subobject:373ed3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin<br />
<br />
===Regimen {{#subobject:af2e64|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359702/ Han et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#8c6bb1" |ORR: 30%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22<br />
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22<br />
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2<br />
<br />
'''28-day cycles''' (number of cycles and criteria to continue therapy varies depending on reference)<br />
<br />
===References===<br />
<br />
#Han KS, Joung JY, Kim TS, Jeong IG, Seo HK, Chung J, Lee KH. Methotrexate, vinblastine, doxorubicin and cisplatin combination regimen as salvage chemotherapy for patients with advanced or metastatic transitional cell carcinoma after failure of gemcitabine and cisplatin chemotherapy. Br J Cancer. 2008 Jan 15;98(1):86-90. Epub 2007 Dec 18. [https://doi.org/10.1038/sj.bjc.6604113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359702/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18087289 PubMed]<br />
<br />
==Nivolumab monotherapy {{#subobject:86b89c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:beb7fa|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |Years of enrollment<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30065-7/fulltext Sharma et al. 2017 (CheckMate 275)]<br />
|2015<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|19.6% overall<br>PD-L1 expression ≥5%: 28.4%<br>PD-L1 expression ≥1%: 23.8%<br>PD-L1 expression <1%: 16.1%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*At least one [[Regimen_classes#Platinum-based_regimen|platinum-based therapy]], with progression<br />
<br />
====Immunotherapy====<br />
<br />
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1<br />
**''The FDA-approved dose which is listed in the package insert is 240 mg IV over 60 minutes once on day 1''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''CheckMate 275:''' Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S, Arranz JÁ, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017 Mar;18(3):312-322. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30065-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/28131785 PubMed] NCT02387996<br />
##'''Update:''' Galsky MD, Saci A, Szabo PM, Han GC, Grossfeld G, Collette S, Siefker-Radtke A, Necchi A, Sharma P. Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275. Clin Cancer Res. 2020 Jun 12. Epub ahead of print. [https://doi.org/10.1158/1078-0432.ccr-19-4162 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32532789 PubMed]<br />
<br />
==nab-Paclitaxel monotherapy {{#subobject:fec6dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7dc525|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70162-1/fulltext Ko et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#8c6bb1" |ORR: 28% (95% CI 17-44)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 260 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
====Dose modifications====<br />
<br />
*"Two dose reductions were permitted, to 240 mg/m<sup>2</sup> and then to 180 mg/m<sup>2</sup>. When further dose reductions were required, study treatment was discontinued. Patients with febrile neutropenia, or delay of cycle because of persistent neutropenia, ANC of less than 500/uL for 1 week, or grade 3 or 4 thrombocytopenia required dose reductions. When sensory neuropathy of grade 2 or higher occurred, study drug was withheld until resolution to grade 2 or better, then reinstituted at the next lower dose. When mucositis or diarrhea of grade 3 or higher occurred, study drug was withheld until resolution to grade 1 or better, then reinstituted at the next lower dose. Patients with mucositis or diarrhea of grade 4 were removed from the trial."<br />
<br />
===References===<br />
<br />
#Ko YJ, Canil CM, Mukherjee SD, Winquist E, Elser C, Eisen A, Reaume MN, Zhang L, Sridhar SS. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study. Lancet Oncol. 2013 Jul;14(8):769-76. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70162-1/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23706985 PubMed] NCT00683059<br />
<br />
==Paclitaxel monotherapy {{#subobject:fec6dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, q3wks {{#subobject:9fddc0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy_5|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<br />
|2015-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm. IMvigor211 allowed up to 2 prior lines of platinum-containing chemotherapy.''<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Regimen variant #2, 3 out of 4 weeks {{#subobject:524ebf|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2002.20.4.937 Vaughn et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#6e016b; color:white" |ORR: 10% (95% CI 0-20)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. [https://doi.org/10.1200/jco.2002.20.4.937 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11844814 PubMed]<br />
#'''Retrospective:''' Sideris S, Aoun F, Zanaty M, Martinez NC, Latifyan S, Awada A, Gil T. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol Clin Oncol. 2016 Jun;4(6):1063-1067. Epub 2016 Mar 17. [https://doi.org/10.3892/mco.2016.821 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887921/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27284445 PubMed]<br />
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28212060 PubMed] NCT02256436<br />
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707 PubMed]<br />
#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29268948 PubMed] NCT02302807<br />
#'''TROPiCS-04:''' NCT04527991<br />
<br />
==Pembrolizumab monotherapy {{#subobject:b0cd2a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8aec07|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|Investigator's choice of:<br> 1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. [[#Paclitaxel_monotherapy|Paclitaxel]]<br> 3. [[#Vinflunine_monotherapy|Vinflunine]]<br />
| style="background-color:#1a9850" |Superior OS <br>Median OS: 10 mo vs 7 mo <br>(HR 0.73, 95% CI 0.59-0.91)<br />
|-<br />
|}<br />
====Biomarker eligibility criteria====<br />
<br />
For the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.<br />
<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28212060 PubMed] NCT02256436<br />
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707 PubMed]<br />
<br />
==Pemetrexed monotherapy {{#subobject:fec6dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7dc525|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.2005.03.6699 Sweeney et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#8c6bb1" |ORR: 28% (95% CI 16-43)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, Nicol SJ, Kaufman DS. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006 Jul 20;24(21):3451-7. [https://doi.org/10.1200/jco.2005.03.6699 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16849761 PubMed]<br />
<br />
==Vinflunine monotherapy {{#subobject:e40f4c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b5b9b9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |Years of enrollment<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.2008.20.5534 Bellmunt et al. 2009 (CA183004)]<br />
|2003-2006<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Bladder_cancer_-_null_regimens#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<sup>1</sup> <br>(HR 0.72, 95% CI 0.57-0.91)<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
|2014-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy_5|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<br />
|2015-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Atezolizumab_monotherapy_2|Atezolizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''<sup>1<sup>Reported efficacy for CA183004 is based on the 2013 update.''<br />
====Chemotherapy====<br />
<br />
*[[Vinflunine (Javlor)]] 320 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#'''CA183004:''' Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, Caty A, Carles J, Jagiello-Gruszfeld A, Karyakin O, Delgado FM, Hurteloup P, Winquist E, Morsli N, Salhi Y, Culine S, von der Maase H. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009 Sep 20;27(27):4454-61. Epub 2009 Aug 17. Erratum in: J Clin Oncol. 2010 Jan 1;28(1):182. Winquist, Eric [added]. [https://doi.org/10.1200/JCO.2008.20.5534 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19687335 PubMed] NCT00315237<br />
##'''Update:''' Bellmunt J, Fougeray R, Rosenberg JE, von der Maase H, Schutz FA, Salhi Y, Culine S, Choueiri TK. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. Ann Oncol. 2013 Jun;24(6):1466-72. Epub 2013 Feb 17. [https://doi.org/10.1093/annonc/mdt007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23419284 PubMed]<br />
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28212060 PubMed] NCT02256436<br />
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707 PubMed]<br />
#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29268948 PubMed] NCT02302807<br />
#'''TROPiCS-04:''' NCT04527991<br />
<br />
=Locally advanced or metastatic disease, after platinum chemotherapy and immune checkpoint inhibitor =<br />
==Enfortumab vedotin monotherapy {{#subobject:dbdcad|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:415bc7|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 15%" |Study<br />
! style="width: 15%" |Years of enrollment<br />
! style="width: 15%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 17%" |Comparator<br />
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784850/ Rosenberg et al. 2018 (EV-201)]<br />
|2017-2018<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|None<br />
|N/A<br />
| style="background-color:#8c96c6" |44% (95% CI 35.2-53.2)<br />
|N/A<br />
|-<br />
|[https://doi.org/10.1056/NEJMoa2035807 Powles et al. 2021 (EV-301)]<br />
|2018-2020<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Investigator-chosen chemotherapy (standard [[Bladder_cancer#Docetaxel_monotherapy | Docetaxel]], [[Bladder_cancer#Paclitaxel_monotherapy | Paclitaxel]], or [[Bladder_cancer#Vinflunine_monotherapy | Vinflunine]])<br />
| style="background-color:#1a9851" |Superior OS<br />
|Intention to treat: 40.6%<br />
|Intention to treat: 17.9%<br />
|}<br />
====Antibody-drug conjugate therapy====<br />
<br />
*[[Enfortumab vedotin (Padcev)]] 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''EV-201:''' Rosenberg JE, O'Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, Galsky MD, Hahn NM, Gartner EM, Pinelli JM, Liang SY, Melhem-Bertrandt A, Petrylak DP. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Oct 10;37(29): 2592-2600. Epub 2019 Jul 29. [https://doi.org/10.1200/JCO.19.01140 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784850/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31356140 Pubmed] NCT03219333<br />
#'''EV-301:''' Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. [https://doi.org/10.1056/NEJMoa2035807 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33577729 Pubmed] NCT03474107<br />
<br />
==Sacituzumab govitecan monotherapy {{#subobject:d9gacd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:417gu7|Variant=1}}===<br />
{| class="wikitable sortable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|No publication yet<br />
|2018-NR<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
''Note: dosing information is from ClinicalTrials.gov.''<br />
====Antibody-drug conjugate therapy====<br />
*[[Sacituzumab govitecan (Trodelvy)]] 10 mg/kg IV once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
#'''TROPHY:''' NCT03547973<br />
<br />
=Links=<br />
<br />
*[http://www.eortc.be/tools/bladdercalculator/ EORTC Risk Tables for Predicting Recurrence and Progression in Individual Patients with Stage Ta T1 Bladder Cancer] - predicts probability of recurrence and progression in 1 to 5 years<br />
<br />
=Urine assays=<br />
''These are assays intended/being investigated as adjuncts to urine cytology and cystoscopy.''<br />
<br />
*[https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=347921 Cxbladder (uRNA-2)], a "urine based bladder cancer test (uRNA-2) which detects RNA markers in urine."<br />
*[http://www.scimedx.com/products/bladder_cancer/bladder_cancer.php ImmunoCyt™/uCyt+™], a cell-based detection assay which "uses fluorescent-labeled antibodies to 3 markers that are commonly found on malignant exfoliated urothelial cells."<ref>Greene KL, Berry A, Konety BR. Diagnostic Utility of the ImmunoCyt/uCyt+ Test in Bladder Cancer. Rev Urol. 2006 Fall;8(4):190-7. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751037/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17192798 PubMed]</ref><br />
*[http://www.abbottmolecular.com/us/products/oncology/fish/bladder-cancer-urovysion.html UroVysion] (Abbott Molecular) "designed to detect aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus via fluorescence in situ hybridization (FISH) in urine specimens from persons with hematuria suspected of having bladder cancer."<br />
<br />
=References=<br />
<references /><br />
<br />
[[Category:Bladder cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Genitourinary cancers]]</div>Karinehttps://hemonc.org/w/index.php?title=Cold_agglutinin_disease&diff=49399Cold agglutinin disease2021-05-08T04:38:39Z<p>Karine: /* Sutimlimab monotherapy */ formating</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#31a354" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
=="How I Treat"==<br />
<br />
*'''2021:''' Berentsen [https://doi.org/10.1182/blood.2019003809 How I treat cold agglutinin disease]<br />
<br />
=All lines of therapy=<br />
<br />
==Bendamustine & Rituximab (BR) {{#subobject:0fde6d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
BR: '''<u>B</u>'''endamustine, '''<u>R</u>'''ituximab<br />
===Regimen {{#subobject:47595c|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/4/537.long Berentsen et al. 2017]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Bendamustine]] 90 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
<br />
====Targeted therapy====<br />
<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#Berentsen S, Randen U, Oksman M, Birgens H, Tvedt THA, Dalgaard J, Galteland E, Haukås E, Brudevold R, Sørbø JH, Næss IA, Malecka A, Tjønnfjord GE. Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial. Blood. 2017 Jul 27;130(4):537-541. Epub 2017 May 22. [http://www.bloodjournal.org/content/130/4/537.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28533306 PubMed] NCT02689986<br />
<br />
==Eculizumab monotherapy {{#subobject:08ef07|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:95a0a9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6177646/ Röth et al. 2018 (DECADE)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
<br />
''Eligible patients had symptomatic cold agglutinin-mediated hemolysis with a serum lactate dehydrogenase (LDH) level greater than or equal to 2 x upper limit of normal and a cold agglutinin titer greater than 1:64 at 4°C.''<br />
====Immunosuppressive therapy====<br />
<br />
*[[Eculizumab (Soliris)]] as follows:<br />
**Cycle 1: 600 mg IV once per day on days 1, 8, 15, 22<br />
**Cycles 2 to 11: 900 mg IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*Patients were vaccinated against ''Neisseria meningitidis'' or received "appropriate antibiotics" if vaccination occurred within 14 days of the first dose<br />
<br />
'''28-day cycle for 1 cycle, then 14-day cycle for 11 cycles'''<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Alexander Röth, MD, Martin Bommer, MD, Andreas Hüttmann, MD, Dörte Herich-Terhürne, Nils Kuklik, PhD, Lenz Veronika, Hubert Schrezenmeier, MD and Ulrich Dührsen, MD. Complement Inhibition with Eculizumab in Patients with Cold Agglutinin Disease (CAD): Results from a Prospective Phase II Trial (DECADE Trial). ASH Annual Meeting 2015 Abstract 274 [https://ash.confex.com/ash/2015/webprogram/Paper79420.html link to abstract] --><br />
<br />
#'''DECADE:''' Röth A, Bommer M, Hüttmann A, Herich-Terhürne D, Kuklik N, Rekowski J, Lenz V, Schrezenmeier H, Dührsen U. Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial. Blood Adv. 2018 Oct 9;2(19):2543-2549. [https://doi.org/10.1182/bloodadvances.2018024190 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6177646/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30291112/ PubMed] NCT01303952<br />
<br />
==FR {{#subobject:96c221|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FR: '''<u>F</u>'''ludarabine & '''<u>R</u>'''ituximab<br />
===Regimen {{#subobject:645885|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/17/3180.long Berentsen et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#e0ecf4" |ORR: 76%<br />
|-<br />
|}<br />
<br />
''Eligible patients had to be diagnosed with cold agglutinin disease and require therapy because of anemia, substantial cold-induced circulatory symptoms, or both.''<br />
====Chemotherapy====<br />
<br />
*[[Fludarabine (Fludara)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 5<br />
<br />
====Targeted therapy====<br />
<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#Berentsen S, Randen U, Vågan AM, Hjorth-Hansen H, Vik A, Dalgaard J, Jacobsen EM, Thoresen AS, Beiske K, Tjønnfjord GE. High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. Blood. 2010 Oct 28;116(17):3180-4. Epub 2010 Jul 15. [http://www.bloodjournal.org/content/116/17/3180.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20634373 PubMed] NCT00373594<br />
<br />
==Rituximab monotherapy {{#subobject:65c6f1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:372fe5|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2925.long Berentsen et al. 2003]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#9ebcda" |ORR: 54%<br />
|-<br />
|[http://www.tandfonline.com/doi/full/10.1080/10428190500286481 Schöllkopf et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#8c96c6" |ORR: 45%<br />
|-<br />
|}<br />
<br />
''Patients in '''Berentsen et al. 2003''' were required to have cold agglutinin disease, as defined by the combination of chronic hemolysis and a cold agglutinin titer of 1:64 or higher, and a typical pattern for the direct antiglobulin test (DAT).''<br />
====Immunosuppressive therapy====<br />
<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day course'''<br />
<br />
===References===<br />
<br />
#Berentsen S, Ulvestad E, Gjertsen BT, Hjorth-Hansen H, Langholm R, Knutsen H, Ghanima W, Shammas FV, Tjønnfjord GE. Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. Blood. 2004 Apr 15;103(8):2925-8. Epub 2003 Dec 30. [http://www.bloodjournal.org/content/103/8/2925.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070665 PubMed]<br />
#Schöllkopf C, Kjeldsen L, Bjerrum OW, Mourits-Andersen HT, Nielsen JL, Christensen BE, Jensen BA, Pedersen BB, Taaning EB, Klausen TW, Birgens H. Rituximab in chronic cold agglutinin disease: a prospective study of 20 patients. Leuk Lymphoma. 2006 Feb;47(2):253-60. [http://www.tandfonline.com/doi/full/10.1080/10428190500286481 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16321854 PubMed]<br />
<br />
==Sutimlimab monotherapy==<br />
===Regimen===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa2027760?query=oncology-hematology.long Röth et al. 2021]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#9ebcda" |ORR: 54%<br />
|-<br />
<br />
|}<br />
====Targeted therapy====<br />
<br />
*[[Sutimlimab]] 6.5 g (for patients who weighed less than 75 kg at baseline) and 7.5g (for patients who weighed 75 kg or more)<br />
<br />
'''7 day course for cycle 1 then every 14 days for 26 weeks'''</div>Karinehttps://hemonc.org/w/index.php?title=Cold_agglutinin_disease&diff=49398Cold agglutinin disease2021-05-08T04:28:44Z<p>Karine: Sutimlimab regimen NEJM 2021</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
!colspan="2" align="center" style="color:white; font-size:125%; background-color:#31a354"|'''Section editor'''<br />
|-<br />
|style="background-color:#F0F0F0; width:15%"|[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
|style="width:35%"|<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
=="How I Treat"==<br />
*'''2021:''' Berentsen [https://doi.org/10.1182/blood.2019003809 How I treat cold agglutinin disease]<br />
<br />
=All lines of therapy=<br />
<br />
==Bendamustine & Rituximab (BR) {{#subobject:0fde6d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
BR: '''<u>B</u>'''endamustine, '''<u>R</u>'''ituximab<br />
===Regimen {{#subobject:47595c|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/4/537.long Berentsen et al. 2017]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bendamustine]] 90 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
====Targeted therapy====<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
# Berentsen S, Randen U, Oksman M, Birgens H, Tvedt THA, Dalgaard J, Galteland E, Haukås E, Brudevold R, Sørbø JH, Næss IA, Malecka A, Tjønnfjord GE. Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial. Blood. 2017 Jul 27;130(4):537-541. Epub 2017 May 22. [http://www.bloodjournal.org/content/130/4/537.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28533306 PubMed] NCT02689986<br />
<br />
==Eculizumab monotherapy {{#subobject:08ef07|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:95a0a9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6177646/ Röth et al. 2018 (DECADE)]<br />
|style="background-color:#ffffbe"|Phase II, <20 pts<br />
|-<br />
|}<br />
<br />
''Eligible patients had symptomatic cold agglutinin-mediated hemolysis with a serum lactate dehydrogenase (LDH) level greater than or equal to 2 x upper limit of normal and a cold agglutinin titer greater than 1:64 at 4°C.''<br />
====Immunosuppressive therapy====<br />
*[[Eculizumab (Soliris)]] as follows:<br />
**Cycle 1: 600 mg IV once per day on days 1, 8, 15, 22<br />
**Cycles 2 to 11: 900 mg IV once on day 1<br />
<br />
====Supportive medications====<br />
* Patients were vaccinated against ''Neisseria meningitidis'' or received "appropriate antibiotics" if vaccination occurred within 14 days of the first dose<br />
<br />
'''28-day cycle for 1 cycle, then 14-day cycle for 11 cycles'''<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Alexander Röth, MD, Martin Bommer, MD, Andreas Hüttmann, MD, Dörte Herich-Terhürne, Nils Kuklik, PhD, Lenz Veronika, Hubert Schrezenmeier, MD and Ulrich Dührsen, MD. Complement Inhibition with Eculizumab in Patients with Cold Agglutinin Disease (CAD): Results from a Prospective Phase II Trial (DECADE Trial). ASH Annual Meeting 2015 Abstract 274 [https://ash.confex.com/ash/2015/webprogram/Paper79420.html link to abstract] --><br />
# '''DECADE:''' Röth A, Bommer M, Hüttmann A, Herich-Terhürne D, Kuklik N, Rekowski J, Lenz V, Schrezenmeier H, Dührsen U. Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial. Blood Adv. 2018 Oct 9;2(19):2543-2549. [https://doi.org/10.1182/bloodadvances.2018024190 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6177646/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30291112/ PubMed] NCT01303952<br />
<br />
==FR {{#subobject:96c221|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FR: '''<u>F</u>'''ludarabine & '''<u>R</u>'''ituximab<br />
===Regimen {{#subobject:645885|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/17/3180.long Berentsen et al. 2010]<br />
|style="background-color:#91cf61"|Phase II<br />
| style="background-color:#e0ecf4" |ORR: 76%<br />
|-<br />
|}<br />
<br />
''Eligible patients had to be diagnosed with cold agglutinin disease and require therapy because of anemia, substantial cold-induced circulatory symptoms, or both.''<br />
====Chemotherapy====<br />
*[[Fludarabine (Fludara)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 5<br />
====Targeted therapy====<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
# Berentsen S, Randen U, Vågan AM, Hjorth-Hansen H, Vik A, Dalgaard J, Jacobsen EM, Thoresen AS, Beiske K, Tjønnfjord GE. High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. Blood. 2010 Oct 28;116(17):3180-4. Epub 2010 Jul 15. [http://www.bloodjournal.org/content/116/17/3180.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20634373 PubMed] NCT00373594<br />
<br />
==Rituximab monotherapy {{#subobject:65c6f1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:372fe5|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2925.long Berentsen et al. 2003]<br />
|style="background-color:#91cf61"|Phase II<br />
| style="background-color:#9ebcda" |ORR: 54%<br />
|-<br />
|[http://www.tandfonline.com/doi/full/10.1080/10428190500286481 Schöllkopf et al. 2006]<br />
|style="background-color:#91cf61"|Phase II<br />
| style="background-color:#8c96c6" |ORR: 45%<br />
|-<br />
|}<br />
<br />
''Patients in '''Berentsen et al. 2003''' were required to have cold agglutinin disease, as defined by the combination of chronic hemolysis and a cold agglutinin titer of 1:64 or higher, and a typical pattern for the direct antiglobulin test (DAT).''<br />
====Immunosuppressive therapy====<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day course'''<br />
<br />
===References===<br />
# Berentsen S, Ulvestad E, Gjertsen BT, Hjorth-Hansen H, Langholm R, Knutsen H, Ghanima W, Shammas FV, Tjønnfjord GE. Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. Blood. 2004 Apr 15;103(8):2925-8. Epub 2003 Dec 30. [http://www.bloodjournal.org/content/103/8/2925.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070665 PubMed]<br />
# Schöllkopf C, Kjeldsen L, Bjerrum OW, Mourits-Andersen HT, Nielsen JL, Christensen BE, Jensen BA, Pedersen BB, Taaning EB, Klausen TW, Birgens H. Rituximab in chronic cold agglutinin disease: a prospective study of 20 patients. Leuk Lymphoma. 2006 Feb;47(2):253-60. [http://www.tandfonline.com/doi/full/10.1080/10428190500286481 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16321854 PubMed]<br />
<br />
==Sutimlimab monotherapy==<br />
===Regimen===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa2027760?query=oncology-hematology.long Röth et al. 2021]<br />
|style="background-color:#91cf61"|Phase II<br />
| style="background-color:#9ebcda" |ORR: 54%<br />
|-<br />
====Targeted therapy====<br />
*[[Sutimlimab]] 6.5 g (for patients who weighed less than 75 kg at baseline) and 7.5g (for patients who weighed 75 kg or more)<br />
'''7 day course for cycle 1 then every 14 days for 26 weeks'''</div>Karinehttps://hemonc.org/w/index.php?title=Cold_agglutinin_disease&diff=49397Cold agglutinin disease2021-05-08T04:15:54Z<p>Karine: removed sutimlimab from investigational agents</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
!colspan="2" align="center" style="color:white; font-size:125%; background-color:#31a354"|'''Section editor'''<br />
|-<br />
|style="background-color:#F0F0F0; width:15%"|[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
|style="width:35%"|<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
=="How I Treat"==<br />
*'''2021:''' Berentsen [https://doi.org/10.1182/blood.2019003809 How I treat cold agglutinin disease]<br />
<br />
=All lines of therapy=<br />
<br />
==Bendamustine & Rituximab (BR) {{#subobject:0fde6d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
BR: '''<u>B</u>'''endamustine, '''<u>R</u>'''ituximab<br />
===Regimen {{#subobject:47595c|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/4/537.long Berentsen et al. 2017]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bendamustine]] 90 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
====Targeted therapy====<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
# Berentsen S, Randen U, Oksman M, Birgens H, Tvedt THA, Dalgaard J, Galteland E, Haukås E, Brudevold R, Sørbø JH, Næss IA, Malecka A, Tjønnfjord GE. Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial. Blood. 2017 Jul 27;130(4):537-541. Epub 2017 May 22. [http://www.bloodjournal.org/content/130/4/537.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28533306 PubMed] NCT02689986<br />
<br />
==Eculizumab monotherapy {{#subobject:08ef07|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:95a0a9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6177646/ Röth et al. 2018 (DECADE)]<br />
|style="background-color:#ffffbe"|Phase II, <20 pts<br />
|-<br />
|}<br />
<br />
''Eligible patients had symptomatic cold agglutinin-mediated hemolysis with a serum lactate dehydrogenase (LDH) level greater than or equal to 2 x upper limit of normal and a cold agglutinin titer greater than 1:64 at 4°C.''<br />
====Immunosuppressive therapy====<br />
*[[Eculizumab (Soliris)]] as follows:<br />
**Cycle 1: 600 mg IV once per day on days 1, 8, 15, 22<br />
**Cycles 2 to 11: 900 mg IV once on day 1<br />
<br />
====Supportive medications====<br />
* Patients were vaccinated against ''Neisseria meningitidis'' or received "appropriate antibiotics" if vaccination occurred within 14 days of the first dose<br />
<br />
'''28-day cycle for 1 cycle, then 14-day cycle for 11 cycles'''<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Alexander Röth, MD, Martin Bommer, MD, Andreas Hüttmann, MD, Dörte Herich-Terhürne, Nils Kuklik, PhD, Lenz Veronika, Hubert Schrezenmeier, MD and Ulrich Dührsen, MD. Complement Inhibition with Eculizumab in Patients with Cold Agglutinin Disease (CAD): Results from a Prospective Phase II Trial (DECADE Trial). ASH Annual Meeting 2015 Abstract 274 [https://ash.confex.com/ash/2015/webprogram/Paper79420.html link to abstract] --><br />
# '''DECADE:''' Röth A, Bommer M, Hüttmann A, Herich-Terhürne D, Kuklik N, Rekowski J, Lenz V, Schrezenmeier H, Dührsen U. Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial. Blood Adv. 2018 Oct 9;2(19):2543-2549. [https://doi.org/10.1182/bloodadvances.2018024190 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6177646/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30291112/ PubMed] NCT01303952<br />
<br />
==FR {{#subobject:96c221|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FR: '''<u>F</u>'''ludarabine & '''<u>R</u>'''ituximab<br />
===Regimen {{#subobject:645885|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/17/3180.long Berentsen et al. 2010]<br />
|style="background-color:#91cf61"|Phase II<br />
| style="background-color:#e0ecf4" |ORR: 76%<br />
|-<br />
|}<br />
<br />
''Eligible patients had to be diagnosed with cold agglutinin disease and require therapy because of anemia, substantial cold-induced circulatory symptoms, or both.''<br />
====Chemotherapy====<br />
*[[Fludarabine (Fludara)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 5<br />
====Targeted therapy====<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
# Berentsen S, Randen U, Vågan AM, Hjorth-Hansen H, Vik A, Dalgaard J, Jacobsen EM, Thoresen AS, Beiske K, Tjønnfjord GE. High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. Blood. 2010 Oct 28;116(17):3180-4. Epub 2010 Jul 15. [http://www.bloodjournal.org/content/116/17/3180.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20634373 PubMed] NCT00373594<br />
<br />
==Rituximab monotherapy {{#subobject:65c6f1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:372fe5|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2925.long Berentsen et al. 2003]<br />
|style="background-color:#91cf61"|Phase II<br />
| style="background-color:#9ebcda" |ORR: 54%<br />
|-<br />
|[http://www.tandfonline.com/doi/full/10.1080/10428190500286481 Schöllkopf et al. 2006]<br />
|style="background-color:#91cf61"|Phase II<br />
| style="background-color:#8c96c6" |ORR: 45%<br />
|-<br />
|}<br />
<br />
''Patients in '''Berentsen et al. 2003''' were required to have cold agglutinin disease, as defined by the combination of chronic hemolysis and a cold agglutinin titer of 1:64 or higher, and a typical pattern for the direct antiglobulin test (DAT).''<br />
====Immunosuppressive therapy====<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day course'''<br />
<br />
===References===<br />
# Berentsen S, Ulvestad E, Gjertsen BT, Hjorth-Hansen H, Langholm R, Knutsen H, Ghanima W, Shammas FV, Tjønnfjord GE. Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. Blood. 2004 Apr 15;103(8):2925-8. Epub 2003 Dec 30. [http://www.bloodjournal.org/content/103/8/2925.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070665 PubMed]<br />
# Schöllkopf C, Kjeldsen L, Bjerrum OW, Mourits-Andersen HT, Nielsen JL, Christensen BE, Jensen BA, Pedersen BB, Taaning EB, Klausen TW, Birgens H. Rituximab in chronic cold agglutinin disease: a prospective study of 20 patients. Leuk Lymphoma. 2006 Feb;47(2):253-60. [http://www.tandfonline.com/doi/full/10.1080/10428190500286481 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16321854 PubMed]<br />
<br />
==Sutimlimab monotherapy==<br />
===Regimen===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa2027760?query=oncology-hematology.long Röth et al. 2021]<br />
|style="background-color:#91cf61"|Phase II<br />
| style="background-color:#9ebcda" |ORR: 54%<br />
|-</div>Karinehttps://hemonc.org/w/index.php?title=Cold_agglutinin_disease&diff=49396Cold agglutinin disease2021-05-08T04:12:05Z<p>Karine: Cold agglutinin disease new regimen with sutimlimab summary table</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
!colspan="2" align="center" style="color:white; font-size:125%; background-color:#31a354"|'''Section editor'''<br />
|-<br />
|style="background-color:#F0F0F0; width:15%"|[[File:Tillman_Benjamin-2.jpg|frameless|upright=0.3|center]]<br />
|style="width:35%"|<big>[[User:Benjamintillman|Benjamin Tillman, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
=="How I Treat"==<br />
*'''2021:''' Berentsen [https://doi.org/10.1182/blood.2019003809 How I treat cold agglutinin disease]<br />
<br />
=All lines of therapy=<br />
<br />
==Bendamustine & Rituximab (BR) {{#subobject:0fde6d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
BR: '''<u>B</u>'''endamustine, '''<u>R</u>'''ituximab<br />
===Regimen {{#subobject:47595c|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/4/537.long Berentsen et al. 2017]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bendamustine]] 90 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
====Targeted therapy====<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
# Berentsen S, Randen U, Oksman M, Birgens H, Tvedt THA, Dalgaard J, Galteland E, Haukås E, Brudevold R, Sørbø JH, Næss IA, Malecka A, Tjønnfjord GE. Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial. Blood. 2017 Jul 27;130(4):537-541. Epub 2017 May 22. [http://www.bloodjournal.org/content/130/4/537.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28533306 PubMed] NCT02689986<br />
<br />
==Eculizumab monotherapy {{#subobject:08ef07|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:95a0a9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6177646/ Röth et al. 2018 (DECADE)]<br />
|style="background-color:#ffffbe"|Phase II, <20 pts<br />
|-<br />
|}<br />
<br />
''Eligible patients had symptomatic cold agglutinin-mediated hemolysis with a serum lactate dehydrogenase (LDH) level greater than or equal to 2 x upper limit of normal and a cold agglutinin titer greater than 1:64 at 4°C.''<br />
====Immunosuppressive therapy====<br />
*[[Eculizumab (Soliris)]] as follows:<br />
**Cycle 1: 600 mg IV once per day on days 1, 8, 15, 22<br />
**Cycles 2 to 11: 900 mg IV once on day 1<br />
<br />
====Supportive medications====<br />
* Patients were vaccinated against ''Neisseria meningitidis'' or received "appropriate antibiotics" if vaccination occurred within 14 days of the first dose<br />
<br />
'''28-day cycle for 1 cycle, then 14-day cycle for 11 cycles'''<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Alexander Röth, MD, Martin Bommer, MD, Andreas Hüttmann, MD, Dörte Herich-Terhürne, Nils Kuklik, PhD, Lenz Veronika, Hubert Schrezenmeier, MD and Ulrich Dührsen, MD. Complement Inhibition with Eculizumab in Patients with Cold Agglutinin Disease (CAD): Results from a Prospective Phase II Trial (DECADE Trial). ASH Annual Meeting 2015 Abstract 274 [https://ash.confex.com/ash/2015/webprogram/Paper79420.html link to abstract] --><br />
# '''DECADE:''' Röth A, Bommer M, Hüttmann A, Herich-Terhürne D, Kuklik N, Rekowski J, Lenz V, Schrezenmeier H, Dührsen U. Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial. Blood Adv. 2018 Oct 9;2(19):2543-2549. [https://doi.org/10.1182/bloodadvances.2018024190 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6177646/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30291112/ PubMed] NCT01303952<br />
<br />
==FR {{#subobject:96c221|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FR: '''<u>F</u>'''ludarabine & '''<u>R</u>'''ituximab<br />
===Regimen {{#subobject:645885|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/17/3180.long Berentsen et al. 2010]<br />
|style="background-color:#91cf61"|Phase II<br />
| style="background-color:#e0ecf4" |ORR: 76%<br />
|-<br />
|}<br />
<br />
''Eligible patients had to be diagnosed with cold agglutinin disease and require therapy because of anemia, substantial cold-induced circulatory symptoms, or both.''<br />
====Chemotherapy====<br />
*[[Fludarabine (Fludara)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 5<br />
====Targeted therapy====<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
# Berentsen S, Randen U, Vågan AM, Hjorth-Hansen H, Vik A, Dalgaard J, Jacobsen EM, Thoresen AS, Beiske K, Tjønnfjord GE. High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. Blood. 2010 Oct 28;116(17):3180-4. Epub 2010 Jul 15. [http://www.bloodjournal.org/content/116/17/3180.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20634373 PubMed] NCT00373594<br />
<br />
==Rituximab monotherapy {{#subobject:65c6f1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:372fe5|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2925.long Berentsen et al. 2003]<br />
|style="background-color:#91cf61"|Phase II<br />
| style="background-color:#9ebcda" |ORR: 54%<br />
|-<br />
|[http://www.tandfonline.com/doi/full/10.1080/10428190500286481 Schöllkopf et al. 2006]<br />
|style="background-color:#91cf61"|Phase II<br />
| style="background-color:#8c96c6" |ORR: 45%<br />
|-<br />
|}<br />
<br />
''Patients in '''Berentsen et al. 2003''' were required to have cold agglutinin disease, as defined by the combination of chronic hemolysis and a cold agglutinin titer of 1:64 or higher, and a typical pattern for the direct antiglobulin test (DAT).''<br />
====Immunosuppressive therapy====<br />
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
'''28-day course'''<br />
<br />
===References===<br />
# Berentsen S, Ulvestad E, Gjertsen BT, Hjorth-Hansen H, Langholm R, Knutsen H, Ghanima W, Shammas FV, Tjønnfjord GE. Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. Blood. 2004 Apr 15;103(8):2925-8. Epub 2003 Dec 30. [http://www.bloodjournal.org/content/103/8/2925.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070665 PubMed]<br />
# Schöllkopf C, Kjeldsen L, Bjerrum OW, Mourits-Andersen HT, Nielsen JL, Christensen BE, Jensen BA, Pedersen BB, Taaning EB, Klausen TW, Birgens H. Rituximab in chronic cold agglutinin disease: a prospective study of 20 patients. Leuk Lymphoma. 2006 Feb;47(2):253-60. [http://www.tandfonline.com/doi/full/10.1080/10428190500286481 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16321854 PubMed]<br />
<br />
==Sutimlimab monotherapy==<br />
===Regimen===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa2027760?query=oncology-hematology.long Röth et al. 2021]<br />
|style="background-color:#91cf61"|Phase II<br />
| style="background-color:#9ebcda" |ORR: 54%<br />
|-<br />
<br />
=Investigational agents=<br />
*[[Sutimlimab (BIVV009)]]<br />
<br />
[[Category:Cold agglutinin disease regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Complementopathies]]<br />
[[Category:Hemolytic process]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=49231Antiemesis2021-04-30T21:10:53Z<p>Karine: minor edit</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://ascopubs.org/doi/abs/10.1200/JCO.20.01296<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Guidelines=<br />
==ASCO==<br />
<br />
*'''2020:''' Hesketh et al. [https://doi.org/10.1200/jco.20.01296 Antiemetics: ASCO Guideline Update]<br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2021)<br />
!ASCO emetogenic potential<br />
(2020)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|Moderate/High<br />
|Moderate/High<br />
|<br />
|NCCN and ASCO did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg/m2<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Low<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|[[Atezolizumab (Tecentriq)]]<br />
|Minimal<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Minimal/Low<br />
|Minimal/Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
|Belinostat<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Blinatumomab<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
|Ceritinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
|Daratumumab<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Niraparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
|Olaparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
|Pembrolizumab<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
|Pixantrone<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
|Rucaparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Trabectedin<br />
|<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Vinflunine<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.31.7859 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://pubmed.ncbi.nlm.nih.gov/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://pubmed.ncbi.nlm.nih.gov/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]<br />
[[Category:Clinical pharmacology]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=49230Antiemesis2021-04-30T20:52:46Z<p>Karine: atezo update and drug index</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://doi.org/10.1200/JCO.2017.74.4789<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Guidelines=<br />
==ASCO==<br />
<br />
*'''2020:''' Hesketh et al. [https://doi.org/10.1200/jco.20.01296 Antiemetics: ASCO Guideline Update]<br />
<br />
===Older===<br />
<br />
*'''2017:''' Hesketh et al. [https://doi.org/10.1200/JCO.2017.74.4789 Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update] [https://pubmed.ncbi.nlm.nih.gov/28759346 PubMed]<br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2021)<br />
!ASCO emetogenic potential<br />
(2020)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|Moderate/High<br />
|Moderate/High<br />
|<br />
|NCCN and ASCO did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg/m2<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Low<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|[[Atezolizumab (Tecentriq)]]<br />
|Minimal<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
|Belinostat<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Blinatumomab<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
|Ceritinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
|Daratumumab<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Niraparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
|Olaparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
|Pembrolizumab<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
|Pixantrone<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
|Rucaparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Trabectedin<br />
|<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Vinflunine<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.31.7859 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://pubmed.ncbi.nlm.nih.gov/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://pubmed.ncbi.nlm.nih.gov/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]<br />
[[Category:Clinical pharmacology]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=49229Antiemesis2021-04-30T20:40:05Z<p>Karine: ado-trastuzumab and altretamine antiemetic updates</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://doi.org/10.1200/JCO.2017.74.4789<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Guidelines=<br />
==ASCO==<br />
<br />
*'''2020:''' Hesketh et al. [https://doi.org/10.1200/jco.20.01296 Antiemetics: ASCO Guideline Update]<br />
<br />
===Older===<br />
<br />
*'''2017:''' Hesketh et al. [https://doi.org/10.1200/JCO.2017.74.4789 Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update] [https://pubmed.ncbi.nlm.nih.gov/28759346 PubMed]<br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2021)<br />
!ASCO emetogenic potential<br />
(2020)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|Moderate/High<br />
|Moderate/High<br />
|<br />
|NCCN and ASCO did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Atezolizumab<br />
|Minimal<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
|Belinostat<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Blinatumomab<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
|Ceritinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
|Daratumumab<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Niraparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
|Olaparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
|Pembrolizumab<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
|Pixantrone<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
|Rucaparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Trabectedin<br />
|<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Vinflunine<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.31.7859 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://pubmed.ncbi.nlm.nih.gov/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://pubmed.ncbi.nlm.nih.gov/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]<br />
[[Category:Clinical pharmacology]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=49228Antiemesis2021-04-30T20:27:09Z<p>Karine: atezolizumab emetic potential update</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://doi.org/10.1200/JCO.2017.74.4789<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Guidelines=<br />
==ASCO==<br />
<br />
*'''2020:''' Hesketh et al. [https://doi.org/10.1200/jco.20.01296 Antiemetics: ASCO Guideline Update]<br />
<br />
===Older===<br />
<br />
*'''2017:''' Hesketh et al. [https://doi.org/10.1200/JCO.2017.74.4789 Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update] [https://pubmed.ncbi.nlm.nih.gov/28759346 PubMed]<br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2021)<br />
!ASCO emetogenic potential<br />
(2020)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|High/Moderate<br />
|High<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Atezolizumab<br />
|Minimal<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
|Belinostat<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Blinatumomab<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
|Ceritinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
|Daratumumab<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Niraparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
|Olaparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
|Pembrolizumab<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
|Pixantrone<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
|Rucaparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Trabectedin<br />
|<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Vinflunine<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.31.7859 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://pubmed.ncbi.nlm.nih.gov/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://pubmed.ncbi.nlm.nih.gov/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]<br />
[[Category:Clinical pharmacology]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=46410Antiemesis2020-10-15T20:38:42Z<p>Karine: /* Emetic risk of chemotherapy, immunotherapy, TKIs and other agents */</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://doi.org/10.1200/JCO.2017.74.4789<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Guidelines=<br />
==ASCO==<br />
<br />
*'''2017:''' Hesketh et al. [https://doi.org/10.1200/JCO.2017.74.4789 Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update] [https://pubmed.ncbi.nlm.nih.gov/28759346 PubMed]<br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2019)<br />
!ASCO emetogenic potential<br />
(2017)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|High/Moderate<br />
|High<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Atezolizumab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
|Belinostat<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Blinatumomab<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
|Ceritinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
|Daratumumab<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Niraparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
|Olaparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
|Pembrolizumab<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
|Pixantrone<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
|Rucaparib<br />
|Moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Trabectedin<br />
|<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Vinflunine<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.31.7859 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://pubmed.ncbi.nlm.nih.gov/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://pubmed.ncbi.nlm.nih.gov/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]<br />
[[Category:Clinical pharmacology]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=46409Antiemesis2020-10-15T20:36:18Z<p>Karine: /* Emetic risk of chemotherapy, immunotherapy, TKIs and other agents */ Olaparib</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://doi.org/10.1200/JCO.2017.74.4789<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Guidelines=<br />
==ASCO==<br />
<br />
*'''2017:''' Hesketh et al. [https://doi.org/10.1200/JCO.2017.74.4789 Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update] [https://pubmed.ncbi.nlm.nih.gov/28759346 PubMed]<br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2019)<br />
!ASCO emetogenic potential<br />
(2017)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|High/Moderate<br />
|High<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Atezolizumab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
|Belinostat<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Blinatumomab<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
|Ceritinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
|Daratumumab<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
|Olaparib<br />
|moderate to high<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential (>30%)<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
|Pembrolizumab<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
|Pixantrone<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Trabectedin<br />
|<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Vinflunine<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.31.7859 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://pubmed.ncbi.nlm.nih.gov/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://pubmed.ncbi.nlm.nih.gov/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]<br />
[[Category:Clinical pharmacology]]</div>Karinehttps://hemonc.org/w/index.php?title=Hematology_Oncology_Fellowship_Programs_Directory&diff=45102Hematology Oncology Fellowship Programs Directory2020-07-20T23:39:07Z<p>Karine: /* Hematology oncology fellowship programs */ JMC</p>
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<div>This is a list of United States Hematology Oncology Fellowship Programs. More detailed information about every program can be found by clicking on the links to each Hematology Oncology Fellowship's individual page. For the official list of currently participating programs, visit AAMC's [https://services.aamc.org/eras/erasstats/par/ ERAS Participating Specialties & Programs] page.<ref>[https://services.aamc.org/eras/erasstats/par/ ERAS Participating Specialties & Programs]</ref><br />
<br />
=Hematology oncology fellowship programs=<br />
You may click on the top of a column to sort by that criteria.<br />
<br />
{| class="wikitable sortable"<br />
|+United States Hematology Oncology Fellowship Programs<br />
!'''State'''<br />
!'''City'''<br />
!'''Program Name'''<br />
!'''Hematology/Oncology (HO)'''<br />
'''Hematology (H)'''<br />
<br />
'''Oncology (O)'''<br />
!'''ACGME ID'''<br />
|-<br />
|AL<br />
|Birmingham<br />
|[[University of Alabama Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1550121001<br />
|-<br />
|AR<br />
|Little Rock<br />
|[[University of Arkansas for Medical Sciences Hematology Oncology Fellowship]]<br />
|HO<br />
|1550421129<br />
|-<br />
|AZ<br />
|Phoenix<br />
|[[Mayo Clinic College of Medicine and Science (Arizona) Hematology Oncology Fellowship]]<br />
|HO<br />
|1550313149<br />
|-<br />
|AZ<br />
|Tucson<br />
|[[University of Arizona Hematology Oncology Fellowship]]<br />
|HO<br />
|1550321003<br />
|-<br />
|CA<br />
|Fresno<br />
|[[University of California (San Francisco) Fresno Hematology Oncology Fellowship]]<br />
|HO<br />
|1550514164<br />
|-<br />
|CA<br />
|La Jolla<br />
|[[Scripps Clinic & Scripps Green Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1550512145<br />
|-<br />
|CA<br />
|La Jolla<br />
|[[University of California (San Diego) Hematology Oncology Fellowship]]<br />
|HO<br />
|1550512007<br />
|-<br />
|CA<br />
|Loma Linda<br />
|[[Loma Linda University Health Education Consortium Hematology Oncology Fellowship]]<br />
|HO<br />
|1550513163<br />
|-<br />
|CA<br />
|Los Angeles<br />
|[[UCLA Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1550521123<br />
|-<br />
|CA<br />
|Los Angeles<br />
|[[University of Southern California (LAC+USC) Medical Center Hematology Fellowship]]<br />
|H<br />
|1450521046<br />
|-<br />
|CA<br />
|Los Angeles<br />
|[[University of Southern California (LAC+USC) Medical Center Oncology Fellowship]]<br />
|O<br />
|1470521045<br />
|-<br />
|CA<br />
|Orange<br />
|[[University of California (Irvine) Hematology Oncology Fellowship]]<br />
|HO<br />
|1550521136<br />
|-<br />
|CA<br />
|Sacramento<br />
|[[University of California (Davis) Health System Hematology Oncology Fellowship]]<br />
|HO<br />
|1550531005<br />
|-<br />
|CA<br />
|San Francisco<br />
|[[University of California (San Francisco) Hematology Oncology Fellowship]]<br />
|HO<br />
|1550521113<br />
|-<br />
|CA<br />
|Stanford<br />
|[[Stanford University Hematology Fellowship]]<br />
|H<br />
|1450521020<br />
|-<br />
|CA<br />
|Stanford<br />
|[[Stanford University Oncology Fellowship]]<br />
|O<br />
|1470521020<br />
|-<br />
|CA<br />
|Sylmar<br />
|[[UCLA Medical Center (Olive View) Hematology Oncology Fellowship]]<br />
|HO<br />
|1550513008<br />
|-<br />
|CA<br />
|Torrance<br />
|[[Los Angeles County-Harbor-UCLA Medical Center Hematology Oncology Fellowship 1]]<br />
|HO<br />
|1550531093<br />
|-<br />
|CO<br />
|Aurora<br />
|[[University of Colorado Hematology Oncology Fellowship]]<br />
|HO<br />
|1550721096<br />
|-<br />
|CT<br />
|Farmington<br />
|[[University of Connecticut Hematology Oncology Fellowship]]<br />
|HO<br />
|1550821009<br />
|-<br />
|CT<br />
|New Haven<br />
|[[Yale-New Haven Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1550814165<br />
|-<br />
|DC<br />
|Washington<br />
|[[George Washington University Hematology Oncology Fellowship]]<br />
|HO<br />
|1551021074<br />
|-<br />
|DC<br />
|Washington<br />
|[[Georgetown University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1551012148<br />
|-<br />
|DC<br />
|Washington<br />
|[[Georgetown University Hospital (Washington Hospital Center) Hematology Oncology Fellowship]]<br />
|HO<br />
|1551031011<br />
|-<br />
|DC<br />
|Washington<br />
|[[Howard University Hematology Oncology Fellowship]]<br />
|HO<br />
|1551012157<br />
|-<br />
|FL<br />
|Gainesville<br />
|[[University of Florida Hematology Oncology Fellowship]]<br />
|HO<br />
|1551121104<br />
|-<br />
|FL<br />
|Jacksonville<br />
|[[Mayo Clinic College of Medicine and Science (Jacksonville) Hematology Oncology Fellowship]]<br />
|HO<br />
|1551131108<br />
|-<br />
|FL<br />
|Jacksonville<br />
|[[University of Florida College of Medicine Jacksonville Oncology Fellowship]]<br />
|O<br />
|1471121022<br />
|-<br />
|FL<br />
|Miami<br />
|[[Jackson Memorial Hospital (Jackson Health System) Hematology Oncology Fellowship]]<br />
|HO<br />
|1551121012<br />
|-<br />
|FL<br />
|Orlando<br />
|[[Orlando Health Hematology Oncology Fellowship]]<br />
|HO<br />
|1551112153<br />
|-<br />
|FL<br />
|Tampa<br />
|[[University of South Florida Morsani Hematology Oncology Fellowship]]<br />
|HO<br />
|1551131013<br />
|-<br />
|GA<br />
|Atlanta<br />
|[[Emory University Hematology Oncology Fellowship]]<br />
|HO<br />
|1551221014<br />
|-<br />
|GA<br />
|Augusta<br />
|[[Medical College of Georgia Hematology Oncology Fellowship]]<br />
|HO<br />
|1551231015<br />
|-<br />
|IA<br />
|Iowa City<br />
|[[University of Iowa Hospitals and Clinics Hematology Oncology Fellowship]]<br />
|HO<br />
|1551821021<br />
|-<br />
|IL<br />
|Chicago<br />
|[[John H Stroger Hospital of Cook County Hematology Oncology Fellowship]]<br />
|HO<br />
|1551621106<br />
|-<br />
|IL<br />
|Chicago<br />
|[[McGaw Medical Center of Northwestern University Hematology Oncology Fellowship]]<br />
|HO<br />
|1551621016<br />
|-<br />
|IL<br />
|Chicago<br />
|[[Rush University Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1551621085<br />
|-<br />
|IL<br />
|Chicago<br />
|[[University of Chicago Hematology Oncology Fellowship]]<br />
|HO<br />
|1551621079<br />
|-<br />
|IL<br />
|Chicago<br />
|[[University of Illinois College of Medicine at Chicago Hematology Oncology Fellowship]]<br />
|HO<br />
|1551631017<br />
|-<br />
|IL<br />
|Maywood<br />
|[[Loyola University Hematology Oncology Fellowship]]<br />
|HO<br />
|1551621110<br />
|-<br />
|IL<br />
|Park Ridge<br />
|[[Advocate Health Care (Advocate Lutheran General Hospital) Hematology Oncology Fellowship]]<br />
|HO<br />
|1551631147<br />
|-<br />
|IN<br />
|Indianapolis<br />
|[[Indiana University School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1551721020<br />
|-<br />
|KS<br />
|Westwood<br />
|[[University of Kansas School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1551912133<br />
|-<br />
|KY<br />
|Lexington<br />
|[[University of Kentucky College of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1552021103<br />
|-<br />
|KY<br />
|Louisville<br />
|[[University of Louisville Hematology Oncology Fellowship]]<br />
|HO<br />
|1552021022<br />
|-<br />
|LA<br />
|New Orleans<br />
|[[Louisiana State University Hematology Oncology Fellowship]]<br />
|HO<br />
|1552121158<br />
|-<br />
|LA<br />
|New Orleans<br />
|[[Ochsner Clinic Foundation Hematology Oncology Fellowship]]<br />
|HO<br />
|1552114159<br />
|-<br />
|LA<br />
|New Orleans<br />
|[[Tulane University Hematology Oncology Fellowship]]<br />
|HO<br />
|1552121023<br />
|-<br />
|LA<br />
|Shreveport<br />
|[[Louisiana State University (Shreveport) Hematology Oncology Fellowship]]<br />
|HO<br />
|1552131024<br />
|-<br />
|MA<br />
|Boston<br />
|[[Beth Israel Deaconess Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552421026<br />
|-<br />
|MA<br />
|Boston<br />
|[[Boston University Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552431027<br />
|-<br />
|MA<br />
|Boston<br />
|[[Brigham and Women's Hospital, Massachusetts General Hospital, and Dana-Farber Cancer Institute Hematology Oncology Fellowship]]<br />
|HO<br />
|1552421073<br />
|-<br />
|MA<br />
|Boston<br />
|[[St Elizabeth's Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552421124<br />
|-<br />
|MA<br />
|Boston<br />
|[[Tufts Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552412029<br />
|-<br />
|MA<br />
|Springfield<br />
|[[UMMS-Baystate Hematology Oncology Fellowship]]<br />
|HO<br />
|1552413030<br />
|-<br />
|MA<br />
|Worcester<br />
|[[University of Massachusetts Hematology Oncology Fellowship]]<br />
|HO<br />
|1552421075<br />
|-<br />
|MD<br />
|Baltimore<br />
|[[Johns Hopkins University Hematology Oncology Fellowship]]<br />
|HO<br />
|1552321154<br />
|-<br />
|MD<br />
|Baltimore<br />
|[[University of Maryland Hematology Oncology Fellowship]]<br />
|HO<br />
|1552321025<br />
|-<br />
|MD<br />
|Bethesda<br />
|[[National Institutes of Health Clinical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552314155<br />
|-<br />
|MD<br />
|Bethesda<br />
|[[National Institutes of Health Clinical Center Oncology Fellowship]]<br />
|O<br />
|1472321183<br />
|-<br />
|MI<br />
|Ann Arbor<br />
|[[University of Michigan Hematology Oncology Fellowship]]<br />
|HO<br />
|1552521098<br />
|-<br />
|MI<br />
|Detroit<br />
|[[Detroit Medical Center (Wayne State University) Hematology Oncology Fellowship]]<br />
|HO<br />
|1552513142<br />
|-<br />
|MI<br />
|Detroit<br />
|[[Henry Ford Hospital (Wayne State University) Hematology Oncology Fellowship]]<br />
|HO<br />
|1552521031<br />
|-<br />
|MI<br />
|Detroit<br />
|[[St John Hospital and Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552514158<br />
|-<br />
|MI<br />
|East Lansing<br />
|[[Michigan State University Hematology Oncology Fellowship]]<br />
|HO<br />
|1552521126<br />
|-<br />
|MI<br />
|Royal Oak<br />
|[[William Beaumont Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1552531156<br />
|-<br />
|MI<br />
|Southfield<br />
|[[Providence-Providence Park Hospital (MSUCHM) Hematology Oncology Fellowship]]<br />
|HO<br />
|1552512140<br />
|-<br />
|MN<br />
|Minneapolis<br />
|[[University of Minnesota Hematology Oncology Fellowship]]<br />
|HO<br />
|1552621032<br />
|-<br />
|MN<br />
|Rochester<br />
|[[Mayo Clinic College of Medicine and Science (Rochester) Hematology Oncology Fellowship]]<br />
|HO<br />
|1552631033<br />
|-<br />
|MO<br />
|Columbia<br />
|[[University of Missouri-Columbia Hematology Oncology Fellowship]]<br />
|HO<br />
|1552821083<br />
|-<br />
|MO<br />
|Kansas City<br />
|[[University of Missouri at Kansas City Hematology Oncology Fellowship]]<br />
|HO<br />
|1552821034<br />
|-<br />
|MO<br />
|St Louis<br />
|[[St Louis University School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1552811036<br />
|-<br />
|MO<br />
|St Louis<br />
|[[Washington University (B-JH and SLCH) Consortium Hematology Oncology Fellowship]]<br />
|HO<br />
|1552831035<br />
|-<br />
|MS<br />
|Jackson<br />
|[[University of Mississippi Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552721114<br />
|-<br />
|NC<br />
|Chapel Hill<br />
|[[University of North Carolina Hospitals Hematology Oncology Fellowship]]<br />
|HO<br />
|1553621055<br />
|-<br />
|NC<br />
|Charlotte<br />
|[[Carolinas Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553614142<br />
|-<br />
|NC<br />
|Durham<br />
|[[Duke University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553631056<br />
|-<br />
|NC<br />
|Greenville<br />
|[[Vidant Medical Center (East Carolina University) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553611141<br />
|-<br />
|NC<br />
|Winston-Salem<br />
|[[Wake Forest University School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1553621076<br />
|-<br />
|NE<br />
|Omaha<br />
|[[University of Nebraska Medical Center College of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1553021037<br />
|-<br />
|NH<br />
|Lebanon<br />
|[[Dartmouth-Hitchcock Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553221038<br />
|-<br />
|NJ<br />
|Camden<br />
|[[Cooper Medical School of Rowan University (Cooper University Hospital) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553321039<br />
|-<br />
|NJ<br />
|New Brunswick<br />
|[[Rutgers Robert Wood Johnson Medical School Hematology Oncology Fellowship]]<br />
|HO<br />
|1553321040<br />
|-<br />
|NJ<br />
|Newark<br />
|[[Newark Beth Israel Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553331132<br />
|-<br />
|NJ<br />
|Paterson<br />
|[[Seton Hall University School of Health and Medical Sciences Hematology Oncology Fellowship]]<br />
|HO<br />
|1553313137<br />
|-<br />
|NM<br />
|Albuquerque<br />
|[[University of New Mexico Hematology Oncology Fellowship]]<br />
|HO<br />
|1553421115<br />
|-<br />
|NY<br />
|Bronx<br />
|[[Montefiore Medical Center & Albert Einstein College of Medicine (Moses and Weiler Campuses) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521127<br />
|-<br />
|NY<br />
|Bronx<br />
|Jacobi Medical Center (opening July 1, 2019)<br />
|HO<br />
|1553514164<br />
|-<br />
|NY<br />
|Brooklyn<br />
|[[Brookdale University Hospital and Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521041<br />
|-<br />
|NY<br />
|Brooklyn<br />
|[[Brooklyn Hospital Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553512135<br />
|-<br />
|NY<br />
|Brooklyn<br />
|[[Maimonides Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553513139<br />
|-<br />
|NY<br />
|Brooklyn<br />
|[[New York Methodist Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521138<br />
|-<br />
|NY<br />
|Brooklyn<br />
|[[SUNY Health Science Center at Brooklyn Hematology Oncology Fellowship]]<br />
|HO<br />
|1553511043<br />
|-<br />
|NY<br />
|Buffalo<br />
|[[University at Buffalo Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521162<br />
|-<br />
|NY<br />
|Lake Success<br />
|[[Hofstra Northwell School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1553522046<br />
|-<br />
|NY<br />
|Mineola<br />
|[[Winthrop-University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553513045<br />
|-<br />
|NY<br />
|New York<br />
|[[Hofstra Northwell School of Medicine at Lenox Hill Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553533049<br />
|-<br />
|NY<br />
|New York<br />
|[[Icahn School of Medicine at Mount Sinai (Beth Israel) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553523047<br />
|-<br />
|NY<br />
|New York<br />
|[[Icahn School of Medicine at Mount Sinai Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521050<br />
|-<br />
|NY<br />
|New York<br />
|[[Memorial Sloan Kettering Cancer Center & New York Presbyterian Hospital (Cornell Campus) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521084<br />
|-<br />
|NY<br />
|New York<br />
|[[New York Presbyterian Hospital (Columbia Campus) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553511052<br />
|-<br />
|NY<br />
|New York<br />
|[[New York Presbyterian Hospital (Cornell Campus) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553531051<br />
|-<br />
|NY<br />
|New York<br />
|[[New York University School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1553531152<br />
|-<br />
|NY<br />
|Rochester<br />
|[[University of Rochester Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521100<br />
|-<br />
|NY<br />
|Staten Island<br />
|[[Hofstra Northwell School of Medicine at Staten Island University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553531144<br />
|-<br />
|NY<br />
|Stony Brook<br />
|[[Stony Brook Medicine (University Hospital) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553513054<br />
|-<br />
|NY<br />
|Syracuse<br />
|[[SUNY Upstate Medical University Hematology Oncology Fellowship]]<br />
|HO<br />
|1553531086<br />
|-<br />
|NY<br />
|Valhalla<br />
|[[New York Medical College at Westchester Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553531101<br />
|-<br />
|OH<br />
|Cincinnati<br />
|[[University of Cincinnati Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553821102<br />
|-<br />
|OH<br />
|Cleveland<br />
|[[Case Western Reserve University (University Hospitals Cleveland Medical Center) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553821117<br />
|-<br />
|OH<br />
|Cleveland<br />
|[[Cleveland Clinic Foundation Hematology Oncology Fellowship]]<br />
|HO<br />
|1553821057<br />
|-<br />
|OH<br />
|Columbus<br />
|[[Ohio State University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553831058<br />
|-<br />
|OH<br />
|Dayton<br />
|[[Wright State University Hematology Oncology Fellowship]]<br />
|HO<br />
|1553811059<br />
|-<br />
|OH<br />
|Toledo<br />
|[[University of Toledo Oncology Fellowship]]<br />
|O<br />
|1473831200<br />
|-<br />
|OK<br />
|Oklahoma City<br />
|[[University of Oklahoma Health Sciences Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553921060<br />
|-<br />
|OR<br />
|Portland<br />
|[[Oregon Health & Science University Hematology Oncology Fellowship]]<br />
|HO<br />
|1554021118<br />
|-<br />
|PA<br />
|Allentown<br />
|[[Lehigh Valley Health Network Hematology Oncology Fellowship]]<br />
|HO<br />
|1554114166<br />
|-<br />
|PA<br />
|Hershey<br />
|[[Penn State Milton S Hershey Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554121061<br />
|-<br />
|PA<br />
|Philadelphia<br />
|[[Albert Einstein Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554114167<br />
|-<br />
|PA<br />
|Philadelphia<br />
|[[Drexel University College of Medicine & Hahnemann University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1554131062<br />
|-<br />
|PA<br />
|Philadelphia<br />
|[[Temple University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1554121091<br />
|-<br />
|PA<br />
|Philadelphia<br />
|[[Thomas Jefferson University Hematology Oncology Fellowship]]<br />
|HO<br />
|1554121130<br />
|-<br />
|PA<br />
|Philadelphia<br />
|[[University of Pennsylvania Hematology Oncology Fellowship]]<br />
|HO<br />
|1554121081<br />
|-<br />
|PA<br />
|Pittsburgh<br />
|[[Allegheny Health Network Medical Education Consortium (WPH & AGH) Hematology Oncology Fellowship]]<br />
|HO<br />
|1554131092<br />
|-<br />
|PA<br />
|Pittsburgh<br />
|[[UPMC Medical Education Hematology Oncology Fellowship]]<br />
|HO<br />
|1554121122<br />
|-<br />
|PA<br />
|Wynnewood<br />
|[[Main Line Health System (Lankenau Medical Center) Hematology Oncology Fellowship]]<br />
|HO<br />
|1554131077<br />
|-<br />
|PR<br />
|San Juan<br />
|[[University of Puerto Rico Hematology Oncology Fellowship]]<br />
|HO<br />
|1554221080<br />
|-<br />
|RI<br />
|Providence<br />
|[[Brown University Hematology Oncology Fellowship]]<br />
|HO<br />
|1554331128<br />
|-<br />
|RI<br />
|Providence<br />
|[[Roger Williams Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554321120<br />
|-<br />
|SC<br />
|Charleston<br />
|[[Medical University of South Carolina Hematology Oncology Fellowship]]<br />
|HO<br />
|1554521063<br />
|-<br />
|TN<br />
|Germantown<br />
|[[University of Tennessee Hematology Oncology Fellowship]]<br />
|HO<br />
|1554721125<br />
|-<br />
|TN<br />
|Nashville<br />
|[[Vanderbilt University Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554731065<br />
|-<br />
|TN<br />
|Johnson City<br />
|[[East Tennessee State University Oncology Fellowship]]<br />
|O<br />
|1474721195<br />
|-<br />
|TX<br />
|Dallas<br />
|[[Baylor University Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554814161<br />
|-<br />
|TX<br />
|Dallas<br />
|[[University of Texas Southwestern Medical School Hematology Oncology Fellowship]]<br />
|HO<br />
|1554821066<br />
|-<br />
|TX<br />
|Galveston<br />
|[[University of Texas Medical Branch Hospitals Oncology Fellowship]]<br />
|O<br />
|1474821053<br />
|-<br />
|TX<br />
|Houston<br />
|[[Baylor College of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1554821146<br />
|-<br />
|TX<br />
|Houston<br />
|[[Methodist Hospital (Houston) Hematology Oncology Fellowship]]<br />
|HO<br />
|1554814158<br />
|-<br />
|TX<br />
|Houston<br />
|[[University of Texas Health Science Center at Houston (M. D. Anderson Cancer Center) Hematology Oncology Fellowship]]<br />
|HO<br />
|1554812150<br />
|-<br />
|TX<br />
|Lubbock<br />
|[[Texas Tech University Health Sciences Center at Lubbock Hematology Oncology Fellowship]]<br />
|HO<br />
|1554814159<br />
|-<br />
|TX<br />
|San Antonio<br />
|[[University of Texas Health Science Center School of Medicine at San Antonio Hematology Oncology Fellowship]]<br />
|HO<br />
|1554821099<br />
|-<br />
|TX<br />
|Temple<br />
|[[Scott and White Memorial Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1554814156<br />
|-<br />
|UT<br />
|Salt Lake City<br />
|[[University of Utah Hematology Oncology Fellowship]]<br />
|HO<br />
|1554921082<br />
|-<br />
|VA<br />
|Charlottesville<br />
|[[University of Virginia Hematology Oncology Fellowship]]<br />
|HO<br />
|1555131078<br />
|-<br />
|VA<br />
|Richmond<br />
|[[Virginia Commonwealth University Health System Hematology Oncology Fellowship]]<br />
|HO<br />
|1555121070<br />
|-<br />
|VT<br />
|Burlington<br />
|[[University of Vermont Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1555021069<br />
|-<br />
|WA<br />
|Seattle<br />
|[[University of Washington Hematology Oncology Fellowship]]<br />
|HO<br />
|1555413151<br />
|-<br />
|WI<br />
|La Crosse<br />
|[[Gundersen Lutheran Medical Foundation Hematology Oncology Fellowship]]<br />
|HO<br />
|1555631160<br />
|-<br />
|WI<br />
|Madison<br />
|[[University of Wisconsin Hematology Oncology Fellowship]]<br />
|HO<br />
|1555612161<br />
|-<br />
|WI<br />
|Milwaukee<br />
|[[Medical College of Wisconsin Affiliated Hospitals Hematology Oncology Fellowship]]<br />
|HO<br />
|1555621119<br />
|-<br />
|WV<br />
|Huntington<br />
|[[Marshall University School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1555514110<br />
|-<br />
|WV<br />
|Morgantown<br />
|[[West Virginia University Hematology Oncology Fellowship]]<br />
|HO<br />
|1555521109<br />
|}<br />
<br />
=By specialty=<br />
<br />
*[[:Category: Hematology & Oncology fellowship programs|Hematology & Oncology fellowship programs]]<br />
*[[:Category: Oncology fellowship programs|Oncology fellowship programs]]<br />
*[[:Category: Hematology fellowship programs|Hematology fellowship programs]]<br />
<br />
=References=<br />
<references /><br />
<br />
[[Category:General reference pages]]</div>Karinehttps://hemonc.org/w/index.php?title=Hematology_Oncology_Fellowship_Programs_Directory&diff=45101Hematology Oncology Fellowship Programs Directory2020-07-20T23:36:13Z<p>Karine: /* Hematology oncology fellowship programs */ JMC</p>
<hr />
<div>This is a list of United States Hematology Oncology Fellowship Programs. More detailed information about every program can be found by clicking on the links to each Hematology Oncology Fellowship's individual page. For the official list of currently participating programs, visit AAMC's [https://services.aamc.org/eras/erasstats/par/ ERAS Participating Specialties & Programs] page.<ref>[https://services.aamc.org/eras/erasstats/par/ ERAS Participating Specialties & Programs]</ref><br />
<br />
=Hematology oncology fellowship programs=<br />
You may click on the top of a column to sort by that criteria.<br />
<br />
{| class="wikitable sortable"<br />
|+United States Hematology Oncology Fellowship Programs<br />
!'''State'''<br />
!'''City'''<br />
!'''Program Name'''<br />
!'''Hematology/Oncology (HO)'''<br />
'''Hematology (H)'''<br />
<br />
'''Oncology (O)'''<br />
!'''ACGME ID'''<br />
|-<br />
|AL<br />
|Birmingham<br />
|[[University of Alabama Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1550121001<br />
|-<br />
|AR<br />
|Little Rock<br />
|[[University of Arkansas for Medical Sciences Hematology Oncology Fellowship]]<br />
|HO<br />
|1550421129<br />
|-<br />
|AZ<br />
|Phoenix<br />
|[[Mayo Clinic College of Medicine and Science (Arizona) Hematology Oncology Fellowship]]<br />
|HO<br />
|1550313149<br />
|-<br />
|AZ<br />
|Tucson<br />
|[[University of Arizona Hematology Oncology Fellowship]]<br />
|HO<br />
|1550321003<br />
|-<br />
|CA<br />
|Fresno<br />
|[[University of California (San Francisco) Fresno Hematology Oncology Fellowship]]<br />
|HO<br />
|1550514164<br />
|-<br />
|CA<br />
|La Jolla<br />
|[[Scripps Clinic & Scripps Green Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1550512145<br />
|-<br />
|CA<br />
|La Jolla<br />
|[[University of California (San Diego) Hematology Oncology Fellowship]]<br />
|HO<br />
|1550512007<br />
|-<br />
|CA<br />
|Loma Linda<br />
|[[Loma Linda University Health Education Consortium Hematology Oncology Fellowship]]<br />
|HO<br />
|1550513163<br />
|-<br />
|CA<br />
|Los Angeles<br />
|[[UCLA Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1550521123<br />
|-<br />
|CA<br />
|Los Angeles<br />
|[[University of Southern California (LAC+USC) Medical Center Hematology Fellowship]]<br />
|H<br />
|1450521046<br />
|-<br />
|CA<br />
|Los Angeles<br />
|[[University of Southern California (LAC+USC) Medical Center Oncology Fellowship]]<br />
|O<br />
|1470521045<br />
|-<br />
|CA<br />
|Orange<br />
|[[University of California (Irvine) Hematology Oncology Fellowship]]<br />
|HO<br />
|1550521136<br />
|-<br />
|CA<br />
|Sacramento<br />
|[[University of California (Davis) Health System Hematology Oncology Fellowship]]<br />
|HO<br />
|1550531005<br />
|-<br />
|CA<br />
|San Francisco<br />
|[[University of California (San Francisco) Hematology Oncology Fellowship]]<br />
|HO<br />
|1550521113<br />
|-<br />
|CA<br />
|Stanford<br />
|[[Stanford University Hematology Fellowship]]<br />
|H<br />
|1450521020<br />
|-<br />
|CA<br />
|Stanford<br />
|[[Stanford University Oncology Fellowship]]<br />
|O<br />
|1470521020<br />
|-<br />
|CA<br />
|Sylmar<br />
|[[UCLA Medical Center (Olive View) Hematology Oncology Fellowship]]<br />
|HO<br />
|1550513008<br />
|-<br />
|CA<br />
|Torrance<br />
|[[Los Angeles County-Harbor-UCLA Medical Center Hematology Oncology Fellowship 1]]<br />
|HO<br />
|1550531093<br />
|-<br />
|CO<br />
|Aurora<br />
|[[University of Colorado Hematology Oncology Fellowship]]<br />
|HO<br />
|1550721096<br />
|-<br />
|CT<br />
|Farmington<br />
|[[University of Connecticut Hematology Oncology Fellowship]]<br />
|HO<br />
|1550821009<br />
|-<br />
|CT<br />
|New Haven<br />
|[[Yale-New Haven Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1550814165<br />
|-<br />
|DC<br />
|Washington<br />
|[[George Washington University Hematology Oncology Fellowship]]<br />
|HO<br />
|1551021074<br />
|-<br />
|DC<br />
|Washington<br />
|[[Georgetown University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1551012148<br />
|-<br />
|DC<br />
|Washington<br />
|[[Georgetown University Hospital (Washington Hospital Center) Hematology Oncology Fellowship]]<br />
|HO<br />
|1551031011<br />
|-<br />
|DC<br />
|Washington<br />
|[[Howard University Hematology Oncology Fellowship]]<br />
|HO<br />
|1551012157<br />
|-<br />
|FL<br />
|Gainesville<br />
|[[University of Florida Hematology Oncology Fellowship]]<br />
|HO<br />
|1551121104<br />
|-<br />
|FL<br />
|Jacksonville<br />
|[[Mayo Clinic College of Medicine and Science (Jacksonville) Hematology Oncology Fellowship]]<br />
|HO<br />
|1551131108<br />
|-<br />
|FL<br />
|Jacksonville<br />
|[[University of Florida College of Medicine Jacksonville Oncology Fellowship]]<br />
|O<br />
|1471121022<br />
|-<br />
|FL<br />
|Miami<br />
|[[Jackson Memorial Hospital (Jackson Health System) Hematology Oncology Fellowship]]<br />
|HO<br />
|1551121012<br />
|-<br />
|FL<br />
|Orlando<br />
|[[Orlando Health Hematology Oncology Fellowship]]<br />
|HO<br />
|1551112153<br />
|-<br />
|FL<br />
|Tampa<br />
|[[University of South Florida Morsani Hematology Oncology Fellowship]]<br />
|HO<br />
|1551131013<br />
|-<br />
|GA<br />
|Atlanta<br />
|[[Emory University Hematology Oncology Fellowship]]<br />
|HO<br />
|1551221014<br />
|-<br />
|GA<br />
|Augusta<br />
|[[Medical College of Georgia Hematology Oncology Fellowship]]<br />
|HO<br />
|1551231015<br />
|-<br />
|IA<br />
|Iowa City<br />
|[[University of Iowa Hospitals and Clinics Hematology Oncology Fellowship]]<br />
|HO<br />
|1551821021<br />
|-<br />
|IL<br />
|Chicago<br />
|[[John H Stroger Hospital of Cook County Hematology Oncology Fellowship]]<br />
|HO<br />
|1551621106<br />
|-<br />
|IL<br />
|Chicago<br />
|[[McGaw Medical Center of Northwestern University Hematology Oncology Fellowship]]<br />
|HO<br />
|1551621016<br />
|-<br />
|IL<br />
|Chicago<br />
|[[Rush University Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1551621085<br />
|-<br />
|IL<br />
|Chicago<br />
|[[University of Chicago Hematology Oncology Fellowship]]<br />
|HO<br />
|1551621079<br />
|-<br />
|IL<br />
|Chicago<br />
|[[University of Illinois College of Medicine at Chicago Hematology Oncology Fellowship]]<br />
|HO<br />
|1551631017<br />
|-<br />
|IL<br />
|Maywood<br />
|[[Loyola University Hematology Oncology Fellowship]]<br />
|HO<br />
|1551621110<br />
|-<br />
|IL<br />
|Park Ridge<br />
|[[Advocate Health Care (Advocate Lutheran General Hospital) Hematology Oncology Fellowship]]<br />
|HO<br />
|1551631147<br />
|-<br />
|IN<br />
|Indianapolis<br />
|[[Indiana University School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1551721020<br />
|-<br />
|KS<br />
|Westwood<br />
|[[University of Kansas School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1551912133<br />
|-<br />
|KY<br />
|Lexington<br />
|[[University of Kentucky College of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1552021103<br />
|-<br />
|KY<br />
|Louisville<br />
|[[University of Louisville Hematology Oncology Fellowship]]<br />
|HO<br />
|1552021022<br />
|-<br />
|LA<br />
|New Orleans<br />
|[[Louisiana State University Hematology Oncology Fellowship]]<br />
|HO<br />
|1552121158<br />
|-<br />
|LA<br />
|New Orleans<br />
|[[Ochsner Clinic Foundation Hematology Oncology Fellowship]]<br />
|HO<br />
|1552114159<br />
|-<br />
|LA<br />
|New Orleans<br />
|[[Tulane University Hematology Oncology Fellowship]]<br />
|HO<br />
|1552121023<br />
|-<br />
|LA<br />
|Shreveport<br />
|[[Louisiana State University (Shreveport) Hematology Oncology Fellowship]]<br />
|HO<br />
|1552131024<br />
|-<br />
|MA<br />
|Boston<br />
|[[Beth Israel Deaconess Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552421026<br />
|-<br />
|MA<br />
|Boston<br />
|[[Boston University Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552431027<br />
|-<br />
|MA<br />
|Boston<br />
|[[Brigham and Women's Hospital, Massachusetts General Hospital, and Dana-Farber Cancer Institute Hematology Oncology Fellowship]]<br />
|HO<br />
|1552421073<br />
|-<br />
|MA<br />
|Boston<br />
|[[St Elizabeth's Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552421124<br />
|-<br />
|MA<br />
|Boston<br />
|[[Tufts Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552412029<br />
|-<br />
|MA<br />
|Springfield<br />
|[[UMMS-Baystate Hematology Oncology Fellowship]]<br />
|HO<br />
|1552413030<br />
|-<br />
|MA<br />
|Worcester<br />
|[[University of Massachusetts Hematology Oncology Fellowship]]<br />
|HO<br />
|1552421075<br />
|-<br />
|MD<br />
|Baltimore<br />
|[[Johns Hopkins University Hematology Oncology Fellowship]]<br />
|HO<br />
|1552321154<br />
|-<br />
|MD<br />
|Baltimore<br />
|[[University of Maryland Hematology Oncology Fellowship]]<br />
|HO<br />
|1552321025<br />
|-<br />
|MD<br />
|Bethesda<br />
|[[National Institutes of Health Clinical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552314155<br />
|-<br />
|MD<br />
|Bethesda<br />
|[[National Institutes of Health Clinical Center Oncology Fellowship]]<br />
|O<br />
|1472321183<br />
|-<br />
|MI<br />
|Ann Arbor<br />
|[[University of Michigan Hematology Oncology Fellowship]]<br />
|HO<br />
|1552521098<br />
|-<br />
|MI<br />
|Detroit<br />
|[[Detroit Medical Center (Wayne State University) Hematology Oncology Fellowship]]<br />
|HO<br />
|1552513142<br />
|-<br />
|MI<br />
|Detroit<br />
|[[Henry Ford Hospital (Wayne State University) Hematology Oncology Fellowship]]<br />
|HO<br />
|1552521031<br />
|-<br />
|MI<br />
|Detroit<br />
|[[St John Hospital and Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552514158<br />
|-<br />
|MI<br />
|East Lansing<br />
|[[Michigan State University Hematology Oncology Fellowship]]<br />
|HO<br />
|1552521126<br />
|-<br />
|MI<br />
|Royal Oak<br />
|[[William Beaumont Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1552531156<br />
|-<br />
|MI<br />
|Southfield<br />
|[[Providence-Providence Park Hospital (MSUCHM) Hematology Oncology Fellowship]]<br />
|HO<br />
|1552512140<br />
|-<br />
|MN<br />
|Minneapolis<br />
|[[University of Minnesota Hematology Oncology Fellowship]]<br />
|HO<br />
|1552621032<br />
|-<br />
|MN<br />
|Rochester<br />
|[[Mayo Clinic College of Medicine and Science (Rochester) Hematology Oncology Fellowship]]<br />
|HO<br />
|1552631033<br />
|-<br />
|MO<br />
|Columbia<br />
|[[University of Missouri-Columbia Hematology Oncology Fellowship]]<br />
|HO<br />
|1552821083<br />
|-<br />
|MO<br />
|Kansas City<br />
|[[University of Missouri at Kansas City Hematology Oncology Fellowship]]<br />
|HO<br />
|1552821034<br />
|-<br />
|MO<br />
|St Louis<br />
|[[St Louis University School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1552811036<br />
|-<br />
|MO<br />
|St Louis<br />
|[[Washington University (B-JH and SLCH) Consortium Hematology Oncology Fellowship]]<br />
|HO<br />
|1552831035<br />
|-<br />
|MS<br />
|Jackson<br />
|[[University of Mississippi Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552721114<br />
|-<br />
|NC<br />
|Chapel Hill<br />
|[[University of North Carolina Hospitals Hematology Oncology Fellowship]]<br />
|HO<br />
|1553621055<br />
|-<br />
|NC<br />
|Charlotte<br />
|[[Carolinas Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553614142<br />
|-<br />
|NC<br />
|Durham<br />
|[[Duke University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553631056<br />
|-<br />
|NC<br />
|Greenville<br />
|[[Vidant Medical Center (East Carolina University) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553611141<br />
|-<br />
|NC<br />
|Winston-Salem<br />
|[[Wake Forest University School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1553621076<br />
|-<br />
|NE<br />
|Omaha<br />
|[[University of Nebraska Medical Center College of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1553021037<br />
|-<br />
|NH<br />
|Lebanon<br />
|[[Dartmouth-Hitchcock Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553221038<br />
|-<br />
|NJ<br />
|Camden<br />
|[[Cooper Medical School of Rowan University (Cooper University Hospital) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553321039<br />
|-<br />
|NJ<br />
|New Brunswick<br />
|[[Rutgers Robert Wood Johnson Medical School Hematology Oncology Fellowship]]<br />
|HO<br />
|1553321040<br />
|-<br />
|NJ<br />
|Newark<br />
|[[Newark Beth Israel Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553331132<br />
|-<br />
|NJ<br />
|Paterson<br />
|[[Seton Hall University School of Health and Medical Sciences Hematology Oncology Fellowship]]<br />
|HO<br />
|1553313137<br />
|-<br />
|NM<br />
|Albuquerque<br />
|[[University of New Mexico Hematology Oncology Fellowship]]<br />
|HO<br />
|1553421115<br />
|-<br />
|NY<br />
|Bronx<br />
|[[Montefiore Medical Center & Albert Einstein College of Medicine (Moses and Weiler Campuses) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521127<br />
|-<br />
|NY<br />
|Bronx<br />
|Jacobi Medical Center (opening July 1, 2019)<br />
|HO<br />
|1553521127<br /><br />
|-<br />
|NY<br />
|Brooklyn<br />
|[[Brookdale University Hospital and Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521041<br />
|-<br />
|NY<br />
|Brooklyn<br />
|[[Brooklyn Hospital Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553512135<br />
|-<br />
|NY<br />
|Brooklyn<br />
|[[Maimonides Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553513139<br />
|-<br />
|NY<br />
|Brooklyn<br />
|[[New York Methodist Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521138<br />
|-<br />
|NY<br />
|Brooklyn<br />
|[[SUNY Health Science Center at Brooklyn Hematology Oncology Fellowship]]<br />
|HO<br />
|1553511043<br />
|-<br />
|NY<br />
|Buffalo<br />
|[[University at Buffalo Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521162<br />
|-<br />
|NY<br />
|Lake Success<br />
|[[Hofstra Northwell School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1553522046<br />
|-<br />
|NY<br />
|Mineola<br />
|[[Winthrop-University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553513045<br />
|-<br />
|NY<br />
|New York<br />
|[[Hofstra Northwell School of Medicine at Lenox Hill Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553533049<br />
|-<br />
|NY<br />
|New York<br />
|[[Icahn School of Medicine at Mount Sinai (Beth Israel) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553523047<br />
|-<br />
|NY<br />
|New York<br />
|[[Icahn School of Medicine at Mount Sinai Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521050<br />
|-<br />
|NY<br />
|New York<br />
|[[Memorial Sloan Kettering Cancer Center & New York Presbyterian Hospital (Cornell Campus) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521084<br />
|-<br />
|NY<br />
|New York<br />
|[[New York Presbyterian Hospital (Columbia Campus) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553511052<br />
|-<br />
|NY<br />
|New York<br />
|[[New York Presbyterian Hospital (Cornell Campus) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553531051<br />
|-<br />
|NY<br />
|New York<br />
|[[New York University School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1553531152<br />
|-<br />
|NY<br />
|Rochester<br />
|[[University of Rochester Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521100<br />
|-<br />
|NY<br />
|Staten Island<br />
|[[Hofstra Northwell School of Medicine at Staten Island University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553531144<br />
|-<br />
|NY<br />
|Stony Brook<br />
|[[Stony Brook Medicine (University Hospital) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553513054<br />
|-<br />
|NY<br />
|Syracuse<br />
|[[SUNY Upstate Medical University Hematology Oncology Fellowship]]<br />
|HO<br />
|1553531086<br />
|-<br />
|NY<br />
|Valhalla<br />
|[[New York Medical College at Westchester Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553531101<br />
|-<br />
|OH<br />
|Cincinnati<br />
|[[University of Cincinnati Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553821102<br />
|-<br />
|OH<br />
|Cleveland<br />
|[[Case Western Reserve University (University Hospitals Cleveland Medical Center) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553821117<br />
|-<br />
|OH<br />
|Cleveland<br />
|[[Cleveland Clinic Foundation Hematology Oncology Fellowship]]<br />
|HO<br />
|1553821057<br />
|-<br />
|OH<br />
|Columbus<br />
|[[Ohio State University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553831058<br />
|-<br />
|OH<br />
|Dayton<br />
|[[Wright State University Hematology Oncology Fellowship]]<br />
|HO<br />
|1553811059<br />
|-<br />
|OH<br />
|Toledo<br />
|[[University of Toledo Oncology Fellowship]]<br />
|O<br />
|1473831200<br />
|-<br />
|OK<br />
|Oklahoma City<br />
|[[University of Oklahoma Health Sciences Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553921060<br />
|-<br />
|OR<br />
|Portland<br />
|[[Oregon Health & Science University Hematology Oncology Fellowship]]<br />
|HO<br />
|1554021118<br />
|-<br />
|PA<br />
|Allentown<br />
|[[Lehigh Valley Health Network Hematology Oncology Fellowship]]<br />
|HO<br />
|1554114166<br />
|-<br />
|PA<br />
|Hershey<br />
|[[Penn State Milton S Hershey Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554121061<br />
|-<br />
|PA<br />
|Philadelphia<br />
|[[Albert Einstein Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554114167<br />
|-<br />
|PA<br />
|Philadelphia<br />
|[[Drexel University College of Medicine & Hahnemann University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1554131062<br />
|-<br />
|PA<br />
|Philadelphia<br />
|[[Temple University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1554121091<br />
|-<br />
|PA<br />
|Philadelphia<br />
|[[Thomas Jefferson University Hematology Oncology Fellowship]]<br />
|HO<br />
|1554121130<br />
|-<br />
|PA<br />
|Philadelphia<br />
|[[University of Pennsylvania Hematology Oncology Fellowship]]<br />
|HO<br />
|1554121081<br />
|-<br />
|PA<br />
|Pittsburgh<br />
|[[Allegheny Health Network Medical Education Consortium (WPH & AGH) Hematology Oncology Fellowship]]<br />
|HO<br />
|1554131092<br />
|-<br />
|PA<br />
|Pittsburgh<br />
|[[UPMC Medical Education Hematology Oncology Fellowship]]<br />
|HO<br />
|1554121122<br />
|-<br />
|PA<br />
|Wynnewood<br />
|[[Main Line Health System (Lankenau Medical Center) Hematology Oncology Fellowship]]<br />
|HO<br />
|1554131077<br />
|-<br />
|PR<br />
|San Juan<br />
|[[University of Puerto Rico Hematology Oncology Fellowship]]<br />
|HO<br />
|1554221080<br />
|-<br />
|RI<br />
|Providence<br />
|[[Brown University Hematology Oncology Fellowship]]<br />
|HO<br />
|1554331128<br />
|-<br />
|RI<br />
|Providence<br />
|[[Roger Williams Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554321120<br />
|-<br />
|SC<br />
|Charleston<br />
|[[Medical University of South Carolina Hematology Oncology Fellowship]]<br />
|HO<br />
|1554521063<br />
|-<br />
|TN<br />
|Germantown<br />
|[[University of Tennessee Hematology Oncology Fellowship]]<br />
|HO<br />
|1554721125<br />
|-<br />
|TN<br />
|Nashville<br />
|[[Vanderbilt University Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554731065<br />
|-<br />
|TN<br />
|Johnson City<br />
|[[East Tennessee State University Oncology Fellowship]]<br />
|O<br />
|1474721195<br />
|-<br />
|TX<br />
|Dallas<br />
|[[Baylor University Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554814161<br />
|-<br />
|TX<br />
|Dallas<br />
|[[University of Texas Southwestern Medical School Hematology Oncology Fellowship]]<br />
|HO<br />
|1554821066<br />
|-<br />
|TX<br />
|Galveston<br />
|[[University of Texas Medical Branch Hospitals Oncology Fellowship]]<br />
|O<br />
|1474821053<br />
|-<br />
|TX<br />
|Houston<br />
|[[Baylor College of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1554821146<br />
|-<br />
|TX<br />
|Houston<br />
|[[Methodist Hospital (Houston) Hematology Oncology Fellowship]]<br />
|HO<br />
|1554814158<br />
|-<br />
|TX<br />
|Houston<br />
|[[University of Texas Health Science Center at Houston (M. D. Anderson Cancer Center) Hematology Oncology Fellowship]]<br />
|HO<br />
|1554812150<br />
|-<br />
|TX<br />
|Lubbock<br />
|[[Texas Tech University Health Sciences Center at Lubbock Hematology Oncology Fellowship]]<br />
|HO<br />
|1554814159<br />
|-<br />
|TX<br />
|San Antonio<br />
|[[University of Texas Health Science Center School of Medicine at San Antonio Hematology Oncology Fellowship]]<br />
|HO<br />
|1554821099<br />
|-<br />
|TX<br />
|Temple<br />
|[[Scott and White Memorial Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1554814156<br />
|-<br />
|UT<br />
|Salt Lake City<br />
|[[University of Utah Hematology Oncology Fellowship]]<br />
|HO<br />
|1554921082<br />
|-<br />
|VA<br />
|Charlottesville<br />
|[[University of Virginia Hematology Oncology Fellowship]]<br />
|HO<br />
|1555131078<br />
|-<br />
|VA<br />
|Richmond<br />
|[[Virginia Commonwealth University Health System Hematology Oncology Fellowship]]<br />
|HO<br />
|1555121070<br />
|-<br />
|VT<br />
|Burlington<br />
|[[University of Vermont Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1555021069<br />
|-<br />
|WA<br />
|Seattle<br />
|[[University of Washington Hematology Oncology Fellowship]]<br />
|HO<br />
|1555413151<br />
|-<br />
|WI<br />
|La Crosse<br />
|[[Gundersen Lutheran Medical Foundation Hematology Oncology Fellowship]]<br />
|HO<br />
|1555631160<br />
|-<br />
|WI<br />
|Madison<br />
|[[University of Wisconsin Hematology Oncology Fellowship]]<br />
|HO<br />
|1555612161<br />
|-<br />
|WI<br />
|Milwaukee<br />
|[[Medical College of Wisconsin Affiliated Hospitals Hematology Oncology Fellowship]]<br />
|HO<br />
|1555621119<br />
|-<br />
|WV<br />
|Huntington<br />
|[[Marshall University School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1555514110<br />
|-<br />
|WV<br />
|Morgantown<br />
|[[West Virginia University Hematology Oncology Fellowship]]<br />
|HO<br />
|1555521109<br />
|}<br />
<br />
=By specialty=<br />
<br />
*[[:Category: Hematology & Oncology fellowship programs|Hematology & Oncology fellowship programs]]<br />
*[[:Category: Oncology fellowship programs|Oncology fellowship programs]]<br />
*[[:Category: Hematology fellowship programs|Hematology fellowship programs]]<br />
<br />
=References=<br />
<references /><br />
<br />
[[Category:General reference pages]]</div>Karinehttps://hemonc.org/w/index.php?title=Talk:Small_cell_lung_cancer&diff=40777Talk:Small cell lung cancer2019-10-29T22:08:36Z<p>Karine: Caspian study</p>
<hr />
<div>Hi, could you please add Caspian study?<br />
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32222-6/fulltext#seccestitle10<br />
<br />
DO you think durvalumab will become more attractive ICP over atezolizumab due to more liberal scheduling q4 weeks?</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=39990Antiemesis2019-09-06T20:15:44Z<p>Karine: Pixantrone and Pembrolizumab emetic MASCC risk</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://ascopubs.org/doi/10.1200/JCO.2017.74.4789<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2019)<br />
!ASCO emetogenic potential<br />
(2017)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|High/Moderate<br />
|High<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Atezolizumab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
|Belinostat<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Blinatumomab<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
|Ceritinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
|Daratumumab<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
|Pembrolizumab<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
|Pixantrone<br />
|<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Trabectedin<br />
|<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Vinflunine<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://ascopubs.org/doi/full/10.1200/JCO.2010.31.7859 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://www.ncbi.nlm.nih.gov/pubmed/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://www.ncbi.nlm.nih.gov/pubmed/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=39989Antiemesis2019-09-06T20:12:08Z<p>Karine: added new agents to main table and emetic risk by MASCC</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://ascopubs.org/doi/10.1200/JCO.2017.74.4789<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2019)<br />
!ASCO emetogenic potential<br />
(2017)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|High/Moderate<br />
|High<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Atezolizumab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
|Belinostat<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Blinatumomab<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
|Ceritinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
|Daratumumab<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Trabectedin<br />
|<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Vinflunine<br />
|<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://ascopubs.org/doi/full/10.1200/JCO.2010.31.7859 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://www.ncbi.nlm.nih.gov/pubmed/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://www.ncbi.nlm.nih.gov/pubmed/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=39988Antiemesis2019-09-06T20:01:17Z<p>Karine: added trabectedine to table with emetic potential by MASCC</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://ascopubs.org/doi/10.1200/JCO.2017.74.4789<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2019)<br />
!ASCO emetogenic potential<br />
(2017)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|High/Moderate<br />
|High<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Atezolizumab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Blinatumomab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
|Ceritinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
|Daratumumab<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Trabectedin<br />
|<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://ascopubs.org/doi/full/10.1200/JCO.2010.31.7859 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://www.ncbi.nlm.nih.gov/pubmed/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://www.ncbi.nlm.nih.gov/pubmed/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=39987Antiemesis2019-09-06T19:54:41Z<p>Karine: MASCC 2019 updates</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://ascopubs.org/doi/10.1200/JCO.2017.74.4789<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2019)<br />
!ASCO emetogenic potential<br />
(2017)<br />
!MASCC/ESMO emetogenic potential (2019)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|High/Moderate<br />
|High<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Atezolizumab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Blinatumomab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
|Ceritinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
|Daratumumab<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://ascopubs.org/doi/full/10.1200/JCO.2010.31.7859 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2019 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://www.ncbi.nlm.nih.gov/pubmed/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://www.ncbi.nlm.nih.gov/pubmed/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=39986Antiemesis2019-09-06T19:51:44Z<p>Karine: MASCC 2019 changes</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://ascopubs.org/doi/10.1200/JCO.2017.74.4789<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2019)<br />
!ASCO emetogenic potential<br />
(2017)<br />
!MASCC/ESMO emetogenic potential (2016)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|High/Moderate<br />
|High<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Atezolizumab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Blinatumomab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
|Ceritinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
|Daratumumab<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
|MASCC 2019<br />
|NK1 + 5-HT3 + DEX +/- OLN<br />
|DEX +/- OLN<br />
<br />
''(if APR on day 1, then + APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [https://ascopubs.org/doi/full/10.1200/JCO.2010.31.7859 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
#''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2016 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://www.ncbi.nlm.nih.gov/pubmed/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://www.ncbi.nlm.nih.gov/pubmed/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10 mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10 mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=37762Antiemesis2019-06-04T02:57:38Z<p>Karine: /* Olanzapine (OLN) containing regimen */ Deleted changes</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://ascopubs.org/doi/10.1200/JCO.2017.74.4789<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2019)<br />
!ASCO emetogenic potential<br />
(2017)<br />
!MASCC/ESMO emetogenic potential (2016)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|High/Moderate<br />
|High<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Atezolizumab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Blinatumomab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
|Ceritinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
|Daratumumab<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then +APR days 2-3)''<br />
|-<br />
|MASCC 2016<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
<br />
''(if APR on day 1, then +APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.7859 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
Reference: <br />
<br />
# ''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br /><br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2016 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://www.ncbi.nlm.nih.gov/pubmed/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://www.ncbi.nlm.nih.gov/pubmed/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=37761Antiemesis2019-06-04T02:55:49Z<p>Karine: Trying to start table formating for evidence</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>ASCO antiemesis guidelines<nowiki/>https://ascopubs.org/doi/10.1200/JCO.2017.74.4789<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2019)<br />
!ASCO emetogenic potential<br />
(2017)<br />
!MASCC/ESMO emetogenic potential (2016)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|High/Moderate<br />
|High<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Atezolizumab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Blinatumomab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
|Ceritinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
|Daratumumab<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then +APR days 2-3)''<br />
|-<br />
|MASCC 2016<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
<br />
''(if APR on day 1, then +APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.7859 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
<br /><br />
{| class="wikitable"<br />
|+<br />
!Study <br />
!Evidence <br />
!Comparator <br />
!Efficacy <br />
|-<br />
|''[https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3" />''<br />
|#1a9851<br /><br />
|<br />
|<br />
|}<br />
<br />
<br />
<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref name=":3">Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2016 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://www.ncbi.nlm.nih.gov/pubmed/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://www.ncbi.nlm.nih.gov/pubmed/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>{{#pmid:25225424}}</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]</div>Karinehttps://hemonc.org/w/index.php?title=Hematology_Oncology_Fellowship_Programs_Directory&diff=37760Hematology Oncology Fellowship Programs Directory2019-06-04T02:36:07Z<p>Karine: /* Hematology oncology fellowship programs */ Jacobi medical center</p>
<hr />
<div>This is a list of United States Hematology Oncology Fellowship Programs. More detailed information about every program can be found by clicking on the links to each Hematology Oncology Fellowship's individual page. For the official list of currently participating programs, visit AAMC's [https://services.aamc.org/eras/erasstats/par/ ERAS Participating Specialties & Programs] page.<ref>[https://services.aamc.org/eras/erasstats/par/ ERAS Participating Specialties & Programs]</ref><br />
<br />
=Hematology oncology fellowship programs=<br />
You may click on the top of a column to sort by that criteria.<br />
<br />
{| class="wikitable sortable"<br />
|+United States Hematology Oncology Fellowship Programs<br />
!'''State'''<br />
!'''City'''<br />
!'''Program Name'''<br />
!'''Hematology/Oncology (HO)'''<br />
'''Hematology (H)'''<br />
<br />
'''Oncology (O)'''<br />
!'''ACGME ID'''<br />
|-<br />
|AL<br />
|Birmingham<br />
|[[University of Alabama Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1550121001<br />
|-<br />
|AR<br />
|Little Rock<br />
|[[University of Arkansas for Medical Sciences Hematology Oncology Fellowship]]<br />
|HO<br />
|1550421129<br />
|-<br />
|AZ<br />
|Phoenix<br />
|[[Mayo Clinic College of Medicine and Science (Arizona) Hematology Oncology Fellowship]]<br />
|HO<br />
|1550313149<br />
|-<br />
|AZ<br />
|Tucson<br />
|[[University of Arizona Hematology Oncology Fellowship]]<br />
|HO<br />
|1550321003<br />
|-<br />
|CA<br />
|Fresno<br />
|[[University of California (San Francisco)/Fresno Hematology Oncology Fellowship]]<br />
|HO<br />
|1550514164<br />
|-<br />
|CA<br />
|La Jolla<br />
|[[Scripps Clinic/Scripps Green Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1550512145<br />
|-<br />
|CA<br />
|La Jolla<br />
|[[University of California (San Diego) Hematology Oncology Fellowship]]<br />
|HO<br />
|1550512007<br />
|-<br />
|CA<br />
|Loma Linda<br />
|[[Loma Linda University Health Education Consortium Hematology Oncology Fellowship]]<br />
|HO<br />
|1550513163<br />
|-<br />
|CA<br />
|Los Angeles<br />
|[[UCLA Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1550521123<br />
|-<br />
|CA<br />
|Los Angeles<br />
|[[University of Southern California/LAC+USC Medical Center Hematology Fellowship]]<br />
|H<br />
|1450521046<br />
|-<br />
|CA<br />
|Los Angeles<br />
|[[University of Southern California/LAC+USC Medical Center Oncology Fellowship]]<br />
|O<br />
|1470521045<br />
|-<br />
|CA<br />
|Orange<br />
|[[University of California (Irvine) Hematology Oncology Fellowship]]<br />
|HO<br />
|1550521136<br />
|-<br />
|CA<br />
|Sacramento<br />
|[[University of California (Davis) Health System Hematology Oncology Fellowship]]<br />
|HO<br />
|1550531005<br />
|-<br />
|CA<br />
|San Francisco<br />
|[[University of California (San Francisco) Hematology Oncology Fellowship]]<br />
|HO<br />
|1550521113<br />
|-<br />
|CA<br />
|Stanford<br />
|[[Stanford University Hematology Fellowship]]<br />
|H<br />
|1450521020<br />
|-<br />
|CA<br />
|Stanford<br />
|[[Stanford University Oncology Fellowship]]<br />
|O<br />
|1470521020<br />
|-<br />
|CA<br />
|Sylmar<br />
|[[Olive View/UCLA Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1550513008<br />
|-<br />
|CA<br />
|Torrance<br />
|[[Los Angeles County-Harbor-UCLA Medical Center Hematology Oncology Fellowship 1]]<br />
|HO<br />
|1550531093<br />
|-<br />
|CO<br />
|Aurora<br />
|[[University of Colorado Hematology Oncology Fellowship]]<br />
|HO<br />
|1550721096<br />
|-<br />
|CT<br />
|Farmington<br />
|[[University of Connecticut Hematology Oncology Fellowship]]<br />
|HO<br />
|1550821009<br />
|-<br />
|CT<br />
|New Haven<br />
|[[Yale-New Haven Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1550814165<br />
|-<br />
|DC<br />
|Washington<br />
|[[George Washington University Hematology Oncology Fellowship]]<br />
|HO<br />
|1551021074<br />
|-<br />
|DC<br />
|Washington<br />
|[[Georgetown University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1551012148<br />
|-<br />
|DC<br />
|Washington<br />
|[[Georgetown University Hospital/Washington Hospital Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1551031011<br />
|-<br />
|DC<br />
|Washington<br />
|[[Howard University Hematology Oncology Fellowship]]<br />
|HO<br />
|1551012157<br />
|-<br />
|FL<br />
|Gainesville<br />
|[[University of Florida Hematology Oncology Fellowship]]<br />
|HO<br />
|1551121104<br />
|-<br />
|FL<br />
|Jacksonville<br />
|[[Mayo Clinic College of Medicine and Science (Jacksonville) Hematology Oncology Fellowship]]<br />
|HO<br />
|1551131108<br />
|-<br />
|FL<br />
|Jacksonville<br />
|[[University of Florida College of Medicine Jacksonville Oncology Fellowship]]<br />
|O<br />
|1471121022<br />
|-<br />
|FL<br />
|Miami<br />
|[[Jackson Memorial Hospital/Jackson Health System Hematology Oncology Fellowship]]<br />
|HO<br />
|1551121012<br />
|-<br />
|FL<br />
|Orlando<br />
|[[Orlando Health Hematology Oncology Fellowship]]<br />
|HO<br />
|1551112153<br />
|-<br />
|FL<br />
|Tampa<br />
|[[University of South Florida Morsani Hematology Oncology Fellowship]]<br />
|HO<br />
|1551131013<br />
|-<br />
|GA<br />
|Atlanta<br />
|[[Emory University Hematology Oncology Fellowship]]<br />
|HO<br />
|1551221014<br />
|-<br />
|GA<br />
|Augusta<br />
|[[Medical College of Georgia Hematology Oncology Fellowship]]<br />
|HO<br />
|1551231015<br />
|-<br />
|IA<br />
|Iowa City<br />
|[[University of Iowa Hospitals and Clinics Hematology Oncology Fellowship]]<br />
|HO<br />
|1551821021<br />
|-<br />
|IL<br />
|Chicago<br />
|[[John H Stroger Hospital of Cook County Hematology Oncology Fellowship]]<br />
|HO<br />
|1551621106<br />
|-<br />
|IL<br />
|Chicago<br />
|[[McGaw Medical Center of Northwestern University Hematology Oncology Fellowship]]<br />
|HO<br />
|1551621016<br />
|-<br />
|IL<br />
|Chicago<br />
|[[Rush University Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1551621085<br />
|-<br />
|IL<br />
|Chicago<br />
|[[University of Chicago Hematology Oncology Fellowship]]<br />
|HO<br />
|1551621079<br />
|-<br />
|IL<br />
|Chicago<br />
|[[University of Illinois College of Medicine at Chicago Hematology Oncology Fellowship]]<br />
|HO<br />
|1551631017<br />
|-<br />
|IL<br />
|Maywood<br />
|[[Loyola University Hematology Oncology Fellowship]]<br />
|HO<br />
|1551621110<br />
|-<br />
|IL<br />
|Park Ridge<br />
|[[Advocate Health Care (Advocate Lutheran General Hospital) Hematology Oncology Fellowship]]<br />
|HO<br />
|1551631147<br />
|-<br />
|IN<br />
|Indianapolis<br />
|[[Indiana University School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1551721020<br />
|-<br />
|KS<br />
|Westwood<br />
|[[University of Kansas School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1551912133<br />
|-<br />
|KY<br />
|Lexington<br />
|[[University of Kentucky College of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1552021103<br />
|-<br />
|KY<br />
|Louisville<br />
|[[University of Louisville Hematology Oncology Fellowship]]<br />
|HO<br />
|1552021022<br />
|-<br />
|LA<br />
|New Orleans<br />
|[[Louisiana State University Hematology Oncology Fellowship]]<br />
|HO<br />
|1552121158<br />
|-<br />
|LA<br />
|New Orleans<br />
|[[Ochsner Clinic Foundation Hematology Oncology Fellowship]]<br />
|HO<br />
|1552114159<br />
|-<br />
|LA<br />
|New Orleans<br />
|[[Tulane University Hematology Oncology Fellowship]]<br />
|HO<br />
|1552121023<br />
|-<br />
|LA<br />
|Shreveport<br />
|[[Louisiana State University (Shreveport) Hematology Oncology Fellowship]]<br />
|HO<br />
|1552131024<br />
|-<br />
|MA<br />
|Boston<br />
|[[Beth Israel Deaconess Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552421026<br />
|-<br />
|MA<br />
|Boston<br />
|[[Boston University Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552431027<br />
|-<br />
|MA<br />
|Boston<br />
|[[Brigham and Women's Hospital/Massachusetts General Hospital/Dana-Farber Cancer Institute Hematology Oncology Fellowship]]<br />
|HO<br />
|1552421073<br />
|-<br />
|MA<br />
|Boston<br />
|[[St Elizabeth's Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552421124<br />
|-<br />
|MA<br />
|Boston<br />
|[[Tufts Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552412029<br />
|-<br />
|MA<br />
|Springfield<br />
|[[UMMS-Baystate Hematology Oncology Fellowship]]<br />
|HO<br />
|1552413030<br />
|-<br />
|MA<br />
|Worcester<br />
|[[University of Massachusetts Hematology Oncology Fellowship]]<br />
|HO<br />
|1552421075<br />
|-<br />
|MD<br />
|Baltimore<br />
|[[Johns Hopkins University Hematology Oncology Fellowship]]<br />
|HO<br />
|1552321154<br />
|-<br />
|MD<br />
|Baltimore<br />
|[[University of Maryland Hematology Oncology Fellowship]]<br />
|HO<br />
|1552321025<br />
|-<br />
|MD<br />
|Bethesda<br />
|[[National Institutes of Health Clinical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552314155<br />
|-<br />
|MD<br />
|Bethesda<br />
|[[National Institutes of Health Clinical Center Oncology Fellowship]]<br />
|O<br />
|1472321183<br />
|-<br />
|MI<br />
|Ann Arbor<br />
|[[University of Michigan Hematology Oncology Fellowship]]<br />
|HO<br />
|1552521098<br />
|-<br />
|MI<br />
|Detroit<br />
|[[Detroit Medical Center/Wayne State University Hematology Oncology Fellowship]]<br />
|HO<br />
|1552513142<br />
|-<br />
|MI<br />
|Detroit<br />
|[[Henry Ford Hospital/Wayne State University Hematology Oncology Fellowship]]<br />
|HO<br />
|1552521031<br />
|-<br />
|MI<br />
|Detroit<br />
|[[St John Hospital and Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552514158<br />
|-<br />
|MI<br />
|East Lansing<br />
|[[Michigan State University Hematology Oncology Fellowship]]<br />
|HO<br />
|1552521126<br />
|-<br />
|MI<br />
|Royal Oak<br />
|[[William Beaumont Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1552531156<br />
|-<br />
|MI<br />
|Southfield<br />
|[[Providence-Providence Park Hospital/MSUCHM Hematology Oncology Fellowship]]<br />
|HO<br />
|1552512140<br />
|-<br />
|MN<br />
|Minneapolis<br />
|[[University of Minnesota Hematology Oncology Fellowship]]<br />
|HO<br />
|1552621032<br />
|-<br />
|MN<br />
|Rochester<br />
|[[Mayo Clinic College of Medicine and Science (Rochester) Hematology Oncology Fellowship]]<br />
|HO<br />
|1552631033<br />
|-<br />
|MO<br />
|Columbia<br />
|[[University of Missouri-Columbia Hematology Oncology Fellowship]]<br />
|HO<br />
|1552821083<br />
|-<br />
|MO<br />
|Kansas City<br />
|[[University of Missouri at Kansas City Hematology Oncology Fellowship]]<br />
|HO<br />
|1552821034<br />
|-<br />
|MO<br />
|St Louis<br />
|[[St Louis University School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1552811036<br />
|-<br />
|MO<br />
|St Louis<br />
|[[Washington University/B-JH/SLCH Consortium Hematology Oncology Fellowship]]<br />
|HO<br />
|1552831035<br />
|-<br />
|MS<br />
|Jackson<br />
|[[University of Mississippi Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1552721114<br />
|-<br />
|NC<br />
|Chapel Hill<br />
|[[University of North Carolina Hospitals Hematology Oncology Fellowship]]<br />
|HO<br />
|1553621055<br />
|-<br />
|NC<br />
|Charlotte<br />
|[[Carolinas Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553614142<br />
|-<br />
|NC<br />
|Durham<br />
|[[Duke University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553631056<br />
|-<br />
|NC<br />
|Greenville<br />
|[[Vidant Medical Center/East Carolina University Hematology Oncology Fellowship]]<br />
|HO<br />
|1553611141<br />
|-<br />
|NC<br />
|Winston-Salem<br />
|[[Wake Forest University School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1553621076<br />
|-<br />
|NE<br />
|Omaha<br />
|[[University of Nebraska Medical Center College of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1553021037<br />
|-<br />
|NH<br />
|Lebanon<br />
|[[Dartmouth-Hitchcock Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553221038<br />
|-<br />
|NJ<br />
|Camden<br />
|[[Cooper Medical School of Rowan University/Cooper University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553321039<br />
|-<br />
|NJ<br />
|New Brunswick<br />
|[[Rutgers Robert Wood Johnson Medical School Hematology Oncology Fellowship]]<br />
|HO<br />
|1553321040<br />
|-<br />
|NJ<br />
|Newark<br />
|[[Newark Beth Israel Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553331132<br />
|-<br />
|NJ<br />
|Paterson<br />
|[[Seton Hall University School of Health and Medical Sciences Hematology Oncology Fellowship]]<br />
|HO<br />
|1553313137<br />
|-<br />
|NM<br />
|Albuquerque<br />
|[[University of New Mexico Hematology Oncology Fellowship]]<br />
|HO<br />
|1553421115<br />
|-<br />
|NY<br />
|Bronx<br />
|[[Montefiore Medical Center/Albert Einstein College of Medicine (Moses and Weiler Campuses) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521127<br />
|-<br />
|NY<br />
|Bronx<br />
|Jacobi Medical Center (opening July 1, 2019)<br />
|HO<br />
|<br />
|-<br />
|NY<br />
|Brooklyn<br />
|[[Brookdale University Hospital and Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521041<br />
|-<br />
|NY<br />
|Brooklyn<br />
|[[Brooklyn Hospital Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553512135<br />
|-<br />
|NY<br />
|Brooklyn<br />
|[[Maimonides Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553513139<br />
|-<br />
|NY<br />
|Brooklyn<br />
|[[New York Methodist Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521138<br />
|-<br />
|NY<br />
|Brooklyn<br />
|[[SUNY Health Science Center at Brooklyn Hematology Oncology Fellowship]]<br />
|HO<br />
|1553511043<br />
|-<br />
|NY<br />
|Buffalo<br />
|[[University at Buffalo Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521162<br />
|-<br />
|NY<br />
|Lake Success<br />
|[[Hofstra Northwell School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1553522046<br />
|-<br />
|NY<br />
|Mineola<br />
|[[Winthrop-University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553513045<br />
|-<br />
|NY<br />
|New York<br />
|[[Hofstra Northwell School of Medicine at Lenox Hill Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553533049<br />
|-<br />
|NY<br />
|New York<br />
|[[Icahn School of Medicine at Mount Sinai (Beth Israel) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553523047<br />
|-<br />
|NY<br />
|New York<br />
|[[Icahn School of Medicine at Mount Sinai Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521050<br />
|-<br />
|NY<br />
|New York<br />
|[[Memorial Sloan Kettering Cancer Center/New York Presbyterian Hospital (Cornell Campus) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521084<br />
|-<br />
|NY<br />
|New York<br />
|[[New York Presbyterian Hospital (Columbia Campus) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553511052<br />
|-<br />
|NY<br />
|New York<br />
|[[New York Presbyterian Hospital (Cornell Campus) Hematology Oncology Fellowship]]<br />
|HO<br />
|1553531051<br />
|-<br />
|NY<br />
|New York<br />
|[[New York University School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1553531152<br />
|-<br />
|NY<br />
|Rochester<br />
|[[University of Rochester Hematology Oncology Fellowship]]<br />
|HO<br />
|1553521100<br />
|-<br />
|NY<br />
|Staten Island<br />
|[[Hofstra Northwell School of Medicine at Staten Island University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553531144<br />
|-<br />
|NY<br />
|Stony Brook<br />
|[[Stony Brook Medicine/University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553513054<br />
|-<br />
|NY<br />
|Syracuse<br />
|[[SUNY Upstate Medical University Hematology Oncology Fellowship]]<br />
|HO<br />
|1553531086<br />
|-<br />
|NY<br />
|Valhalla<br />
|[[New York Medical College at Westchester Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553531101<br />
|-<br />
|OH<br />
|Cincinnati<br />
|[[University of Cincinnati Medical Center/College of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1553821102<br />
|-<br />
|OH<br />
|Cleveland<br />
|[[Case Western Reserve University/University Hospitals Cleveland Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553821117<br />
|-<br />
|OH<br />
|Cleveland<br />
|[[Cleveland Clinic Foundation Hematology Oncology Fellowship]]<br />
|HO<br />
|1553821057<br />
|-<br />
|OH<br />
|Columbus<br />
|[[Ohio State University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1553831058<br />
|-<br />
|OH<br />
|Dayton<br />
|[[Wright State University Hematology Oncology Fellowship]]<br />
|HO<br />
|1553811059<br />
|-<br />
|OH<br />
|Toledo<br />
|[[University of Toledo Oncology Fellowship]]<br />
|O<br />
|1473831200<br />
|-<br />
|OK<br />
|Oklahoma City<br />
|[[University of Oklahoma Health Sciences Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1553921060<br />
|-<br />
|OR<br />
|Portland<br />
|[[Oregon Health & Science University Hematology Oncology Fellowship]]<br />
|HO<br />
|1554021118<br />
|-<br />
|PA<br />
|Allentown<br />
|[[Lehigh Valley Health Network Hematology Oncology Fellowship]]<br />
|HO<br />
|1554114166<br />
|-<br />
|PA<br />
|Hershey<br />
|[[Penn State Milton S Hershey Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554121061<br />
|-<br />
|PA<br />
|Philadelphia<br />
|[[Albert Einstein Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554114167<br />
|-<br />
|PA<br />
|Philadelphia<br />
|[[Drexel University College of Medicine/Hahnemann University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1554131062<br />
|-<br />
|PA<br />
|Philadelphia<br />
|[[Temple University Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1554121091<br />
|-<br />
|PA<br />
|Philadelphia<br />
|[[Thomas Jefferson University Hematology Oncology Fellowship]]<br />
|HO<br />
|1554121130<br />
|-<br />
|PA<br />
|Philadelphia<br />
|[[University of Pennsylvania Hematology Oncology Fellowship]]<br />
|HO<br />
|1554121081<br />
|-<br />
|PA<br />
|Pittsburgh<br />
|[[Allegheny Health Network Medical Education Consortium (WPH/AGH) Hematology Oncology Fellowship]]<br />
|HO<br />
|1554131092<br />
|-<br />
|PA<br />
|Pittsburgh<br />
|[[UPMC Medical Education Hematology Oncology Fellowship]]<br />
|HO<br />
|1554121122<br />
|-<br />
|PA<br />
|Wynnewood<br />
|[[Main Line Health System/Lankenau Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554131077<br />
|-<br />
|PR<br />
|San Juan<br />
|[[University of Puerto Rico Hematology Oncology Fellowship]]<br />
|HO<br />
|1554221080<br />
|-<br />
|RI<br />
|Providence<br />
|[[Brown University Hematology Oncology Fellowship]]<br />
|HO<br />
|1554331128<br />
|-<br />
|RI<br />
|Providence<br />
|[[Roger Williams Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554321120<br />
|-<br />
|SC<br />
|Charleston<br />
|[[Medical University of South Carolina Hematology Oncology Fellowship]]<br />
|HO<br />
|1554521063<br />
|-<br />
|TN<br />
|Germantown<br />
|[[University of Tennessee Hematology Oncology Fellowship]]<br />
|HO<br />
|1554721125<br />
|-<br />
|TN<br />
|Nashville<br />
|[[Vanderbilt University Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554731065<br />
|-<br />
|TN<br />
|Johnson City<br />
|[[East Tennessee State University Oncology Fellowship]]<br />
|O<br />
|1474721195<br />
|-<br />
|TX<br />
|Dallas<br />
|[[Baylor University Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554814161<br />
|-<br />
|TX<br />
|Dallas<br />
|[[University of Texas Southwestern Medical School Hematology Oncology Fellowship]]<br />
|HO<br />
|1554821066<br />
|-<br />
|TX<br />
|Galveston<br />
|[[University of Texas Medical Branch Hospitals Oncology Fellowship]]<br />
|O<br />
|1474821053<br />
|-<br />
|TX<br />
|Houston<br />
|[[Baylor College of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1554821146<br />
|-<br />
|TX<br />
|Houston<br />
|[[Methodist Hospital (Houston) Hematology Oncology Fellowship]]<br />
|HO<br />
|1554814158<br />
|-<br />
|TX<br />
|Houston<br />
|[[University of Texas Health Science Center at Houston/M D Anderson Cancer Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1554812150<br />
|-<br />
|TX<br />
|Lubbock<br />
|[[Texas Tech University Health Sciences Center at Lubbock Hematology Oncology Fellowship]]<br />
|HO<br />
|1554814159<br />
|-<br />
|TX<br />
|San Antonio<br />
|[[University of Texas Health Science Center School of Medicine at San Antonio Hematology Oncology Fellowship]]<br />
|HO<br />
|1554821099<br />
|-<br />
|TX<br />
|Temple<br />
|[[Scott and White Memorial Hospital Hematology Oncology Fellowship]]<br />
|HO<br />
|1554814156<br />
|-<br />
|UT<br />
|Salt Lake City<br />
|[[University of Utah Hematology Oncology Fellowship]]<br />
|HO<br />
|1554921082<br />
|-<br />
|VA<br />
|Charlottesville<br />
|[[University of Virginia Hematology Oncology Fellowship]]<br />
|HO<br />
|1555131078<br />
|-<br />
|VA<br />
|Richmond<br />
|[[Virginia Commonwealth University Health System Hematology Oncology Fellowship]]<br />
|HO<br />
|1555121070<br />
|-<br />
|VT<br />
|Burlington<br />
|[[University of Vermont Medical Center Hematology Oncology Fellowship]]<br />
|HO<br />
|1555021069<br />
|-<br />
|WA<br />
|Seattle<br />
|[[University of Washington Hematology Oncology Fellowship]]<br />
|HO<br />
|1555413151<br />
|-<br />
|WI<br />
|La Crosse<br />
|[[Gundersen Lutheran Medical Foundation Hematology Oncology Fellowship]]<br />
|HO<br />
|1555631160<br />
|-<br />
|WI<br />
|Madison<br />
|[[University of Wisconsin Hematology Oncology Fellowship]]<br />
|HO<br />
|1555612161<br />
|-<br />
|WI<br />
|Milwaukee<br />
|[[Medical College of Wisconsin Affiliated Hospitals Hematology Oncology Fellowship]]<br />
|HO<br />
|1555621119<br />
|-<br />
|WV<br />
|Huntington<br />
|[[Marshall University School of Medicine Hematology Oncology Fellowship]]<br />
|HO<br />
|1555514110<br />
|-<br />
|WV<br />
|Morgantown<br />
|[[West Virginia University Hematology Oncology Fellowship]]<br />
|HO<br />
|1555521109<br />
|}<br />
<br />
=By specialty=<br />
<br />
*[[:Category: Hematology & Oncology fellowship programs|Hematology & Oncology fellowship programs]]<br />
*[[:Category: Oncology fellowship programs|Oncology fellowship programs]]<br />
*[[:Category: Hematology fellowship programs|Hematology fellowship programs]]<br />
<br />
=References=<br />
<references /><br />
<br />
[[Category:General reference pages]]</div>Karinehttps://hemonc.org/w/index.php?title=Acute_myeloid_leukemia&diff=37759Acute myeloid leukemia2019-06-04T02:31:01Z<p>Karine: Formating Wei 2019</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:MartinSchoen.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Marteens|Martin W. Schoen, MD, MPH]]<br>Saint Louis University<br>St. Louis, MO</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/mwschoen mwschoen]<br />
|-<br />
|}<br />
''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Acute_myeloid_leukemia_-_historical|historical regimens page]]. If you still can't find it, please let us know so we can add it!''<br><br />
<big>'''Note: biomarker-specific regimens have been moved to dedicated pages:'''<br />
*'''[[Acute_myeloid_leukemia,_FLT3-positive|AML, FLT3-positive]]'''<br />
*'''[[Acute_myeloid_leukemia,_IDH-mutated|AML, IDH-mutated]]'''<br />
</big><br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==ELN==<br />
====Current====<br />
<br />
*'''2017:''' [http://www.bloodjournal.org/content/129/4/424.long Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291965/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27895058 PubMed]<br />
<br />
====Older====<br />
<br />
*'''2010:''' [http://www.bloodjournal.org/content/115/3/453.long Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet] [https://www.ncbi.nlm.nih.gov/pubmed/19880497 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2013:''' Fey et al. [https://www.esmo.org/Guidelines/Haematological-Malignancies/Acute-Myeloblastic-Leukaemia-in-Adult-Patients Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
<br />
=="How I treat"==<br />
<br />
*'''2016:''' Ofran Y, Tallman MS, Rowe JM. How I treat acute myeloid leukemia presenting with preexisting comorbidities. Blood. 2016 Jul 28;128(4):488-96. Epub 2016 May 27. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524532/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27235136 PubMed]<br />
*'''2015:''' Röllig C, Ehninger G. How I treat hyperleukocytosis in acute myeloid leukemia. Blood. 2015 May 21;125(21):3246-52. Epub 2015 Mar 16. [http://www.bloodjournal.org/content/125/21/3246.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25778528 PubMed]<br />
*'''2014:''' Ossenkoppele G, Löwenberg B. How I treat the older patient with acute myeloid leukemia. Blood. 2015 Jan 29;125(5):767-74. Epub 2014 Dec 16. [http://www.bloodjournal.org/content/125/5/767.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515963 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf NCCN Guidelines - Acute Myeloid Leukemia]<br />
<br />
=Upfront induction therapy, standard and older "fit" patients=<br />
''These are aggressive remission induction regimens given with curative intent.''<br />
==7+3d (standard-dose) {{#subobject:9f31ad|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
7+3d: '''<u>7</u>''' days of cytarabine + '''<u>3</u>''' days of '''<u>d</u>'''aunorubicin<br />
<br>AD: '''<u>A</u>'''ra-C (Cytarabine) & '''<u>D</u>'''aunorubicin<br />
<br>DA: '''<u>D</u>'''aunorubicin & '''<u>A</u>'''ra-C (Cytarabine)<br />
===Variant #1, 700/135 (CI Ara-C) {{#subobject:bb27bc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/4586956 Yates et al. 1973]<br />
| style="background-color:#ffffbe" |Non-randomized, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="3" |[http://www.bloodjournal.org/content/58/6/1203.long Rai et al. 1981 (CALGB 7421)]<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#7.2B3d_.28standard-dose.29|7+3d (bolus Ara-C)]]<br />
| style="background-color:#91cf60" |Seems to have superior CR rate<br />
|-<br />
|2. 5+2d<br />
| style="background-color:#1a9850" |Superior CR rate<br />
|-<br />
|3. 5+2d (bolus Ara-C)<br />
| style="background-color:#1a9850" |Superior CR rate<br />
|-<br />
| rowspan="2" |[https://onlinelibrary.wiley.com/doi/epdf/10.1002/1097-0142%2819820415%2949%3A8%3C1530%3A%3AAID-CNCR2820490804%3E3.0.CO%3B2-1 Omura et al. 1982]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. AVML<br />
| style="background-color:#d3d3d3" |Not directly compared<br />
|-<br />
|2. [[Acute_myeloid_leukemia_-_historical#DAT|TAD]]<br />
| style="background-color:#1a9850" |Superior time to CR<br />
|-<br />
| rowspan="2" |[http://www.bloodjournal.org/content/60/2/454.long Yates et al. 1982 (CALGB 7721)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[Acute_myeloid_leukemia_-_historical#7.2B3d_.28low-dose.29|7+3d (low-dose)]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. 7+3a (30 mg/m<sup>2</sup>)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/63/5/1039.long Vogler et al. 1984]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[http://www.bloodjournal.org/content/69/5/1441.long Preisler et al. 1987 (CALGB 7921)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. 10+3d<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. [[Acute_myeloid_leukemia_-_historical#DAT|TAD]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/014521269090179D Stein et al. 1990]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MA<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/2179638 Arlin et al. 1990]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3m|7+3m]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/78/10/2520.long Dillman et al. 1991 (CALGB 8321)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3d_.28standard-dose.29|7+3d (higher-dose Ara-C)]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/79/2/313 Wiernik et al. 1992]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3i|7+3i]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://ascopubs.org/doi/10.1200/JCO.1992.10.7.1103 Vogler et al. 1992]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3i|7+3i]]<br />
| style="background-color:#fc8d59" |Seems to have inferior CR rate<br />
|-<br />
|[http://www.bloodjournal.org/content/103/2/479.long Rowe et al. 2004 (ECOG E3993)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. 7+3d + GM-CSF<br> 2. [[#7.2B3i|7+3i]]<br> 3. 7+3i + GM-CSF<br> 4. [[#7.2B3m|7+3m]]<br> 5. 7+3m + GM-CSF<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2008.07400.x Latagliata et al. 2008 (GIMEMA GSI 103 AMLE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|7+3 (Daunoxome)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480917/ Fernandez et al. 2009 (ECOG E1900)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3d_.28high-dose.29|7+3d (high-dose)]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ Dombret et al. 2015 (AZA-AML-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Azacitidine_monotherapy|Azacitidine]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
''Note: this was the lower bound of the allowable daunorubicin dose in AZA-AML-001.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*ECOG E3993: Patients with persistent disease at day 14 (greater than 5% blasts) underwent an identical second cycle of 7+3i<br />
<br />
===Variant #2, 700/150 (CI Ara-C) {{#subobject:9934a6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/75/1/27.long Bishop et al. 1990]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADE_.28standard-dose_Ara-C.29|ADE]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV bolus once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
<br />
===Variant #3, 1120/120 (intermittent Ara-C) {{#subobject:1f1bb5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/8916311 Masaoka et al. 1996]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#7.2B3i|7+3i]]<br />
| style="background-color:#fc8d59" |Seems to have inferior CR rate<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 80 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 1 to 7<br />
*[[Daunorubicin (Cerubidine)]] 40 mg/m<sup>2</sup> IV bolus once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
<br />
===Variant #4, 1400/135 (CI Ara-C) {{#subobject:635ecb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/78/10/2520.long Dillman et al. 1991 (CALGB 8321)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28standard-dose.29|7+3d (lower-dose Ara-C)]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/88/8/2841.long Weick et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|HDAC+3d<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/100/12/3869.long Anderson et al. 2002 (SWOG S9333)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ME<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895015/ Moore et al. 2004 (CALGB 9222)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0901409 Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3d_.28high-dose.29|7+3d (high-dose)]]<br />
| style="background-color:#d73027" |Inferior CR rate<br />
|-<br />
|[http://www.bloodjournal.org/content/118/14/3832.long Lee et al. 2011 (ADcomparison)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3d_.28high-dose.29|7+3d (high-dose)]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345117/ Hengeveld et al. 2012 (AML 8B)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://jco.ascopubs.org/content/33/11/1252.full Stone et al. 2015 (ACCEDE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Amonafide & Cytarabine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*CALGB 9222: [[#HiDAC|HiDAC]] versus multi-agent chemotherapy consolidation<br />
*HOVON 43 AML/SAKK 30/01: [[#IDAC|MiDAC consolidation]]<br />
*ACCEDE: patients received a second course of the same regimen if their day 14 bone marrow was positive. Patients with PR or better at time of count recovery received allogeneic stem cell transplant if eligible, otherwise [[#HiDAC|HiDAC]] if younger than 60 or [[#IDAC|MiDAC]] if greater than or equal to 60.<br />
<br />
===References===<br />
<br />
#Yates JW, Wallace HJ Jr, Ellison RR, Holland JF. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep. 1973 Nov-Dec;57(4):485-8. [https://www.ncbi.nlm.nih.gov/pubmed/4586956 PubMed]<br />
#'''CALGB 7421:''' Rai KR, Holland JF, Glidewell OJ, Weinberg V, Brunner K, Obrecht JP, Preisler HD, Nawabi IW, Prager D, Carey RW, Cooper MR, Haurani F, Hutchison JL, Silver RT, Falkson G, Wiernik P, Hoagland HC, Bloomfield CD, James GW, Gottlieb A, Ramanan SV, Blom J, Nissen NI, Bank A, Ellison RR, Kung F, Henry P, McIntyre OR, Kaan SK. Treatment of acute myelocytic leukemia: a study by Cancer and Leukemia Group B. Blood. 1981 Dec;58(6):1203-12. [http://www.bloodjournal.org/content/58/6/1203.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/6946847 PubMed]<br />
#Omura GA, Vogler WR, Lefante J, Silberman H, Knospe W, Gordon D, Jarrell R. Treatment of acute myelogenous leukemia: influence of three induction regimens and maintenance with chemotherapy or BCG immunotherapy. Cancer. 1982 Apr 15;49(8):1530-6. [https://onlinelibrary.wiley.com/doi/epdf/10.1002/1097-0142%2819820415%2949%3A8%3C1530%3A%3AAID-CNCR2820490804%3E3.0.CO%3B2-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7039813 PubMed]<br />
#'''CALGB 7721:''' Yates J, Glidewell O, Wiernik P, Cooper MR, Steinberg D, Dosik H, Levy R, Hoagland C, Henry P, Gottlieb A, Cornell C, Berenberg J, Hutchison JL, Raich P, Nissen N, Ellison RR, Frelick R, James GW, Falkson G, Silver RT, Haurani F, Green M, Henderson E, Leone L, Holland JF. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood. 1982 Aug;60(2):454-62. [http://www.bloodjournal.org/content/60/2/454.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/6953986 PubMed]<br />
#Vogler WR, Winton EF, Gordon DS, Raney MR, Go B, Meyer L. A randomized comparison of postremission therapy in acute myelogenous leukemia: a Southeastern Cancer Study Group trial. Blood. 1984 May;63(5):1039-45. [http://www.bloodjournal.org/content/63/5/1039.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6201211 PubMed]<br />
#'''CALGB 7921:''' Preisler H, Davis RB, Kirshner J, Dupre E, Richards F 3rd, Hoagland HC, Kopel S, Levy RN, Carey R, Schulman P, Gottlieb AJ, McIntyre OR. Comparison of three remission induction regimens and two postinduction strategies for the treatment of acute nonlymphocytic leukemia: a Cancer and Leukemia Group B study. Blood. 1987 May;69(5):1441-9. [http://www.bloodjournal.org/content/69/5/1441.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/3552076 PubMed]<br />
#Stein RS, Vogler WR, Winton EF, Cohen HJ, Raney MR, Bartolucci A. Therapy of acute myelogenous leukemia in patients over the age of 50: a randomized Southeastern Cancer Study Group trial. Leuk Res. 1990;14(10):895-903. [https://www.sciencedirect.com/science/article/pii/014521269090179D link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/2259226 PubMed]<br />
#Bishop JF, Lowenthal RM, Joshua D, Matthews JP, Todd D, Cobcroft R, Whiteside MG, Kronenberg H, Ma D, Dodds A, Herrmann R, Szer J, Wolf MM, Young G; Australian Leukemia Study Group. Etoposide in acute nonlymphocytic leukemia. Blood. 1990 Jan 1;75(1):27-32. [http://www.bloodjournal.org/content/75/1/27.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2403818 PubMed]<br />
#Arlin Z, Case DC Jr, Moore J, Wiernik P, Feldman E, Saletan S, Desai P, Sia L, Cartwright K; Lederle Cooperative Group. Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Leukemia. 1990 Mar;4(3):177-83. [https://www.ncbi.nlm.nih.gov/pubmed/2179638 PubMed]<br />
#'''CALGB 8321:''' Dillman RO, Davis RB, Green MR, Weiss RB, Gottlieb AJ, Caplan S, Kopel S, Preisler H, McIntyre OR, Schiffer C. A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood. 1991 Nov 15;78(10):2520-6. [http://www.bloodjournal.org/content/78/10/2520.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1824249 PubMed]<br />
#Wiernik PH, Banks PL, Case DC Jr, Arlin ZA, Periman PO, Todd MB, Ritch PS, Enck RE, Weitberg AB. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992 Jan 15;79(2):313-9. [http://www.bloodjournal.org/content/79/2/313 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1730080 PubMed]<br />
#Vogler WR, Velez-Garcia E, Weiner RS, Flaum MA, Bartolucci AA, Omura GA, Gerber MC, Banks PL. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study. J Clin Oncol. 1992 Jul;10(7):1103-11. [http://ascopubs.org/doi/10.1200/JCO.1992.10.7.1103 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1607916 PubMed]<br />
#Masaoka T, Ogawa M, Yamada K, Kimura K, Ohashi Y. A phase II comparative study of idarubicin plus cytarabine versus daunorubicin plus cytarabine in adult acute myeloid leukemia. Semin Hematol. 1996 Oct;33(4 Suppl 3):12-7. '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8916311 PubMed]<br />
#Weick JK, Kopecky KJ, Appelbaum FR, Head DR, Kingsbury LL, Balcerzak SP, Bickers JN, Hynes HE, Welborn JL, Simon SR, Grever M. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood. 1996 Oct 15;88(8):2841-51. [http://www.bloodjournal.org/content/88/8/2841.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8874180 PubMed]<br />
#'''SWOG S9333:''' Anderson JE, Kopecky KJ, Willman CL, Head D, O'Donnell MR, Luthardt FW, Norwood TH, Chen IM, Balcerzak SP, Johnson DB, Appelbaum FR. Outcome after induction chemotherapy for older patients with acute myeloid leukemia is not improved with mitoxantrone and etoposide compared to cytarabine and daunorubicin: a Southwest Oncology Group study. Blood. 2002 Dec 1;100(12):3869-76. Epub 2002 Aug 1. [http://www.bloodjournal.org/content/100/12/3869.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12393614 PubMed]<br />
#'''ECOG E3993:''' Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, Makary AZ, Liesveld JL, Abboud CN, Dewald G, Hayes FA, Tallman MS, Wiernik PH; Eastern Cooperative Oncology. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004 Jan 15;103(2):479-85. Epub 2003 Sep 25. [http://www.bloodjournal.org/content/103/2/479.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14512295 PubMed]<br />
#'''CALGB 9222:''' Moore JO, George SL, Dodge RK, Amrein PC, Powell BL, Kolitz JE, Baer MR, Davey FR, Bloomfield CD, Larson RA, Schiffer CA. Sequential multiagent chemotherapy is not superior to high-dose cytarabine alone as postremission intensification therapy for acute myeloid leukemia in adults under 60 years of age: Cancer and Leukemia Group B Study 9222. Blood. 2005 May 1;105(9):3420-7. Epub 2004 Nov 30. [http://www.bloodjournal.org/content/105/9/3420.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895015/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15572587 PubMed]<br />
#'''GIMEMA GSI 103 AMLE:''' Latagliata R, Breccia M, Fazi P, Iacobelli S, Martinelli G, Di Raimondo F, Sborgia M, Fabbiano F, Pirrotta MT, Zaccaria A, Amadori S, Caramatti C, Falzetti F, Candoni A, Mattei D, Morselli M, Alimena G, Vignetti M, Baccarani M, Mandelli F. Liposomal daunorubicin versus standard daunorubicin: long term follow-up of the GIMEMA GSI 103 AMLE randomized trial in patients older than 60 years with acute myelogenous leukaemia. Br J Haematol. 2008 Dec;143(5):681-9. Epub 2008 Oct 20. [https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2008.07400.x link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18950458 PubMed]<br />
#'''HOVON 43 AML/SAKK 30/01:''' Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Döhner H, Gratwohl A, Pabst T, Verhoef G; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. [https://www.nejm.org/doi/full/10.1056/NEJMoa0901409 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19776405 PubMed]<br />
#'''ECOG E1900:''' Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald GW, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Tallman MS. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1249-59. [https://www.nejm.org/doi/full/10.1056/NEJMoa0904544 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480917/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19776406 PubMed]<br />
##'''Update:''' Luskin MR, Lee JW, Fernandez HF, Abdel-Wahab O, Bennett JM, Ketterling RP, Lazarus HM, Levine RL, Litzow MR, Paietta EM, Patel JP, Racevskis J, Rowe JM, Tallman MS, Sun Z, Luger SM. Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups. Blood. 2016 Mar 24;127(12):1551-8. Epub 2016 Jan 11. [http://www.bloodjournal.org/content/127/12/1551.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807422/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26755712 PubMed]<br />
#'''ADcomparison:''' Lee JH, Joo YD, Kim H, Bae SH, Kim MK, Zang DY, Lee JL, Lee GW, Lee JH, Park JH, Kim DY, Lee WS, Ryoo HM, Hyun MS, Kim HJ, Min YJ, Jang YE, Lee KH; Cooperative Study Group A for Hematology. A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia. Blood. 2011 Oct 6;118(14):3832-41. Epub 2011 Aug 9. [http://www.bloodjournal.org/content/118/14/3832.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21828126 PubMed]<br />
#'''AML 8B:''' Hengeveld M, Suciu S, Karrasch M, Specchia G, Marie JP, Muus P, Petti MC, Rotoli B, Amadori S, Fioritoni G, Leoni P, Morra E, Thaler J, Resegotti L, Fazi P, Vignetti M, Mandelli F, Zittoun R, de Witte T. Intensive consolidation therapy compared with standard consolidation and maintenance therapy for adults with acute myeloid leukaemia aged between 46 and 60 years: final results of the randomized phase III study (AML 8B) of the European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. Ann Hematol. 2012 Jun;91(6):825-35. Epub 2012 Mar 31. [https://link.springer.com/article/10.1007%2Fs00277-012-1436-z link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345117/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22460947 PubMed]<br />
#'''ACCEDE:''' Stone RM, Mazzola E, Neuberg D, Allen SL, Pigneux A, Stuart RK, Wetzler M, Rizzieri D, Erba HP, Damon L, Jang JH, Tallman MS, Warzocha K, Masszi T, Sekeres MA, Egyed M, Horst HA, Selleslag D, Solomon SR, Venugopal P, Lundberg AS, Powell B. Phase III open-label randomized study of cytarabine in combination with amonafide l-malate or daunorubicin as induction therapy for patients with secondary acute myeloid leukemia. J Clin Oncol. 2015 Apr 10;33(11):1252-7. Epub 2015 Mar 2. [http://jco.ascopubs.org/content/33/11/1252.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25732165 PubMed]<br />
#'''AZA-AML-001:''' Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/3/291.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25987659 PubMed]<br />
##'''Subgroup analysis:''' Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3803-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731212/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29241450 PubMed]<br />
<br />
==7+3d (intermediate-dose) {{#subobject:e82156|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
7+3d: '''<u>7</u>''' days of cytarabine + '''<u>3</u>''' days of '''<u>d</u>'''aunorubicin<br />
===Variant #1, CI Ara-C (100 mg/m<sup>2</sup>) {{#subobject:bb27bc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2012.46.4743 Schaich et al. 2013 (AML2003)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2012.46.4990 Serve et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|7+3d & Sorafenib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682338/ Petersdorf et al. 2013 (SWOG S0106)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|7+3d & GO<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nature.com/articles/leu2015306 Müller-Tidow et al. 2015 (AML-AZA)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|7+3d & Azacitidine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ Dombret et al. 2015 (AZA-AML-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Azacitidine_monotherapy|Azacitidine]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00362-9/fulltext Röllig et al. 2015 (SORAML)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|7+3d & Sorafenib<br />
| style="background-color:#fc8d59" |Seems to have inferior EFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6112 Lancet et al. 2018 (CLTR0310-301)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CPX-351_monotherapy|CPX-351]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Note: this was the upper bound of the allowable daunorubicin dose in AZA-AML-001.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
**Note: Dombret et al. 2015 did not specify which days the daunorubicin is administered; some protocols give daunorubicin on days 3 to 5<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*AML2003: [[#HiDAC|HiDAC]] versus MAC/MAMAC/MAC consolidation<br />
*SWOG S0106: [[#HiDAC|HiDAC consolidation]] x 3<br />
*CLTR0310-301: [[#5.2B2d|5+2d consolidation]]<br />
<br />
===Variant #2, CI Ara-C (200 mg/m<sup>2</sup>) {{#subobject:cf53dd|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v18/n5/full/2403336a.html Holowiecki et al. 2004 (PALG AML1/1999)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#DAC|DAC]]<br />
| style="background-color:#d73027" |Inferior CR rate after first induction<br />
|-<br />
|[https://www.nature.com/articles/leu2010111 Chevallier et al. 2010 (LAM-2001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Acute_myeloid_leukemia_-_historical#7.2B5i|7+5i]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://jco.ascopubs.org/content/30/20/2441.full Holowiecki et al. 2012 (PALG AML1/2004)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#DAC|DAC]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. DAF<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60485-1/fulltext Castaigne et al. 2012 (ALFA-0701)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3d_.26_GO|7+3d & GO]]<br />
| style="background-color:#d73027" |Inferior EFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ Stone et al. 2017 (RATIFY)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Acute_myeloid_leukemia,_FLT3-positive#7.2B3d_.26_Midostaurin|7+3d & Midostaurin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Note: patients in RATIFY had FLT3+ disease.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV over 5 minutes once per day on days 1 to 3<br />
<br />
====Supportive medications====<br />
<br />
*"According to commonly accepted guidelines with no prophylactic IV antibiotics"<br />
*[[:Category:Granulocyte_colony-stimulating_factors|Granulocyte colony-stimulating factor]] recommended only for patients older than 50 years old whose leukemic blasts were negative for CD114 expression<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*Patients with only partial remission in both PALG studies underwent a second course with the same drugs, doses, and schedule.<br />
*PALG AML1/1999, non-responders: [[#CLAG|CLAG salvage]].<br />
*Patients in remission in both PALG studies: [[#HAM|HAM]], then [[#HiDAC|HiDAC]] consolidation<br />
*ALFA-0701, CR or CRp: [[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin consolidation]]<br />
<br />
===References===<br />
<br />
#'''PALG AML1/1999:''' Holowiecki J, Grosicki S, Robak T, Kyrcz-Krzemien S, Giebel S, Hellmann A, Skotnicki A, Jedrzejczak WW, Konopka L, Kuliczkowski K, Zdziarska B, Dmoszyńska A, Marianska B, Pluta A, Zawilska K, Komarnicki M, Kloczko J, Sulek K, Haus O, Stella-Holowiecka B, Baran W, Jakubas B, Paluszewska M, Wierzbowska A, Kielbinski M, Jagoda K; Polish Adult Leukemia Group (PALG). Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia: multicenter, phase III study. Leukemia. 2004 May;18(5):989-97. [https://www.nature.com/leu/journal/v18/n5/full/2403336a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14999298 PubMed]<br />
#'''LAM-2001:''' Chevallier P, Fornecker L, Lioure B, Béné MC, Pigneux A, Recher C, Witz B, Fegueux N, Bulabois CE, Daliphard S, Bouscary D, Vey N, Delain M, Bay JO, Turlure P, Bernard M, Himberlin C, Luquet I, Ifrah N, Harousseau JL; GOELAMS. Tandem versus single autologous peripheral blood stem cell transplantation as post-remission therapy in adult acute myeloid leukemia patients under 60 in first complete remission: results of the multicenter prospective phase III GOELAMS LAM-2001 trial. Leukemia. 2010 Jul;24(7):1380-5. Epub 2010 May 27. [https://www.nature.com/articles/leu2010111 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20508614 PubMed]<br />
#'''PALG AML1/2004:''' Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszyńska A, Kloczko J, Jedrzejczak WW, Zdziarska B, Warzocha K, Zawilska K, Komarnicki M, Kielbinski M, Piatkowska-Jakubas B, Wierzbowska A, Wach M, Haus O. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012 Jul 10;30(20):2441-8. Epub 2012 Apr 16. [http://jco.ascopubs.org/content/30/20/2441.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22508825 PubMed]<br />
#'''ALFA-0701:''' Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. Epub 2012 Apr 5. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60485-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22482940 PubMed]<br />
##'''Update:''' Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019 Jan;104(1):113-119. Epub 2018 Aug 3. [http://www.haematologica.org/content/104/1/113 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312010/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30076173 PubMed]<br />
#'''AML2003:''' Schaich M, Parmentier S, Kramer M, Illmer T, Stölzel F, Röllig C, Thiede C, Hänel M, Schäfer-Eckart K, Aulitzky W, Einsele H, Ho AD, Serve H, Berdel WE, Mayer J, Schmitz N, Krause SW, Neubauer A, Baldus CD, Schetelig J, Bornhäuser M, Ehninger G. High-dose cytarabine consolidation with or without additional amsacrine and mitoxantrone in acute myeloid leukemia: results of the prospective randomized AML2003 trial. J Clin Oncol. 2013 Jun 10;31(17):2094-102. Epub 2013 Apr 29. [http://ascopubs.org/doi/full/10.1200/JCO.2012.46.4743 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23630210 PubMed]<br />
#Serve H, Krug U, Wagner R, Sauerland MC, Heinecke A, Brunnberg U, Schaich M, Ottmann O, Duyster J, Wandt H, Fischer T, Giagounidis A, Neubauer A, Reichle A, Aulitzky W, Noppeney R, Blau I, Kunzmann V, Stuhlmann R, Krämer A, Kreuzer KA, Brandts C, Steffen B, Thiede C, Müller-Tidow C, Ehninger G, Berdel WE. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013 Sep 1;31(25):3110-8. Epub 2013 Jul 29. [http://ascopubs.org/doi/full/10.1200/JCO.2012.46.4990 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23897964 PubMed]<br />
#'''SWOG S0106:''' Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013 Jun 13;121(24):4854-60. Epub 2013 Apr 16. [http://bloodjournal.hematologylibrary.org/content/121/24/4854.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682338/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23591789 PubMed]<br />
#'''AZA-AML-001:''' Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/3/291.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25987659 PubMed]<br />
##'''Subgroup analysis:''' Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3803-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731212/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29241450 PubMed]<br />
#'''AML-AZA:''' Müller-Tidow C, Tschanter P, Röllig C, Thiede C, Koschmieder A, Stelljes M, Koschmieder S, Dugas M, Gerss J, Butterfaß-Bahloul T, Wagner R, Eveslage M, Thiem U, Krause SW, Kaiser U, Kunzmann V, Steffen B, Noppeney R, Herr W, Baldus CD, Schmitz N, Götze K, Reichle A, Kaufmann M, Neubauer A, Schäfer-Eckart K, Hänel M, Peceny R, Frickhofen N, Kiehl M, Giagounidis A, Görner M, Repp R, Link H, Kiani A, Naumann R, Brümmendorf TH, Serve H, Ehninger G, Berdel WE, Krug U; Study Alliance Leukemia Group. Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the Study Alliance Leukemia. Leukemia. 2016 Mar;30(3):555-61. Epub 2015 Nov 2. [https://www.nature.com/articles/leu2015306 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26522083 PubMed]<br />
#'''SORAML:''' Röllig C, Serve H, Hüttmann A, Noppeney R, Müller-Tidow C, Krug U, Baldus CD, Brandts CH, Kunzmann V, Einsele H, Krämer A, Schäfer-Eckart K, Neubauer A, Burchert A, Giagounidis A, Krause SW, Mackensen A, Aulitzky W, Herbst R, Hänel M, Kiani A, Frickhofen N, Kullmer J, Kaiser U, Link H, Geer T, Reichle A, Junghanß C, Repp R, Heits F, Dürk H, Hase J, Klut IM, Illmer T, Bornhäuser M, Schaich M, Parmentier S, Görner M, Thiede C, von Bonin M, Schetelig J, Kramer M, Berdel WE, Ehninger G; Study Alliance Leukaemia. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015 Dec;16(16):1691-9. Epub 2015 Nov 6. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00362-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26549589 PubMed]<br />
<!-- # '''Abstract:''' R. M. Stone, H. Dohner, G. Ehninger, M. Villeneuve, T. Teasdale, J. D. Virkus, L. R. Bressler, M. M. Seiler, G. Marcucci, R. A. Larson. CALGB 10603 (RATIFY): A randomized phase III study of induction (daunorubicin/cytarabine) and consolidation (high-dose cytarabine) chemotherapy combined with midostaurin or placebo in treatment-naive patients with FLT3 mutated AML. 2011 ASCO Annual Meeting abstract TPS199. [http://meetinglibrary.asco.org/content/81555-102 link to abstract]<br />
# '''Abstract:''' Richard M. Stone, Sumithra Mandrekar, Ben L Sanford, Susan Geyer, Clara D. Bloomfield, Konstanze Dohner, Christian Thiede, Guido Marcucci, Francesco Lo-Coco, Rebecca B. Klisovic, Andrew Wei, Jorge Sierra, Miguel A. Sanz, Joseph M. Brandwein, Theo de Witte, Dietger Niederwieser, Frederick R. Appelbaum, Bruno C. Medeiros, Martin S Tallman, Jurgen Krauter, Richard F. Schlenk, Arnold Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori, Richard A. Larson, Hartmut Dohner. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). 2015 ASH Annual Meeting plenary abstract 6. [https://ash.confex.com/ash/2015/webprogramscheduler/Paper80269.html link to abstract] '''contains protocol''' [https://clinicaltrials.gov/ct2/show/NCT00651261 Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia (NCT00651261) at ClinicalTrials.gov] --><br />
#'''RATIFY:''' Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1614359 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28644114 PubMed]<br />
<!-- # '''Abstract:''' Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Chiarella M, Louie AC, Medeiros BC. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol. 2016 34:15_suppl, 7000-7000 [http://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.7000 link to abstract] '''contains partial protocol''' [https://clinicaltrials.gov/ct2/show/NCT01696084 ClinicalTrials.gov] --><br />
#'''CLTR0310-301:''' Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018 Sep 10;36(26):2684-2692. Epub 2018 Jul 19. [http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6112 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30024784 PubMed]<br />
<br />
==7+3d (high-dose) {{#subobject:9e2666|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
7+3d: '''<u>7</u>''' days of cytarabine + '''<u>3</u>''' days of '''<u>d</u>'''aunorubicin<br />
===Variant #1, 700/270 {{#subobject:70583e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480917/ Fernandez et al. 2009 (ECOG E1900)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800702/ Zeidner et al. 2015 (JHOC-J1101)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|FLAM<br />
| style="background-color:#d73027" |Inferior CR rate<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 90 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*JHOC-J1101: Patients with residual leukemia at day 14 underwent [[#5.2B2d_2|5+2d salvage]]<br />
<br />
===Variant #2, 1400/240 {{#subobject:a33bec|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/104/8/2467.long Castaigne et al. 2004 (ALFA 9000)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#7.2B3d_.28high-dose.29|7+3d]] x 2<br> 2. Timed sequential induction<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 80 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
<br />
===Variant #3, 1400/270 {{#subobject:664ec|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0901409 Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br />
| style="background-color:#1a9850" |Superior CR rate<br />
|-<br />
|[http://www.bloodjournal.org/content/118/14/3832.long Lee et al. 2011 (ADcomparison)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 Lee et al. 2017 (COSAH C-022)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3i|7+3i]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 90 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*HOVON 43 AML/SAKK 30/01: [[#IDAC|MiDAC consolidation]]<br />
*COSAH C-022, with CR: [[#HiDAC|HiDAC consolidation]] if good- or intermediate-risk cytogenetics, or cytarabine & etoposide consolidation if high-risk cytogenetics.<br />
<br />
===References===<br />
<br />
#'''ALFA 9000:''' Castaigne S, Chevret S, Archimbaud E, Fenaux P, Bordessoule D, Tilly H, de Revel T, Simon M, Dupriez B, Renoux M, Janvier M, Micléa JM, Thomas X, Bastard C, Preudhomme C, Bauters F, Degos L, Dombret H. Randomized comparison of double induction and timed-sequential induction to a "3 + 7" induction in adults with AML: long-term analysis of the Acute Leukemia French Association (ALFA) 9000 study. Blood. 2004 Oct 15;104(8):2467-74. Epub 2004 May 13. [http://www.bloodjournal.org/content/104/8/2467.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15142880 PubMed]<br />
#'''HOVON 43 AML/SAKK 30/01:''' Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Döhner H, Gratwohl A, Pabst T, Verhoef G; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. [https://www.nejm.org/doi/full/10.1056/NEJMoa0901409 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19776405 PubMed]<br />
#'''ECOG E1900:''' Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald GW, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Tallman MS. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1249-59. [https://www.nejm.org/doi/full/10.1056/NEJMoa0904544 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480917/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19776406 PubMed]<br />
##'''Update:''' Luskin MR, Lee JW, Fernandez HF, Abdel-Wahab O, Bennett JM, Ketterling RP, Lazarus HM, Levine RL, Litzow MR, Paietta EM, Patel JP, Racevskis J, Rowe JM, Tallman MS, Sun Z, Luger SM. Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups. Blood. 2016 Mar 24;127(12):1551-8. Epub 2016 Jan 11. [http://www.bloodjournal.org/content/127/12/1551.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807422/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26755712 PubMed]<br />
#'''ADcomparison:''' Lee JH, Joo YD, Kim H, Bae SH, Kim MK, Zang DY, Lee JL, Lee GW, Lee JH, Park JH, Kim DY, Lee WS, Ryoo HM, Hyun MS, Kim HJ, Min YJ, Jang YE, Lee KH; Cooperative Study Group A for Hematology. A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia. Blood. 2011 Oct 6;118(14):3832-41. Epub 2011 Aug 9. [http://www.bloodjournal.org/content/118/14/3832.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21828126 PubMed]<br />
#'''JHOC-J1101:''' Zeidner JF, Foster MC, Blackford AL, Litzow MR, Morris LE, Strickland SA, Lancet JE, Bose P, Levy MY, Tibes R, Gojo I, Gocke CD, Rosner GL, Little RF, Wright JJ, Doyle LA, Smith BD, Karp JE. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015 Sep;100(9):1172-9. Epub 2015 May 28. [http://www.haematologica.org/content/100/9/1172 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800702/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26022709 PubMed]<br />
#'''COSAH C-022:''' Lee JH, Kim H, Joo YD, Lee WS, Bae SH, Zang DY, Kwon J, Kim MK, Lee J, Lee GW, Lee JH, Choi Y, Kim DY, Hur EH, Lim SN, Lee SM, Ryoo HM, Kim HJ, Hyun MS, Lee KH; Cooperative Study Group A for Hematology. Prospective randomized comparison of idarubicin and high-dose daunorubicin in induction chemotherapy for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2017 Aug 20;35(24):2754-2763. Epub 2017 Jun 20. [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28632487 PubMed]<br />
<br />
==7+3d & GO {{#subobject:869f84|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
7+3d & GO: '''<u>7</u>''' days of Cytarabine, '''<u>3</u>''' days of '''<u>d</u>'''aunorubicin, '''<u>G</u>'''emtuzumab '''<u>O</u>'''zogamicin<br />
===Regimen {{#subobject:4c0a05|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60485-1/fulltext Castaigne et al. 2012 (ALFA-0701)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]]<br />
| style="background-color:#1a9850" |Superior EFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Gemtuzumab ozogamicin (Mylotarg)]] 3 mg/m<sup>2</sup> (maximum dose of 5 mg) IV over 2 hours once per day on days 1, 4, 7<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*Patients in CR or CRp and platelet count at least 100 x 10<sup>9</sup> by day 45 after the initiation of chemotherapy: [[#Cytarabine.2C_Daunorubicin.2C_Gemtuzumab_ozogamicin|Cytarabine, Daunorubicin, Gemtuzumab ozogamicin consolidation]]<br />
*Patients in CR or CRp and platelet count less than 100 x 10<sup>9</sup> by day 45 after the initiation of chemotherapy: [[#Cytarabine_.26_Daunorubicin|Cytarabine & Daunorubicin consolidation]]<br />
<br />
===References===<br />
<br />
#'''ALFA-0701:''' Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60485-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22482940 PubMed]<br />
##'''Update:''' Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019 Jan;104(1):113-119. Epub 2018 Aug 3. [http://www.haematologica.org/content/104/1/113 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312010/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30076173 PubMed]<br />
<br />
==7+3i {{#subobject:717935|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
7+3i: '''<u>7</u>''' days of cytarabine + '''<u>3</u>''' days of '''<u>i</u>'''darubicin<br />
<br>AI: '''<u>A</u>'''ra-C (Cytarabine) & '''<u>I</u>'''darubicin<br />
<br>IA: '''<u>I</u>'''darubicin & '''<u>A</u>'''ra-C (Cytarabine)<br />
===Variant #1, 80/12, intermittent Ara-C {{#subobject:bdc11c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/8916311 Masaoka et al. 1996]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br />
| style="background-color:#91cf60" |Seems to have superior CR rate<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 80 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 1 to 7<br />
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV bolus once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
<br />
===Variant #2, 100/12, CI Ara-C {{#subobject:c6cda|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/10.1200/JCO.1992.10.7.1103 Vogler et al. 1992]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28standard-dose.29|7+3d]]<br />
| style="background-color:#91cf60" |Seems to have superior CR rate<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/8290968 Haas et al. 1993]<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://www.bloodjournal.org/content/103/2/479.long Rowe et al. 2004 (ECOG E3993)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br> 2. 7+3d + GM-CSF<br> 3. 7+3i + GM-CSF<br> 4. [[#7.2B3m|7+3m]]<br> 5. 7+3m + GM-CSF<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.21493 Miyawaki et al. 2005 (JALSG AML97)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs12185-009-0480-5 Ohtake et al. 2010 (JALSG AML95)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Individualized chemotherapy<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/117/8/2358 Ohtake et al. 2010 (JALSG AML201)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|7+5d<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
<br />
''Patients in ECOG E3993 with persistent disease at day 14 (greater than 5% blasts) underwent an identical second cycle of 7+3i.''<br />
<br />
===Variant #3, 100/13, CI Ara-C {{#subobject:7f2eec|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/79/2/313 Wiernik et al. 1992]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Idarubicin (Idamycin)]] 13 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
<br />
===Variant #4, 200/12, CI Ara-C {{#subobject:f33de6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025406 Löwenberg et al. 2003 (HOVON/SAKK AML 29)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|7+3i & G-CSF<br />
| style="background-color:#fc8d59" |Seems to have inferior DFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.23.2652 Pautas et al. 2010 (ALFA-9801)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#7.2B3d_.28high-dose.29|7+3d (high-dose)]]<br> 2. 7+4i<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1010222 Löwenberg et al. 2011 (HOVON/SAKK AML 42)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|HDAC+3i<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/129/12/1636.long Löwenberg et al. 2017 (HOVON-102)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|7+3i & Clofarabine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 Lee et al. 2017 (COSAH C-022)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3d_.28high-dose.29|7+3d (high-dose)]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>)<br />
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 to 3<br />
**Note: in HOVON/SAKK AML 29 & AML 42, idarubicin was given on days 5 to 7<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*HOVON/SAKK AML 29 & AML 42: Amsacrine & Cytarabine<br />
*ALFA-9801, patients achieiving CR: [[#Cytarabine_.26_Idarubicin_2|cytarabine & idarubicin consolidation]]<br />
*COSAH C-022, patients achieving CR, good- or intermediate-risk cytogenetics: [[#HiDAC|HiDAC consolidation]]<br />
*COSAH C-022, patients achieving CR, high-risk cytogenetics: [[#CYVE|CYVE consolidation]]<br />
<br />
===Variant #5, with range {{#subobject:eb0168|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ Dombret et al. 2015 (AZA-AML-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Azacitidine_monotherapy|Azacitidine]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 to 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 to 1400 mg/m<sup>2</sup>)<br />
*[[Idarubicin (Idamycin)]] 9 to 12 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
===References===<br />
<br />
#Wiernik PH, Banks PL, Case DC Jr, Arlin ZA, Periman PO, Todd MB, Ritch PS, Enck RE, Weitberg AB. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992 Jan 15;79(2):313-9. [http://www.bloodjournal.org/content/79/2/313 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1730080 PubMed]<br />
#Vogler WR, Velez-Garcia E, Weiner RS, Flaum MA, Bartolucci AA, Omura GA, Gerber MC, Banks PL. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study. J Clin Oncol. 1992 Jul;10(7):1103-11. [http://ascopubs.org/doi/10.1200/JCO.1992.10.7.1103 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1607916 PubMed]<br />
#Haas R, Ho AD, Del Valle F, Fischer JT, Ehrhardt R, Döhner H, Witt B, Huberts H, Kaplan E, Hunstein W. Idarubicin/cytosine arabinoside and mitoxantrone/etoposide for the treatment of de novo acute myelogenous leukemia. Semin Oncol. 1993 Dec;20(6 Suppl 8):20-6. [https://www.ncbi.nlm.nih.gov/pubmed/8290968 PubMed]<br />
#Masaoka T, Ogawa M, Yamada K, Kimura K, Ohashi Y. A phase II comparative study of idarubicin plus cytarabine versus daunorubicin plus cytarabine in adult acute myeloid leukemia. Semin Hematol. 1996 Oct;33(4 Suppl 3):12-7. '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8916311 PubMed]<br />
#'''HOVON/SAKK AML 29:''' Löwenberg B, van Putten W, Theobald M, Gmür J, Verdonck L, Sonneveld P, Fey M, Schouten H, de Greef G, Ferrant A, Kovacsovics T, Gratwohl A, Daenen S, Huijgens P, Boogaerts M; Dutch-Belgian Hemato-Oncology Cooperative Group; Swiss Group for Clinical Cancer Research. Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med. 2003 Aug 21;349(8):743-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa025406 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12930926 PubMed]<br />
#'''ECOG E3993:''' Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, Makary AZ, Liesveld JL, Abboud CN, Dewald G, Hayes FA, Tallman MS, Wiernik PH; Eastern Cooperative Oncology. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004 Jan 15;103(2):479-85. Epub 2003 Sep 25. [http://www.bloodjournal.org/content/103/2/479.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14512295 PubMed]<br />
#'''JALSG AML97:''' Miyawaki S, Sakamaki H, Ohtake S, Emi N, Yagasaki F, Mitani K, Matsuda S, Kishimoto Y, Miyazaki Y, Asou N, Matsushima T, Takahashi M, Ogawa Y, Honda S, Ohno R; Japan Adult Leukemia Study Group AML 97 Study. A randomized, postremission comparison of four courses of standard-dose consolidation therapy without maintenance therapy versus three courses of standard-dose consolidation with maintenance therapy in adults with acute myeloid leukemia: the Japan Adult Leukemia Study Group AML 97 study. Cancer. 2005 Dec 15;104(12):2726-34. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.21493 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16284985 PubMed]<br />
#'''ALFA-9801:''' Pautas C, Merabet F, Thomas X, Raffoux E, Gardin C, Corm S, Bourhis JH, Reman O, Turlure P, Contentin N, de Revel T, Rousselot P, Preudhomme C, Bordessoule D, Fenaux P, Terré C, Michallet M, Dombret H, Chevret S, Castaigne S. Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol. 2010 Feb 10;28(5):808-14. Epub 2010 Jan 4. [http://ascopubs.org/doi/full/10.1200/JCO.2009.23.2652 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20048183 PubMed]<br />
#'''JALSG AML95:''' Ohtake S, Miyawaki S, Kiyoi H, Miyazaki Y, Okumura H, Matsuda S, Nagai T, Kishimoto Y, Okada M, Takahashi M, Handa H, Takeuchi J, Kageyama S, Asou N, Yagasaki F, Maeda Y, Ohnishi K, Naoe T, Ohno R. Randomized trial of response-oriented individualized versus fixed-schedule induction chemotherapy with idarubicin and cytarabine in adult acute myeloid leukemia: the JALSG AML95 study. Int J Hematol. 2010 Mar;91(2):276-83. [https://link.springer.com/article/10.1007%2Fs12185-009-0480-5 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20054669 PubMed]<br />
#'''JALSG AML201:''' Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N, Okumura H, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R. Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood. 2011 Feb 24;117(8):2358-65. Epub 2010 Aug 6. [http://www.bloodjournal.org/content/117/8/2358 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20693429 PubMed]<br />
#'''HOVON/SAKK AML 42:''' Löwenberg B, Pabst T, Vellenga E, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Biemond BJ, Gratwohl A, de Greef GE, Verdonck LF, Schaafsma MR, Gregor M, Theobald M, Schanz U, Maertens J, Ossenkoppele GJ; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. Cytarabine dose for acute myeloid leukemia. N Engl J Med. 2011 Mar 17;364(11):1027-36. [https://www.nejm.org/doi/full/10.1056/NEJMoa1010222 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21410371 PubMed]<br />
#'''AZA-AML-001:''' Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/3/291.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25987659 PubMed]<br />
##'''Subgroup analysis:''' Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3803-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731212/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29241450 PubMed]<br />
#Löwenberg B, Pabst T, Maertens J, van Norden Y, Biemond BJ, Schouten HC, Spertini O, Vellenga E, Graux C, Havelange V, de Greef GE, de Weerdt O, Legdeur MJ, Kuball J, Kooy MV, Gjertsen BT, Jongen-Lavrencic M, van de Loosdrecht AA, van Lammeren-Venema D, Hodossy B, Breems DA, Chalandon Y, Passweg J, Valk PJ, Manz MG, Ossenkoppele GJ; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) and Swiss Group for Clinical Cancer Research (SAKK). Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML. Blood. 2017 Mar 23;129(12):1636-1645. Epub 2017 Jan 3. [http://www.bloodjournal.org/content/129/12/1636.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28049642 PubMed]<br />
#'''COSAH C-022:''' Lee JH, Kim H, Joo YD, Lee WS, Bae SH, Zang DY, Kwon J, Kim MK, Lee J, Lee GW, Lee JH, Choi Y, Kim DY, Hur EH, Lim SN, Lee SM, Ryoo HM, Kim HJ, Hyun MS, Lee KH; Cooperative Study Group A for Hematology. Prospective randomized comparison of idarubicin and high-dose daunorubicin in induction chemotherapy for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2017 Aug 20;35(24):2754-2763. Epub 2017 Jun 20. [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28632487 PubMed]<br />
<br />
==7+3i & Sorafenib {{#subobject:ab6409|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:567ab9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930809/ Ravandi et al. 2010<sub>AML</sub>]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Note: Regimen details are from the phase II part of the published phase I/II trial. This trial should not be confused for the one by the same name in Ph+ B-ALL.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1500 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose: 6000 mg/m<sup>2</sup>)<br />
**Patients older than 60 received: 1500 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose: 4500 mg/m<sup>2</sup>)<br />
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3<br />
*[[Sorafenib (Nexavar)]] 400 mg PO twice per day on days 1 to 7<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*[[#Cytarabine.2C_Idarubicin.2C_Sorafenib|Cytarabine, idarubicin, sorafenib consolidation]]<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
<br />
#Ravandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce SR, Brandt M, Byrd A, Bekele BN, Pratz K, Luthra R, Levis M, Andreeff M, Kantarjian HM. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010 Apr 10;28(11):1856-62. Epub 2010 Mar 8. [http://jco.ascopubs.org/content/28/11/1856.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930809/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20212254 PubMed]<br />
##'''Update:''' Ravandi F, Arana Yi C, Cortes JE, Levis M, Faderl S, Garcia-Manero G, Jabbour E, Konopleva M, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce S, Brandt M, Pratz K, Luthra R, Andreeff M, Kantarjian H. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia. 2014 Jul;28(7):1543-5. Epub 2014 Feb 3. [https://www.nature.com/leu/journal/v28/n7/full/leu201454a.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091714/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24487412 PubMed]<br />
<br />
==7+3d & Glasdegib {{#subobject:61520d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:0e6b97|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1002/ajh.25238 Cortes et al. 2018]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Glasdegib (Daurismo)]]100 mg PO Qday for 28 days, started on day -3 for 6 cycles<br />
<br />
'''28-day course'''<br />
====Subsequent treatment====<br />
<br />
*[[#IDAC|Cytarabine consolidation]]<br />
<br />
===References===<br />
<br />
#Cortes JE, Douglas Smith B, Wang ES, Merchant A, Oehler VG, Arellano M, DeAngelo DJ, Pollyea DA, Sekeres MA, Robak T, Ma WW, Zeremski M, Naveed Shaik M, Douglas Laird A, O'Connell A, Chan G, Schroeder MA. Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results. Am J Hematol. 2018 Nov;93(11):1301-1310. Epub 2018 Sep 9. [https://doi.org/10.1002/ajh.25238 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221102/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30074259 PubMed]<br />
<br />
==7+3m {{#subobject:240c72|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
7+3m: '''<u>7</u>''' days of cytarabine + '''<u>3</u>''' days of '''<u>m</u>'''itoxantrone<br />
<br>MAC: '''<u>M</u>'''itoxantrone & '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
===Regimen {{#subobject:7d87af|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/2/479.long Rowe et al. 2004 (ECOG E3993)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br> 2. 7+3d + GM-CSF<br> 3. [[#7.2B3i|7+3i]]<br> 4. 7+3i + GM-CSF<br> 5. 7+3m + GM-CSF<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Mitoxantrone (Novantrone)]] 12 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*Patients with persistent disease at day 14 (greater than 5% blasts) underwent an identical second cycle of 7+3m<br />
<br />
===References===<br />
<br />
#'''ECOG E3993:''' Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, Makary AZ, Liesveld JL, Abboud CN, Dewald G, Hayes FA, Tallman MS, Wiernik PH; Eastern Cooperative Oncology. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004 Jan 15;103(2):479-85. Epub 2003 Sep 25. [http://www.bloodjournal.org/content/103/2/479.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14512295 PubMed]<br />
<br />
==ADE (standard-dose Ara-C) {{#subobject:e221d7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADE: '''<u>A</u>'''ra-C (Cytarabine), '''<u>D</u>'''aunorubicin, '''<u>E</u>'''toposide<br />
<br>7-3-7: '''<u>7</u>''' days of Cytarabine, '''<u>3</u>''' days of Daunorubicin, '''<u>7</u>''' days of Etoposide<br />
<br>8-3-5: '''<u>8</u>''' days of Cytarabine, '''<u>3</u>''' days of Daunorubicin, '''<u>5</u>''' days of Etoposide<br />
<br>10-3-5: '''<u>10</u>''' days of Cytarabine, '''<u>3</u>''' days of Daunorubicin, '''<u>5</u>''' days of Etoposide<br />
===Variant #1, 7-3-3, 700/180/300 {{#subobject:31dcd2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/100/4/1224.long Baer et al. 2002 (CALGB 9720)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ADEP<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''One course'''<br />
<br />
===Variant #2, 7-3-7, 700/150/525 {{#subobject:386fd2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/87/5/1710.long Bishop et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADE_.28high-dose_Ara-C.29|ADE (high-dose Ara-C)]]<br />
| style="background-color:#d73027" |Inferior DFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Etoposide (Vepesid)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 7<br />
<br />
'''7-day course, can be repeated up to 3 times if CR not achieved'''<br />
====Subsequent treatment====<br />
<br />
*5-2-5 consolidation x 2<br />
<br />
===Variant #3, 8-3-5, 1600/150/500, intermittent Ara-C {{#subobject:f7e0ca|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/89/7/2311.long Hann et al. 1997 (UK MRC AML10)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[Acute_myeloid_leukemia_-_historical#DAT|DAT 3+8]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
| style="background-color:#d3d3d3" |See note<br />
| style="background-color:#d3d3d3" |See note<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ Gamis et al. 2014 (COG AAML0531)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
| style="background-color:#d3d3d3" |See note<br />
| style="background-color:#d3d3d3" |See note<br />
|-<br />
|}<br />
''Note: these trials have complicated treatment schemas; see papers for details.''<br />
====Preceding treatment====<br />
<br />
*[[#ADE_.28standard-dose_Ara-C.29|ADE 10-3-5 induction]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV every 12 hours on days 1 to 8<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''8-day course'''<br />
====Subsequent treatment====<br />
<br />
*UK MRC AML10: MACE consolidation<br />
*Other trials: Consolidation (see paper for details)<br />
<br />
===Variant #4, 10-3-5, 1000/150/250, CI Ara-C {{#subobject:7ce6f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/32/3/219.full Willemze et al. 2013 (EORTC-GIMEMA AML-12)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADE_.28high-dose_Ara-C.29|ADE (high-dose Ara-C)]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 10 days, started on day 1 (total dose: 1000 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 5 minutes once per day on days 1, 3, 5<br />
*[[Etoposide (Vepesid)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
'''10-day course'''<br />
<br />
===Variant #5, 10-3-5, 1025/150/500, CI Ara-C {{#subobject:7ce6f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773224/ Mandelli et al. 2009 (EORTC-GIMEMA AML-10)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. AIE<br> 2. AME<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 25 mg/m<sup>2</sup>/day IV bolus once on day 1, then 100 mg/m<sup>2</sup>/day IV continuous infusion over 10 days (total dose: 1025 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 5 minutes once per day on days 1, 3, 5<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
'''10-day course'''<br />
<br />
===Variant #6, 10-3-5, 2000/150/500, intermittent Ara-C {{#subobject:77fe46|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/89/7/2311.long Hann et al. 1997 (UK MRC AML10)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[Acute_myeloid_leukemia_-_historical#DAT|DAT 3+10]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/93/12/4131.long Burnett et al. 1999 (UK MRC AML12)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
| style="background-color:#d3d3d3" |See note<br />
| style="background-color:#d3d3d3" |See note<br />
|-<br />
|[http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
| style="background-color:#d3d3d3" |See note<br />
| style="background-color:#d3d3d3" |See note<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ Gamis et al. 2014 (COG AAML0531)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
| style="background-color:#d3d3d3" |See note<br />
| style="background-color:#d3d3d3" |See note<br />
|-<br />
|}<br />
''Note: these trials have complicated treatment schemas; see papers for details.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV every 12 hours on days 1 to 10<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
'''10-day course'''<br />
====Subsequent treatment====<br />
<br />
*ADE 8-3-5<br />
<br />
===References===<br />
<br />
#Bishop JF, Matthews JP, Young GA, Szer J, Gillett A, Joshua D, Bradstock K, Enno A, Wolf MM, Fox R, Cobcroft R, Herrmann R, Van Der Weyden M, Lowenthal RM, Page F, Garson OM, Juneja S. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood. 1996 Mar 1;87(5):1710-7. [http://www.bloodjournal.org/content/87/5/1710.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8634416 PubMed]<br />
#'''UK MRC AML10:''' Hann IM, Stevens RF, Goldstone AH, Rees JK, Wheatley K, Gray RG, Burnett AK; Adult and Childhood Leukaemia Working Parties of the Medical Research Council. Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia: results of the Medical Research Council's 10th AML trial (MRC AML10). Blood. 1997 Apr 1;89(7):2311-8. [http://www.bloodjournal.org/content/89/7/2311.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9116274 PubMed]<br />
##'''Update:''' Burnett AK, Goldstone AH, Stevens RM, Hann IM, Rees JK, Gray RG, Wheatley K; UK Medical Research Council Adult and Children's Leukaemia Working Parties. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet. 1998 Mar 7;351(9104):700-8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)09214-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9504514 PubMed]<br />
#'''UK MRC AML12:''' Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the randomized MRC trial. Blood. 1999 Jun 15;93(12):4131-43. [http://www.bloodjournal.org/content/93/12/4131.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10361110 PubMed]<br />
##'''Update:''' Burnett AK, Hills RK, Milligan DW, Goldstone AH, Prentice AG, McMullin MF, Duncombe A, Gibson B, Wheatley K. Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial. J Clin Oncol. 2010 Feb 1;28(4):586-95. Epub 2009 Dec 28. [http://ascopubs.org/doi/full/10.1200/JCO.2009.22.9088 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20038732 PubMed]<br />
#'''CALGB 9720:''' Baer MR, George SL, Dodge RK, O'Loughlin KL, Minderman H, Caligiuri MA, Anastasi J, Powell BL, Kolitz JE, Schiffer CA, Bloomfield CD, Larson RA. Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720. Blood. 2002 Aug 15;100(4):1224-32. [http://www.bloodjournal.org/content/100/4/1224.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12149202 PubMed]<br />
##'''Update:''' Baer MR, George SL, Caligiuri MA, Sanford BL, Bothun SM, Mrózek K, Kolitz JE, Powell BL, Moore JO, Stone RM, Anastasi J, Bloomfield CD, Larson RA. Low-dose interleukin-2 immunotherapy does not improve outcome of patients age 60 years and older with acute myeloid leukemia in first complete remission: Cancer and Leukemia Group B Study 9720. J Clin Oncol. 2008 Oct 20;26(30):4934-9. Epub 2008 Jun 30. [http://ascopubs.org/doi/full/10.1200/JCO.2008.17.0472 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652081/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18591543 PubMed]<br />
#'''EORTC-GIMEMA AML-10:''' Mandelli F, Vignetti M, Suciu S, Stasi R, Petti MC, Meloni G, Muus P, Marmont F, Marie JP, Labar B, Thomas X, Di Raimondo F, Willemze R, Liso V, Ferrara F, Baila L, Fazi P, Zittoun R, Amadori S, de Witte T. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. J Clin Oncol. 2009 Nov 10;27(32):5397-403. Epub 2009 Oct 13. Erratum in: J Clin Oncol. 2010 Mar 10;28(8):1438. [http://ascopubs.org/doi/full/10.1200/JCO.2008.20.6490 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773224/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826132 PubMed]<br />
#'''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21172891 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [http://jco.ascopubs.org/content/31/27/3360.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23940227 PubMed]<br />
<!-- Presented at the 53rd American Society of Hematology Annual Meeting and Exposition, San Diego, CA, December 10-13, 2011. --><br />
#'''EORTC-GIMEMA AML-12:''' Willemze R, Suciu S, Meloni G, Labar B, Marie JP, Halkes CJ, Muus P, Mistrik M, Amadori S, Specchia G, Fabbiano F, Nobile F, Sborgia M, Camera A, Selleslag DL, Lefrère F Sr, Magro D, Sica S, Cantore N, Beksac M, Berneman Z, Thomas X, Melillo L, Guimaraes JE, Leoni P, Luppi M, Mitra ME, Bron D, Fillet G, Marijt EW, Venditti A, Hagemeijer A, Mancini M, Jansen J, Cilloni D, Meert L, Fazi P, Vignetti M, Trisolini SM, Mandelli F, de Witte T. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: Results of the EORTC-GIMEMA AML-12 trial. J Clin Oncol. 2014 Jan 20;32(3):219-28. Epub 2013 Dec 2. [http://jco.ascopubs.org/content/32/3/219.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24297940 PubMed]<br />
#'''COG AAML0531:''' Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. [http://ascopubs.org/doi/full/10.1200/JCO.2014.55.3628 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25092781 PubMed]<br />
<br />
==ADE (high-dose Ara-C) {{#subobject:c7eb71|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADE: '''<u>A</u>'''ra-C (Cytarabine), '''<u>D</u>'''aunorubicin, '''<u>E</u>'''toposide<br />
<br>HIDAC-3-5: '''<u>HI</u>'''gh-'''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine), '''<u>3</u>''' days of Daunorubicin, '''<u>5</u>''' days of Etoposide<br />
<br>HIDAC-3-7: '''<u>HI</u>'''gh-'''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine), '''<u>3</u>''' days of Daunorubicin, '''<u>7</u>''' days of Etoposide<br />
===Variant #1, HIDAC-3-5 {{#subobject:b1a101|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/32/3/219.full Willemze et al. 2013 (EORTC-GIMEMA AML-12)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#ADE_.28standard-dose_Ara-C.29|ADE (standard-dose Ara-C)]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 3, 5, 7 (8 doses per cycle)<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 5 minutes once per day on days 1, 3, 5<br />
*[[Etoposide (Vepesid)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
'''7-day course'''<br />
<br />
===Variant #2, HIDAC-3-7 {{#subobject:386df8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/87/5/1710.long Bishop et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#ADE_.28standard-dose_Ara-C.29|ADE (standard-dose Ara-C)]]<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV every 12 hours on days 1, 3, 5, 7 (8 doses per cycle)<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Etoposide (Vepesid)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 7<br />
<br />
'''7-day course, can be repeated up to 3 times if CR not achieved'''<br />
====Subsequent treatment====<br />
<br />
*5-2-5 consolidation x 2<br />
<br />
===References===<br />
<br />
#Bishop JF, Matthews JP, Young GA, Szer J, Gillett A, Joshua D, Bradstock K, Enno A, Wolf MM, Fox R, Cobcroft R, Herrmann R, Van Der Weyden M, Lowenthal RM, Page F, Garson OM, Juneja S. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood. 1996 Mar 1;87(5):1710-7. [http://www.bloodjournal.org/content/87/5/1710.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8634416 PubMed]<br />
<!-- Presented at the 53rd American Society of Hematology Annual Meeting and Exposition, San Diego, CA, December 10-13, 2011. --><br />
#'''EORTC-GIMEMA AML-12:''' Willemze R, Suciu S, Meloni G, Labar B, Marie JP, Halkes CJ, Muus P, Mistrik M, Amadori S, Specchia G, Fabbiano F, Nobile F, Sborgia M, Camera A, Selleslag DL, Lefrère F Sr, Magro D, Sica S, Cantore N, Beksac M, Berneman Z, Thomas X, Melillo L, Guimaraes JE, Leoni P, Luppi M, Mitra ME, Bron D, Fillet G, Marijt EW, Venditti A, Hagemeijer A, Mancini M, Jansen J, Cilloni D, Meert L, Fazi P, Vignetti M, Trisolini SM, Mandelli F, de Witte T. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: Results of the EORTC-GIMEMA AML-12 trial. J Clin Oncol. 2014 Jan 20;32(3):219-28. Epub 2013 Dec 2. [http://jco.ascopubs.org/content/32/3/219.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24297940 PubMed]<br />
<br />
==CIA {{#subobject:de6dec|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CIA: '''<u>C</u>'''lofarabine, '''<u>I</u>'''darubicin, '''<u>A</u>'''ra-C (Cytarabine)<br />
===Variant #1, 15/10/1000 {{#subobject:c6c8ec|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739034/ Jabbour et al. 2017]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|FIA<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given 4 hours before cytarabine'''<br />
*[[Idarubicin (Idamycin)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*Patients not achieving CR or CRp could undergo a second induction<br />
*Patients achieving CR or CRp: [[#CIA_2|CIA consolidation]]<br />
<br />
===Variant #2, 20/10/1000 {{#subobject:4a7d81|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110914/ Nazha et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
*[[Idarubicin (Idamycin)]] 10 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 3<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5<br />
<br />
====Supportive medications====<br />
<br />
*[[Levofloxacin (Levaquin)]]<br />
*[[Itraconazole (Sporanox)]]<br />
*[[Valacyclovir (Valtrex)]]<br />
*[[:Category:Granulocyte_colony-stimulating_factors|Granulocyte colony-stimulating factor]] neither mandated nor forbidden and given per physician discretion<br />
<br />
'''5-day course'''<br />
====Subsequent treatment====<br />
<br />
*Patients with PR: a second course with the same drugs, doses, and schedule.<br />
*Patients achieving CR or CRi: [[#CIA_2|CIA consolidation]]<br />
<br />
===References===<br />
<br />
#Nazha A, Kantarjian H, Ravandi F, Huang X, Choi S, Garcia-Manero G, Jabbour E, Borthakur G, Kadia T, Konopleva M, Cortes J, Ferrajoli A, Kornblau S, Daver N, Pemmaraju N, Andreeff M, Estrov Z, Du M, Brandt M, Faderl S. Clofarabine, idarubicin, and cytarabine (CIA) as frontline therapy for patients ≤60 years with newly diagnosed acute myeloid leukemia. Am J Hematol. 2013 Nov;88(11):961-6. Epub 2013 Sep 9. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110914/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23877926 PubMed]<br />
#Jabbour E, Short NJ, Ravandi F, Huang X, Xiao L, Garcia-Manero G, Plunkett W, Gandhi V, Sasaki K, Pemmaraju N, Daver NG, Borthakur G, Jain N, Konopleva M, Estrov Z, Kadia TM, Wierda WG, DiNardo CD, Brandt M, O'Brien SM, Cortes JE, Kantarjian H. A randomized phase 2 study of idarubicin and cytarabine with clofarabine or fludarabine in patients with newly diagnosed acute myeloid leukemia. Cancer. 2017 Nov 15;123(22):4430-4439. Epub 2017 Jul 14. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.30883/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739034/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28708931 PubMed]<br />
<br />
==DA 3 + 10, GO {{#subobject:e6f5bb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
DA 3 + 10, GO: '''<u>D</u>'''aunorubicin & '''<u>A</u>'''ra-C (Cytarabine), '''<u>3</u>''' days of daunorubicin '''<u>+ 10</u>''' days of cytarabine, '''<u>G</u>'''emtuzumab '''<u>O</u>'''zogamicin<br />
===Regimen {{#subobject:6a938e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|See note<br />
|See note<br />
|-<br />
|[http://jco.ascopubs.org/content/30/32/3924.long Burnett et al. 2012 (UK NCRI AML16)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#DA_3_.2B_10|DA 3 + 10]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Both trials have complicated treatment schemas; see papers for details.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV every 12 hours on days 1 to 10<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5<br />
*[[Gemtuzumab ozogamicin (Mylotarg)]] 3 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*See paper for details (to be completed).<br />
<br />
===References===<br />
<br />
#'''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21172891 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [http://jco.ascopubs.org/content/31/27/3360.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23940227 PubMed]<br />
#'''UK NCRI AML16:''' Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L, Hunter AE, Yin J, Craddock CF, Dufva IH, Wheatley K, Milligan D. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012 Nov 10;30(32):3924-31. Epub 2012 Jul 30. [http://jco.ascopubs.org/content/30/32/3924.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22851554 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, Yin J, McMullin MF, Ali S, Bowen D, Hills RK; UK National Cancer Research Institute AML Working Group. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013 Aug 22;122(8):1384-94. Epub 2013 Jul 9. [http://www.bloodjournal.org/content/122/8/1384.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23838349 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hills RK, Kell J, Nielsen OJ, Dennis M, Cahalin P, Pocock C, Ali S, Burns S, Freeman S, Milligan D, Clark RE. A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia. Leukemia. 2017 Feb;31(2):310-317. Epub 2016 Sep 2. [https://www.nature.com/leu/journal/v31/n2/fig_tab/leu2016225f1.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292678/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27624670 PubMed]<br />
<br />
==DA 3 + 10 {{#subobject:5c0062|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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DA 3 + 10: '''<u>D</u>'''aunorubicin & '''<u>A</u>'''ra-C (Cytarabine), '''<u>3</u>''' days of daunorubicin '''<u>+ 10</u>''' days of cytarabine<br />
===Variant #1, 50 mg/m<sup>2</sup> dauno {{#subobject:99321e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|See note<br />
|See note<br />
|-<br />
|[http://jco.ascopubs.org/content/30/32/3924.long Burnett et al. 2012 (UK NCRI AML16)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#DA_3_.2B_10.2C_GO|DA 3 + 10, GO]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: this regimen is very similar to [[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]; however, 1) there is slightly more cytarabine given, in an intermittent schedule, and 2) the daunorubicin is given intermittently over 5 days, not 3. Both trials have complicated treatment schemas; see papers for details.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV every 12 hours on days 1 to 10<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*See papers for details (to be completed).<br />
<br />
===Variant #2, 60 mg/m<sup>2</sup> dauno {{#subobject:211741|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505010/ Burnett et al. 2015 (UK NCRI AML17)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|DA 3 + 10 (high-dose)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: this regimen is very similar to [[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]]; however, 1) there is slightly more cytarabine given, in an intermittent schedule, and 2) the daunorubicin is given intermittently over 5 days, not 3.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV every 12 hours on days 1 to 10<br />
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 1, 3, 5<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*Complex randomization; see paper for details (to be completed).<br />
<br />
===References===<br />
<br />
#'''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21172891 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [http://jco.ascopubs.org/content/31/27/3360.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23940227 PubMed]<br />
#'''UK NCRI AML16:''' Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L, Hunter AE, Yin J, Craddock CF, Dufva IH, Wheatley K, Milligan D. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012 Nov 10;30(32):3924-31. Epub 2012 Jul 30. [http://jco.ascopubs.org/content/30/32/3924.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22851554 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, Yin J, McMullin MF, Ali S, Bowen D, Hills RK; UK National Cancer Research Institute AML Working Group. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013 Aug 22;122(8):1384-94. Epub 2013 Jul 9. [http://www.bloodjournal.org/content/122/8/1384.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23838349 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hills RK, Kell J, Nielsen OJ, Dennis M, Cahalin P, Pocock C, Ali S, Burns S, Freeman S, Milligan D, Clark RE. A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia. Leukemia. 2017 Feb;31(2):310-317. Epub 2016 Sep 2. [https://www.nature.com/leu/journal/v31/n2/fig_tab/leu2016225f1.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292678/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27624670 PubMed]<br />
#'''UK NCRI AML17:''' Burnett AK, Russell NH, Hills RK, Kell J, Cavenagh J, Kjeldsen L, McMullin MF, Cahalin P, Dennis M, Friis L, Thomas IF, Milligan D, Clark RE; UK NCRI AML Study Group. A randomized comparison of daunorubicin 90 mg/m<sup>2</sup> vs 60 mg/m<sup>2</sup> in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood. 2015 Jun 18;125(25):3878-85. Epub 2015 Apr 1. [http://www.bloodjournal.org/content/125/25/3878.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505010/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25833957 PubMed]<br />
<br />
==DAC {{#subobject:9b1553|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
DAC: '''<u>D</u>'''aunorubicin, '''<u>A</u>'''ra-C (Cytarabine), '''<u>C</u>'''ladribine<br />
===Regimen {{#subobject:f00b8a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v18/n5/full/2403336a.html Holowiecki et al. 2004 (PALG AML1/1999)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28intermediate-dose.29|DA]]<br />
| style="background-color:#1a9850" |Superior CR rate after first induction<br />
|-<br />
| rowspan="2" |[http://jco.ascopubs.org/content/30/20/2441.full Holowiecki et al. 2012 (PALG AML1/2004)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#7.2B3d_.28intermediate-dose.29|DA]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. DAF<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV over 5 minutes once per day on days 1 to 3<br />
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>)<br />
*[[Cladribine (Leustatin)]] 5 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 to 5<br />
<br />
====Supportive medications====<br />
<br />
*"According to commonly accepted guidelines with no prophylactic IV antibiotics"<br />
*[[:Category:Granulocyte_colony-stimulating_factors|Granulocyte colony-stimulating factor]] recommended only for patients older than 50 years old whose leukemic blasts were negative for CD114 expression<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*Patients with only partial remission in both studies underwent a second course with the same drugs, doses, and schedule.<br />
*Non-responders in PALG AML1/1999: [[#CLAG|CLAG salvage]]<br />
*Patients in remission in both studies: [[#HAM|HAM]], then [[#HiDAC|HiDAC]] consolidation<br />
<br />
===References===<br />
<br />
#'''PALG AML1/1999:''' Holowiecki J, Grosicki S, Robak T, Kyrcz-Krzemien S, Giebel S, Hellmann A, Skotnicki A, Jedrzejczak WW, Konopka L, Kuliczkowski K, Zdziarska B, Dmoszyńska A, Marianska B, Pluta A, Zawilska K, Komarnicki M, Kloczko J, Sulek K, Haus O, Stella-Holowiecka B, Baran W, Jakubas B, Paluszewska M, Wierzbowska A, Kielbinski M, Jagoda K; Polish Adult Leukemia Group (PALG). Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia: multicenter, phase III study. Leukemia. 2004 May;18(5):989-97. [https://www.nature.com/leu/journal/v18/n5/full/2403336a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14999298 PubMed]<br />
#'''PALG AML1/2004:''' Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszyńska A, Kloczko J, Jedrzejczak WW, Zdziarska B, Warzocha K, Zawilska K, Komarnicki M, Kielbinski M, Piatkowska-Jakubas B, Wierzbowska A, Wach M, Haus O. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012 Jul 10;30(20):2441-8. Epub 2012 Apr 16. [http://jco.ascopubs.org/content/30/20/2441.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22508825 PubMed]<br />
<br />
==FLAG-Ida {{#subobject:7fc219|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FLAG-Ida: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF (Lenograstim), '''<u>Ida</u>'''rubicin<br />
===Regimen {{#subobject:44e85e|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]<br />
| style="background-color:#1a9851" |Phase III (*)<br />
|-<br />
|}<br />
''This trial has a complex randomization; to be completed.''<br />
====Chemotherapy====<br />
<br />
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days 2 to 6<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 2 to 6, '''given 4 hours after fludarabine'''<br />
*[[Lenograstim (Granocyte)]] 263 mcg SC once per day on days 1 to 7<br />
*[[Idarubicin (Idamycin)]] 8 mg/m<sup>2</sup> IV once per day on days 4 to 6<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*See paper for details<br />
<br />
===References===<br />
<br />
#'''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21172891 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [http://jco.ascopubs.org/content/31/27/3360.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23940227 PubMed]<br />
<br />
==HAA {{#subobject:0788e0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
HAA: '''<u>H</u>'''omoharringtonine (Omacetaxine), '''<u>A</u>'''ra-C (Cytarabine), '''<u>A</u>'''clarubicin<br />
===Regimen {{#subobject:5c5c2e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70152-9/fulltext Jin et al. 2013]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#7.2B3d_.28standard-dose.29|DA]]<br />
| style="background-color:#1a9850" |Superior EFS<br />
|-<br />
|2. [[#HAD|HAD]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Unlikely to be completed since there were significantly more deaths in this arm, despite a superior primary efficacy endpoint.''<br />
====Chemotherapy====<br />
<br />
*[[Omacetaxine (Synribo)]]<br />
*[[Cytarabine (Ara-C)]]<br />
*[[Aclarubicin (Aclacinon)]]<br />
<br />
===References===<br />
<br />
#Jin J, Wang JX, Chen FF, Wu DP, Hu J, Zhou JF, Hu JD, Wang JM, Li JY, Huang XJ, Ma J, Ji CY, Xu XP, Yu K, Ren HY, Zhou YH, Tong Y, Lou YJ, Ni WM, Tong HY, Wang HF, Mi YC, Du X, Chen BA, Shen Y, Chen Z, Chen SJ. Homoharringtonine-based induction regimens for patients with de-novo acute myeloid leukaemia: a multicentre, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2013 Jun;14(7):599-608. Epub 2013 May 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70152-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23664707 PubMed]<br />
<br />
==HAD {{#subobject:30f8fa|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
HAD: '''<u>H</u>'''omoharringtonine (Omacetaxine), '''<u>A</u>'''ra-C (Cytarabine), '''<u>D</u>'''aunorubicin<br />
===Regimen {{#subobject:1d644a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70152-9/fulltext Jin et al. 2013]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#7.2B3d_.28standard-dose.29|DA]]<br />
| style="background-color:#d9ef8b" |Might have superior EFS<br />
|-<br />
|2. [[#HAA|HAA]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Unlikely to be completed since there were significantly more deaths in this arm, despite a trend towards a superior primary efficacy endpoint.''<br />
====Chemotherapy====<br />
<br />
*[[Omacetaxine (Synribo)]]<br />
*[[Cytarabine (Ara-C)]]<br />
*[[Daunorubicin (Cerubidine)]]<br />
<br />
===References===<br />
<br />
#Jin J, Wang JX, Chen FF, Wu DP, Hu J, Zhou JF, Hu JD, Wang JM, Li JY, Huang XJ, Ma J, Ji CY, Xu XP, Yu K, Ren HY, Zhou YH, Tong Y, Lou YJ, Ni WM, Tong HY, Wang HF, Mi YC, Du X, Chen BA, Shen Y, Chen Z, Chen SJ. Homoharringtonine-based induction regimens for patients with de-novo acute myeloid leukaemia: a multicentre, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2013 Jun;14(7):599-608. Epub 2013 May 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70152-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23664707 PubMed]<br />
<br />
==ICE (Idarubicin) {{#subobject:948b49|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ICE: '''<u>I</u>'''darubicin, '''<u>C</u>'''ytarabine, '''<u>E</u>'''toposide<br />
===Regimen {{#subobject:c7b35a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/105/2/481.long Bradstock et al. 2004 (ALLG M7)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nature.com/articles/2403528 Schlenk et al. 2004]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|A-ICE<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2005.05745.x Russo et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FLAI<br />
| style="background-color:#d73027" |Inferior CR rate<br />
|-<br />
|[https://www.nature.com/articles/2403932 Entz-Werle et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MCE<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948102/ de Witte et al. 2010 (CRIANT)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457212/ Bassan et al. 2019 (NILG AML 02/06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|sHD<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 3<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV over 30 minutes twice per day on days 1 to 7 (total dose: 1400 mg/m<sup>2</sup>)<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*ALLG M7: ICE versus IcE consolidation<br />
*NILG AML 02/06, early CR: IC consolidation<br />
<br />
===References===<br />
<br />
#'''ALLG M7:''' Bradstock KF, Matthews JP, Lowenthal RM, Baxter H, Catalano J, Brighton T, Gill D, Eliadis P, Joshua D, Cannell P, Schwarer AP, Durrant S, Gillett A, Koutts J, Taylor K, Bashford J, Arthur C, Enno A, Dunlop L, Szer J, Leahy M, Juneja S, Young GA; Australasian Leukaemia and Lymphoma Group. A randomized trial of high-versus conventional-dose cytarabine in consolidation chemotherapy for adult de novo acute myeloid leukemia in first remission after induction therapy containing high-dose cytarabine. Blood. 2005 Jan 15;105(2):481-8. Epub 2004 Jun 22. [http://www.bloodjournal.org/content/105/2/481.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15213095 PubMed]<br />
#Schlenk RF, Fröhling S, Hartmann F, Fischer JT, Glasmacher A, del Valle F, Grimminger W, Götze K, Waterhouse C, Schoch R, Pralle H, Mergenthaler HG, Hensel M, Koller E, Kirchen H, Preiss J, Salwender H, Biedermann HG, Kremers S, Griesinger F, Benner A, Addamo B, Döhner K, Haas R, Döhner H; AML Study Group Ulm. Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia. Leukemia. 2004 Nov;18(11):1798-803. [https://www.nature.com/articles/2403528 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15385923 PubMed]<br />
#Russo D, Malagola M, de Vivo A, Fiacchini M, Martinelli G, Piccaluga PP, Damiani D, Candoni A, Michielutti A, Castelli M, Testoni N, Ottaviani E, Rondoni M, Pricolo G, Mazza P, Zuffa E, Zaccaria A, Raspadori D, Bocchia M, Lauria F, Bonini A, Avanzini P, Gugliotta L, Visani G, Fanin R, Baccarani M. Multicentre phase III trial on fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukaemia patients. Br J Haematol. 2005 Oct;131(2):172-9. Erratum in: Br J Haematol. 2006 Mar;132(6):804. [https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2005.05745.x link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16197446 PubMed]<br />
#'''EORTC 58921:''' Entz-Werle N, Suciu S, van der Werff ten Bosch J, Vilmer E, Bertrand Y, Benoit Y, Margueritte G, Plouvier E, Boutard P, Vandecruys E, Ferster A, Lutz P, Uyttebroeck A, Hoyoux C, Thyss A, Rialland X, Norton L, Pages MP, Philippe N, Otten J, Behar C; EORTC Children Leukemia Group. Results of 58872 and 58921 trials in acute myeloblastic leukemia and relative value of chemotherapy vs allogeneic bone marrow transplantation in first complete remission: the EORTC Children Leukemia Group report. Leukemia. 2005 Dec;19(12):2072-81. [https://www.nature.com/articles/2403932 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16136166 PubMed]<br />
#'''CRIANT:''' de Witte T, Hagemeijer A, Suciu S, Belhabri A, Delforge M, Kobbe G, Selleslag D, Schouten HC, Ferrant A, Biersack H, Amadori S, Muus P, Jansen JH, Hellström-Lindberg E, Kovacsovics T, Wijermans P, Ossenkoppele G, Gratwohl A, Marie JP, Willemze R. Value of allogeneic versus autologous stem cell transplantation and chemotherapy in patients with myelodysplastic syndromes and secondary acute myeloid leukemia: final results of a prospective randomized European Intergroup Trial. Haematologica. 2010 Oct;95(10):1754-61. Epub 2010 May 21. [http://www.haematologica.org/content/95/10/1754.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948102/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20494931 PubMed]<br />
#'''NILG AML 02/06:''' Bassan R, Intermesoli T, Masciulli A, Pavoni C, Boschini C, Gianfaldoni G, Marmont F, Cavattoni I, Mattei D, Terruzzi E, De Paoli L, Cattaneo C, Borlenghi E, Ciceri F, Bernardi M, Scattolin AM, Todisco E, Campiotti L, Corradini P, Cortelezzi A, Ferrero D, Zanghì P, Oldani E, Spinelli O, Audisio E, Cortelazzo S, Bosi A, Falini B, Pogliani EM, Rambaldi A. Randomized trial comparing standard vs sequential high-dose chemotherapy for inducing early CR in adult AML. Blood Adv. 2019 Apr 9;3(7):1103-1117. [http://www.bloodadvances.org/content/3/7/1103.abstract link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457212/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30948365 PubMed]<br />
<br />
==ICL {{#subobject:a904d7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ICL: '''<u>I</u>'''darubicin, '''<u>C</u>'''ytarabine, '''<u>L</u>'''omustine<br />
===Regimen {{#subobject:909d7e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/10.1200/JCO.2018.78.7366 Pigneux et al. 2017 (LAM-SA 2007)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3i|IA]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Idarubicin (Idamycin)]] 8 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Lomustine (CCNU)]] 200 mg/m<sup>2</sup> PO once on day 1<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*[[Acute_myeloid_leukemia#IC_.26_Norethandrolone|IC and methotrexate/mercaptopurine with norethandrolone]]<br />
<br />
===References===<br />
<br />
#'''LAM-SA 2007:''' Pigneux A, Béné MC, Salmi LR, Dumas PY, Delaunay J, Bonmati C, Guièze R, Luquet I, Cornillet-Lefebvre P, Delabesse E, Ianotto JC, Ojeda-Uribe M, Hunault M, Banos A, Fornecker LM, Bernard M, Jourdan E, Vey N, Zerazhi H, Hishri Y, Mineur A, Asselineau J, Delepine R, Cahn JY, Ifrah N, Récher C; French Innovative Leukemia Organization. Improved survival by adding lomustine to conventional chemotherapy for elderly patients with aml without unfavorable cytogenetics: results of the LAM-SA 2007 FILO trial. J Clin Oncol. 2018 36:32, 3203-3210. Epub 2018 Sep 27. [http://ascopubs.org/doi/10.1200/JCO.2018.78.7366 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30260758 PubMed]<br />
<br />
==MEC {{#subobject:324735|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MEC: '''<u>M</u>'''itoxantrone, '''<u>E</u>'''toposide, '''<u>C</u>'''ytarabine<br />
<br>MICE: '''<u>MI</u>'''toxantrone, '''<u>C</u>'''ytarabine, '''<u>E</u>'''toposide<br />
===Regimen {{#subobject:33e408|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/2404356 Jehn et al. 2006 (EORTC/GIMEMA AML-13)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2013.49.0771 Amadori et al. 2013 (EORTC/GIMEMA AML-17)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GO, then MICE<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Mitoxantrone (Novantrone)]] 7 mg/m<sup>2</sup> IV once per day on days 1, 3, 5<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
<br />
'''One course'''<br />
<br />
===References===<br />
<br />
#'''EORTC/GIMEMA AML-13:''' Jehn U, Suciu S, Thomas X, Lefrère F, Muus P, Berneman Z, Marie JP, Adamo F, Fillet G, Nobile F, Ricciuti F, Leone G, Rizzoli V, Montanaro M, Beeldens F, Fazi P, Mandelli F, Willemze R, de Witte T, Amadori S. Non-infusional vs intravenous consolidation chemotherapy in elderly patients with acute myeloid leukemia: final results of the EORTC-GIMEMA AML-13 randomized phase III trial. Leukemia. 2006 Oct;20(10):1723-30. Epub 2006 Aug 17. [https://www.nature.com/articles/2404356 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16932345 PubMed]<br />
#'''EORTC/GIMEMA AML-17:''' Amadori S, Suciu S, Stasi R, Salih HR, Selleslag D, Muus P, De Fabritiis P, Venditti A, Ho AD, Lübbert M, Thomas X, Latagliata R, Halkes CJ, Falzetti F, Magro D, Guimaraes JE, Berneman Z, Specchia G, Karrasch M, Fazi P, Vignetti M, Willemze R, de Witte T, Marie JP. Sequential combination of gemtuzumab ozogamicin and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia: results of a randomized phase III trial by the EORTC and GIMEMA consortium (AML-17). J Clin Oncol. 2013 Dec 10;31(35):4424-30. Epub 2013 Oct 14. [http://ascopubs.org/doi/full/10.1200/JCO.2013.49.0771 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24127442 PubMed]<br />
<br />
=First-line induction therapy, older or "unfit" patients=<br />
''Note: these regimens are generally considered to be part of a non-curative line of treatment.''<br />
==Azacitidine monotherapy {{#subobject:791718|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7509ab|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.23.8329 Fenaux et al. 2009 (AZA PH GL 2003)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Investigator's choice of:<br> 1. Best supportive care<br> 2. [[#LoDAC|LoDAC]]<br> 3. Intensive chemotherapy<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ Dombret et al. 2015 (AZA-AML-001)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Investigator's choice of:<br> 1. [[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br> 2. [[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]]<br> 3. [[#7.2B3i|7+3i]]<br> 4. [[#Best_supportive_care|Best supportive care]]<br> 5. [[#LoDAC|LoDAC]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Azacitidine (Vidaza)]] 75 mg/m<sup>2</sup> SC once per day on days 1 to 7<br />
<br />
'''28-day cycle for at least 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''AZA PH GL 2003:''' Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010 Feb 1;28(4):562-9. Epub 2009 Dec 21. [http://ascopubs.org/doi/full/10.1200/JCO.2009.23.8329 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20026804 PubMed]<br />
#'''AZA-AML-001:''' Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/3/291.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25987659 PubMed]<br />
##'''Subgroup analysis:''' Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3803-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731212/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29241450 PubMed]<br />
<br />
==Azacitidine & Venetoclax {{#subobject:73ce92|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1ea50d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30010-X/fulltext DiNardo et al. 2018 (M14-358)]<br />
| style="background-color:#91cf61" |Phase Ib, >20 pts<br />
|-<br />
|}<br />
<br />
''Patients with WBC greater than 25 x 10<sup>9</sup>/L at presentation were pre-treated with hydroxyurea or leukapheresis.''<br />
<br />
====Chemotherapy, induction====<br />
<br />
*[[Azacitidine (Vidaza)]] 75 mg/m<sup>2</sup> IV or SC once per day on days 1 to 7<br />
*[[Venetoclax (Venclexta)]] 400, 800, or 1200 mg PO once per day<br />
<br />
===References===<br />
<br />
#'''M14-358:''' DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, Arellano M, Frattini MG, Kantarjian H, Popovic R, Chyla B, Xu T, Dunbar M, Agarwal SK, Humerickhouse R, Mabry M, Potluri J, Konopleva M, Pollyea DA. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018 Feb;19(2):216-228. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30010-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29339097 PubMed] [https://clinicaltrials.gov/ct2/show/NCT02203773 NCT02203773]<br />
##'''Update:''' DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, Frankfurt O, Konopleva M, Wei AH, Kantarjian HM, Xu T, Hong WJ, Chyla B, Potluri J, Pollyea DA, Letai A. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2018 Oct 25. [Epub ahead of print] [http://www.bloodjournal.org/content/133/1/7 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30361262 PubMed]<br />
<br />
==Azacitidine & Gemtuzumab ozogamicin {{#subobject:6f77be|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:188f5c|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.tandfonline.com/doi/full/10.1080/10428190802451254 Nand et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829116/ Nand et al. 2013 (SWOG S0703)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Patients with WBC greater than 10 x 10<sup>9</sup>/L at presentation were pre-treated with Hydrea. Leukapheresis was recommended for patients with WBC greater than x 10<sup>9</sup>/L. Nand et al. 2008 did not describe the maintenance portion of the regimen, and used only SC azacitidine.''<br />
<br />
====Supportive medications, pre-treatment phase====<br />
<br />
*[[Hydroxyurea (Hydrea)]] 1500 mg PO twice per day or in higher doses if necessary<br />
<br />
''Once WBC is less than 10 x 10<sup>9</sup>/L, stop Hydrea and proceed:''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Azacitidine (Vidaza)]] 75 mg/m<sup>2</sup> IV or SC once per day on days 1 to 7<br />
*[[Gemtuzumab ozogamicin (Mylotarg)]] 3 mg/m<sup>2</sup> IV once on day 8<br />
<br />
====Supportive medications====<br />
<br />
*"Appropriate premedications" which were not specified, for [[Gemtuzumab ozogamicin (Mylotarg)]]<br />
<br />
'''One cycle'''<br />
====Subsequent treatment====<br />
<br />
*If D14 bone marrow with 5% or more blasts, a second induction cycle identical to the first was administered<br />
*Patients achieving CR or CRi: [[#Azacitidine_.26_Gemtuzumab_ozogamicin_2|Azacitidine and gemtuzumab ozogamicin consolidation]], within 60 days<br />
<br />
===References===<br />
<br />
#Nand S, Godwin J, Smith S, Barton K, Michaelis L, Alkan S, Veerappan R, Rychlik K, Germano E, Stiff P. Hydroxyurea, azacitidine and gemtuzumab ozogamicin therapy in patients with previously untreated non-M3 acute myeloid leukemia and high-risk myelodysplastic syndromes in the elderly: results from a pilot trial. Leuk Lymphoma. 2008 Nov;49(11):2141-7. [https://www.tandfonline.com/doi/full/10.1080/10428190802451254 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19021057 PubMed]<br />
<!-- Presented in part at the American Society of Clinical Oncology annual meeting (Chicago, IL, June 1-5, 2012) and at the American Society of Hematology annual meeting (Atlanta, GA, December 8-11, 2012). --><br />
#'''SWOG S0703:''' Nand S, Othus M, Godwin JE, Willman CL, Norwood TH, Howard DS, Coutre SE, Erba HP, Appelbaum FR. A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood. 2013 Nov 14;122(20):3432-9. Epub 2013 Oct 3. [http://www.bloodjournal.org/content/122/20/3432.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829116/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24092933 PubMed]<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/abs/10.1200/JCO.1989.7.9.1268 Löwenberg et al. 1989]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Acute_myeloid_leukemia_-_historical#Cytarabine.2C_Daunorubicin.2C_Vincristine|Cytarabine, Daunorubicin, Vincristine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://www.bloodjournal.org/content/114/6/1166.long Harousseau et al. 2009 (FIGHT-AML-301)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Tipifarnib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874148/ Kantarjian et al. 2012 (DACO-016)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Decitabine_monotherapy|Decitabine]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ Dombret et al. 2015 (AZA-AML-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Azacitidine_monotherapy|Azacitidine]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/34/9/972.full Amadori et al. 2016 (EORTC/GIMEMA AML-19)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemtuzumab_ozogamicin_monotherapy|Gemtuzumab ozogamicin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment, although some trials consider [[Hydroxyurea (Hydrea)]] to be a component of best supportive care.''<br />
<br />
===References===<br />
<br />
#Löwenberg B, Zittoun R, Kerkhofs H, Jehn U, Abels J, Debusscher L, Cauchie C, Peetermans M, Solbu G, Suciu S, Stryckmans P. On the value of intensive remission-induction chemotherapy in elderly patients of 65+ years with acute myeloid leukemia: a randomized phase III study of the European Organization for Research and Treatment of Cancer Leukemia Group. J Clin Oncol. 1989 Sep;7(9):1268-74. [http://ascopubs.org/doi/abs/10.1200/JCO.1989.7.9.1268 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2475589 PubMed]<br />
#'''FIGHT-AML-301:''' Harousseau JL, Martinelli G, Jedrzejczak WW, Brandwein JM, Bordessoule D, Masszi T, Ossenkoppele GJ, Alexeeva JA, Beutel G, Maertens J, Vidriales MB, Dombret H, Thomas X, Burnett AK, Robak T, Khuageva NK, Golenkov AK, Tothova E, Mollgard L, Park YC, Bessems A, De Porre P, Howes AJ; FIGHT-AML-301 Investigators. A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood. 2009 Aug 6;114(6):1166-73. Epub 2009 May 21. [http://www.bloodjournal.org/content/114/6/1166.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19470696 PubMed]<br />
<!-- Presented in part at the 47th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2011. --><br />
#'''DACO-016:''' Kantarjian HM, Thomas XG, Dmoszyńska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysák D, Minden M, Arthur C. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012 Jul 20;30(21):2670-7. Epub 2012 Jun 11. [http://jco.ascopubs.org/content/30/21/2670.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874148/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22689805 PubMed]<br />
##'''Subgroup analysis:''' Wierzbowska A, Wawrzyniak E, Pluta A, Robak T, Mazur GJ, Dmoszynska A, Cermak J, Oriol A, Lysak D, Arthur C, Doyle M, Xiu L, Ravandi F, Kantarjian HM. Decitabine improves response rate and prolongs progression-free survival in older patients with newly diagnosed acute myeloid leukemia and with monosomal karyotype: A subgroup analysis of the DACO-016 trial. Am J Hematol. 2018 May;93(5):E125-E127. Epub 2018 Feb 24. [https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.25062 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29417613 PubMed]<br />
#'''AZA-AML-001:''' Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/3/291.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25987659 PubMed]<br />
##'''Subgroup analysis:''' Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3803-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731212/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29241450 PubMed]<br />
<!-- Presented in part at the 56th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 6-9, 2014. --><br />
#'''EORTC/GIMEMA AML-19:''' Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M, Annino L, Venditti A, Voso MT, Mazzone C, Magro D, De Fabritiis P, Muus P, Alimena G, Mancini M, Hagemeijer A, Paoloni F, Vignetti M, Fazi P, Meert L, Ramadan SM, Willemze R, de Witte T, Baron F. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016 Mar 20;34(9):972-9. Epub 2016 Jan 25. [http://jco.ascopubs.org/content/34/9/972.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26811524 PubMed]<br />
<br />
==Clofarabine monotherapy {{#subobject:18ac50|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 20 mg/m<sup>2</sup> {{#subobject:42be8e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/30/32/3924.long Burnett et al. 2012 (UK NCRI AML16)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#LoDAC|LoDAC]]<br />
| style="background-color:#ffffbf" |Seems not superior (*)<br />
|-<br />
|}<br />
''Note: reported efficacy is based on the 2013 update.''<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
'''4- to 6-week cycle for 4 cycles'''<br />
<br />
===Variant #2, 30 mg/m<sup>2</sup> {{#subobject:f9ef00|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081352/ Faderl et al. 2008]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#Clofarabine_.26_LoDAC|Clofarabine & LoDAC]]<br />
| style="background-color:#fc8d59" |Seems to have inferior EFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.26.4242 Burnett et al. 2010 (UWCM-001 and BIOV-121)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 30 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*A second induction was permitted for SD or better.<br />
*Faderl et al. 2008: Responders proceeded to clofarabine & cytarabine consolidation<br />
<br />
===References===<br />
<br />
#Faderl S, Ravandi F, Huang X, Garcia-Manero G, Ferrajoli A, Estrov Z, Borthakur G, Verstovsek S, Thomas DA, Kwari M, Kantarjian HM. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2008 Sep 1;112(5):1638-45. Epub 2008 Jun 18. [http://www.bloodjournal.org/content/112/5/1638.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081352/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18565853 PubMed]<br />
#Burnett AK, Russell NH, Kell J, Dennis M, Milligan D, Paolini S, Yin J, Culligan D, Johnston P, Murphy J, McMullin MF, Hunter A, Das-Gupta E, Clark R, Carr R, Hills RK. European development of clofarabine as treatment for older patients with acute myeloid leukemia considered unsuitable for intensive chemotherapy. J Clin Oncol. 2010 May 10;28(14):2389-95. Epub 2010 Apr 12. [http://ascopubs.org/doi/full/10.1200/JCO.2009.26.4242 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20385984 PubMed]<br />
#'''UK NCRI AML16:''' Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L, Hunter AE, Yin J, Craddock CF, Dufva IH, Wheatley K, Milligan D. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012 Nov 10;30(32):3924-31. Epub 2012 Jul 30. [http://jco.ascopubs.org/content/30/32/3924.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22851554 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, Yin J, McMullin MF, Ali S, Bowen D, Hills RK; UK National Cancer Research Institute AML Working Group. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013 Aug 22;122(8):1384-94. Epub 2013 Jul 9. [http://www.bloodjournal.org/content/122/8/1384.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23838349 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hills RK, Kell J, Nielsen OJ, Dennis M, Cahalin P, Pocock C, Ali S, Burns S, Freeman S, Milligan D, Clark RE. A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia. Leukemia. 2017 Feb;31(2):310-317. Epub 2016 Sep 2. [https://www.nature.com/leu/journal/v31/n2/fig_tab/leu2016225f1.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292678/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27624670 PubMed]<br />
<br />
==Clofarabine & LoDAC {{#subobject:7a3edd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Clofarabine & LoDAC: Clofarabine & '''<u>Lo</u>'''w '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
===Variant #1 {{#subobject:12351c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081352/ Faderl et al. 2008]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#Clofarabine_monotherapy|Clofarabine]]<br />
| style="background-color:#91cf60" |Seems to have superior EFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 30 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, '''given first'''<br />
*[[Cytarabine (Ara-C)]] 20 mg SC once per day on days 1 to 14, '''given 4 hours after clofarabine on days 1 to 5'''<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*A second induction was permitted for SD or better<br />
*Responders proceeded to clofarabine & cytarabine consolidation<br />
<br />
===Variant #2 {{#subobject:7d207f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907176/ Faderl et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
*[[Cytarabine (Ara-C)]] 20 mg SC twice per day on days 1 to 10<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*Patients not achieving CR could undergo an identical second induction after at least 28 days. <br />
**Patients not achieving CR after the second induction were given [[#Decitabine_monotherapy_3|salvage decitabine]]<br />
*Patients achieving CR: [[#Clofarabine_.26_LoDAC.2FDecitabine|Clofarabine & low-dose cytarabine alternating with decitabine consolidation]]<br />
<br />
===References===<br />
<br />
#Faderl S, Ravandi F, Huang X, Garcia-Manero G, Ferrajoli A, Estrov Z, Borthakur G, Verstovsek S, Thomas DA, Kwari M, Kantarjian HM. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2008 Sep 1;112(5):1638-45. Epub 2008 Jun 18. [http://www.bloodjournal.org/content/112/5/1638.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081352/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18565853 PubMed]<br />
#Faderl S, Ravandi F, Huang X, Wang X, Jabbour E, Garcia-Manero G, Kadia T, Ferrajoli A, Konopleva M, Borthakur G, Burger J, Feliu J, Kantarjian HM. Clofarabine plus low-dose cytarabine followed by clofarabine plus low-dose cytarabine alternating with decitabine in acute myeloid leukemia frontline therapy for older patients. Cancer. 2012 Sep 15;118(18):4471-7. Epub 2012 Jan 26. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.27429/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907176/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22282348 PubMed]<br />
##'''Update:''' Kadia TM, Faderl S, Ravandi F, Jabbour E, Garcia-Manero G, Borthakur G, Ferrajoli A, Konopleva M, Burger J, Huang X, Wang X, Pierce S, Brandt M, Feliu J, Cortes J, Kantarjian H. Final results of a phase 2 trial of clofarabine and low-dose cytarabine alternating with decitabine in older patients with newly diagnosed acute myeloid leukemia. Cancer. 2015 Jul 15;121(14):2375-82. Epub 2015 Mar 25. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.29367/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436272/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25809968 PubMed]<br />
<br />
==CPX-351 monotherapy {{#subobject:03f404|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CPX-351: Liposomal Cytarabine and Daunorubicin<br />
===Regimen {{#subobject:0b4cdf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624448/ Lancet et al. 2014 (CLTR0308-204)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]]<br />
| style="background-color:#d9ef8b" |Might have superior ORR<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6112 Lancet et al. 2018 (CLTR0310-301)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]]<br />
| style="background-color:#1a9851" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine and daunorubicin liposomal (Vyxeos)|CPX-351 (Vyxeos)]] as follows:<br />
**First induction: 100 units/m<sup>2</sup> IV over 90 minutes once per day on days 1, 3, 5<br />
**Second induction (if needed): 100 units/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 3<br />
<br />
'''One or two courses'''<br />
====Subsequent treatment====<br />
<br />
*CR/CRi: [[#CPX-351_monotherapy_2|CPX-351 monotherapy consolidation]]<br />
<br />
===References===<br />
<!-- Presented in part in abstract form at the 52nd annual meeting of the American Society of Hematology, Orlando, FL December 4-7, 2010. --><br />
<br />
#'''CLTR0308-204:''' Lancet JE, Cortes JE, Hogge DE, Tallman MS, Kovacsovics TJ, Damon LE, Komrokji R, Solomon SR, Kolitz JE, Cooper M, Yeager AM, Louie AC, Feldman EJ. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014 May 22;123(21):3239-46. Epub 2014 Mar 31. [http://bloodjournal.hematologylibrary.org/content/123/21/3239.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624448/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24687088 PubMed]<br />
<!-- # '''Abstract:''' Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Chiarella M, Louie AC, Medeiros BC. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol. 2016 34:15_suppl, 7000-7000 [http://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.7000 link to abstract] '''contains partial protocol''' [https://clinicaltrials.gov/ct2/show/NCT01696084 ClinicalTrials.gov] --><br />
#'''CLTR0310-301:''' Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018 Sep 10;36(26):2684-2692. Epub 2018 Jul 19. [http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6112 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30024784 PubMed]<br />
<br />
==Decitabine monotherapy {{#subobject:2d1dad|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1 {{#subobject:b60a91|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320000/ Issa et al. 2014]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[Acute_myeloid_leukemia_-_historical#Decitabine_.26_Valproate|Decitabine & Valproate]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Decitabine (Dacogen)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
'''4- to 6-week cycles'''<br />
<br />
===Variant #2 {{#subobject:22a24e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874148/ Kantarjian et al. 2012 (DACO-016)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#LoDAC|LoDAC]]<br> 2. [[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Decitabine (Dacogen)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
====Supportive medications====<br />
<br />
*[[Hydroxyurea (Hydrea)]] (dose not specified) could be used up until cycle 1 day 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:c6ffdd|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867720/ Blum et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1605949 Welch et al. 2016]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Decitabine (Dacogen)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
<br />
*[[Hydroxyurea (Hydrea)]] (dose not specified) allowed during and prior to cycle 1<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
<br />
*Blum et al. 2010, persistent AML (greater than or equal to 5% blasts): repeated cycles with 10 days of decitabine as described above<br />
*Blum et al. 2010, no morphologic evidence of AML (less than 5% blasts): received 5 days of decitabine as described by [[#Decitabine_monotherapy_2|decitabine maintenance]]<br />
<br />
===References===<br />
<br />
#Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, Liu S, Havelange V, Becker H, Schaaf L, Mickle J, Devine H, Kefauver C, Devine SM, Chan KK, Heerema NA, Bloomfield CD, Grever MR, Byrd JC, Villalona-Calero M, Croce CM, Marcucci G. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7473-8. Epub 2010 Apr 5. [http://www.pnas.org/content/107/16/7473.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867720/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20368434 PubMed]<br />
<!-- Presented in part at the 47th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2011. --><br />
#'''DACO-016:''' Kantarjian HM, Thomas XG, Dmoszyńska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysák D, Minden M, Arthur C. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012 Jul 20;30(21):2670-7. Epub 2012 Jun 11. [http://jco.ascopubs.org/content/30/21/2670.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874148/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22689805 PubMed]<br />
##'''Subgroup analysis:''' Wierzbowska A, Wawrzyniak E, Pluta A, Robak T, Mazur GJ, Dmoszynska A, Cermak J, Oriol A, Lysak D, Arthur C, Doyle M, Xiu L, Ravandi F, Kantarjian HM. Decitabine improves response rate and prolongs progression-free survival in older patients with newly diagnosed acute myeloid leukemia and with monosomal karyotype: A subgroup analysis of the DACO-016 trial. Am J Hematol. 2018 May;93(5):E125-E127. Epub 2018 Feb 24. [https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.25062 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29417613 PubMed]<br />
#Issa JP, Garcia-Manero G, Huang X, Cortes J, Ravandi F, Jabbour E, Borthakur G, Brandt M, Pierce S, Kantarjian HM. Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer. 2015 Feb 15;121(4):556-61. Epub 2014 Oct 21. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.29085/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320000/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25336333 PubMed]<br />
#Welch JS, Petti AA, Miller CA, Fronick CC, O'Laughlin M, Fulton RS, Wilson RK, Baty JD, Duncavage EJ, Tandon D, Lee Y, Wartman LD, Uy GL, Ghobadi A, Tomasson MH, Pusic I, Romee R, Fehniger TA, Stockerl-Goldstein KE, Vij R, Oh ST, Abboud CN, Cashen AF, Schroeder MA, Jacoby MA, Heath SE, Luber K, Janke MR, Hantel A, Khan N, Sukhanova MJ, Knoebel RW, Stock W, Graubert TA, Walter MJ, Westervelt P, Link DC, DiPersio JF, Ley TJ. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016 Nov 24;375(21):2023-2036. [https://www.nejm.org/doi/full/10.1056/NEJMoa1605949#article_supplementary_material link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217532/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27959731 PubMed]<br />
<br />
==Decitabine & Venetoclax {{#subobject:30c499|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 5 days of decitabine {{#subobject:2aab30|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30010-X/fulltext DiNardo et al. 2018 (M14-358)]<br />
| style="background-color:#91cf61" |Phase Ib, >20 pts<br />
|-<br />
|}<br />
<br />
''Patients with WBC greater than 25 x 10<sup>9</sup>/L at presentation were pre-treated with hydroxyurea or leukapheresis.''<br />
<br />
====Chemotherapy, induction====<br />
<br />
*[[Decitabine (Dacogen)]] 20 mg/m<sup>2</sup> IV or SC once per day on days 1 to 5<br />
*[[Venetoclax (Venclexta)]] 400, 800, or 1200 mg PO once per day<br />
<br />
===Variant #2, 10 days of decitabine {{#subobject:08cde2|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/132/Suppl_1/286 Maiti et al. 2018 (DEC10-VEN)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Therapy with hydroxyurea or one dose of cytarabine up to 2g/m<sup>2</sup> was allowed during cycle 1.''<br />
<br />
====Chemotherapy, induction====<br />
<br />
*[[Decitabine (Dacogen)]] 20 mg/m<sup>2</sup> IV or SC once per day on days 1 to 10<br />
*[[Venetoclax (Venclexta)]] 400, 800, or 1200 mg PO once per day<br />
<br />
===References===<br />
<br />
#'''M14-358:''' DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, Arellano M, Frattini MG, Kantarjian H, Popovic R, Chyla B, Xu T, Dunbar M, Agarwal SK, Humerickhouse R, Mabry M, Potluri J, Konopleva M, Pollyea DA. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018 Feb;19(2):216-228. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30010-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29339097 PubMed] [https://clinicaltrials.gov/ct2/show/NCT02203773 NCT02203773]<br />
##'''Update:''' DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, Frankfurt O, Konopleva M, Wei AH, Kantarjian HM, Xu T, Hong WJ, Chyla B, Potluri J, Pollyea DA, Letai A. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019 Jan 3;133(1):7-17. Epub 2018 Oct 25. [http://www.bloodjournal.org/content/133/1/7 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30361262 PubMed]<br />
#'''Abstract:''' Maiti A, DiNardo CD, Cortes JE, Borthakur G, Pemmaraju,N, Benton CB, Kadia TM, Takahashi K, Naqvi K, Ravandi F, Alvarado Y, Short NJ, Daver NG, Sasaki K, Ohanian MN, Garcia-Manero G, Thompson PA, Kornblau SM, Masarova L, Jain N, Jabbour EJ, Andreeff M, Maduike R, Guerrero JA, Zhang Q, Cavazos A, Ma H, Rausch CR, Bivins CA, Vaughan K, Pierce SA, Ning J, Qiao W, Welch JS, Kantarjian HM, Konopleva MY. Interim Analysis of Phase II Study of Venetoclax with 10-Day Decitabine (DEC10-VEN) in Acute Myeloid Leukemia and Myelodysplastic Syndrome. Blood, 132(Suppl 1), 286. [http://www.bloodjournal.org/content/132/Suppl_1/286 link to original abstract] [https://clinicaltrials.gov/ct2/show/NCT03404193 NCT03404193]<br />
<br />
==Gemtuzumab ozogamicin monotherapy {{#subobject:4e3c9a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e01685|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/34/9/972.full Amadori et al. 2016 (EORTC/GIMEMA AML-19)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemtuzumab ozogamicin (Mylotarg)]] 6 mg/m<sup>2</sup> IV once on day 1, then 3 mg/m<sup>2</sup> IV once on day 8<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*Patients with benefit: [[#Gemtuzumab_ozogamicin_monotherapy_2|Gemtuzumab ozogamicin maintenance]]<br />
<br />
===References===<br />
<!-- Presented in part at the 56th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 6-9, 2014. --><br />
<br />
#'''EORTC/GIMEMA AML-19:''' Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M, Annino L, Venditti A, Voso MT, Mazzone C, Magro D, De Fabritiis P, Muus P, Alimena G, Mancini M, Hagemeijer A, Paoloni F, Vignetti M, Fazi P, Meert L, Ramadan SM, Willemze R, de Witte T, Baron F. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016 Mar 20;34(9):972-9. Epub 2016 Jan 25. [http://jco.ascopubs.org/content/34/9/972.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26811524 PubMed]<br />
<br />
==Glasdegib & LoDAC {{#subobject:ba44c2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Glasdegib & LoDAC: Glasdegib & '''<u>Lo</u>'''w '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
===Regimen {{#subobject:e4c7c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365492/ Cortes et al. 2018 (BRIGHT AML 1003)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#LoDAC|LoDAC]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Glasdegib (Daurismo)]] 100 mg PO once per day<br />
*[[Cytarabine (Ara-C)]] 20 mg SC twice per day on days 1 to 10<br />
<br />
'''28-day cycles'''<br />
===References===<br />
<!-- # '''Abstract:''' Cortes JE, Heidel FH, Heuser M, Fiedler W, Smith BD, Robak T. Montesinos Fernandez P, Ma WW, Shaik MN, Zeremski M, O'Connell A, Chan, G. A Phase 2 Randomized Study of Low Dose Ara-C with or without Glasdegib (PF-04449913) in Untreated Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome. Blood 2016, 128(22), 99. [http://www.bloodjournal.org/content/128/22/99 link to original article] '''contains verified protocol''' --><br />
<br />
#'''BRIGHT AML 1003:''' Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, Montesinos P, Pollyea DA, DesJardins P, Ottmann O, Ma WW, Shaik MN, Laird AD, Zeremski M, O'Connell A, Chan G, Heuser M. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019 Feb;33(2):379-389. Epub 2018 Dec 16. [https://www.nature.com/articles/s41375-018-0312-9 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365492/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30555165 PubMed]<br />
<br />
==LoDAC {{#subobject:25e1c6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
LoDAC: '''<u>Lo</u>'''w '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
<br>LDAC: '''<u>L</u>'''ow-dose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
===Variant #1, 20 mg twice per day, indefinite duration {{#subobject:a3d4fb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132839/ Kantarjian et al. 2013 (SPARK-AML1)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Barasertib & LoDAC<br />
| style="background-color:#fc8d59" |Seems to have inferior OCRR<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148765/ Döhner et al. 2014 (BI 1230.4)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|LoDAC & Volasertib<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365492/ Cortes et al. 2018 (BRIGHT AML 1003)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Glasdegib_.26_LoDAC|Glasdegib & LoDAC]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 20 mg SC twice per day on days 1 to 10<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 20 mg/m<sup>2</sup> twice per day, limited duration {{#subobject:d5c6f7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533673/ Sekeres et al. 2012 (SG033-0003)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|LDAC & Lintuzumab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/30/32/3924.long Burnett et al. 2012 (UK NCRI AML16)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Clofarabine_monotherapy|Clofarabine]]<br />
| style="background-color:#ffffbf" |Seems not superior (*)<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536889/ Dennis et al. 2015]<br />
| rowspan="2" style="background-color:#1a9851" |Randomized (C)<br />
|1. LDAC & Vosaroxin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. Vosaroxin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nature.com/leu/journal/v29/n6/full/leu201538a.html Burnett et al. 2015]<br />
| style="background-color:#1a9851" |Randomized (C)<br />
|Sapacitabine<br />
| style="background-color:#fee08b" |Might have inferior CR rate<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ Dombret et al. 2015 (AZA-AML-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Azacitidine_monotherapy|Azacitidine]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
''Note: reported efficacy for UK NCRI AML16 is based on the 2016 update.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 20 mg/m<sup>2</sup> SC twice per day on days 1 to 10<br />
<br />
'''4- to 6-week cycle for up to 4 cycles'''<br />
<br />
===Variant #3, 20 mg/m<sup>2</sup> once per day, indefinite duration {{#subobject:fd61d0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874148/ Kantarjian et al. 2012 (DACO-016)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Decitabine_monotherapy|Decitabine]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 20 mg/m<sup>2</sup> SC once per day on days 1 to 10<br />
<br />
'''28-day cycles until progression or intolerance'''<br />
<br />
===References===<br />
<!-- Presented in part at the 47th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2011. --><br />
<br />
#'''DACO-016:''' Kantarjian HM, Thomas XG, Dmoszyńska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysák D, Minden M, Arthur C. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012 Jul 20;30(21):2670-7. Epub 2012 Jun 11. [http://jco.ascopubs.org/content/30/21/2670.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874148/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22689805 PubMed]<br />
##'''Subgroup analysis:''' Wierzbowska A, Wawrzyniak E, Pluta A, Robak T, Mazur GJ, Dmoszynska A, Cermak J, Oriol A, Lysak D, Arthur C, Doyle M, Xiu L, Ravandi F, Kantarjian HM. Decitabine improves response rate and prolongs progression-free survival in older patients with newly diagnosed acute myeloid leukemia and with monosomal karyotype: A subgroup analysis of the DACO-016 trial. Am J Hematol. 2018 May;93(5):E125-E127. Epub 2018 Feb 24. [https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.25062 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29417613 PubMed]<br />
#'''SG033-0003:''' Sekeres MA, Lancet JE, Wood BL, Grove LE, Sandalic L, Sievers EL, Jurcic JG. Randomized phase IIb study of low-dose cytarabine and lintuzumab versus low-dose cytarabine and placebo in older adults with untreated acute myeloid leukemia. Haematologica. 2013 Jan;98(1):119-28. Epub 2012 Jul 16. [http://www.haematologica.org/content/98/1/119.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533673/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22801961 PubMed]<br />
#'''UK NCRI AML16:''' Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L, Hunter AE, Yin J, Craddock CF, Dufva IH, Wheatley K, Milligan D. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012 Nov 10;30(32):3924-31. Epub 2012 Jul 30. [http://jco.ascopubs.org/content/30/32/3924.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22851554 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, Yin J, McMullin MF, Ali S, Bowen D, Hills RK; UK National Cancer Research Institute AML Working Group. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013 Aug 22;122(8):1384-94. Epub 2013 Jul 9. [http://www.bloodjournal.org/content/122/8/1384.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23838349 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hills RK, Kell J, Nielsen OJ, Dennis M, Cahalin P, Pocock C, Ali S, Burns S, Freeman S, Milligan D, Clark RE. A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia. Leukemia. 2017 Feb;31(2):310-317. Epub 2016 Sep 2. [https://www.nature.com/leu/journal/v31/n2/fig_tab/leu2016225f1.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292678/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27624670 PubMed]<br />
#'''SPARK-AML1:''' Kantarjian HM, Martinelli G, Jabbour EJ, Quintás-Cardama A, Ando K, Bay JO, Wei A, Gröpper S, Papayannidis C, Owen K, Pike L, Schmitt N, Stockman PK, Giagounidis A; SPARK-AML1 Investigators. Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia. Cancer. 2013 Jul 15;119(14):2611-9. Epub 2013 Apr 19. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.28113 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132839/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23605952 PubMed]<br />
#'''BI 1230.4:''' Döhner H, Lübbert M, Fiedler W, Fouillard L, Haaland A, Brandwein JM, Lepretre S, Reman O, Turlure P, Ottmann OG, Müller-Tidow C, Krämer A, Raffoux E, Döhner K, Schlenk RF, Voss F, Taube T, Fritsch H, Maertens J. Randomized, phase 2 trial comparing low-dose cytarabine with or without volasertib in AML patients not suitable for intensive induction therapy. Blood. 2014 Aug 28;124(9):1426-33. Epub 2014 Jul 8. [http://www.bloodjournal.org/content/124/9/1426.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148765/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25006120 PubMed]<br />
#Dennis M, Russell N, Hills RK, Hemmaway C, Panoskaltsis N, McMullin MF, Kjeldsen L, Dignum H, Thomas IF, Clark RE, Milligan D, Burnett AK. Vosaroxin and vosaroxin plus low-dose Ara-C (LDAC) vs low-dose Ara-C alone in older patients with acute myeloid leukemia. Blood. 2015 May 7;125(19):2923-32. Epub 2015 Mar 24. [http://www.bloodjournal.org/content/125/19/2923.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536889/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25805811 PubMed]<br />
#Burnett AK, Russell N, Hills RK, Panoskaltsis N, Khwaja A, Hemmaway C, Cahalin P, Clark RE, Milligan D. A randomised comparison of the novel nucleoside analogue sapacitabine with low-dose cytarabine in older patients with acute myeloid leukaemia. Leukemia. 2015 Jun;29(6):1312-9. Epub 2015 Feb 13. [https://www.nature.com/leu/journal/v29/n6/full/leu201538a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25676423 PubMed]<br />
#'''AZA-AML-001:''' Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/3/291.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25987659 PubMed]<br />
##'''Subgroup analysis:''' Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3803-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731212/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29241450 PubMed]<br />
#'''BRIGHT AML 1003:''' Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, Montesinos P, Pollyea DA, DesJardins P, Ottmann O, Ma WW, Shaik MN, Laird AD, Zeremski M, O'Connell A, Chan G, Heuser M. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019 Feb;33(2):379-389. Epub 2018 Dec 16. [https://www.nature.com/articles/s41375-018-0312-9 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365492/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30555165 PubMed]<br />
<br />
==LoDAC & Venetoclax {{#subobject:b84441|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
LoDAC & Venetoclax: '''<u>Lo</u>'''w '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine) & Venetoclax<br />
===Regimen {{#subobject:e84ab4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.18.01600?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed Wei et. al. 2019] <br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 20 mg/m<sup>2</sup> SC once per day on days 1 to 10<br />
*[[Venetoclax (Venclexta)]] 600 mg PO once per day (dose reduction indicated when used when with CYP3A inhibitors)<br />
<br />
'''28-day cycles'''<br />
===References===<br />
=== <small>1.</small> <small>Wei AH, Strickland Jr SA, Hou JZ, Fiedler W, Lin TL, Walter RB, Enjeti A, Tiong IS, Savona M, Lee S, Chyla B. Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study. Journal of Clinical Oncology. 2019 Mar 20:JCO-18. [https://ascopubs.org/doi/full/10.1200/JCO.18.01600?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed link to abstract] contains protocol</small>===<br />
<br />
#[https://clinicaltrials.gov/ct2/show/NCT02287233 NCT02287233] '''contains protocol'''<br />
<br />
==Temozolomide monotherapy {{#subobject:261bcb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:fb4aeb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13094/full Brandwein et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Patient selection was based on MGMT expression by Western blot. See article for details.''<br />
====Chemotherapy====<br />
<br />
*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup>/day PO on days 1 to 7<br />
**Complete responders could receive: 200 mg/m<sup>2</sup>/day PO on days 1 to 5<br />
<br />
'''28-day cycle for up to 12 cycles'''<br />
<br />
===References===<br />
<br />
#Brandwein JM, Kassis J, Leber B, Hogge D, Howson-Jan K, Minden MD, Galarneau A, Pouliot JF. Phase II study of targeted therapy with temozolomide in acute myeloid leukaemia and high-risk myelodysplastic syndrome patients pre-screened for low O(6) -methylguanine DNA methyltransferase expression. Br J Haematol. 2014 Dec;167(5):664-70. Epub 2014 Aug 27. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13094/full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25160658 PubMed]<br />
<br />
=Consolidation after upfront therapy=<br />
==5+2d {{#subobject:b409f7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a67da7|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6112 Lancet et al. 2018 (CLTR0310-301)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose: 500 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
<br />
'''5-day course'''<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Chiarella M, Louie AC, Medeiros BC. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol. 2016 34:15_suppl, 7000-7000 [http://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.7000 link to abstract] '''contains partial protocol''' [https://clinicaltrials.gov/ct2/show/NCT01696084 ClinicalTrials.gov] --><br />
<br />
#'''CLTR0310-301:''' Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018 Sep 10;36(26):2684-2692. Epub 2018 Jul 19. [http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6112 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30024784 PubMed]<br />
<br />
==HiDAC {{#subobject:caa3a2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
HiDAC: '''<u>Hi</u>'''gh '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
<br>HDAC: '''<u>H</u>'''igh '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
<br>HDAraC: '''<u>H</u>'''igh '''<u>D</u>'''ose '''<u>AraC</u>''' (Cytarabine)<br />
===Variant #1, 2000 mg/m<sup>2</sup> every 12 hours x 6 {{#subobject:4e73ae|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/30/20/2441.full Holowiecki et al. 2012 (PALG AML1/2004)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Details in the text are scant.''<br />
====Preceding treatment====<br />
<br />
*[[#Cytarabine_.26_Mitoxantrone|Cytarabine & Mitoxantrone consolidation]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV every 12 hours on days 1, 3, 5 (6 total doses)<br />
<br />
===Variant #2, 2 cycles of 2000 mg/m<sup>2</sup> every 12 hours x 10 {{#subobject:2a4b32|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ar.iiarjournals.org/content/32/2/643.long Fukushima et al. 2012]<br />
| style="background-color:#91cf61" |Randomized, <20 pts in this arm (C)<br />
|[[#IDAC|mIDAC]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*BHAC-MMV<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 60 minutes every 12 hours on days 1 to 5 (10 total doses)<br />
<br />
'''2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*A-VVV<br />
<br />
===Variant #3, 1 cycle of 3000 mg/m<sup>2</sup> every 12 hours x 12 {{#subobject:a0e7d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJM199812033392301 Cassileth et al. 1998]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#BuCy.2C_then_auto_HSCT|BuCy, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*5+2i<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1 to 6 (12 total doses)<br />
<br />
'''One course'''<br />
<br />
===Variant #4, 3 cycles of 3000 mg/m<sup>2</sup> every 12 hours x 6 {{#subobject:746f61|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895015/ Moore et al. 2004 (CALGB 9222)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|HiDAC, then CYVE, then AZQ & Mitoxantrone<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682338/ Petersdorf et al. 2013 (SWOG S0106)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2012.46.4743 Schaich et al. 2013 (AML2003)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MAC/MAMAC/MAC<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/33/11/1252.full Stone et al. 2015 (ACCEDE)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00362-9/fulltext Röllig et al. 2015 (SORAML)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|HiDAC & Sorafenib<br />
| style="background-color:#fc8d59" |Seems to have inferior EFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 Stone et al. 2015 (COSAH C-022)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: CALGB 9222 specified that each cycle begins within 2 weeks after hematopoietic recovery from the preceding cycle. SORAML specified a 28-day (minimum) cycle or 1 week after marrow recovery, whichever comes later.''<br />
====Preceding treatment====<br />
<br />
*CALGB 9222: [[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br />
*SWOG S0106: [[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]] versus [[#7.2B3d_.26_GO|7+3d & GO]]<br />
*AML2003: [[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]] x 2<br />
*ACCEDE: Amonafide & Cytarabine versus [[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br />
*SORAML: [[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]] versus 7+3d & Sorafenib<br />
*COSAH C-022: [[#7.2B3d_.28high-dose.29|7+3d (high-dose)]] versus [[#7.2B3i|7+3i]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 3, 5 (6 total doses)<br />
<br />
'''3 cycles of varying durations'''<br />
====Subsequent treatment====<br />
<br />
*SWOG S0106: GO maintenance versus [[#Observation|no further treatment]]<br />
<br />
===Variant #5, 3 cycles of 2000 mg/m<sup>2</sup> every 12 hours x 10 {{#subobject:8887b8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/117/8/2358 Ohtake et al. 2010 (JALSG AML201)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Multiagent chemotherapy<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: this was considered an experimental arm in Japan, given the timing of HiDAC approval. Reported efficacy is based on the 2010 update by Miyawaki et al.''<br />
====Preceding treatment====<br />
<br />
*7+5d or [[#7.2B3i|7+3i]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1 to 5 (10 total doses)<br />
<br />
'''3 cycles, started 1 week after neutrophils, WBCs, and platelets recovered to more than 1500/uL, 3 × 10<sup>9</sup>/L, and 100 × 10<sup>9</sup>/L'''<br />
<br />
===Variant #6, 4 cycles of 3000 mg/m<sup>2</sup> every 12 hours x 6 {{#subobject:0c2779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199410063311402 Mayer et al. 1994 (CALGB 8525)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Low-dose continuous infusion cytarabine<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://www.bloodjournal.org/content/118/7/1754.long Thomas et al. 2011 (ALFA-9802)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Timed sequential chemotherapy (TSC)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 Lee et al. 2017 (COSAH C-022)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*ALFA-9802: Timed sequential therapy +/- GM-CSF priming<br />
*COSAH C-022: [[#7.2B3d_.28high-dose.29|7+3d (high-dose)]] versus [[#7.2B3i|7+3i]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 3, 5 (6 total doses)<br />
<br />
'''Up to 4 cycles'''<br />
====Subsequent treatment====<br />
<br />
*ALFA-9802: Cytarabine & Daunorubicin maintenance<br />
<br />
===References===<br />
<br />
#'''CALGB 8525:''' Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, Omura GA, Moore JO, McIntyre OR, Frei E 3rd; Cancer and Leukemia Group B. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med. 1994 Oct 6;331(14):896-903. [https://www.nejm.org/doi/full/10.1056/NEJM199410063311402 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8078551 PubMed]<br />
#Cassileth PA, Harrington DP, Appelbaum FR, Lazarus HM, Rowe JM, Paietta E, Willman C, Hurd DD, Bennett JM, Blume KG, Head DR, Wiernik PH. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med. 1998 Dec 3;339(23):1649-56. [https://www.nejm.org/doi/10.1056/NEJM199812033392301 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9834301 PubMed]<br />
#'''CALGB 9222:''' Moore JO, George SL, Dodge RK, Amrein PC, Powell BL, Kolitz JE, Baer MR, Davey FR, Bloomfield CD, Larson RA, Schiffer CA. Sequential multiagent chemotherapy is not superior to high-dose cytarabine alone as postremission intensification therapy for acute myeloid leukemia in adults under 60 years of age: Cancer and Leukemia Group B Study 9222. Blood. 2005 May 1;105(9):3420-7. Epub 2004 Nov 30. [http://www.bloodjournal.org/content/105/9/3420.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895015/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15572587 PubMed]<br />
#'''JALSG AML201:''' Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N, Okumura H, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R. Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood. 2011 Feb 24;117(8):2358-65. Epub 2010 Aug 6. [http://www.bloodjournal.org/content/117/8/2358 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20693429 PubMed]<br />
##'''Update:''' Miyawaki S, Ohtake S, Fujisawa S, Kiyoi H, Shinagawa K, Usui N, Sakura T, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R. A randomized comparison of 4 courses of standard-dose multiagent chemotherapy versus 3 courses of high-dose cytarabine alone in postremission therapy for acute myeloid leukemia in adults: the JALSG AML201 Study. Blood. 2011 Feb 24;117(8):2366-72. Epub 2010 Dec 29. [http://www.bloodjournal.org/content/117/8/2366.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21190996 PubMed]<br />
#'''ALFA-9802:''' Thomas X, Elhamri M, Raffoux E, Renneville A, Pautas C, de Botton S, de Revel T, Reman O, Terré C, Gardin C, Chelghoum Y, Boissel N, Quesnel B, Hicheri Y, Bourhis JH, Fenaux P, Preudhomme C, Michallet M, Castaigne S, Dombret H. Comparison of high-dose cytarabine and timed-sequential chemotherapy as consolidation for younger adults with AML in first remission: the ALFA-9802 study. Blood. 2011 Aug 18;118(7):1754-62. Epub 2011 Jun 20. [http://www.bloodjournal.org/content/118/7/1754.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21690555 PubMed]<br />
#Fukushima T, Urasaki Y, Yamaguchi M, Ueda M, Morinaga K, Haba T, Sugiyama T, Nakao S, Origasa H, Umehara H, Ueda T. A randomized comparison of modified intermediate-dose Ara-C versus high-dose ara-c in post-remission therapy for acute myeloid leukemia. Anticancer Res. 2012 Feb;32(2):643-7. [http://ar.iiarjournals.org/content/32/2/643.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22287757 PubMed]<br />
#'''SWOG S0106:''' Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013 Jun 13;121(24):4854-60. Epub 2013 Apr 16. [http://bloodjournal.hematologylibrary.org/content/121/24/4854.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682338/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23591789 PubMed]<br />
#'''AML2003:''' Schaich M, Parmentier S, Kramer M, Illmer T, Stölzel F, Röllig C, Thiede C, Hänel M, Schäfer-Eckart K, Aulitzky W, Einsele H, Ho AD, Serve H, Berdel WE, Mayer J, Schmitz N, Krause SW, Neubauer A, Baldus CD, Schetelig J, Bornhäuser M, Ehninger G. High-dose cytarabine consolidation with or without additional amsacrine and mitoxantrone in acute myeloid leukemia: results of the prospective randomized AML2003 trial. J Clin Oncol. 2013 Jun 10;31(17):2094-102. Epub 2013 Apr 29. [http://ascopubs.org/doi/full/10.1200/JCO.2012.46.4743 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23630210 PubMed]<br />
#'''ACCEDE:''' Stone RM, Mazzola E, Neuberg D, Allen SL, Pigneux A, Stuart RK, Wetzler M, Rizzieri D, Erba HP, Damon L, Jang JH, Tallman MS, Warzocha K, Masszi T, Sekeres MA, Egyed M, Horst HA, Selleslag D, Solomon SR, Venugopal P, Lundberg AS, Powell B. Phase III open-label randomized study of cytarabine in combination with amonafide l-malate or daunorubicin as induction therapy for patients with secondary acute myeloid leukemia. J Clin Oncol. 2015 Apr 10;33(11):1252-7. Epub 2015 Mar 2. [http://jco.ascopubs.org/content/33/11/1252.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25732165 PubMed]<br />
#'''PALG AML1/2004:''' Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszyńska A, Kloczko J, Jedrzejczak WW, Zdziarska B, Warzocha K, Zawilska K, Komarnicki M, Kielbinski M, Piatkowska-Jakubas B, Wierzbowska A, Wach M, Haus O. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012 Jul 10;30(20):2441-8. Epub 2012 Apr 16. [http://jco.ascopubs.org/content/30/20/2441.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22508825 PubMed]<br />
#'''SORAML:''' Röllig C, Serve H, Hüttmann A, Noppeney R, Müller-Tidow C, Krug U, Baldus CD, Brandts CH, Kunzmann V, Einsele H, Krämer A, Schäfer-Eckart K, Neubauer A, Burchert A, Giagounidis A, Krause SW, Mackensen A, Aulitzky W, Herbst R, Hänel M, Kiani A, Frickhofen N, Kullmer J, Kaiser U, Link H, Geer T, Reichle A, Junghanß C, Repp R, Heits F, Dürk H, Hase J, Klut IM, Illmer T, Bornhäuser M, Schaich M, Parmentier S, Görner M, Thiede C, von Bonin M, Schetelig J, Kramer M, Berdel WE, Ehninger G; Study Alliance Leukaemia. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015 Dec;16(16):1691-9. Epub 2015 Nov 6. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00362-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26549589 PubMed]<br />
#'''COSAH C-022:''' Lee JH, Kim H, Joo YD, Lee WS, Bae SH, Zang DY, Kwon J, Kim MK, Lee J, Lee GW, Lee JH, Choi Y, Kim DY, Hur EH, Lim SN, Lee SM, Ryoo HM, Kim HJ, Hyun MS, Lee KH; Cooperative Study Group A for Hematology. Prospective randomized comparison of idarubicin and high-dose daunorubicin in induction chemotherapy for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2017 Aug 20;35(24):2754-2763. Epub 2017 Jun 20. [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28632487 PubMed]<br />
<br />
==IDAC {{#subobject:f5cd74|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
IDAC: '''<u>I</u>'''ntermediate '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
<br>mIDAC: '''<u>m</u>'''odified '''<u>I</u>'''ntermediate '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
<br />
===Variant #1, 1000 mg/m<sup>2</sup> x 3 {{#subobject:0340ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/11/1252.full Stone et al. 2015 (ACCEDE)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Amonafide & Cytarabine versus [[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br />
*7+3d & Glasdegib<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 3 hours once per day on days 1, 3, 5 (3 total doses)<br />
<br />
===Variant #2, 1000 mg/m<sup>2</sup> x 10 {{#subobject:cbba35|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ar.iiarjournals.org/content/32/2/643.long Fukushima et al. 2012]<br />
| style="background-color:#91cf61" |Randomized, <20 pts in this arm (E)<br />
|[[#HiDAC|HDAC]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*BHAC-MMV<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 60 minutes every 12 hours on days 1 to 5 (10 total doses)<br />
<br />
'''Two cycles'''<br />
====Subsequent treatment====<br />
<br />
*A-VVV<br />
<br />
===Variant #3, 1000 mg/m<sup>2</sup> x 12 {{#subobject:22eda3|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0901409 Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]] versus [[#7.2B3d_.28high-dose.29|7+3d (high-dose)]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 6 hours every 12 hours on days 1 to 6 (12 total doses)<br />
<br />
'''One cycle'''<br />
====Subsequent treatment====<br />
<br />
*Transplant eligible patients: [[#Allogeneic_hematopoietic_stem_cell_transplant|allogeneic HSCT]]<br />
*Transplant ineligible patients: Gemtuzumab ozogamicin maintenance versus [[#Observation|no further treatment]]<br />
<br />
===References===<br />
<br />
#'''HOVON 43 AML/SAKK 30/01:''' Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Döhner H, Gratwohl A, Pabst T, Verhoef G; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. [https://www.nejm.org/doi/full/10.1056/NEJMoa0901409 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19776405 PubMed]<br />
#Fukushima T, Urasaki Y, Yamaguchi M, Ueda M, Morinaga K, Haba T, Sugiyama T, Nakao S, Origasa H, Umehara H, Ueda T. A randomized comparison of modified intermediate-dose Ara-C versus high-dose ara-c in post-remission therapy for acute myeloid leukemia. Anticancer Res. 2012 Feb;32(2):643-7. [http://ar.iiarjournals.org/content/32/2/643.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22287757 PubMed]<br />
#'''ACCEDE:''' Stone RM, Mazzola E, Neuberg D, Allen SL, Pigneux A, Stuart RK, Wetzler M, Rizzieri D, Erba HP, Damon L, Jang JH, Tallman MS, Warzocha K, Masszi T, Sekeres MA, Egyed M, Horst HA, Selleslag D, Solomon SR, Venugopal P, Lundberg AS, Powell B. Phase III open-label randomized study of cytarabine in combination with amonafide l-malate or daunorubicin as induction therapy for patients with secondary acute myeloid leukemia. J Clin Oncol. 2015 Apr 10;33(11):1252-7. Epub 2015 Mar 2. [http://jco.ascopubs.org/content/33/11/1252.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25732165 PubMed]<br />
<br />
==HDAC & G-CSF {{#subobject:e0396d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
HDAC & G-CSF: '''<u>H</u>'''igh '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine) & '''<u>G</u>'''ranulocyte '''<u>C</u>'''olony '''<u>S</u>'''timulating '''<u>F</u>'''actor<br />
<br />
===Regimen {{#subobject:d8edc4|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2016.70.4551 Thomas et al. 2017 (ALFA-0702)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#CLARA|CLARA]]<br />
| style="background-color:#fc8d59" |Seems to have inferior RFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Cytarabine, Daunorubicin, G-CSF induction<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 3, 5 (6 total doses)<br />
*[[Filgrastim (Neupogen)]] 5 mcg/kg IV once per day on days 1 to 5<br />
<br />
'''35-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''ALFA-0702:''' Thomas X, de Botton S, Chevret S, Caillot D, Raffoux E, Lemasle E, Marolleau JP, Berthon C, Pigneux A, Vey N, Reman O, Simon M, Recher C, Cahn JY, Hermine O, Castaigne S, Celli-Lebras K, Ifrah N, Preudhomme C, Terré C, Dombret H. Randomized phase II study of clofarabine-based consolidation for younger adults with acute myeloid leukemia in first remission. J Clin Oncol. 2017 Apr 10;35(11):1223-1230. Epub 2017 Feb 21. [http://ascopubs.org/doi/full/10.1200/JCO.2016.70.4551 link to original article] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/28221862 PubMed]<br />
<br />
==Azacitidine monotherapy {{#subobject:7abfd6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f7e3f6|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829116/ Nand et al. 2013 (SWOG S0703)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Azacitidine_.26_Gemtuzumab_ozogamicin_2|Azacitidine & Gemtuzumab ozogamicin consolidation]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Azacitidine (Vidaza)]] 75 mg/m<sup>2</sup> SC once on day 1<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<!-- Presented in part at the American Society of Clinical Oncology annual meeting (Chicago, IL, June 1-5, 2012) and at the American Society of Hematology annual meeting (Atlanta, GA, December 8-11, 2012). --><br />
<br />
#'''SWOG S0703:''' Nand S, Othus M, Godwin JE, Willman CL, Norwood TH, Howard DS, Coutre SE, Erba HP, Appelbaum FR. A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood. 2013 Nov 14;122(20):3432-9. Epub 2013 Oct 3. [http://www.bloodjournal.org/content/122/20/3432.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829116/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24092933 PubMed]<br />
<br />
==Azacitidine & Gemtuzumab ozogamicin {{#subobject:e5ff95|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:eb3f69|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829116/ Nand et al. 2013 (SWOG S0703)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Azacitidine_.26_Gemtuzumab_ozogamicin|Azacitidine & Gemtuzumab ozogamicin induction]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Azacitidine (Vidaza)]] 75 mg/m<sup>2</sup> IV or SC once per day on days 1 to 7<br />
*[[Gemtuzumab ozogamicin (Mylotarg)]] 3 mg/m<sup>2</sup> IV once on day 8<br />
<br />
====Supportive medications====<br />
<br />
*"Appropriate premedications" which were not specified, for [[Gemtuzumab ozogamicin (Mylotarg)]]<br />
*Growth factors per physician discretion<br />
<br />
'''1 cycle'''<br />
====Subsequent treatment====<br />
<br />
*[[#Azacitidine_monotherapy_2|Azacitidine maintenance]], within 42 days of completion of consolidation<br />
<br />
===References===<br />
<!-- Presented in part at the American Society of Clinical Oncology annual meeting (Chicago, IL, June 1-5, 2012) and at the American Society of Hematology annual meeting (Atlanta, GA, December 8-11, 2012). --><br />
<br />
#'''SWOG S0703:''' Nand S, Othus M, Godwin JE, Willman CL, Norwood TH, Howard DS, Coutre SE, Erba HP, Appelbaum FR. A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood. 2013 Nov 14;122(20):3432-9. Epub 2013 Oct 3. [http://www.bloodjournal.org/content/122/20/3432.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829116/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24092933 PubMed]<br />
<br />
==BuCy, then auto HSCT {{#subobject:9acbe9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
BuCy: '''<u>Bu</u>'''sulfan & '''<u>Cy</u>'''clophosphamide<br />
===Variant #1, 16/120 {{#subobject:6ccf66|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/23/6037.long Vellenga et al. 2011 (HOVON-SAKK AML-29/AML-42)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Etoposide_.26_Mitoxantrone|Etoposide & Mitoxantrone]]<br />
| style="background-color:#d9ef8b" |Might have superior RFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3i|7+3i]], then amsacrine & cytarabine<br />
{{#lst:Autologous HSCT|6ccf66}}<br />
===Variant #2, 16/200 {{#subobject:5d4efb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJM199605303342203 Ravindranath et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Intensive chemotherapy<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3d_.28standard-dose.29|7+3d]], then [[#HiDAC|HiDAC]]<br />
{{#lst:Autologous HSCT|5d4efb}}<br />
===References===<br />
<br />
#Ravindranath Y, Yeager AM, Chang MN, Steuber CP, Krischer J, Graham-Pole J, Carroll A, Inoue S, Camitta B, Weinstein HJ; Pediatric Oncology Group. Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. N Engl J Med. 1996 May 30;334(22):1428-34. [https://www.nejm.org/doi/10.1056/NEJM199605303342203 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8618581 PubMed]<br />
#'''HOVON-SAKK AML-29/AML-42:''' Vellenga E, van Putten W, Ossenkoppele GJ, Verdonck LF, Theobald M, Cornelissen JJ, Huijgens PC, Maertens J, Gratwohl A, Schaafsma R, Schanz U, Graux C, Schouten HC, Ferrant A, Bargetzi M, Fey MF, Löwenberg B; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON); Swiss Group for Clinical Cancer Research Collaborative Group (SAKK). Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood. 2011 Dec 1;118(23):6037-42. Epub 2011 Sep 27. [http://www.bloodjournal.org/content/118/23/6037.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21951683 PubMed]<br />
<br />
==BuFlu, then allo HSCT {{#subobject:3fe0f0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
BuFlu: '''<u>Bu</u>'''sulfan & '''<u>Flu</u>'''darabine<br />
===Regimen {{#subobject:a7e574|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658453/ Devine et al. 2015 (CALGB 100103)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts in subgroup<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|a7e574}}<br />
===References===<br />
<!-- Presented in part as an oral presentation at the 54th American Society of Hematology Annual Meeting and Exposition, Atlanta, GA, December 8-11, 2012. --><br />
<br />
#Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, Champlin RE, Chen YB, Vij R, Slack J, Soiffer RJ, Larson RA, Shea TC, Hars V, Sibley AB, Giralt S, Carter S, Horowitz MM, Linker C, Alyea EP. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. 2015 Dec 10;33(35):4167-75. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/35/4167.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658453/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527780 PubMed]<br />
<br />
==CIA {{#subobject:db5c09|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CIA: '''<u>C</u>'''lofarabine, '''<u>I</u>'''darubicin, '''<u>A</u>'''ra-C (Cytarabine)<br />
===Regimen {{#subobject:1bbed8|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/ajh.23544/references Nazha et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#CIA|CIA induction]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Idarubicin (Idamycin)]] 8 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Cytarabine (Ara-C)]] 750 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''3-day course; repeated every 3 to 4 weeks depending on disease response and recovery from regimen toxicity for up to six cycles'''<br />
<br />
===References===<br />
<br />
#Nazha A, Kantarjian H, Ravandi F, Huang X, Choi S, Garcia-Manero G, Jabbour E, Borthakur G, Kadia T, Konopleva M, Cortes J, Ferrajoli A, Kornblau S, Daver N, Pemmaraju N, Andreeff M, Estrov Z, Du M, Brandt M, Faderl S. Clofarabine, idarubicin, and cytarabine (CIA) as frontline therapy for patients ≤60 years with newly diagnosed acute myeloid leukemia. Am J Hematol. 2013 Nov;88(11):961-6. Epub 2013 Sep 9. [https://onlinelibrary.wiley.com/doi/10.1002/ajh.23544/references long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110914/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23877926 PubMed]<br />
<br />
==CLARA {{#subobject:6160cf|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CLARA: '''<u>CL</u>'''ofarabine and '''<u>ARA</u>'''-C (Cytarabine)<br />
===Regimen {{#subobject:6ed739|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2016.70.4551 Thomas et al. 2017 (ALFA-0702)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#HDAC_.26_G-CSF|HDAC & G-CSF]]<br />
| style="background-color:#91cf60" |Seems to have superior RFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Cytarabine, Daunorubicin, G-CSF induction<br />
<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 30 mg/m<sup>2</sup> IV over 2 hours once per day on days 2 to 6, '''given first'''<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given second, 4 hours after clofarabine, on days 2 to 5'''<br />
*[[Filgrastim (Neupogen)]] 5 mcg/kg IV once per day on days 1 to 6<br />
<br />
'''35-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''ALFA-0702:''' Thomas X, de Botton S, Chevret S, Caillot D, Raffoux E, Lemasle E, Marolleau JP, Berthon C, Pigneux A, Vey N, Reman O, Simon M, Recher C, Cahn JY, Hermine O, Castaigne S, Celli-Lebras K, Ifrah N, Preudhomme C, Terré C, Dombret H. Randomized phase II study of clofarabine-based consolidation for younger adults with acute myeloid leukemia in first remission. J Clin Oncol. 2017 Apr 10;35(11):1223-1230. Epub 2017 Feb 21. [http://ascopubs.org/doi/full/10.1200/JCO.2016.70.4551 link to original article] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/28221862 PubMed]<br />
<br />
==Clofarabine & LoDAC/Decitabine {{#subobject:756e06|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Clofarabine & LoDAC/Decitabine: Clofarabine & '''<u>Lo</u>'''w '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine) alternating with Decitabine<br />
===Regimen {{#subobject:0ac883|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907176/ Faderl et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Clofarabine_.26_LoDAC|Clofarabine & LoDAC]], which is counted as "Cycle 1". Cycles are given every 4 to 7 weeks pending hematologic recovery and resolution of other toxicities.<br />
<br />
====Chemotherapy, clofarabine & LoDAC portion====<br />
<br />
*[[Clofarabine (Clolar)]] as follows:<br />
**Cycles 2, 3, 7 to 9, 13 to 15: 20 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Cytarabine (Ara-C)]] as follows:<br />
**Cycles 2, 3, 7 to 9, 13 to 15: 20 mg SC twice per day on days 1 to 7<br />
<br />
'''4- to 7-week cycles, depending on count recovery'''<br />
<br />
====Chemotherapy, decitabine portion====<br />
<br />
*[[Decitabine (Dacogen)]] as follows:<br />
**Cycles 4 to 6, 10 to 12, 16 to 18: 20 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''4- to 7-week cycles, depending on count recovery'''<br />
<br />
===References===<br />
<br />
#Faderl S, Ravandi F, Huang X, Wang X, Jabbour E, Garcia-Manero G, Kadia T, Ferrajoli A, Konopleva M, Borthakur G, Burger J, Feliu J, Kantarjian HM. Clofarabine plus low-dose cytarabine followed by clofarabine plus low-dose cytarabine alternating with decitabine in acute myeloid leukemia frontline therapy for older patients. Cancer. 2012 Sep 15;118(18):4471-7. Epub 2012 Jan 26. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.27429/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907176/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22282348 PubMed]<br />
##'''Update:''' Kadia TM, Faderl S, Ravandi F, Jabbour E, Garcia-Manero G, Borthakur G, Ferrajoli A, Konopleva M, Burger J, Huang X, Wang X, Pierce S, Brandt M, Feliu J, Cortes J, Kantarjian H. Final results of a phase 2 trial of clofarabine and low-dose cytarabine alternating with decitabine in older patients with newly diagnosed acute myeloid leukemia. Cancer. 2015 Jul 15;121(14):2375-82. Epub 2015 Mar 25. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.29367/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436272/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25809968 PubMed]<br />
<br />
==CPX-351 monotherapy {{#subobject:6a5fb5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CPX-351: Liposomal Cytarabine and Daunorubicin<br />
===Regimen {{#subobject:896083|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6112 Lancet et al. 2018 (CLTR0310-301)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#CPX-351_monotherapy|CPX-351 monotherapy induction]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine and daunorubicin liposomal (Vyxeos)|CPX-351 (Vyxeos)]] 65 units/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 3<br />
<br />
'''Up to two courses'''<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Chiarella M, Louie AC, Medeiros BC. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol. 2016 34:15_suppl, 7000-7000 [http://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.7000 link to abstract] '''contains partial protocol''' [https://clinicaltrials.gov/ct2/show/NCT01696084 ClinicalTrials.gov] --><br />
<br />
#'''CLTR0310-301:''' Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018 Sep 10;36(26):2684-2692. Epub 2018 Jul 19. [http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6112 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30024784 PubMed]<br />
<br />
==Cytarabine & Daunorubicin {{#subobject:d6f810|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:c39b55|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60485-1/fulltext Castaigne et al. 2012 (ALFA-0701)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: the preceding treatment is not a true randomization because only patients in the gemtuzumab ozogamicin arm with platelet count less than 100 x 10<sup>9</sup> at day 45 from initiation of chemotherapy were assigned to this regimen. Length of courses is not specified.''<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]] or [[#7.2B3d_.26_GO|7+3d & GO]] induction<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 4 (8 total doses)<br />
*[[Daunorubicin (Cerubidine)]] as follows:<br />
**Course 1: 60 mg/m<sup>2</sup> IV once on day 1<br />
**Course 2: 60 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
<br />
'''2 courses'''<br />
<br />
===Variant #2 {{#subobject:59874e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/12/5129.full Gardin et al. 2007 (ALFA 9803)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|4 + 7 with daunorubicin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*4d + 7 induction<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 60 mg/m<sup>2</sup> SC every 12 hours on days 1 to 5 (10 total doses)<br />
*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''1-month cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Gardin C, Turlure P, Fagot T, Thomas X, Terre C, Contentin N, Raffoux E, de Botton S, Pautas C, Reman O, Bourhis JH, Fenaux P, Castaigne S, Michallet M, Preudhomme C, de Revel T, Bordessoule D, Dombret H. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood. 2007 Jun 15;109(12):5129-35. Epub 2007 Mar 6. [http://www.bloodjournal.org/content/109/12/5129.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17341661 PubMed]<br />
#'''ALFA-0701:''' Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60485-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22482940 PubMed]<br />
##'''Update:''' Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019 Jan;104(1):113-119. Epub 2018 Aug 3. [http://www.haematologica.org/content/104/1/113 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312010/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30076173 PubMed]<br />
<br />
==Cytarabine, Daunorubicin, Gemtuzumab ozogamicin {{#subobject:0f7f87|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c56261|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60485-1/fulltext Castaigne et al. 2012 (ALFA-0701)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: length of courses is not specified.''<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3d_.26_GO|7+3d & GO]] induction<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 4 (8 total doses)<br />
*[[Daunorubicin (Cerubidine)]] as follows:<br />
**Course 1: 60 mg/m<sup>2</sup> IV once on day 1<br />
**Course 2: 60 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Gemtuzumab ozogamicin (Mylotarg)]] 3 mg/m<sup>2</sup> (maximum dose of 5 mg) IV once on day 1<br />
<br />
'''2 courses'''<br />
<br />
===References===<br />
<br />
#'''ALFA-0701:''' Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60485-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22482940 PubMed]<br />
##'''Update:''' Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019 Jan;104(1):113-119. Epub 2018 Aug 3. [http://www.haematologica.org/content/104/1/113 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312010/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30076173 PubMed]<br />
<br />
==CYVE {{#subobject:f8d436|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CYVE: '''<u>CY</u>'''tarabine & '''<u>VE</u>'''pesid (Etoposide)<br />
===Regimen {{#subobject:79438d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 Lee et al. 2017 (COSAH C-022)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this consolidation regimen was for patients with high-risk cytogenetics.''<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3d_.28high-dose.29|7+3d (high-dose)]] versus [[#7.2B3i|7+3i]]<br />
<div class="toccolours" style="width:100%; overflow:auto;"><br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 6<br />
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''4 courses'''<br />
</div><br />
====Subsequent treatment====<br />
<br />
*Transplant eligible patients with available donors usually proceeded to [[#Allogeneic_hematopoietic_stem_cell_transplant|allogeneic HSCT]] after 2 courses (details not specified)<br />
<br />
===References===<br />
<br />
#'''COSAH C-022:''' Lee JH, Kim H, Joo YD, Lee WS, Bae SH, Zang DY, Kwon J, Kim MK, Lee J, Lee GW, Lee JH, Choi Y, Kim DY, Hur EH, Lim SN, Lee SM, Ryoo HM, Kim HJ, Hyun MS, Lee KH; Cooperative Study Group A for Hematology. Prospective randomized comparison of idarubicin and high-dose daunorubicin in induction chemotherapy for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2017 Aug 20;35(24):2754-2763. Epub 2017 Jun 20. [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28632487 PubMed]<br />
<br />
==Cytarabine & Idarubicin {{#subobject:f8c456|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:099908|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/12/5129.full Gardin et al. 2007 (ALFA 9803)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|4 + 7 with idarubicin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*4i + 7 induction<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 60 mg/m<sup>2</sup> SC every 12 hours on days 1 to 5 (10 total doses)<br />
*[[Idarubicin (Idamycin)]] 9 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''1-month cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Gardin C, Turlure P, Fagot T, Thomas X, Terre C, Contentin N, Raffoux E, de Botton S, Pautas C, Reman O, Bourhis JH, Fenaux P, Castaigne S, Michallet M, Preudhomme C, de Revel T, Bordessoule D, Dombret H. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood. 2007 Jun 15;109(12):5129-35. Epub 2007 Mar 6. [http://www.bloodjournal.org/content/109/12/5129.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17341661 PubMed]<br />
<br />
==Cytarabine, Idarubicin, Sorafenib {{#subobject:8c0061|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:97a478|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930809/ Ravandi et al. 2010<sub>AML</sub>]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Regimen details are from the phase II part of the published phase I/II trial. This trial should not be confused for the one by the same name in Ph+ B-ALL.''<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3i_.26_Sorafenib|7+3i & Sorafenib induction]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 750 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 2250 mg/m<sup>2</sup>)<br />
*[[Idarubicin (Idamycin)]] 8 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 2<br />
*[[Sorafenib (Nexavar)]] 400 mg PO twice per day for up to 28 days<br />
<br />
'''4 to 6-week cycle for up to 5 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[#Sorafenib_monotherapy|Sorafenib maintenance]]<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
<br />
#Ravandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce SR, Brandt M, Byrd A, Bekele BN, Pratz K, Luthra R, Levis M, Andreeff M, Kantarjian HM. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010 Apr 10;28(11):1856-62. Epub 2010 Mar 8. [http://jco.ascopubs.org/content/28/11/1856.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930809/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20212254 PubMed]<br />
##'''Update:''' Ravandi F, Arana Yi C, Cortes JE, Levis M, Faderl S, Garcia-Manero G, Jabbour E, Konopleva M, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce S, Brandt M, Pratz K, Luthra R, Andreeff M, Kantarjian H. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia. 2014 Jul;28(7):1543-5. Epub 2014 Feb 3. [https://www.nature.com/leu/journal/v28/n7/full/leu201454a.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091714/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24487412 PubMed]<br />
<br />
==Cyclophosphamide & TBI, then allo HSCT {{#subobject:a9f7e8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Cy/TBI: '''<u>Cy</u>'''clophosphamide & '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation<br />
===Regimen {{#subobject:6ca28d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Non-relapse mortality]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM198005083021901 Blume et al. 1980]<br />
| style="background-color:#ffffbe" |Non-randomized, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM198712243172602 Brochstein et al. 1987]<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199501263320403 Zittoun et al. 1995]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Intensive chemotherapy<br />
| style="background-color:#1a9850" |Superior DFS<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70349-2/fulltext Bornhäuser et al. 2012]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fludarabine_.26_TBI.2C_then_allo_HSCT|Fludarabine & TBI, then allo HSCT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Zittoun et al. 1995: [[#7.2B3d_.28standard-dose.29|7+3d]] with CR, then amsacrine & IDAC<br />
{{#lst:Allogeneic HSCT|6ca28d}}<br />
===References===<br />
<br />
#Blume KG, Beutler E, Bross KJ, Chillar RK, Ellington OB, Fahey JL, Farbstein MJ, Forman SJ, Schmidt GM, Scott EP, Spruce WE, Turner MA, Wolf JL. Bone-marrow ablation and allogeneic marrow transplantation in acute leukemia. N Engl J Med. 1980 May 8;302(19):1041-6. [https://www.nejm.org/doi/full/10.1056/NEJM198005083021901 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6245359 PubMed]<br />
#Brochstein JA, Kernan NA, Groshen S, Cirrincione C, Shank B, Emanuel D, Laver J, O'Reilly RJ. Allogeneic bone marrow transplantation after hyperfractionated total-body irradiation and cyclophosphamide in children with acute leukemia. N Engl J Med. 1987 Dec 24;317(26):1618-24. [https://www.nejm.org/doi/full/10.1056/NEJM198712243172602 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3317056 PubMed]<br />
#Zittoun RA, Mandelli F, Willemze R, de Witte T, Labar B, Resegotti L, Leoni F, Damasio E, Visani G, Papa G, Caronia F, Hayat M, Stryckmans P, Rotoli B, Leoni P, Peetermans ME, Dardenne M, Vegna ML, Petti MC, Solbu G, Suciu S; European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med. 1995 Jan 26;332(4):217-23. [https://www.nejm.org/doi/full/10.1056/NEJM199501263320403 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7808487 PubMed]<br />
#Bornhäuser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, Baurmann H, Schäfer-Eckart K, Holler E, Kröger N, Schmid C, Einsele H, Kiehl MG, Hiddemann W, Schwerdtfeger R, Buchholz S, Dreger P, Neubauer A, Berdel WE, Ehninger G, Beelen DW, Schetelig J, Stelljes M. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012 Oct;13(10):1035-44. Epub 2012 Sep 7. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70349-2/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22959335 PubMed]<br />
#'''Retrospective:''' Copelan EA, Hamilton BK, Avalos B, Ahn KW, Bolwell BJ, Zhu X, Aljurf M, van Besien K, Bredeson C, Cahn JY, Costa LJ, de Lima M, Gale RP, Hale GA, Halter J, Hamadani M, Inamoto Y, Kamble RT, Litzow MR, Loren AW, Marks DI, Olavarria E, Roy V, Sabloff M, Savani BN, Seftel M, Schouten HC, Ustun C, Waller EK, Weisdorf DJ, Wirk B, Horowitz MM, Arora M, Szer J, Cortes J, Kalaycio ME, Maziarz RT, Saber W. Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood. 2013 Dec 5;122(24):3863-70. Epub 2013 Sep 24. [http://www.bloodjournal.org/content/122/24/3863.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854108/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24065243 PubMed]<br />
<br />
==Etoposide & Mitoxantrone {{#subobject:ab1766|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:780933|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/23/6037.long Vellenga et al. 2011 (HOVON-SAKK AML-29/AML-42)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#BuCy.2C_then_auto_HSCT|Bu/Cy, then auto HSCT]]<br />
| style="background-color:#fee08b" |Might have inferior RFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3i|7+3i]], then Amsacrine & Cytarabine<br />
<br />
====Chemotherapy====<br />
<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
===References===<br />
<br />
#'''HOVON-SAKK AML-29/AML-42:''' Vellenga E, van Putten W, Ossenkoppele GJ, Verdonck LF, Theobald M, Cornelissen JJ, Huijgens PC, Maertens J, Gratwohl A, Schaafsma R, Schanz U, Graux C, Schouten HC, Ferrant A, Bargetzi M, Fey MF, Löwenberg B; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON).; Swiss Group for Clinical Cancer Research Collaborative Group (SAKK). Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood. 2011 Dec 1;118(23):6037-42. Epub 2011 Sep 27. [http://www.bloodjournal.org/content/118/23/6037.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21951683 PubMed]<br />
<br />
==Fludarabine & TBI, then allo HSCT {{#subobject:53c6af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:be3609|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Non-relapse mortality]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70349-2/fulltext Bornhäuser et al. 2012]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Cyclophosphamide_.26_TBI.2C_then_allo_HSCT|Cyclophosphamide & TBI, then allo HSCT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|be3609}}<br />
===Variant #2, low-dose TBI{{#subobject:7fa6ce|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903320/ Gyukocza et al. 2010]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|7fa6ce}}<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
<br />
#Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA, Langston AA, Pulsipher MA, Bredeson CN, Maziarz RT, Bruno B, Petersen FB, Maris MB, Agura E, Yeager A, Bethge W, Sahebi F, Appelbaum FR, Maloney DG, Sandmaier BM. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010 Jun 10;28(17):2859-67. Epub 2010 May 3. [http://jco.ascopubs.org/content/28/17/2859.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903320/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20439626 PubMed]<br />
#Bornhäuser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, Baurmann H, Schäfer-Eckart K, Holler E, Kröger N, Schmid C, Einsele H, Kiehl MG, Hiddemann W, Schwerdtfeger R, Buchholz S, Dreger P, Neubauer A, Berdel WE, Ehninger G, Beelen DW, Schetelig J, Stelljes M. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012 Oct;13(10):1035-44. Epub 2012 Sep 7. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70349-2/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22959335 PubMed]<br />
<br />
==Fludarabine, Busulfan, ATG, then allo HSCT {{#subobject:ed545b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dd1486|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658453/ Devine et al. 2015 (CALGB 100103)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|dd1486}}<br />
===References===<br />
<!-- Presented in part as an oral presentation at the 54th American Society of Hematology Annual Meeting and Exposition, Atlanta, GA, December 8-11, 2012. --><br />
<br />
#'''CALGB 100103:''' Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, Champlin RE, Chen YB, Vij R, Slack J, Soiffer RJ, Larson RA, Shea TC, Hars V, Sibley AB, Giralt S, Carter S, Horowitz MM, Linker C, Alyea EP. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. 2015 Dec 10;33(35):4167-75. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/35/4167.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658453/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527780 PubMed]<br />
<br />
==HAM {{#subobject:1da5a5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
HAM: '''<u>H</u>'''igh-dose '''<u>A</u>'''ra-C (Cytarabine), '''<u>M</u>'''itoxantrone<br />
<br />
===Regimen {{#subobject:eb86c6|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0609.2007.00988.x/abstract Wierzbowksa et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[http://jco.ascopubs.org/content/30/20/2441.full Holowiecki et al. 2012 (PALG AML1/2004)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Wierzbowska et al. 2007: [[#CLAG-M|CLAG-M]]<br />
*PALG AML1/2004: [[#7.2B3d_.28intermediate-dose.29|DA]] versus [[#DAC|DAC]] versus DAF<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1500 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 3 to 5<br />
<br />
====Subsequent treatment====<br />
<br />
*[[#HiDAC|HiDAC consolidation]]<br />
<br />
===References===<br />
<br />
#Wierzbowska A, Robak T, Pluta A, Wawrzyniak E, Cebula B, Holowiecki J, Kyrcz-Krzemien S, Grosicki S, Giebel S, Skotnicki AB, Piatkowska-Jakubas B, Kuliczkowski K, Kielbinski M, Zawilska K, Kloczko J, Wrzesień-Kuś A; Polish Adult Leukemia Group. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol. 2008 Feb;80(2):115-26. Epub 2007 Dec 11. [https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0609.2007.00988.x/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18076637 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
#'''PALG AML1/2004:''' Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszyńska A, Kloczko J, Jedrzejczak WW, Zdziarska B, Warzocha K, Zawilska K, Komarnicki M, Kielbinski M, Piatkowska-Jakubas B, Wierzbowska A, Wach M, Haus O. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012 Jul 10;30(20):2441-8. Epub 2012 Apr 16. [http://jco.ascopubs.org/content/30/20/2441.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22508825 PubMed]<br />
<br />
==IC & Norethandrolone/6-MP, MTX, Norethandrolone {{#subobject:2034a1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
IC & Norethandrolone: '''<u>I</u>'''darubicin, '''<u>C</u>'''ytarabine, Norethandrolone<br />
===Regimen {{#subobject:0849b9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2016.67.6213 Pigneux et al. 2016 (GOELAMS LAM-SA2002)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|IC/6-MP & MTX<br />
| style="background-color:#1a9850" |Superior OS<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#ICL|7+3i & Lomustine]]<br />
<br />
====Chemotherapy, reinduction====<br />
<br />
*[[Idarubicin (Idamycin)]] 8 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 500 mg/m<sup>2</sup>)<br />
<br />
====Hormonotherapy, reinduction====<br />
<br />
*[[Norethandrolone (Nilevar)]] as follows:<br />
**If less than 60 kg: 10 mg PO once per day<br />
**If greater than 60 kg: 20 mg PO once per day<br />
<br />
'''3-month cycle for 6 cycles, alternating with maintenance'''<br />
====Chemotherapy, maintenance====<br />
<br />
*[[Methotrexate (MTX)]] as follows:<br />
**If less than 60 kg: 20 mg PO twice per week in weeks 1 & 2<br />
**If greater than 60 kg: 25 mg PO twice per week in weeks 1 & 2<br />
*[[Mercaptopurine (6-MP)]] as follows:<br />
**If less than 60 kg: 100 mg PO once per day on days 15 to 30<br />
**If greater than 60 kg: 150 mg PO once per day on days 15 to 30<br />
<br />
====Hormonotherapy, maintenance====<br />
<br />
*[[Norethandrolone (Nilevar)]] as follows:<br />
**If less than 60 kg: 10 mg PO once per day<br />
**If greater than 60 kg: 20 mg PO once per day<br />
<br />
'''3-month cycle for 6 cycles, alternating with re-induction courses'''<br />
<br />
===References===<br />
<br />
#'''GOELAMS LAM-SA2002:''' Pigneux A, Béné MC, Guardiola P, Recher C, Hamel JF, Sauvezie M, Harousseau JL, Tournilhac O, Witz F, Berthou C, Escoffre-Barbe M, Guyotat D, Fegueux N, Himberlin C, Hunault M, Delain M, Lioure B, Jourdan E, Bauduer F, Dreyfus F, Cahn JY, Sotto JJ, Ifrah N. Addition of androgens improves survival in elderly patients with acute myeloid leukemia: a GOELAMS study. J Clin Oncol. 2017 Feb;35(4):387-393. Epub 2016 Oct 24. [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.6213 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129526 PubMed]<br />
<br />
==Low-dose TBI, then allo HSCT {{#subobject:529ee7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TBI: '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation<br />
===Regimen {{#subobject:174a8e|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903320/ Gyukocza et al. 2010]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|174a8e}}<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
<br />
#Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA, Langston AA, Pulsipher MA, Bredeson CN, Maziarz RT, Bruno B, Petersen FB, Maris MB, Agura E, Yeager A, Bethge W, Sahebi F, Appelbaum FR, Maloney DG, Sandmaier BM. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010 Jun 10;28(17):2859-67. Epub 2010 May 3. [http://jco.ascopubs.org/content/28/17/2859.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903320/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20439626 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
''Note: with a few exceptions, these regimens are given as part of a non-curative line of therapy.''<br />
==Azacitidine monotherapy {{#subobject:887fd6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:482f11|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2010.08235.x/full Grövdal et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Intended to be used for transformed MDS patients in remission after AML induction therapy.''<br />
====Preceding treatment====<br />
<br />
*7+2d<br />
<br />
====Chemotherapy====<br />
<br />
*[[Azacitidine (Vidaza)]] 60 mg/m<sup>2</sup> SC once per day on days 1 to 5<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Grövdal M, Karimi M, Khan R, Aggerholm A, Antunovic P, Astermark J, Bernell P, Engström LM, Kjeldsen L, Linder O, Nilsson L, Olsson A, Holm MS, Tangen JM, Wallvik J, Oberg G, Hokland P, Jacobsen SE, Porwit A, Hellström-Lindberg E. Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy. Br J Haematol. 2010 Aug;150(3):293-302. Epub 2010 May 20. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2010.08235.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20497178 PubMed]<br />
<br />
==Decitabine monotherapy {{#subobject:d8250a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:4726aa|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867720/ Blum et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Blum et al. 2010 did not clearly state whether decitabine maintenance is at the same dosage/frequency as induction therapy. This is the inferred dosage from the paper.''<br />
====Preceding treatment====<br />
<br />
*[[#Decitabine_monotherapy|Decitabine induction]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Decitabine (Dacogen)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
**Patients with no evidence of residual disease by flow cytometry or cytogenetics who had grade 4 neutropenia (ANC less than 500/uL) persisting greater than or equal to 14 days received 4 days instead of 5 days of decitabine starting with the following cycle. If neutropenia occurred again as above with 4 days of decitabine, patients received 3 days instead of 4 days of decitabine starting with the following cycle.<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, Liu S, Havelange V, Becker H, Schaaf L, Mickle J, Devine H, Kefauver C, Devine SM, Chan KK, Heerema NA, Bloomfield CD, Grever MR, Byrd JC, Villalona-Calero M, Croce CM, Marcucci G. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7473-8. Epub 2010 Apr 5. [http://www.pnas.org/content/107/16/7473.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867720/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20368434 PubMed]<br />
<br />
==Gemtuzumab ozogamicin monotherapy {{#subobject:39de3d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b7c813|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/34/9/972.full Amadori et al. 2016 (EORTC/GIMEMA AML-19)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Gemtuzumab_ozogamicin_monotherapy|Gemtuzumab ozogamicin induction]], with clinical benefit<br />
<br />
====Chemotherapy====<br />
<br />
*[[Gemtuzumab ozogamicin (Mylotarg)]] 2 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''1-month cycle for up to 8 cycles'''<br />
<br />
===References===<br />
<!-- Presented in part at the 56th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 6-9, 2014. --><br />
<br />
#'''EORTC/GIMEMA AML-19:''' Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M, Annino L, Venditti A, Voso MT, Mazzone C, Magro D, De Fabritiis P, Muus P, Alimena G, Mancini M, Hagemeijer A, Paoloni F, Vignetti M, Fazi P, Meert L, Ramadan SM, Willemze R, de Witte T, Baron F. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016 Mar 20;34(9):972-9. Epub 2016 Jan 25. [http://jco.ascopubs.org/content/34/9/972.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26811524 PubMed]<br />
<br />
==LoDAC {{#subobject:4c65c8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
LoDAC: '''<u>Lo</u>'''w '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (cytarabine)<br />
<br>LDAC: '''<u>L</u>'''ow '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (cytarabine)<br />
<br />
===Regimen {{#subobject:2f5aa0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/2401850 Robles et al. 2000 (ECOG E5483)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#d9ef8b" |Might have superior DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*HiDAC, then amsacrine induction<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 10 mg/m<sup>2</sup> SC twice per day on days 1 to 21<br />
<br />
'''8-week cycles'''<br />
<br />
===References===<br />
<br />
#'''ECOG E5483:''' Robles C, Kim KM, Oken MM, Bennett JM, Letendre L, Wiernik PH, O'Connell MJ, Cassileth PA. Low-dose cytarabine maintenance therapy vs observation after remission induction in advanced acute myeloid leukemia: an Eastern Cooperative Oncology Group Trial (E5483). Leukemia. 2000 Aug;14(8):1349-53. [https://www.nature.com/articles/2401850 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10942228 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(84)90424-0/fulltext Sauter et al. 1984]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Maintenance chemotherapy<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nature.com/articles/2401850 Robles et al. 2000 (ECOG E5483)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#LoDAC_2|LoDAC]]<br />
| style="background-color:#fee08b" |Might have inferior DFS<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2004.05282.x Breems et al. 2005 (HOVON/SAKK AML4)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Auto HSCT<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/108/1/88.long Brune et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|HDC/IL-2<br />
| style="background-color:#d73027" |Inferior DFS<br />
|-<br />
|[http://www.bloodjournal.org/content/100/4/1224.long Baer et al. 2002 (CALGB 9720)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Low-dose IL-2<br />
| style="background-color:#ffffbf" |Seems not superior (*)<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0901409 Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemtuzumab_ozogamicin_monotherapy_2|Gemtuzumab ozogamicin]]<br />
| style="background-color:#ffffbf" |Seems not superior (*)<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682338/ Petersdorf et al. 2013 (SWOG S0106)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemtuzumab_ozogamicin_monotherapy_2|Gemtuzumab ozogamicin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139069/ Kolitz et al. 2013 (CALGB 19808)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Low-dose IL-2<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''No further antineoplastic treatment. Reported efficacy for CALGB 9720 is based on the 2008 update. Reported efficacy for HOVON 43 AML/SAKK 30/01 is based on the 2010 update.''<br />
====Preceding treatment====<br />
<br />
*ECOG E5483: HiDAC, then amsacrine induction<br />
*HOVON 43 AML/SAKK 30/01: [[#IDAC|IDAC consolidation]] x 1<br />
*SWOG S0106: [[#HiDAC|HiDAC consolidation]] x 3<br />
<br />
===References===<br />
<br />
#Sauter C, Berchtold W, Fopp M, Gratwohl A, Imbach P, Maurice P, Tschopp L, von Fliedner V, Cavalli F. Acute myelogenous leukaemia: maintenance chemotherapy after early consolidation treatment does not prolong survival. Lancet. 1984 Feb 18;1(8373):379-82. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(84)90424-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6141436 PubMed]<br />
#'''ECOG E5483:''' Robles C, Kim KM, Oken MM, Bennett JM, Letendre L, Wiernik PH, O'Connell MJ, Cassileth PA. Low-dose cytarabine maintenance therapy vs observation after remission induction in advanced acute myeloid leukemia: an Eastern Cooperative Oncology Group Trial (E5483). Leukemia. 2000 Aug;14(8):1349-53. [https://www.nature.com/articles/2401850 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10942228 PubMed]<br />
#'''HOVON/SAKK AML4:''' Breems DA, Boogaerts MA, Dekker AW, Van Putten WL, Sonneveld P, Huijgens PC, Van der Lelie J, Vellenga E, Gratwohl A, Verhoef GE, Verdonck LF, Löwenberg B. Autologous bone marrow transplantation as consolidation therapy in the treatment of adult patients under 60 years with acute myeloid leukaemia in first complete remission: a prospective randomized Dutch-Belgian Haemato-Oncology Co-operative Group (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) trial. Br J Haematol. 2005 Jan;128(1):59-65. [https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2004.05282.x link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15606550 PubMed]<br />
#Brune M, Castaigne S, Catalano J, Gehlsen K, Ho AD, Hofmann WK, Hogge DE, Nilsson B, Or R, Romero AI, Rowe JM, Simonsson B, Spearing R, Stadtmauer EA, Szer J, Wallhult E, Hellstrand K. Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trial. Blood. 2006 Jul 1;108(1):88-96. Epub 2006 Mar 23. [http://www.bloodjournal.org/content/108/1/88.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16556892 PubMed]<br />
#'''CALGB 9720:''' Baer MR, George SL, Dodge RK, O'Loughlin KL, Minderman H, Caligiuri MA, Anastasi J, Powell BL, Kolitz JE, Schiffer CA, Bloomfield CD, Larson RA. Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720. Blood. 2002 Aug 15;100(4):1224-32. [http://www.bloodjournal.org/content/100/4/1224.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12149202 PubMed]<br />
##'''Update:''' Baer MR, George SL, Caligiuri MA, Sanford BL, Bothun SM, Mrózek K, Kolitz JE, Powell BL, Moore JO, Stone RM, Anastasi J, Bloomfield CD, Larson RA. Low-dose interleukin-2 immunotherapy does not improve outcome of patients age 60 years and older with acute myeloid leukemia in first complete remission: Cancer and Leukemia Group B Study 9720. J Clin Oncol. 2008 Oct 20;26(30):4934-9. Epub 2008 Jun 30. [http://ascopubs.org/doi/full/10.1200/JCO.2008.17.0472 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652081/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18591543 PubMed]<br />
#'''HOVON 43 AML/SAKK 30/01:''' Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Döhner H, Gratwohl A, Pabst T, Verhoef G; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. [https://www.nejm.org/doi/full/10.1056/NEJMoa0901409 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19776405 PubMed]<br />
##'''Update:''' Löwenberg B, Beck J, Graux C, van Putten W, Schouten HC, Verdonck LF, Ferrant A, Sonneveld P, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, Breems D, de Muijnck H, Schaafsma R, Verhoef G, Döhner H, Gratwohl A, Pabst T, Ossenkoppele GJ, Maertens J; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON); German Austrian AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research Collaborative Group (SAKK). Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study. Blood. 2010 Apr 1;115(13):2586-91. Epub 2010 Jan 26. [http://www.bloodjournal.org/content/115/13/2586.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20103782 PubMed]<br />
#'''SWOG S0106:''' Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013 Jun 13;121(24):4854-60. Epub 2013 Apr 16. [http://bloodjournal.hematologylibrary.org/content/121/24/4854.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682338/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23591789 PubMed]<br />
#'''CALGB 19808:''' Kolitz JE, George SL, Benson DM Jr, Maharry K, Marcucci G, Vij R, Powell BL, Allen SL, Deangelo DJ, Shea TC, Stock W, Bakan CE, Hars V, Hoke E, Bloomfield CD, Caligiuri MA, Larson RA; Alliance for Clinical Trials in Oncology. Recombinant interleukin-2 in patients aged younger than 60 years with acute myeloid leukemia in first complete remission: results from Cancer and Leukemia Group B 19808. Cancer. 2014 Apr 1;120(7):1010-7. Epub 2013 Dec 31. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.28516 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139069/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24382782 PubMed]<br />
<br />
==Sorafenib monotherapy {{#subobject:23822e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:b50325|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930809/ Ravandi et al. 2010<sub>AML</sub>]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Note: This trial should not be confused for the one by the same name in Ph+ B-ALL.''<br />
====Preceding treatment====<br />
<br />
*[[#Cytarabine.2C_Idarubicin.2C_Sorafenib|Cytarabine, Idarubicin, Sorafenib consolidation]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Sorafenib (Nexavar)]] 400 mg PO twice per day<br />
<br />
'''Up to one year of sorafenib therapy, including consolidation course(s)'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
<br />
#Ravandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce SR, Brandt M, Byrd A, Bekele BN, Pratz K, Luthra R, Levis M, Andreeff M, Kantarjian HM. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010 Apr 10;28(11):1856-62. Epub 2010 Mar 8. [http://jco.ascopubs.org/content/28/11/1856.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930809/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20212254 PubMed]<br />
##'''Update:''' Ravandi F, Arana Yi C, Cortes JE, Levis M, Faderl S, Garcia-Manero G, Jabbour E, Konopleva M, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce S, Brandt M, Pratz K, Luthra R, Andreeff M, Kantarjian H. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia. 2014 Jul;28(7):1543-5. Epub 2014 Feb 3. [https://www.nature.com/leu/journal/v28/n7/full/leu201454a.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091714/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24487412 PubMed]<br />
<br />
=Relapsed or refractory, salvage therapy=<br />
''Note: these are generally aggressive regimens intended to induce a second remission as part of a path towards pre-planned allogeneic HSCT.''<br />
==5+2d {{#subobject:df9bab|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c9d569|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800702/ Zeidner et al. 2015 (JHOC-J1101)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3d_.28high-dose.29|7+3d (high-dose)]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose: 500 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
<br />
'''5-day course'''<br />
<br />
===References===<br />
<br />
#'''JHOC-J1101:''' Zeidner JF, Foster MC, Blackford AL, Litzow MR, Morris LE, Strickland SA, Lancet JE, Bose P, Levy MY, Tibes R, Gojo I, Gocke CD, Rosner GL, Little RF, Wright JJ, Doyle LA, Smith BD, Karp JE. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015 Sep;100(9):1172-9. Epub 2015 May 28. [http://www.haematologica.org/content/100/9/1172 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800702/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26022709 PubMed]<br />
<br />
==ADE (standard-dose Ara-C) {{#subobject:d16134|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADE: '''<u>A</u>'''ra-C (Cytarabine), '''<u>D</u>'''aunorubicin, '''<u>E</u>'''toposide <br />
<br />
===Regimen {{#subobject:a99e51|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/107/12/4614.long Milligan et al. 2006 (MRC AML-HR)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FLA<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
<br />
====Chemotherapy, Course 1====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV push every 12 hours on days 1 to 10 (20 total doses)<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV slow push once per day on days 1, 3, 5<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
====Chemotherapy, Course 2====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV push every 12 hours on days 1 to 8 (16 total doses)<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV slow push once per day on days 1, 3, 5<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
===References===<br />
<br />
#'''MRC AML-HR:''' Milligan DW, Wheatley K, Littlewood T, Craig JI, Burnett AK; NCRI Haematological Oncology Clinical Studies Group. Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial. Blood. 2006 Jun 15;107(12):4614-22. Epub 2006 Feb 16. [http://www.bloodjournal.org/content/107/12/4614.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16484584 PubMed]<br />
<br />
==CLAG {{#subobject:702383|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CLAG: '''<u>CL</u>'''adribine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF<br />
<br />
===Regimen {{#subobject:12d1bb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.tandfonline.com/doi/full/10.3109/10428190009053545 Robak et al. 2000]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cladribine (Leustatin)]] 5 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given first'''<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 5, '''given second, 2 hours after cladribine'''<br />
*[[Filgrastim (Neupogen)]] 300 mcg SC once per day on days -1 to 5 (first dose is given 24 hours before first dose of cladribine)<br />
<br />
===References===<br />
<br />
#Robak T, Wrzesień-Kuś A, Lech-Marańda E, Kowal M, Dmoszyńska A. Combination regimen of cladribine (2-chlorodeoxyadenosine), cytarabine and G-CSF (CLAG) as induction therapy for patients with relapsed or refractory acute myeloid leukemia. Leuk Lymphoma. 2000 Sep;39(1-2):121-9. [https://www.tandfonline.com/doi/full/10.3109/10428190009053545 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10975390 PubMed]<br />
#'''Retrospective:''' Martin MG, Welch JS, Augustin K, Hladnik L, DiPersio JF, Abboud CN. Cladribine in the treatment of acute myeloid leukemia: a single-institution experience. Clin Lymphoma Myeloma. 2009 Aug;9(4):298-301. [https://www.ncbi.nlm.nih.gov/pubmed/19717379 PubMed]<br />
<br />
==CLAG-M {{#subobject:51b417|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CLAG-M: '''<u>CL</u>'''adribine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF, '''<u>M</u>'''itoxantrone <br />
===Regimen {{#subobject:e0b308|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0609.2007.00988.x/abstract Wierzbowksa et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cladribine (Leustatin)]] 5 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given first'''<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 5, '''given second, 2 hours after cladribine'''<br />
*[[Filgrastim (Neupogen)]] based on WBC count:<br />
**WBC count less than or equal to 20 x 10<sup>9</sup>/L: 300 mcg SC once per day on days 0 to 5, '''started 24 hours prior to chemotherapy'''<br />
**WBC count greater than 20 x 10<sup>9</sup>/L: 300 mcg SC once per day on days 1 to 5, '''started simultaneously to cladribine'''<br />
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*Patients with PR were recommended to undergo a second course of CLAG-M. <br />
**Primary refractory patients achieving CR after 2nd CLAG-M: [[#HAM|HAM consolidation]]<br />
*Others could receive another course of CLAG-M or [[#HAM|HAM consolidation]] per investigator discretion<br />
<br />
===References===<br />
<br />
#Wierzbowska A, Robak T, Pluta A, Wawrzyniak E, Cebula B, Holowiecki J, Kyrcz-Krzemien S, Grosicki S, Giebel S, Skotnicki AB, Piatkowska-Jakubas B, Kuliczkowski K, Kielbinski M, Zawilska K, Kloczko J, Wrzesień-Kuś A; Polish Adult Leukemia Group. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol. 2008 Feb;80(2):115-26. Epub 2007 Dec 11. [https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0609.2007.00988.x/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18076637 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
#'''Retrospective:''' Martin MG, Welch JS, Augustin K, Hladnik L, DiPersio JF, Abboud CN. Cladribine in the treatment of acute myeloid leukemia: a single-institution experience. Clin Lymphoma Myeloma. 2009 Aug;9(4):298-301. [https://www.ncbi.nlm.nih.gov/pubmed/19717379 PubMed]<br />
<br />
==CLARA {{#subobject:48978a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CLARA: '''<u>CL</u>'''ofarabine and '''<u>ARA</u>'''-C (Cytarabine)<br />
<br>GCLAC: '''<u>G</u>'''-CSF, '''<u>C</u>'''lofarabine, '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
===Regimen {{#subobject:b8a3a2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834701/ Becker et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 25 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, '''given first'''<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 5, '''given second, 4 hours after start of clofarabine infusion'''<br />
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting day -1, continuing until ANC at least 2000/uL for 2 consecutive days<br />
<br />
'''One course with one re-induction allowed for patients with greater than 5% blasts at day 21''' <br />
====Subsequent treatment====<br />
<br />
*Patients achieving CR could receive consolidation with clofarabine reduced to 20 mg/m<sup>2</sup>, and cytarabine reduced to 1000 mg/m<sup>2</sup>, up to 2 cycles<br />
<br />
===References===<br />
<br />
#Becker PS, Kantarjian HM, Appelbaum FR, Petersdorf SH, Storer B, Pierce S, Shan J, Hendrie PC, Pagel JM, Shustov AR, Stirewalt DL, Faderl S, Harrington E, Estey EH. Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia. Br J Haematol. 2011 Oct;155(2):182-9. Epub 2011 Aug 18. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2011.08831.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834701/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21848522 PubMed]<br />
<br />
==Clofarabine & Cytarabine {{#subobject:23e3f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 20/20 {{#subobject:d4a73c|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13437/full Buckley et al. 2015]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''The dose of clofarabine is the one reported as the MTD. Note that the doses of both drugs are much lower than the other variants here.''<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 20 mg PO once per day on days 1 to 5<br />
*[[Cytarabine (Ara-C)]] as follows (per physician choice):<br />
**20 mg/m<sup>2</sup> SC twice per day on days 1 to 10<br />
**20 mg/m<sup>2</sup> SC once per day on days 1 to 14<br />
<br />
'''Cycle duration not explicitly defined; presumably 28 days'''<br />
<br />
===Variant #2, 30/1000 {{#subobject:f6ada8|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v30/n2/full/leu2015226a.html Middeke et al. 2015 (BRIDGE)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''At least one cycle'''<br />
====Subsequent treatment====<br />
<br />
*Chemo-responsive patients: [[#Clofarabine_.26_Melphalan.2C_then_allo_HSCT|Clofarabine & Melphalan, then allo HSCT]]<br />
<br />
===Variant #3, 40/1000 {{#subobject:d95457|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/105/3/940.long Faderl et al. 2004]<br />
| style="background-color:#91cf61" |Phase I/II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228084/ Agura et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874149/ Faderl et al. 2012 (CLASSIC I)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[Acute_myeloid_leukemia_-_historical#IDAC|IDAC]]<br />
| style="background-color:#1a9850" |Superior EFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 40 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, '''given first'''<br />
**Note: in Faderl et al. 2004, clofarabine was given on days 2 to 6<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given second, 3 to 4 hours after completion of clofarabine infusion'''<br />
<br />
====Supportive medications====<br />
<br />
*Best described in Agura et al. 2011<br />
*[[Dexamethasone (Decadron)]] 10 mg IV once per day<br />
*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonists]] on each day of chemotherapy<br />
*Hydration at 150 mL/m<sup>2</sup>/H "to prevent tumor lysis syndrome" during chemotherapy<br />
*[[Bumetanide (Bumex)]] 2 to 4 mg IV push once to twice per day as needed to keep weight within 1 kg of patient's initial weight<br />
*[[Levofloxacin (Levaquin)]] 500 mg IV or PO once per day<br />
*[[Acyclovir (Zovirax)]] 500 mg IV Q12H<br />
*One of the following antifungals:<br />
**[[Caspofungin (Cancidas)]] 50 mg IV once per day<br />
**[[Voriconazole (Vfend)]] 200 mg (route not specified) twice per day<br />
*Parenteral nutrition allowed<br />
*No routine use of growth factors<br />
<br />
'''1 to 4 cycles''' <br />
====Subsequent treatment====<br />
<br />
*See individual papers for details<br />
<br />
===References===<br />
<br />
#Faderl S, Gandhi V, O'Brien S, Bonate P, Cortes J, Estey E, Beran M, Wierda W, Garcia-Manero G, Ferrajoli A, Estrov Z, Giles FJ, Du M, Kwari M, Keating M, Plunkett W, Kantarjian H. Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood. 2005 Feb 1;105(3):940-7. Epub 2004 Oct 14. [http://www.bloodjournal.org/content/105/3/940.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15486072 PubMed]<br />
#Agura E, Cooper B, Holmes H, Vance E, Berryman RB, Maisel C, Li S, Saracino G, Tadic-Ovcina M, Fay J. Report of a phase II study of clofarabine and cytarabine in de novo and relapsed and refractory AML patients and in selected elderly patients at high risk for anthracycline toxicity. Oncologist. 2011;16(2):197-206. Epub 2011 Jan 27. [http://theoncologist.alphamedpress.org/content/16/2/197.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228084/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21273514 PubMed]<br />
<!-- Presented in part at the 53rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2011, and at the 16th Congress of the European Hematology Association, London, United Kingdom, June 9-12, 2011. --><br />
#'''CLASSIC I:''' Faderl S, Wetzler M, Rizzieri D, Schiller G, Jagasia M, Stuart R, Ganguly S, Avigan D, Craig M, Collins R, Maris M, Kovacsovics T, Goldberg S, Seiter K, Hari P, Greiner J, Vey N, Recher C, Ravandi F, Wang ES, Vasconcelles M, Huebner D, Kantarjian HM. Clofarabine plus cytarabine compared with cytarabine alone in older patients with relapsed or refractory acute myelogenous leukemia: results from the CLASSIC I Trial. J Clin Oncol. 2012 Jul 10;30(20):2492-9. Epub 2012 May 14. [http://jco.ascopubs.org/content/30/20/2492.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874149/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22585697 PubMed]<br />
#Buckley SA, Mawad R, Gooley TA, Becker PS, Sandhu V, Hendrie P, Scott BL, Wood BL, Walter RB, Smith K, Dean C, Estey EH, Pagel JM. A phase I/II study of oral clofarabine plus low-dose cytarabine in previously treated acute myeloid leukaemia and high-risk myelodysplastic syndrome patients at least 60 years of age. Br J Haematol. 2015 Aug;170(3):349-55. Epub 2015 Apr 8. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13437/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25854284 PubMed]<br />
#'''BRIDGE:''' Middeke JM, Herbst R, Parmentier S, Bug G, Hänel M, Stuhler G, Schäfer-Eckart K, Rösler W, Klein S, Bethge W, Bitz U, Büttner B, Knoth H, Alakel N, Schaich M, Morgner A, Kramer M, Sockel K, von Bonin M, Stölzel F, Platzbecker U, Röllig C, Thiede C, Ehninger G, Bornhäuser M, Schetelig J. Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial. Leukemia. 2016 Feb;30(2):261-7. Epub 2015 Aug 18. [https://www.nature.com/leu/journal/v30/n2/full/leu2015226a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26283567 PubMed]<br />
<br />
==Cytarabine & Mitoxantrone {{#subobject:fba448|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MIDAC: '''<u>M</u>'''itoxantrone & '''<u>I</u>'''ntermediate-'''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
===Variant #1, 6000/25 {{#subobject:5bf868|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/%28SICI%291097-0142%2820000501%2988:9%3C2037::AID-CNCR8%3E3.0.CO;2-K/full Sternberg et al. 2000]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 500 mg/m<sup>2</sup> IV over 90 minutes every 12 hours on days 1 to 6 (12 total doses)<br />
*[[Mitoxantrone (Novantrone)]] 5 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
<br />
'''One course'''<br />
<br />
===Variant #2, 10,000/48 {{#subobject:4a2f44|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/88/4/1198.long Solary et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cytarabine, Mitoxantrone, Quinine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once every 12 hours on days 1 to 5 (10 total doses)<br />
*[[Mitoxantrone (Novantrone)]] 12 mg/m<sup>2</sup> IV bolus once per day on days 2 to 5<br />
<br />
'''One course'''<br />
===References===<br />
<br />
#Solary E, Witz B, Caillot D, Moreau P, Desablens B, Cahn JY, Sadoun A, Pignon B, Berthou C, Maloisel F, Guyotat D, Casassus P, Ifrah N, Lamy Y, Audhuy B, Colombat P, Harousseau JL. Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study. Blood. 1996 Aug 15;88(4):1198-205. [http://www.bloodjournal.org/content/88/4/1198.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8695837 PubMed]<br />
#Sternberg DW, Aird W, Neuberg D, Thompson L, MacNeill K, Amrein P, Shulman LN. Treatment of patients with recurrent and primary refractory acute myelogenous leukemia using mitoxantrone and intermediate-dose cytarabine: a pharmacologically based regimen. Cancer. 2000 May 1;88(9):2037-41. [https://onlinelibrary.wiley.com/doi/10.1002/%28SICI%291097-0142%2820000501%2988:9%3C2037::AID-CNCR8%3E3.0.CO;2-K/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10813714 PubMed]<br />
<br />
==Etoposide & Mitoxantrone {{#subobject:3f0d63|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7683cc|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/6/2/213.abstract Ho et al. 1988]<br />
| style="background-color:#91cf61" |Phase II<br />
|ORR: 54%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5<br />
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV over 15 minutes once per day on days 1 to 5<br />
<br />
===References===<br />
<br />
#Ho AD, Lipp T, Ehninger G, Illiger HJ, Meyer P, Freund M, Hunstein W. Combination of mitoxantrone and etoposide in refractory acute myelogenous leukemia--an active and well-tolerated regimen. J Clin Oncol. 1988 Feb;6(2):213-7. [http://jco.ascopubs.org/content/6/2/213.abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3422260 PubMed]<br />
<br />
==FLAG {{#subobject:551761|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FLAG: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF<br />
===Variant #1, weight-based G-CSF {{#subobject:9501d2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/%28SICI%291096-8652%28199806%2958:2%3C105::AID-AJH3%3E3.0.CO;2-W/abstract Montillo et al. 1998]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first'''<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 5, '''given second, 4 hours after the start of fludarabine'''<br />
*G-CSF with one of the following:<br />
**[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day -1 (the paper described this as day 0), first dose given 24 hours before first dose of chemotherapy, to continue until neutrophil recovery<br />
**[[Lenograstim (Granocyte)]] 5 mcg/kg SC once per day, starting on day -1 (the paper described this as day 0), first dose given 24 hours before first dose of chemotherapy, to continue until neutrophil recovery<br />
<br />
'''One course'''<br />
<br />
===Variant #2, BSA-based G-CSF {{#subobject:bdc7e4|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.7384 Kaspers et al. 2013 (I-BFM-SG 2001/01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Acute_myeloid_leukemia_-_historical#FLAG-DNX|FLAG-DNX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior CR rate<br />
|-<br />
|}<br />
''Note: this regimen was studied in patients up to 21 years of age.''<br />
====Chemotherapy====<br />
<br />
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second'''<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given third, 4 hours after the start of fludarabine'''<br />
*[[Filgrastim (Neupogen)]] 200 mcg/m<sup>2</sup> (route not specified) once per day on days 0 to 5, '''given first'''<br />
<br />
'''Two cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[#CYVE_2|CYVE]] or [[#Cytarabine_.26_Thioguanine|Cytarabine & Thioguanine]] consolidation, as a bridge to [[#Allogeneic_hematopoietic_stem_cell_transplant_2|allogeneic HSCT]]<br />
<br />
===References===<br />
<br />
#Montillo M, Mirto S, Petti MC, Latagliata R, Magrin S, Pinto A, Zagonel V, Mele G, Tedeschi A, Ferrara F. Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of poor risk acute myeloid leukemia. Am J Hematol. 1998 Jun;58(2):105-9. [https://onlinelibrary.wiley.com/doi/10.1002/%28SICI%291096-8652%28199806%2958:2%3C105::AID-AJH3%3E3.0.CO;2-W/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9625576 PubMed]<br />
#'''I-BFM-SG 2001/01:''' Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.7384 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23319696 PubMed]<br />
<br />
==FLAG-Ida {{#subobject:d8c75b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FLAG-Ida: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF (Filgrastim), '''<u>Ida</u>'''rubicin<br />
===Regimen {{#subobject:5fa1bb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/9432047 Parker et al. 1997]<br />
| style="background-color:#ffffbe" |Phase II, <20 patients<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00277-003-0624-2 Pastore et al. 2003]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first'''<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 5, '''given second, 4 hours after fludarabine'''<br />
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 6, to continue until neutrophil recovery<br />
*[[Idarubicin (Idamycin)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
===References===<br />
<br />
#Parker JE, Pagliuca A, Mijovic A, Cullis JO, Czepulkowski B, Rassam SM, Samaratunga IR, Grace R, Gover PA, Mufti GJ. Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia. Br J Haematol. 1997 Dec;99(4):939-44. [https://www.ncbi.nlm.nih.gov/pubmed/9432047 PubMed]<br />
#Pastore D, Specchia G, Carluccio P, Liso A, Mestice A, Rizzi R, Greco G, Buquicchio C, Liso V. FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience. Ann Hematol. 2003 Apr;82(4):231-5. Epub 2003 Mar 15. [https://link.springer.com/article/10.1007%2Fs00277-003-0624-2 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12707726 PubMed]<br />
<br />
==F-SHAI {{#subobject:9e1c5f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
F-SHAI: '''<u>F</u>'''ludarabine, '''<u>S</u>'''equential '''<u>H</u>'''igh-dose '''<u>A</u>'''ra-C (cytarabine), '''<u>I</u>'''darubicin<br />
<br />
===Regimen {{#subobject:b50224|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v28/n5/full/leu2013297a.html Fiegl et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[Acute_myeloid_leukemia_-_historical#SHAI|SHAI]]<br />
| style="background-color:#91cf60" |Seems to have superior TTTF<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fludarabine (Fludara)]] 15 mg/m<sup>2</sup> IV twice per day on days 1, 2, 8, 9, '''given 4 hours prior to each cytarabine dose'''<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV twice per day on days 1, 2, 8, 9<br />
**Dose increased to 3000 mg/m<sup>2</sup> for patients 60 or younger with refractory AML or greater than or equal to 2nd relapse<br />
*[[Idarubicin (Idamycin)]] 10 mg/m<sup>2</sup> IV once per day on days 3, 4, 10, 11<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] 5 mcg/kg SC once per day from day 14 until ANC greater than 1500/uL<br />
**Discontinued if the post-treatment bmbx had greater than 5% bone marrow blasts<br />
<br />
'''One course'''<br />
<br />
===References===<br />
<br />
#Fiegl M, Unterhalt M, Kern W, Braess J, Spiekermann K, Staib P, Grüneisen A, Wörmann B, Schöndube D, Serve H, Reichle A, Hentrich M, Schiel X, Sauerland C, Heinecke A, Rieger C, Beelen D, Berdel WE, Büchner T, Hiddemann W. Chemomodulation of sequential high-dose cytarabine by fludarabine in relapsed or refractory acute myeloid leukemia: a randomized trial of the AMLCG. Leukemia. 2014 May;28(5):1001-7. Epub 2013 Oct 22. [https://www.nature.com/leu/journal/v28/n5/full/leu2013297a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24150216 PubMed]<br />
<br />
==HiDAC {{#subobject:1dddf5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
HiDAC: '''<u>Hi</u>'''gh '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
===Variant #1, CI {{#subobject:e8a7af|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/114/19/4027.long Giles et al. 2009 (VION-CLI-037)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|HiDAC & Laromustine<br />
| style="background-color:#ffffbf" |Mixed response (see note)<br />
|-<br />
|}<br />
''Note: while the experimental arm of this trial met the primary endpoint of ORR, the control arm had superior PFS.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1500 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose: 7500 mg/m<sup>2</sup>)<br />
<br />
'''One course'''<br />
<br />
===Variant #2, intermittent {{#subobject:ab6f08|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0145212699000879 Karanes et al. 1999]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|HiDAC & Mitoxantrone<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 6<br />
<br />
'''One course'''<br />
===References===<br />
<br />
#Karanes C, Kopecky KJ, Head DR, Grever MR, Hynes HE, Kraut EH, Vial RH, Lichtin A, Nand S, Samlowski WE, Appelbaum FR. A phase III comparison of high dose ARA-C (HIDAC) versus HIDAC plus mitoxantrone in the treatment of first relapsed or refractory acute myeloid leukemia Southwest Oncology Group Study. Leuk Res. 1999 Sep;23(9):787-94. [https://www.sciencedirect.com/science/article/pii/S0145212699000879 link to SD article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10475617 PubMed]<br />
#'''VION-CLI-037:''' Giles F, Vey N, DeAngelo D, Seiter K, Stock W, Stuart R, Boskovic D, Pigneux A, Tallman M, Brandwein J, Kell J, Robak T, Staib P, Thomas X, Cahill A, Albitar M, O'Brien S. Phase 3 randomized, placebo-controlled, double-blind study of high-dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse. Blood. 2009 Nov 5;114(19):4027-33. Epub 2009 Aug 26. [http://www.bloodjournal.org/content/114/19/4027.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19710500 PubMed]<br />
<br />
==MEC {{#subobject:48e49b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MEC: '''<u>M</u>'''itoxantrone, '''<u>E</u>'''toposide, '''<u>C</u>'''ytarabine<br />
===Variant #1, 6/80/1000 {{#subobject:ac3985|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/9/7/1210.long Amadori et al. 1991]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Mitoxantrone (Novantrone)]] 6 mg/m<sup>2</sup> IV bolus once per day on days 1 to 6<br />
*[[Etoposide (Vepesid)]] 80 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 6<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 6 hours once per day on days 1 to 6<br />
<br />
'''One course'''<br />
<br />
===Variant #2, 8/80/1000 {{#subobject:9ad362|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/18/4110.long Feldman et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MEC & Lintuzumab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Mitoxantrone (Novantrone)]] 8 mg/m<sup>2</sup> IV once per day on days 1 to 6<br />
*[[Etoposide (Vepesid)]] 80 mg/m<sup>2</sup> IV once per day on days 1 to 6<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 6<br />
<br />
'''One course'''<br />
<br />
===Variant #3, 8/100/1000 {{#subobject:bd7f87|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457168/ Greenberg et al. 2004 (ECOG E2995)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MEC & Valspodar<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542857/ Cortes et al. 2014 (CLTR0308-205)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|CPX-351<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: this was the most commonly used salvage regimen in the control arm of CLTR0308-205; exact dosing details were not described in the paper.''<br />
====Chemotherapy====<br />
<br />
*[[Mitoxantrone (Novantrone)]] 8 mg/m<sup>2</sup> IV push once per day on days 1 to 5, '''given third'''<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given first'''<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second'''<br />
<br />
'''One course'''<br />
===References===<br />
<br />
#Amadori S, Arcese W, Isacchi G, Meloni G, Petti MC, Monarca B, Testi AM, Mandelli F. Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. J Clin Oncol. 1991 Jul;9(7):1210-4. [http://jco.ascopubs.org/content/9/7/1210.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2045861 PubMed]<br />
#'''ECOG E2995:''' Greenberg PL, Lee SJ, Advani R, Tallman MS, Sikic BI, Letendre L, Dugan K, Lum B, Chin DL, Dewald G, Paietta E, Bennett JM, Rowe JM. Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). J Clin Oncol. 2004 Mar 15;22(6):1078-86. Erratum in: J Clin Oncol. 2004 Jul 1;22(13):2747. [http://ascopubs.org/doi/full/10.1200/JCO.2004.07.048 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457168/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15020609 PubMed]<br />
#Feldman EJ, Brandwein J, Stone R, Kalaycio M, Moore J, O'Connor J, Wedel N, Roboz GJ, Miller C, Chopra R, Jurcic JC, Brown R, Ehmann WC, Schulman P, Frankel SR, De Angelo D, Scheinberg D. Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia. J Clin Oncol. 2005 Jun 20;23(18):4110-6. [http://jco.ascopubs.org/content/23/18/4110.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15961759 PubMed]<br />
#'''CLTR0308-205:''' Cortes JE, Goldberg SL, Feldman EJ, Rizzeri DA, Hogge DE, Larson M, Pigneux A, Recher C, Schiller G, Warzocha K, Kantarjian H, Louie AC, Kolitz JE. Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML. Cancer. 2015 Jan 15;121(2):234-42. Epub 2014 Sep 15. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.28974/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542857/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25223583 PubMed]<br />
<br />
=Consolidation after salvage therapy=<br />
==BuCy, then allo HSCT {{#subobject:83e07a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
BuCy: '''<u>Bu</u>'''sulfan & '''<u>Cy</u>'''clophosphamide<br />
===Variant #1, 12.8/120 {{#subobject:eeaff3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00200-4/abstract Rambaldi et al. 2015]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#BuFlu.2C_then_allo_HSCT|BuFlu, then allo HSCT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior 1-year non-relapse mortality<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455603/ Scott et al. 2017 (BMT CTN 0901)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|RIC allo HSCT<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|eeaff3}}<br />
===Variant #2, 16/200 {{#subobject:334af6|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM198312013092202 Santos et al. 1983]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|334af6}}<br />
===References===<br />
<br />
#Santos GW, Tutschka PJ, Brookmeyer R, Saral R, Beschorner WE, Bias WB, Braine HG, Burns WH, Elfenbein GJ, Kaizer H, Mellits D, Sensenbrenner LL, Stuart RK, Yeager AM. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med. 1983 Dec 1;309(22):1347-53. [https://www.nejm.org/doi/full/10.1056/NEJM198312013092202 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/6355849 PubMed]<br />
#Rambaldi A, Grassi A, Masciulli A, Boschini C, Micò MC, Busca A, Bruno B, Cavattoni I, Santarone S, Raimondi R, Montanari M, Milone G, Chiusolo P, Pastore D, Guidi S, Patriarca F, Risitano AM, Saporiti G, Pini M, Terruzzi E, Arcese W, Marotta G, Carella AM, Nagler A, Russo D, Corradini P, Alessandrino EP, Torelli GF, Scimè R, Mordini N, Oldani E, Marfisi RM, Bacigalupo A, Bosi A. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1525-36. Epub 2015 Sep 28. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00200-4/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26429297 PubMed]<br />
#'''BMT CTN 0901:''' Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, Maziarz RT, Warlick ED, Fernandez HF, Alyea EP, Hamadani M, Bashey A, Giralt S, Geller NL, Leifer E, Le-Rademacher J, Mendizabal AM, Horowitz MM, Deeg HJ, Horwitz ME. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol. 2017 Apr 10;35(11):1154-1161. Epub 2017 Feb 13. [http://ascopubs.org/doi/full/10.1200/JCO.2016.70.7091 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455603/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28380315 PubMed]<br />
<br />
==BuFlu, then allo HSCT {{#subobject:576283|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
BuFlu: '''<u>Bu</u>'''sulfan & '''<u>Flu</u>'''darabine<br />
<br>Flu/Bu: '''<u>Flu</u>'''darabine & '''<u>Bu</u>'''sulfan<br />
===Variant #1 {{#subobject:d415a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00200-4/abstract Rambaldi et al. 2015]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#BuCy.2C_then_allo_HSCT|BuCy, then allo HSCT]]<br />
| style="background-color:#fc8d59" |Seems to improve 1 & 2 year NRM, similar OS<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|d415a}}<br />
===Variant #2 {{#subobject:d415b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230823/ Andersson et al. 2008]<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#fc8d59" |Suggested improved outcomes, but shorter follow up<br />
|}<br />
{{#lst:Allogeneic HSCT|d415b}}<br />
===Variant #3 {{#subobject:d415c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/31/6/701.full Lee et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#BuCy.2C_then_allo_HSCT|BuCy, then allo HSCT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|d415c}}<br />
===References===<br />
<br />
#Andersson BS, de Lima M, Thall PF, Wang X, Couriel D, Korbling M, Roberson S, Giralt S, Pierre B, Russell JA, Shpall EJ, Jones RB, Champlin RE. Once daily IV busulfan and fludarabine (IV Bu-Flu) compares favorably with IV busulfan and cyclophosphamide (IV BuCy2) as pretransplant conditioning therapy in AML/MDS. Biol Blood Marrow Transplant. 2008;14(6):672-84. [http://www.bbmt.org/article/S1083-8791(08)00118-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230823/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18489993 Pubmed]<br />
#Lee JH, Joo YD, Kim H, Ryoo HM, Kim MK, Lee GW, Lee JH, Lee WS, Park JH, Bae SH, Hyun MS, Kim DY, Kim SD, Min YJ, Lee KH. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol. 2013 Feb 20;31(6):701-9. Epub 2012 Nov 5. [http://jco.ascopubs.org/content/31/6/701.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23129746 PubMed]<br />
#Rambaldi A, Grassi A, Masciulli A, Boschini C, Micò MC, Busca A, Bruno B, Cavattoni I, Santarone S, Raimondi R, Montanari M, Milone G, Chiusolo P, Pastore D, Guidi S, Patriarca F, Risitano AM, Saporiti G, Pini M, Terruzzi E, Arcese W, Marotta G, Carella AM, Nagler A, Russo D, Corradini P, Alessandrino EP, Torelli GF, Scimè R, Mordini N, Oldani E, Marfisi RM, Bacigalupo A, Bosi A. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1525-36. Epub 2015 Sep 28. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00200-4/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26429297 PubMed]<br />
<br />
==Clofarabine & Melphalan, then allo HSCT {{#subobject:08947a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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===Regimen {{#subobject:a408ed|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v30/n2/full/leu2015226a.html Middeke et al. 2015 (BRIDGE)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Limited details are available in the abstract. Treatment is meant to be given during aplasia.''<br />
====Preceding treatment====<br />
<br />
*[[#Clofarabine_.26_Cytarabine|Clofarabine & Cytarabine salvage]]<br />
{{#lst:Allogeneic HSCT|a408ed}}<br />
===References===<br />
<br />
#'''BRIDGE:''' Middeke JM, Herbst R, Parmentier S, Bug G, Hänel M, Stuhler G, Schäfer-Eckart K, Rösler W, Klein S, Bethge W, Bitz U, Büttner B, Knoth H, Alakel N, Schaich M, Morgner A, Kramer M, Sockel K, von Bonin M, Stölzel F, Platzbecker U, Röllig C, Thiede C, Ehninger G, Bornhäuser M, Schetelig J. Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial. Leukemia. 2016 Feb;30(2):261-7. Epub 2015 Aug 18. [https://www.nature.com/leu/journal/v30/n2/full/leu2015226a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26283567 PubMed]<br />
<br />
==Cytarabine & Thioguanine {{#subobject:3c38bc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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===Regimen {{#subobject:f2728e|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.7384 Kaspers et al. 2013 (I-BFM-SG 2001/01)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this regimen was studied in patients up to 21 years of age, and was intended for use when the time to transplant would be relatively short or for patients in "poor condition".''<br />
====Preceding treatment====<br />
<br />
*[[#FLAG|FLAG]] versus [[Acute_myeloid_leukemia_-_historical#FLAG-DNX|FLAG-DNX]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC once per day on days 1 to 4, every other week<br />
*[[Thioguanine (Tabloid)]] 100 mg/m<sup>2</sup> PO once per day for up to 4 weeks maximum<br />
<br />
====Subsequent treatment====<br />
<br />
*Allogeneic HSCT<br />
<br />
===References===<br />
<br />
#'''I-BFM-SG 2001/01:''' Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.7384 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23319696 PubMed]<br />
<br />
==CYVE {{#subobject:4bd791|Regimen=1}}==<br />
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CYVE: '''<u>CY</u>'''tarabine & '''<u>VE</u>'''pesid (Etoposide)<br />
===Regimen {{#subobject:a16529|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.7384 Kaspers et al. 2013 (I-BFM-SG 2001/01)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this regimen was studied in patients up to 21 years of age. It is unclear if the course is repeated more than once.''<br />
====Preceding treatment====<br />
<br />
*[[#FLAG|FLAG]] versus [[Acute_myeloid_leukemia_-_historical#FLAG-DNX|FLAG-DNX]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 500 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose: 2000 mg/m<sup>2</sup>)<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV twice per day on days 1 to 4<br />
<br />
====Subsequent treatment====<br />
<br />
*[[#Allogeneic_hematopoietic_stem_cell_transplant_2|allogeneic HSCT]]<br />
<br />
===References===<br />
<br />
#'''I-BFM-SG 2001/01:''' Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.7384 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23319696 PubMed]<br />
<br />
=Relapsed or refractory, subsequent lines of therapy=<br />
''Note: these regimens are generally intended to delay progression of disease and are of non-curative intent.''<br />
<br />
==Azacitidine monotherapy {{#subobject:531b70|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:39f96a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/19/3735.long Thepot et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Azacitidine (Vidaza)]] 75 mg/m<sup>2</sup> SC once per day on days 1 to 7<br />
<br />
'''28-day cycle for at least 4 to 6 cycles'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
<br />
#Thepot S, Itzykson R, Seegers V, Raffoux E, Quesnel B, Chait Y, Sorin L, Dreyfus F, Cluzeau T, Delaunay J, Sanhes L, Eclache V, Dartigeas C, Turlure P, Harel S, Salanoubat C, Kiladjian JJ, Fenaux P, Adès L; Groupe Francophone des Myelodysplasies (GFM). Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM). Blood. 2010 Nov 11;116(19):3735-42. Epub 2010 Jul 27. [http://www.bloodjournal.org/content/116/19/3735.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20664061 PubMed]<br />
<br />
==Ruxolitinib monotherapy {{#subobject:ad5c7c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:596d8b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081383/ Eghtedar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Ruxolitinib (Jakafi)]] 25 mg PO twice per day<br />
<br />
'''28-day cycles'''<br />
<br />
''Patients with progression were allowed to increase the dose to 50 mg PO twice per day''<br />
<br />
===References===<br />
<!-- This study was presented in part at the American Society of Hematology annual meeting, December 2010, Orlando, FL. --><br />
<br />
#Eghtedar A, Verstovsek S, Estrov Z, Burger J, Cortes J, Bivins C, Faderl S, Ferrajoli A, Borthakur G, George S, Scherle PA, Newton RC, Kantarjian HM, Ravandi F. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood. 2012 May 17;119(20):4614-8. Epub 2012 Mar 15. [http://www.bloodjournal.org/content/119/20/4614.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081383/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22422826 PubMed]<br />
<br />
=Response criteria=<br />
==NCI-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia (1990)==<br />
<br />
#Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD, Brunning R, Gale RP, Grever MR, Keating MJ, et al. Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol. 1990 May;8(5):813-9. Review. [http://jco.ascopubs.org/content/8/5/813.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2185339 PubMed]<br />
<br />
==Revised International Working Group recommendations (2003)==<br />
<br />
#Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Löwenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-9. Erratum in: J Clin Oncol. 2004 Feb 1;22(3):576. LoCocco, Francesco [corrected to Lo-Coco, Francesco]. [http://jco.ascopubs.org/content/21/24/4642.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14673054 PubMed]<br />
<br />
=Prognosis=<br />
<br />
==Prognostic Index for Adult Patients With Acute Myeloid Leukemia in First Relapse (2005)==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<br />
*Relapse-free interval from first complete remission<br />
**Greater than 18 months (0 points)<br />
**7 to 18 months ('''3 points''')<br />
**Less than or equal to 6 months ('''5 points''')<br />
*Cytogenetics at diagnosis<br />
**t(16;16) or inv(16) with or without additional cytogenetic abnormalities (0 points)<br />
**t(8;21) with or without additional cytogenetic abnormalities ('''3 points''')<br />
**Normal, intermediate, unfavorable, or unknown cytogenetics ('''5 points''')<br />
*Age at time of first relapse<br />
**Less than or equal to 35 years (0 points)<br />
**36 to 45 years ('''1 point''')<br />
**Greater than 45 years ('''2 points''')<br />
*Stem cell transplantation performed before first relapse<br />
**No (0 points)<br />
**Yes, autologous or allogeneic ('''2 points''')<br />
<br />
Risk stratification:<br />
<br />
*'''1 to 6 points''': Favorable risk (1-year OS of 70%; 5-year OS of 46%)<br />
*'''7 to 9 points''': Intermediate risk (1-year OS of 49%; 5-year OS of 18%)<br />
*'''10 to 14 points''': Poor risk (1-year OS of 16%; 5-year OS of 4%)<br />
<br />
===References===<br />
<br />
#Breems DA, Van Putten WL, Huijgens PC, Ossenkoppele GJ, Verhoef GE, Verdonck LF, Vellenga E, De Greef GE, Jacky E, Van der Lelie J, Boogaerts MA, Löwenberg B. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol. 2005 Mar 20;23(9):1969-78. Epub 2005 Jan 4. [http://jco.ascopubs.org/content/23/9/1969.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15632409 PubMed]<br />
<br />
==Prognosis in cytogenetically normal AML==<br />
<br />
#''Seminal paper comparing the mutational status of NPM1, FLT3, CEBPA, MLL, and NRAS with clinical outcome:'' Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H; German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008 May 1;358(18):1909-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa074306 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18450602 PubMed]<br />
<br />
=Investigational agents=<br />
<br />
''These are drugs under study with at least some promising results for this disease.''<br />
<br />
*[[Alvocidib (Flavopiridol)]]<br />
*[[Vadastuximab talirine (SGN-CD33A)]]<br />
*[[Volasertib (BI 6727)]]<br />
*[[Vosaroxin (SNS 595)]]<br />
<br />
=Additional information=<br />
<br />
==Antifungal prophylaxis==<br />
<br />
#'''Review:''' Halpern AB, Lyman GH, Walsh TJ, Kontoyiannis DP, Walter RB. Primary antifungal prophylaxis during curative-intent therapy for acute myeloid leukemia. Blood. 2015 Dec 24;126(26):2790-7. Epub 2015 Oct 26. [http://www.bloodjournal.org/content/126/26/2790.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26504183 PubMed]<br />
<br />
[[Category:Acute myeloid leukemia regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Acute leukemias]]</div>Karinehttps://hemonc.org/w/index.php?title=Acute_myeloid_leukemia&diff=37758Acute myeloid leukemia2019-06-04T02:27:19Z<p>Karine: /* Chemotherapy */ AML loDAC venetoclax Wei 2019 update with venetoclax dose reduction</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:MartinSchoen.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Marteens|Martin W. Schoen, MD, MPH]]<br>Saint Louis University<br>St. Louis, MO</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/mwschoen mwschoen]<br />
|-<br />
|}<br />
''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Acute_myeloid_leukemia_-_historical|historical regimens page]]. If you still can't find it, please let us know so we can add it!''<br><br />
<big>'''Note: biomarker-specific regimens have been moved to dedicated pages:'''<br />
*'''[[Acute_myeloid_leukemia,_FLT3-positive|AML, FLT3-positive]]'''<br />
*'''[[Acute_myeloid_leukemia,_IDH-mutated|AML, IDH-mutated]]'''<br />
</big><br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==ELN==<br />
====Current====<br />
<br />
*'''2017:''' [http://www.bloodjournal.org/content/129/4/424.long Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291965/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27895058 PubMed]<br />
<br />
====Older====<br />
<br />
*'''2010:''' [http://www.bloodjournal.org/content/115/3/453.long Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet] [https://www.ncbi.nlm.nih.gov/pubmed/19880497 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2013:''' Fey et al. [https://www.esmo.org/Guidelines/Haematological-Malignancies/Acute-Myeloblastic-Leukaemia-in-Adult-Patients Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
<br />
=="How I treat"==<br />
<br />
*'''2016:''' Ofran Y, Tallman MS, Rowe JM. How I treat acute myeloid leukemia presenting with preexisting comorbidities. Blood. 2016 Jul 28;128(4):488-96. Epub 2016 May 27. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524532/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27235136 PubMed]<br />
*'''2015:''' Röllig C, Ehninger G. How I treat hyperleukocytosis in acute myeloid leukemia. Blood. 2015 May 21;125(21):3246-52. Epub 2015 Mar 16. [http://www.bloodjournal.org/content/125/21/3246.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25778528 PubMed]<br />
*'''2014:''' Ossenkoppele G, Löwenberg B. How I treat the older patient with acute myeloid leukemia. Blood. 2015 Jan 29;125(5):767-74. Epub 2014 Dec 16. [http://www.bloodjournal.org/content/125/5/767.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25515963 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf NCCN Guidelines - Acute Myeloid Leukemia]<br />
<br />
=Upfront induction therapy, standard and older "fit" patients=<br />
''These are aggressive remission induction regimens given with curative intent.''<br />
==7+3d (standard-dose) {{#subobject:9f31ad|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
7+3d: '''<u>7</u>''' days of cytarabine + '''<u>3</u>''' days of '''<u>d</u>'''aunorubicin<br />
<br>AD: '''<u>A</u>'''ra-C (Cytarabine) & '''<u>D</u>'''aunorubicin<br />
<br>DA: '''<u>D</u>'''aunorubicin & '''<u>A</u>'''ra-C (Cytarabine)<br />
===Variant #1, 700/135 (CI Ara-C) {{#subobject:bb27bc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/4586956 Yates et al. 1973]<br />
| style="background-color:#ffffbe" |Non-randomized, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="3" |[http://www.bloodjournal.org/content/58/6/1203.long Rai et al. 1981 (CALGB 7421)]<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#7.2B3d_.28standard-dose.29|7+3d (bolus Ara-C)]]<br />
| style="background-color:#91cf60" |Seems to have superior CR rate<br />
|-<br />
|2. 5+2d<br />
| style="background-color:#1a9850" |Superior CR rate<br />
|-<br />
|3. 5+2d (bolus Ara-C)<br />
| style="background-color:#1a9850" |Superior CR rate<br />
|-<br />
| rowspan="2" |[https://onlinelibrary.wiley.com/doi/epdf/10.1002/1097-0142%2819820415%2949%3A8%3C1530%3A%3AAID-CNCR2820490804%3E3.0.CO%3B2-1 Omura et al. 1982]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. AVML<br />
| style="background-color:#d3d3d3" |Not directly compared<br />
|-<br />
|2. [[Acute_myeloid_leukemia_-_historical#DAT|TAD]]<br />
| style="background-color:#1a9850" |Superior time to CR<br />
|-<br />
| rowspan="2" |[http://www.bloodjournal.org/content/60/2/454.long Yates et al. 1982 (CALGB 7721)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[Acute_myeloid_leukemia_-_historical#7.2B3d_.28low-dose.29|7+3d (low-dose)]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. 7+3a (30 mg/m<sup>2</sup>)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/63/5/1039.long Vogler et al. 1984]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[http://www.bloodjournal.org/content/69/5/1441.long Preisler et al. 1987 (CALGB 7921)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. 10+3d<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. [[Acute_myeloid_leukemia_-_historical#DAT|TAD]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/014521269090179D Stein et al. 1990]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MA<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/2179638 Arlin et al. 1990]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3m|7+3m]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/78/10/2520.long Dillman et al. 1991 (CALGB 8321)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3d_.28standard-dose.29|7+3d (higher-dose Ara-C)]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/79/2/313 Wiernik et al. 1992]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3i|7+3i]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://ascopubs.org/doi/10.1200/JCO.1992.10.7.1103 Vogler et al. 1992]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3i|7+3i]]<br />
| style="background-color:#fc8d59" |Seems to have inferior CR rate<br />
|-<br />
|[http://www.bloodjournal.org/content/103/2/479.long Rowe et al. 2004 (ECOG E3993)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. 7+3d + GM-CSF<br> 2. [[#7.2B3i|7+3i]]<br> 3. 7+3i + GM-CSF<br> 4. [[#7.2B3m|7+3m]]<br> 5. 7+3m + GM-CSF<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2008.07400.x Latagliata et al. 2008 (GIMEMA GSI 103 AMLE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|7+3 (Daunoxome)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480917/ Fernandez et al. 2009 (ECOG E1900)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3d_.28high-dose.29|7+3d (high-dose)]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ Dombret et al. 2015 (AZA-AML-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Azacitidine_monotherapy|Azacitidine]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
''Note: this was the lower bound of the allowable daunorubicin dose in AZA-AML-001.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*ECOG E3993: Patients with persistent disease at day 14 (greater than 5% blasts) underwent an identical second cycle of 7+3i<br />
<br />
===Variant #2, 700/150 (CI Ara-C) {{#subobject:9934a6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/75/1/27.long Bishop et al. 1990]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADE_.28standard-dose_Ara-C.29|ADE]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV bolus once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
<br />
===Variant #3, 1120/120 (intermittent Ara-C) {{#subobject:1f1bb5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/8916311 Masaoka et al. 1996]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#7.2B3i|7+3i]]<br />
| style="background-color:#fc8d59" |Seems to have inferior CR rate<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 80 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 1 to 7<br />
*[[Daunorubicin (Cerubidine)]] 40 mg/m<sup>2</sup> IV bolus once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
<br />
===Variant #4, 1400/135 (CI Ara-C) {{#subobject:635ecb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/78/10/2520.long Dillman et al. 1991 (CALGB 8321)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28standard-dose.29|7+3d (lower-dose Ara-C)]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/88/8/2841.long Weick et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|HDAC+3d<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/100/12/3869.long Anderson et al. 2002 (SWOG S9333)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ME<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895015/ Moore et al. 2004 (CALGB 9222)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0901409 Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3d_.28high-dose.29|7+3d (high-dose)]]<br />
| style="background-color:#d73027" |Inferior CR rate<br />
|-<br />
|[http://www.bloodjournal.org/content/118/14/3832.long Lee et al. 2011 (ADcomparison)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3d_.28high-dose.29|7+3d (high-dose)]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345117/ Hengeveld et al. 2012 (AML 8B)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://jco.ascopubs.org/content/33/11/1252.full Stone et al. 2015 (ACCEDE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Amonafide & Cytarabine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*CALGB 9222: [[#HiDAC|HiDAC]] versus multi-agent chemotherapy consolidation<br />
*HOVON 43 AML/SAKK 30/01: [[#IDAC|MiDAC consolidation]]<br />
*ACCEDE: patients received a second course of the same regimen if their day 14 bone marrow was positive. Patients with PR or better at time of count recovery received allogeneic stem cell transplant if eligible, otherwise [[#HiDAC|HiDAC]] if younger than 60 or [[#IDAC|MiDAC]] if greater than or equal to 60.<br />
<br />
===References===<br />
<br />
#Yates JW, Wallace HJ Jr, Ellison RR, Holland JF. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep. 1973 Nov-Dec;57(4):485-8. [https://www.ncbi.nlm.nih.gov/pubmed/4586956 PubMed]<br />
#'''CALGB 7421:''' Rai KR, Holland JF, Glidewell OJ, Weinberg V, Brunner K, Obrecht JP, Preisler HD, Nawabi IW, Prager D, Carey RW, Cooper MR, Haurani F, Hutchison JL, Silver RT, Falkson G, Wiernik P, Hoagland HC, Bloomfield CD, James GW, Gottlieb A, Ramanan SV, Blom J, Nissen NI, Bank A, Ellison RR, Kung F, Henry P, McIntyre OR, Kaan SK. Treatment of acute myelocytic leukemia: a study by Cancer and Leukemia Group B. Blood. 1981 Dec;58(6):1203-12. [http://www.bloodjournal.org/content/58/6/1203.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/6946847 PubMed]<br />
#Omura GA, Vogler WR, Lefante J, Silberman H, Knospe W, Gordon D, Jarrell R. Treatment of acute myelogenous leukemia: influence of three induction regimens and maintenance with chemotherapy or BCG immunotherapy. Cancer. 1982 Apr 15;49(8):1530-6. [https://onlinelibrary.wiley.com/doi/epdf/10.1002/1097-0142%2819820415%2949%3A8%3C1530%3A%3AAID-CNCR2820490804%3E3.0.CO%3B2-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7039813 PubMed]<br />
#'''CALGB 7721:''' Yates J, Glidewell O, Wiernik P, Cooper MR, Steinberg D, Dosik H, Levy R, Hoagland C, Henry P, Gottlieb A, Cornell C, Berenberg J, Hutchison JL, Raich P, Nissen N, Ellison RR, Frelick R, James GW, Falkson G, Silver RT, Haurani F, Green M, Henderson E, Leone L, Holland JF. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood. 1982 Aug;60(2):454-62. [http://www.bloodjournal.org/content/60/2/454.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/6953986 PubMed]<br />
#Vogler WR, Winton EF, Gordon DS, Raney MR, Go B, Meyer L. A randomized comparison of postremission therapy in acute myelogenous leukemia: a Southeastern Cancer Study Group trial. Blood. 1984 May;63(5):1039-45. [http://www.bloodjournal.org/content/63/5/1039.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6201211 PubMed]<br />
#'''CALGB 7921:''' Preisler H, Davis RB, Kirshner J, Dupre E, Richards F 3rd, Hoagland HC, Kopel S, Levy RN, Carey R, Schulman P, Gottlieb AJ, McIntyre OR. Comparison of three remission induction regimens and two postinduction strategies for the treatment of acute nonlymphocytic leukemia: a Cancer and Leukemia Group B study. Blood. 1987 May;69(5):1441-9. [http://www.bloodjournal.org/content/69/5/1441.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/3552076 PubMed]<br />
#Stein RS, Vogler WR, Winton EF, Cohen HJ, Raney MR, Bartolucci A. Therapy of acute myelogenous leukemia in patients over the age of 50: a randomized Southeastern Cancer Study Group trial. Leuk Res. 1990;14(10):895-903. [https://www.sciencedirect.com/science/article/pii/014521269090179D link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/2259226 PubMed]<br />
#Bishop JF, Lowenthal RM, Joshua D, Matthews JP, Todd D, Cobcroft R, Whiteside MG, Kronenberg H, Ma D, Dodds A, Herrmann R, Szer J, Wolf MM, Young G; Australian Leukemia Study Group. Etoposide in acute nonlymphocytic leukemia. Blood. 1990 Jan 1;75(1):27-32. [http://www.bloodjournal.org/content/75/1/27.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2403818 PubMed]<br />
#Arlin Z, Case DC Jr, Moore J, Wiernik P, Feldman E, Saletan S, Desai P, Sia L, Cartwright K; Lederle Cooperative Group. Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Leukemia. 1990 Mar;4(3):177-83. [https://www.ncbi.nlm.nih.gov/pubmed/2179638 PubMed]<br />
#'''CALGB 8321:''' Dillman RO, Davis RB, Green MR, Weiss RB, Gottlieb AJ, Caplan S, Kopel S, Preisler H, McIntyre OR, Schiffer C. A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood. 1991 Nov 15;78(10):2520-6. [http://www.bloodjournal.org/content/78/10/2520.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1824249 PubMed]<br />
#Wiernik PH, Banks PL, Case DC Jr, Arlin ZA, Periman PO, Todd MB, Ritch PS, Enck RE, Weitberg AB. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992 Jan 15;79(2):313-9. [http://www.bloodjournal.org/content/79/2/313 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1730080 PubMed]<br />
#Vogler WR, Velez-Garcia E, Weiner RS, Flaum MA, Bartolucci AA, Omura GA, Gerber MC, Banks PL. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study. J Clin Oncol. 1992 Jul;10(7):1103-11. [http://ascopubs.org/doi/10.1200/JCO.1992.10.7.1103 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1607916 PubMed]<br />
#Masaoka T, Ogawa M, Yamada K, Kimura K, Ohashi Y. A phase II comparative study of idarubicin plus cytarabine versus daunorubicin plus cytarabine in adult acute myeloid leukemia. Semin Hematol. 1996 Oct;33(4 Suppl 3):12-7. '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8916311 PubMed]<br />
#Weick JK, Kopecky KJ, Appelbaum FR, Head DR, Kingsbury LL, Balcerzak SP, Bickers JN, Hynes HE, Welborn JL, Simon SR, Grever M. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood. 1996 Oct 15;88(8):2841-51. [http://www.bloodjournal.org/content/88/8/2841.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8874180 PubMed]<br />
#'''SWOG S9333:''' Anderson JE, Kopecky KJ, Willman CL, Head D, O'Donnell MR, Luthardt FW, Norwood TH, Chen IM, Balcerzak SP, Johnson DB, Appelbaum FR. Outcome after induction chemotherapy for older patients with acute myeloid leukemia is not improved with mitoxantrone and etoposide compared to cytarabine and daunorubicin: a Southwest Oncology Group study. Blood. 2002 Dec 1;100(12):3869-76. Epub 2002 Aug 1. [http://www.bloodjournal.org/content/100/12/3869.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12393614 PubMed]<br />
#'''ECOG E3993:''' Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, Makary AZ, Liesveld JL, Abboud CN, Dewald G, Hayes FA, Tallman MS, Wiernik PH; Eastern Cooperative Oncology. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004 Jan 15;103(2):479-85. Epub 2003 Sep 25. [http://www.bloodjournal.org/content/103/2/479.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14512295 PubMed]<br />
#'''CALGB 9222:''' Moore JO, George SL, Dodge RK, Amrein PC, Powell BL, Kolitz JE, Baer MR, Davey FR, Bloomfield CD, Larson RA, Schiffer CA. Sequential multiagent chemotherapy is not superior to high-dose cytarabine alone as postremission intensification therapy for acute myeloid leukemia in adults under 60 years of age: Cancer and Leukemia Group B Study 9222. Blood. 2005 May 1;105(9):3420-7. Epub 2004 Nov 30. [http://www.bloodjournal.org/content/105/9/3420.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895015/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15572587 PubMed]<br />
#'''GIMEMA GSI 103 AMLE:''' Latagliata R, Breccia M, Fazi P, Iacobelli S, Martinelli G, Di Raimondo F, Sborgia M, Fabbiano F, Pirrotta MT, Zaccaria A, Amadori S, Caramatti C, Falzetti F, Candoni A, Mattei D, Morselli M, Alimena G, Vignetti M, Baccarani M, Mandelli F. Liposomal daunorubicin versus standard daunorubicin: long term follow-up of the GIMEMA GSI 103 AMLE randomized trial in patients older than 60 years with acute myelogenous leukaemia. Br J Haematol. 2008 Dec;143(5):681-9. Epub 2008 Oct 20. [https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2008.07400.x link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18950458 PubMed]<br />
#'''HOVON 43 AML/SAKK 30/01:''' Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Döhner H, Gratwohl A, Pabst T, Verhoef G; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. [https://www.nejm.org/doi/full/10.1056/NEJMoa0901409 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19776405 PubMed]<br />
#'''ECOG E1900:''' Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald GW, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Tallman MS. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1249-59. [https://www.nejm.org/doi/full/10.1056/NEJMoa0904544 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480917/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19776406 PubMed]<br />
##'''Update:''' Luskin MR, Lee JW, Fernandez HF, Abdel-Wahab O, Bennett JM, Ketterling RP, Lazarus HM, Levine RL, Litzow MR, Paietta EM, Patel JP, Racevskis J, Rowe JM, Tallman MS, Sun Z, Luger SM. Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups. Blood. 2016 Mar 24;127(12):1551-8. Epub 2016 Jan 11. [http://www.bloodjournal.org/content/127/12/1551.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807422/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26755712 PubMed]<br />
#'''ADcomparison:''' Lee JH, Joo YD, Kim H, Bae SH, Kim MK, Zang DY, Lee JL, Lee GW, Lee JH, Park JH, Kim DY, Lee WS, Ryoo HM, Hyun MS, Kim HJ, Min YJ, Jang YE, Lee KH; Cooperative Study Group A for Hematology. A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia. Blood. 2011 Oct 6;118(14):3832-41. Epub 2011 Aug 9. [http://www.bloodjournal.org/content/118/14/3832.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21828126 PubMed]<br />
#'''AML 8B:''' Hengeveld M, Suciu S, Karrasch M, Specchia G, Marie JP, Muus P, Petti MC, Rotoli B, Amadori S, Fioritoni G, Leoni P, Morra E, Thaler J, Resegotti L, Fazi P, Vignetti M, Mandelli F, Zittoun R, de Witte T. Intensive consolidation therapy compared with standard consolidation and maintenance therapy for adults with acute myeloid leukaemia aged between 46 and 60 years: final results of the randomized phase III study (AML 8B) of the European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. Ann Hematol. 2012 Jun;91(6):825-35. Epub 2012 Mar 31. [https://link.springer.com/article/10.1007%2Fs00277-012-1436-z link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345117/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22460947 PubMed]<br />
#'''ACCEDE:''' Stone RM, Mazzola E, Neuberg D, Allen SL, Pigneux A, Stuart RK, Wetzler M, Rizzieri D, Erba HP, Damon L, Jang JH, Tallman MS, Warzocha K, Masszi T, Sekeres MA, Egyed M, Horst HA, Selleslag D, Solomon SR, Venugopal P, Lundberg AS, Powell B. Phase III open-label randomized study of cytarabine in combination with amonafide l-malate or daunorubicin as induction therapy for patients with secondary acute myeloid leukemia. J Clin Oncol. 2015 Apr 10;33(11):1252-7. Epub 2015 Mar 2. [http://jco.ascopubs.org/content/33/11/1252.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25732165 PubMed]<br />
#'''AZA-AML-001:''' Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/3/291.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25987659 PubMed]<br />
##'''Subgroup analysis:''' Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3803-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731212/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29241450 PubMed]<br />
<br />
==7+3d (intermediate-dose) {{#subobject:e82156|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
7+3d: '''<u>7</u>''' days of cytarabine + '''<u>3</u>''' days of '''<u>d</u>'''aunorubicin<br />
===Variant #1, CI Ara-C (100 mg/m<sup>2</sup>) {{#subobject:bb27bc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2012.46.4743 Schaich et al. 2013 (AML2003)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2012.46.4990 Serve et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|7+3d & Sorafenib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682338/ Petersdorf et al. 2013 (SWOG S0106)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|7+3d & GO<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nature.com/articles/leu2015306 Müller-Tidow et al. 2015 (AML-AZA)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|7+3d & Azacitidine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ Dombret et al. 2015 (AZA-AML-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Azacitidine_monotherapy|Azacitidine]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00362-9/fulltext Röllig et al. 2015 (SORAML)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|7+3d & Sorafenib<br />
| style="background-color:#fc8d59" |Seems to have inferior EFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6112 Lancet et al. 2018 (CLTR0310-301)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CPX-351_monotherapy|CPX-351]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Note: this was the upper bound of the allowable daunorubicin dose in AZA-AML-001.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
**Note: Dombret et al. 2015 did not specify which days the daunorubicin is administered; some protocols give daunorubicin on days 3 to 5<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*AML2003: [[#HiDAC|HiDAC]] versus MAC/MAMAC/MAC consolidation<br />
*SWOG S0106: [[#HiDAC|HiDAC consolidation]] x 3<br />
*CLTR0310-301: [[#5.2B2d|5+2d consolidation]]<br />
<br />
===Variant #2, CI Ara-C (200 mg/m<sup>2</sup>) {{#subobject:cf53dd|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v18/n5/full/2403336a.html Holowiecki et al. 2004 (PALG AML1/1999)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#DAC|DAC]]<br />
| style="background-color:#d73027" |Inferior CR rate after first induction<br />
|-<br />
|[https://www.nature.com/articles/leu2010111 Chevallier et al. 2010 (LAM-2001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Acute_myeloid_leukemia_-_historical#7.2B5i|7+5i]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://jco.ascopubs.org/content/30/20/2441.full Holowiecki et al. 2012 (PALG AML1/2004)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#DAC|DAC]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. DAF<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60485-1/fulltext Castaigne et al. 2012 (ALFA-0701)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3d_.26_GO|7+3d & GO]]<br />
| style="background-color:#d73027" |Inferior EFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ Stone et al. 2017 (RATIFY)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Acute_myeloid_leukemia,_FLT3-positive#7.2B3d_.26_Midostaurin|7+3d & Midostaurin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Note: patients in RATIFY had FLT3+ disease.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV over 5 minutes once per day on days 1 to 3<br />
<br />
====Supportive medications====<br />
<br />
*"According to commonly accepted guidelines with no prophylactic IV antibiotics"<br />
*[[:Category:Granulocyte_colony-stimulating_factors|Granulocyte colony-stimulating factor]] recommended only for patients older than 50 years old whose leukemic blasts were negative for CD114 expression<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*Patients with only partial remission in both PALG studies underwent a second course with the same drugs, doses, and schedule.<br />
*PALG AML1/1999, non-responders: [[#CLAG|CLAG salvage]].<br />
*Patients in remission in both PALG studies: [[#HAM|HAM]], then [[#HiDAC|HiDAC]] consolidation<br />
*ALFA-0701, CR or CRp: [[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin consolidation]]<br />
<br />
===References===<br />
<br />
#'''PALG AML1/1999:''' Holowiecki J, Grosicki S, Robak T, Kyrcz-Krzemien S, Giebel S, Hellmann A, Skotnicki A, Jedrzejczak WW, Konopka L, Kuliczkowski K, Zdziarska B, Dmoszyńska A, Marianska B, Pluta A, Zawilska K, Komarnicki M, Kloczko J, Sulek K, Haus O, Stella-Holowiecka B, Baran W, Jakubas B, Paluszewska M, Wierzbowska A, Kielbinski M, Jagoda K; Polish Adult Leukemia Group (PALG). Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia: multicenter, phase III study. Leukemia. 2004 May;18(5):989-97. [https://www.nature.com/leu/journal/v18/n5/full/2403336a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14999298 PubMed]<br />
#'''LAM-2001:''' Chevallier P, Fornecker L, Lioure B, Béné MC, Pigneux A, Recher C, Witz B, Fegueux N, Bulabois CE, Daliphard S, Bouscary D, Vey N, Delain M, Bay JO, Turlure P, Bernard M, Himberlin C, Luquet I, Ifrah N, Harousseau JL; GOELAMS. Tandem versus single autologous peripheral blood stem cell transplantation as post-remission therapy in adult acute myeloid leukemia patients under 60 in first complete remission: results of the multicenter prospective phase III GOELAMS LAM-2001 trial. Leukemia. 2010 Jul;24(7):1380-5. Epub 2010 May 27. [https://www.nature.com/articles/leu2010111 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20508614 PubMed]<br />
#'''PALG AML1/2004:''' Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszyńska A, Kloczko J, Jedrzejczak WW, Zdziarska B, Warzocha K, Zawilska K, Komarnicki M, Kielbinski M, Piatkowska-Jakubas B, Wierzbowska A, Wach M, Haus O. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012 Jul 10;30(20):2441-8. Epub 2012 Apr 16. [http://jco.ascopubs.org/content/30/20/2441.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22508825 PubMed]<br />
#'''ALFA-0701:''' Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. Epub 2012 Apr 5. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60485-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22482940 PubMed]<br />
##'''Update:''' Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019 Jan;104(1):113-119. Epub 2018 Aug 3. [http://www.haematologica.org/content/104/1/113 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312010/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30076173 PubMed]<br />
#'''AML2003:''' Schaich M, Parmentier S, Kramer M, Illmer T, Stölzel F, Röllig C, Thiede C, Hänel M, Schäfer-Eckart K, Aulitzky W, Einsele H, Ho AD, Serve H, Berdel WE, Mayer J, Schmitz N, Krause SW, Neubauer A, Baldus CD, Schetelig J, Bornhäuser M, Ehninger G. High-dose cytarabine consolidation with or without additional amsacrine and mitoxantrone in acute myeloid leukemia: results of the prospective randomized AML2003 trial. J Clin Oncol. 2013 Jun 10;31(17):2094-102. Epub 2013 Apr 29. [http://ascopubs.org/doi/full/10.1200/JCO.2012.46.4743 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23630210 PubMed]<br />
#Serve H, Krug U, Wagner R, Sauerland MC, Heinecke A, Brunnberg U, Schaich M, Ottmann O, Duyster J, Wandt H, Fischer T, Giagounidis A, Neubauer A, Reichle A, Aulitzky W, Noppeney R, Blau I, Kunzmann V, Stuhlmann R, Krämer A, Kreuzer KA, Brandts C, Steffen B, Thiede C, Müller-Tidow C, Ehninger G, Berdel WE. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013 Sep 1;31(25):3110-8. Epub 2013 Jul 29. [http://ascopubs.org/doi/full/10.1200/JCO.2012.46.4990 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23897964 PubMed]<br />
#'''SWOG S0106:''' Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013 Jun 13;121(24):4854-60. Epub 2013 Apr 16. [http://bloodjournal.hematologylibrary.org/content/121/24/4854.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682338/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23591789 PubMed]<br />
#'''AZA-AML-001:''' Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/3/291.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25987659 PubMed]<br />
##'''Subgroup analysis:''' Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3803-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731212/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29241450 PubMed]<br />
#'''AML-AZA:''' Müller-Tidow C, Tschanter P, Röllig C, Thiede C, Koschmieder A, Stelljes M, Koschmieder S, Dugas M, Gerss J, Butterfaß-Bahloul T, Wagner R, Eveslage M, Thiem U, Krause SW, Kaiser U, Kunzmann V, Steffen B, Noppeney R, Herr W, Baldus CD, Schmitz N, Götze K, Reichle A, Kaufmann M, Neubauer A, Schäfer-Eckart K, Hänel M, Peceny R, Frickhofen N, Kiehl M, Giagounidis A, Görner M, Repp R, Link H, Kiani A, Naumann R, Brümmendorf TH, Serve H, Ehninger G, Berdel WE, Krug U; Study Alliance Leukemia Group. Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the Study Alliance Leukemia. Leukemia. 2016 Mar;30(3):555-61. Epub 2015 Nov 2. [https://www.nature.com/articles/leu2015306 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26522083 PubMed]<br />
#'''SORAML:''' Röllig C, Serve H, Hüttmann A, Noppeney R, Müller-Tidow C, Krug U, Baldus CD, Brandts CH, Kunzmann V, Einsele H, Krämer A, Schäfer-Eckart K, Neubauer A, Burchert A, Giagounidis A, Krause SW, Mackensen A, Aulitzky W, Herbst R, Hänel M, Kiani A, Frickhofen N, Kullmer J, Kaiser U, Link H, Geer T, Reichle A, Junghanß C, Repp R, Heits F, Dürk H, Hase J, Klut IM, Illmer T, Bornhäuser M, Schaich M, Parmentier S, Görner M, Thiede C, von Bonin M, Schetelig J, Kramer M, Berdel WE, Ehninger G; Study Alliance Leukaemia. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015 Dec;16(16):1691-9. Epub 2015 Nov 6. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00362-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26549589 PubMed]<br />
<!-- # '''Abstract:''' R. M. Stone, H. Dohner, G. Ehninger, M. Villeneuve, T. Teasdale, J. D. Virkus, L. R. Bressler, M. M. Seiler, G. Marcucci, R. A. Larson. CALGB 10603 (RATIFY): A randomized phase III study of induction (daunorubicin/cytarabine) and consolidation (high-dose cytarabine) chemotherapy combined with midostaurin or placebo in treatment-naive patients with FLT3 mutated AML. 2011 ASCO Annual Meeting abstract TPS199. [http://meetinglibrary.asco.org/content/81555-102 link to abstract]<br />
# '''Abstract:''' Richard M. Stone, Sumithra Mandrekar, Ben L Sanford, Susan Geyer, Clara D. Bloomfield, Konstanze Dohner, Christian Thiede, Guido Marcucci, Francesco Lo-Coco, Rebecca B. Klisovic, Andrew Wei, Jorge Sierra, Miguel A. Sanz, Joseph M. Brandwein, Theo de Witte, Dietger Niederwieser, Frederick R. Appelbaum, Bruno C. Medeiros, Martin S Tallman, Jurgen Krauter, Richard F. Schlenk, Arnold Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori, Richard A. Larson, Hartmut Dohner. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). 2015 ASH Annual Meeting plenary abstract 6. [https://ash.confex.com/ash/2015/webprogramscheduler/Paper80269.html link to abstract] '''contains protocol''' [https://clinicaltrials.gov/ct2/show/NCT00651261 Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia (NCT00651261) at ClinicalTrials.gov] --><br />
#'''RATIFY:''' Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1614359 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28644114 PubMed]<br />
<!-- # '''Abstract:''' Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Chiarella M, Louie AC, Medeiros BC. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol. 2016 34:15_suppl, 7000-7000 [http://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.7000 link to abstract] '''contains partial protocol''' [https://clinicaltrials.gov/ct2/show/NCT01696084 ClinicalTrials.gov] --><br />
#'''CLTR0310-301:''' Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018 Sep 10;36(26):2684-2692. Epub 2018 Jul 19. [http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6112 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30024784 PubMed]<br />
<br />
==7+3d (high-dose) {{#subobject:9e2666|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
7+3d: '''<u>7</u>''' days of cytarabine + '''<u>3</u>''' days of '''<u>d</u>'''aunorubicin<br />
===Variant #1, 700/270 {{#subobject:70583e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480917/ Fernandez et al. 2009 (ECOG E1900)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800702/ Zeidner et al. 2015 (JHOC-J1101)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|FLAM<br />
| style="background-color:#d73027" |Inferior CR rate<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 90 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*JHOC-J1101: Patients with residual leukemia at day 14 underwent [[#5.2B2d_2|5+2d salvage]]<br />
<br />
===Variant #2, 1400/240 {{#subobject:a33bec|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/104/8/2467.long Castaigne et al. 2004 (ALFA 9000)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#7.2B3d_.28high-dose.29|7+3d]] x 2<br> 2. Timed sequential induction<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 80 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
<br />
===Variant #3, 1400/270 {{#subobject:664ec|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0901409 Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br />
| style="background-color:#1a9850" |Superior CR rate<br />
|-<br />
|[http://www.bloodjournal.org/content/118/14/3832.long Lee et al. 2011 (ADcomparison)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 Lee et al. 2017 (COSAH C-022)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3i|7+3i]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 90 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*HOVON 43 AML/SAKK 30/01: [[#IDAC|MiDAC consolidation]]<br />
*COSAH C-022, with CR: [[#HiDAC|HiDAC consolidation]] if good- or intermediate-risk cytogenetics, or cytarabine & etoposide consolidation if high-risk cytogenetics.<br />
<br />
===References===<br />
<br />
#'''ALFA 9000:''' Castaigne S, Chevret S, Archimbaud E, Fenaux P, Bordessoule D, Tilly H, de Revel T, Simon M, Dupriez B, Renoux M, Janvier M, Micléa JM, Thomas X, Bastard C, Preudhomme C, Bauters F, Degos L, Dombret H. Randomized comparison of double induction and timed-sequential induction to a "3 + 7" induction in adults with AML: long-term analysis of the Acute Leukemia French Association (ALFA) 9000 study. Blood. 2004 Oct 15;104(8):2467-74. Epub 2004 May 13. [http://www.bloodjournal.org/content/104/8/2467.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15142880 PubMed]<br />
#'''HOVON 43 AML/SAKK 30/01:''' Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Döhner H, Gratwohl A, Pabst T, Verhoef G; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. [https://www.nejm.org/doi/full/10.1056/NEJMoa0901409 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19776405 PubMed]<br />
#'''ECOG E1900:''' Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald GW, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Tallman MS. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1249-59. [https://www.nejm.org/doi/full/10.1056/NEJMoa0904544 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480917/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19776406 PubMed]<br />
##'''Update:''' Luskin MR, Lee JW, Fernandez HF, Abdel-Wahab O, Bennett JM, Ketterling RP, Lazarus HM, Levine RL, Litzow MR, Paietta EM, Patel JP, Racevskis J, Rowe JM, Tallman MS, Sun Z, Luger SM. Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups. Blood. 2016 Mar 24;127(12):1551-8. Epub 2016 Jan 11. [http://www.bloodjournal.org/content/127/12/1551.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807422/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26755712 PubMed]<br />
#'''ADcomparison:''' Lee JH, Joo YD, Kim H, Bae SH, Kim MK, Zang DY, Lee JL, Lee GW, Lee JH, Park JH, Kim DY, Lee WS, Ryoo HM, Hyun MS, Kim HJ, Min YJ, Jang YE, Lee KH; Cooperative Study Group A for Hematology. A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia. Blood. 2011 Oct 6;118(14):3832-41. Epub 2011 Aug 9. [http://www.bloodjournal.org/content/118/14/3832.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21828126 PubMed]<br />
#'''JHOC-J1101:''' Zeidner JF, Foster MC, Blackford AL, Litzow MR, Morris LE, Strickland SA, Lancet JE, Bose P, Levy MY, Tibes R, Gojo I, Gocke CD, Rosner GL, Little RF, Wright JJ, Doyle LA, Smith BD, Karp JE. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015 Sep;100(9):1172-9. Epub 2015 May 28. [http://www.haematologica.org/content/100/9/1172 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800702/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26022709 PubMed]<br />
#'''COSAH C-022:''' Lee JH, Kim H, Joo YD, Lee WS, Bae SH, Zang DY, Kwon J, Kim MK, Lee J, Lee GW, Lee JH, Choi Y, Kim DY, Hur EH, Lim SN, Lee SM, Ryoo HM, Kim HJ, Hyun MS, Lee KH; Cooperative Study Group A for Hematology. Prospective randomized comparison of idarubicin and high-dose daunorubicin in induction chemotherapy for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2017 Aug 20;35(24):2754-2763. Epub 2017 Jun 20. [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28632487 PubMed]<br />
<br />
==7+3d & GO {{#subobject:869f84|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
7+3d & GO: '''<u>7</u>''' days of Cytarabine, '''<u>3</u>''' days of '''<u>d</u>'''aunorubicin, '''<u>G</u>'''emtuzumab '''<u>O</u>'''zogamicin<br />
===Regimen {{#subobject:4c0a05|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60485-1/fulltext Castaigne et al. 2012 (ALFA-0701)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]]<br />
| style="background-color:#1a9850" |Superior EFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Gemtuzumab ozogamicin (Mylotarg)]] 3 mg/m<sup>2</sup> (maximum dose of 5 mg) IV over 2 hours once per day on days 1, 4, 7<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*Patients in CR or CRp and platelet count at least 100 x 10<sup>9</sup> by day 45 after the initiation of chemotherapy: [[#Cytarabine.2C_Daunorubicin.2C_Gemtuzumab_ozogamicin|Cytarabine, Daunorubicin, Gemtuzumab ozogamicin consolidation]]<br />
*Patients in CR or CRp and platelet count less than 100 x 10<sup>9</sup> by day 45 after the initiation of chemotherapy: [[#Cytarabine_.26_Daunorubicin|Cytarabine & Daunorubicin consolidation]]<br />
<br />
===References===<br />
<br />
#'''ALFA-0701:''' Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60485-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22482940 PubMed]<br />
##'''Update:''' Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019 Jan;104(1):113-119. Epub 2018 Aug 3. [http://www.haematologica.org/content/104/1/113 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312010/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30076173 PubMed]<br />
<br />
==7+3i {{#subobject:717935|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
7+3i: '''<u>7</u>''' days of cytarabine + '''<u>3</u>''' days of '''<u>i</u>'''darubicin<br />
<br>AI: '''<u>A</u>'''ra-C (Cytarabine) & '''<u>I</u>'''darubicin<br />
<br>IA: '''<u>I</u>'''darubicin & '''<u>A</u>'''ra-C (Cytarabine)<br />
===Variant #1, 80/12, intermittent Ara-C {{#subobject:bdc11c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/8916311 Masaoka et al. 1996]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br />
| style="background-color:#91cf60" |Seems to have superior CR rate<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 80 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 1 to 7<br />
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV bolus once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
<br />
===Variant #2, 100/12, CI Ara-C {{#subobject:c6cda|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/10.1200/JCO.1992.10.7.1103 Vogler et al. 1992]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28standard-dose.29|7+3d]]<br />
| style="background-color:#91cf60" |Seems to have superior CR rate<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/8290968 Haas et al. 1993]<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://www.bloodjournal.org/content/103/2/479.long Rowe et al. 2004 (ECOG E3993)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br> 2. 7+3d + GM-CSF<br> 3. 7+3i + GM-CSF<br> 4. [[#7.2B3m|7+3m]]<br> 5. 7+3m + GM-CSF<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.21493 Miyawaki et al. 2005 (JALSG AML97)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs12185-009-0480-5 Ohtake et al. 2010 (JALSG AML95)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Individualized chemotherapy<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/117/8/2358 Ohtake et al. 2010 (JALSG AML201)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|7+5d<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
<br />
''Patients in ECOG E3993 with persistent disease at day 14 (greater than 5% blasts) underwent an identical second cycle of 7+3i.''<br />
<br />
===Variant #3, 100/13, CI Ara-C {{#subobject:7f2eec|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/79/2/313 Wiernik et al. 1992]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Idarubicin (Idamycin)]] 13 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
<br />
===Variant #4, 200/12, CI Ara-C {{#subobject:f33de6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa025406 Löwenberg et al. 2003 (HOVON/SAKK AML 29)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|7+3i & G-CSF<br />
| style="background-color:#fc8d59" |Seems to have inferior DFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.23.2652 Pautas et al. 2010 (ALFA-9801)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#7.2B3d_.28high-dose.29|7+3d (high-dose)]]<br> 2. 7+4i<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1010222 Löwenberg et al. 2011 (HOVON/SAKK AML 42)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|HDAC+3i<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/129/12/1636.long Löwenberg et al. 2017 (HOVON-102)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|7+3i & Clofarabine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 Lee et al. 2017 (COSAH C-022)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#7.2B3d_.28high-dose.29|7+3d (high-dose)]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>)<br />
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 to 3<br />
**Note: in HOVON/SAKK AML 29 & AML 42, idarubicin was given on days 5 to 7<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*HOVON/SAKK AML 29 & AML 42: Amsacrine & Cytarabine<br />
*ALFA-9801, patients achieiving CR: [[#Cytarabine_.26_Idarubicin_2|cytarabine & idarubicin consolidation]]<br />
*COSAH C-022, patients achieving CR, good- or intermediate-risk cytogenetics: [[#HiDAC|HiDAC consolidation]]<br />
*COSAH C-022, patients achieving CR, high-risk cytogenetics: [[#CYVE|CYVE consolidation]]<br />
<br />
===Variant #5, with range {{#subobject:eb0168|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ Dombret et al. 2015 (AZA-AML-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Azacitidine_monotherapy|Azacitidine]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 to 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 to 1400 mg/m<sup>2</sup>)<br />
*[[Idarubicin (Idamycin)]] 9 to 12 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
===References===<br />
<br />
#Wiernik PH, Banks PL, Case DC Jr, Arlin ZA, Periman PO, Todd MB, Ritch PS, Enck RE, Weitberg AB. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992 Jan 15;79(2):313-9. [http://www.bloodjournal.org/content/79/2/313 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1730080 PubMed]<br />
#Vogler WR, Velez-Garcia E, Weiner RS, Flaum MA, Bartolucci AA, Omura GA, Gerber MC, Banks PL. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study. J Clin Oncol. 1992 Jul;10(7):1103-11. [http://ascopubs.org/doi/10.1200/JCO.1992.10.7.1103 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1607916 PubMed]<br />
#Haas R, Ho AD, Del Valle F, Fischer JT, Ehrhardt R, Döhner H, Witt B, Huberts H, Kaplan E, Hunstein W. Idarubicin/cytosine arabinoside and mitoxantrone/etoposide for the treatment of de novo acute myelogenous leukemia. Semin Oncol. 1993 Dec;20(6 Suppl 8):20-6. [https://www.ncbi.nlm.nih.gov/pubmed/8290968 PubMed]<br />
#Masaoka T, Ogawa M, Yamada K, Kimura K, Ohashi Y. A phase II comparative study of idarubicin plus cytarabine versus daunorubicin plus cytarabine in adult acute myeloid leukemia. Semin Hematol. 1996 Oct;33(4 Suppl 3):12-7. '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8916311 PubMed]<br />
#'''HOVON/SAKK AML 29:''' Löwenberg B, van Putten W, Theobald M, Gmür J, Verdonck L, Sonneveld P, Fey M, Schouten H, de Greef G, Ferrant A, Kovacsovics T, Gratwohl A, Daenen S, Huijgens P, Boogaerts M; Dutch-Belgian Hemato-Oncology Cooperative Group; Swiss Group for Clinical Cancer Research. Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med. 2003 Aug 21;349(8):743-52. [https://www.nejm.org/doi/full/10.1056/NEJMoa025406 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12930926 PubMed]<br />
#'''ECOG E3993:''' Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, Makary AZ, Liesveld JL, Abboud CN, Dewald G, Hayes FA, Tallman MS, Wiernik PH; Eastern Cooperative Oncology. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004 Jan 15;103(2):479-85. Epub 2003 Sep 25. [http://www.bloodjournal.org/content/103/2/479.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14512295 PubMed]<br />
#'''JALSG AML97:''' Miyawaki S, Sakamaki H, Ohtake S, Emi N, Yagasaki F, Mitani K, Matsuda S, Kishimoto Y, Miyazaki Y, Asou N, Matsushima T, Takahashi M, Ogawa Y, Honda S, Ohno R; Japan Adult Leukemia Study Group AML 97 Study. A randomized, postremission comparison of four courses of standard-dose consolidation therapy without maintenance therapy versus three courses of standard-dose consolidation with maintenance therapy in adults with acute myeloid leukemia: the Japan Adult Leukemia Study Group AML 97 study. Cancer. 2005 Dec 15;104(12):2726-34. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.21493 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16284985 PubMed]<br />
#'''ALFA-9801:''' Pautas C, Merabet F, Thomas X, Raffoux E, Gardin C, Corm S, Bourhis JH, Reman O, Turlure P, Contentin N, de Revel T, Rousselot P, Preudhomme C, Bordessoule D, Fenaux P, Terré C, Michallet M, Dombret H, Chevret S, Castaigne S. Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol. 2010 Feb 10;28(5):808-14. Epub 2010 Jan 4. [http://ascopubs.org/doi/full/10.1200/JCO.2009.23.2652 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20048183 PubMed]<br />
#'''JALSG AML95:''' Ohtake S, Miyawaki S, Kiyoi H, Miyazaki Y, Okumura H, Matsuda S, Nagai T, Kishimoto Y, Okada M, Takahashi M, Handa H, Takeuchi J, Kageyama S, Asou N, Yagasaki F, Maeda Y, Ohnishi K, Naoe T, Ohno R. Randomized trial of response-oriented individualized versus fixed-schedule induction chemotherapy with idarubicin and cytarabine in adult acute myeloid leukemia: the JALSG AML95 study. Int J Hematol. 2010 Mar;91(2):276-83. [https://link.springer.com/article/10.1007%2Fs12185-009-0480-5 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20054669 PubMed]<br />
#'''JALSG AML201:''' Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N, Okumura H, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R. Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood. 2011 Feb 24;117(8):2358-65. Epub 2010 Aug 6. [http://www.bloodjournal.org/content/117/8/2358 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20693429 PubMed]<br />
#'''HOVON/SAKK AML 42:''' Löwenberg B, Pabst T, Vellenga E, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Biemond BJ, Gratwohl A, de Greef GE, Verdonck LF, Schaafsma MR, Gregor M, Theobald M, Schanz U, Maertens J, Ossenkoppele GJ; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. Cytarabine dose for acute myeloid leukemia. N Engl J Med. 2011 Mar 17;364(11):1027-36. [https://www.nejm.org/doi/full/10.1056/NEJMoa1010222 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21410371 PubMed]<br />
#'''AZA-AML-001:''' Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/3/291.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25987659 PubMed]<br />
##'''Subgroup analysis:''' Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3803-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731212/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29241450 PubMed]<br />
#Löwenberg B, Pabst T, Maertens J, van Norden Y, Biemond BJ, Schouten HC, Spertini O, Vellenga E, Graux C, Havelange V, de Greef GE, de Weerdt O, Legdeur MJ, Kuball J, Kooy MV, Gjertsen BT, Jongen-Lavrencic M, van de Loosdrecht AA, van Lammeren-Venema D, Hodossy B, Breems DA, Chalandon Y, Passweg J, Valk PJ, Manz MG, Ossenkoppele GJ; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) and Swiss Group for Clinical Cancer Research (SAKK). Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML. Blood. 2017 Mar 23;129(12):1636-1645. Epub 2017 Jan 3. [http://www.bloodjournal.org/content/129/12/1636.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28049642 PubMed]<br />
#'''COSAH C-022:''' Lee JH, Kim H, Joo YD, Lee WS, Bae SH, Zang DY, Kwon J, Kim MK, Lee J, Lee GW, Lee JH, Choi Y, Kim DY, Hur EH, Lim SN, Lee SM, Ryoo HM, Kim HJ, Hyun MS, Lee KH; Cooperative Study Group A for Hematology. Prospective randomized comparison of idarubicin and high-dose daunorubicin in induction chemotherapy for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2017 Aug 20;35(24):2754-2763. Epub 2017 Jun 20. [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28632487 PubMed]<br />
<br />
==7+3i & Sorafenib {{#subobject:ab6409|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:567ab9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930809/ Ravandi et al. 2010<sub>AML</sub>]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Note: Regimen details are from the phase II part of the published phase I/II trial. This trial should not be confused for the one by the same name in Ph+ B-ALL.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1500 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose: 6000 mg/m<sup>2</sup>)<br />
**Patients older than 60 received: 1500 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose: 4500 mg/m<sup>2</sup>)<br />
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3<br />
*[[Sorafenib (Nexavar)]] 400 mg PO twice per day on days 1 to 7<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*[[#Cytarabine.2C_Idarubicin.2C_Sorafenib|Cytarabine, idarubicin, sorafenib consolidation]]<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
<br />
#Ravandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce SR, Brandt M, Byrd A, Bekele BN, Pratz K, Luthra R, Levis M, Andreeff M, Kantarjian HM. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010 Apr 10;28(11):1856-62. Epub 2010 Mar 8. [http://jco.ascopubs.org/content/28/11/1856.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930809/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20212254 PubMed]<br />
##'''Update:''' Ravandi F, Arana Yi C, Cortes JE, Levis M, Faderl S, Garcia-Manero G, Jabbour E, Konopleva M, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce S, Brandt M, Pratz K, Luthra R, Andreeff M, Kantarjian H. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia. 2014 Jul;28(7):1543-5. Epub 2014 Feb 3. [https://www.nature.com/leu/journal/v28/n7/full/leu201454a.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091714/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24487412 PubMed]<br />
<br />
==7+3d & Glasdegib {{#subobject:61520d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:0e6b97|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1002/ajh.25238 Cortes et al. 2018]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Glasdegib (Daurismo)]]100 mg PO Qday for 28 days, started on day -3 for 6 cycles<br />
<br />
'''28-day course'''<br />
====Subsequent treatment====<br />
<br />
*[[#IDAC|Cytarabine consolidation]]<br />
<br />
===References===<br />
<br />
#Cortes JE, Douglas Smith B, Wang ES, Merchant A, Oehler VG, Arellano M, DeAngelo DJ, Pollyea DA, Sekeres MA, Robak T, Ma WW, Zeremski M, Naveed Shaik M, Douglas Laird A, O'Connell A, Chan G, Schroeder MA. Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results. Am J Hematol. 2018 Nov;93(11):1301-1310. Epub 2018 Sep 9. [https://doi.org/10.1002/ajh.25238 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221102/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30074259 PubMed]<br />
<br />
==7+3m {{#subobject:240c72|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
7+3m: '''<u>7</u>''' days of cytarabine + '''<u>3</u>''' days of '''<u>m</u>'''itoxantrone<br />
<br>MAC: '''<u>M</u>'''itoxantrone & '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
===Regimen {{#subobject:7d87af|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/2/479.long Rowe et al. 2004 (ECOG E3993)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br> 2. 7+3d + GM-CSF<br> 3. [[#7.2B3i|7+3i]]<br> 4. 7+3i + GM-CSF<br> 5. 7+3m + GM-CSF<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Mitoxantrone (Novantrone)]] 12 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*Patients with persistent disease at day 14 (greater than 5% blasts) underwent an identical second cycle of 7+3m<br />
<br />
===References===<br />
<br />
#'''ECOG E3993:''' Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, Makary AZ, Liesveld JL, Abboud CN, Dewald G, Hayes FA, Tallman MS, Wiernik PH; Eastern Cooperative Oncology. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004 Jan 15;103(2):479-85. Epub 2003 Sep 25. [http://www.bloodjournal.org/content/103/2/479.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14512295 PubMed]<br />
<br />
==ADE (standard-dose Ara-C) {{#subobject:e221d7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADE: '''<u>A</u>'''ra-C (Cytarabine), '''<u>D</u>'''aunorubicin, '''<u>E</u>'''toposide<br />
<br>7-3-7: '''<u>7</u>''' days of Cytarabine, '''<u>3</u>''' days of Daunorubicin, '''<u>7</u>''' days of Etoposide<br />
<br>8-3-5: '''<u>8</u>''' days of Cytarabine, '''<u>3</u>''' days of Daunorubicin, '''<u>5</u>''' days of Etoposide<br />
<br>10-3-5: '''<u>10</u>''' days of Cytarabine, '''<u>3</u>''' days of Daunorubicin, '''<u>5</u>''' days of Etoposide<br />
===Variant #1, 7-3-3, 700/180/300 {{#subobject:31dcd2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/100/4/1224.long Baer et al. 2002 (CALGB 9720)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ADEP<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''One course'''<br />
<br />
===Variant #2, 7-3-7, 700/150/525 {{#subobject:386fd2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/87/5/1710.long Bishop et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADE_.28high-dose_Ara-C.29|ADE (high-dose Ara-C)]]<br />
| style="background-color:#d73027" |Inferior DFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Etoposide (Vepesid)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 7<br />
<br />
'''7-day course, can be repeated up to 3 times if CR not achieved'''<br />
====Subsequent treatment====<br />
<br />
*5-2-5 consolidation x 2<br />
<br />
===Variant #3, 8-3-5, 1600/150/500, intermittent Ara-C {{#subobject:f7e0ca|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/89/7/2311.long Hann et al. 1997 (UK MRC AML10)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[Acute_myeloid_leukemia_-_historical#DAT|DAT 3+8]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
| style="background-color:#d3d3d3" |See note<br />
| style="background-color:#d3d3d3" |See note<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ Gamis et al. 2014 (COG AAML0531)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
| style="background-color:#d3d3d3" |See note<br />
| style="background-color:#d3d3d3" |See note<br />
|-<br />
|}<br />
''Note: these trials have complicated treatment schemas; see papers for details.''<br />
====Preceding treatment====<br />
<br />
*[[#ADE_.28standard-dose_Ara-C.29|ADE 10-3-5 induction]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV every 12 hours on days 1 to 8<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''8-day course'''<br />
====Subsequent treatment====<br />
<br />
*UK MRC AML10: MACE consolidation<br />
*Other trials: Consolidation (see paper for details)<br />
<br />
===Variant #4, 10-3-5, 1000/150/250, CI Ara-C {{#subobject:7ce6f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/32/3/219.full Willemze et al. 2013 (EORTC-GIMEMA AML-12)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ADE_.28high-dose_Ara-C.29|ADE (high-dose Ara-C)]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 10 days, started on day 1 (total dose: 1000 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 5 minutes once per day on days 1, 3, 5<br />
*[[Etoposide (Vepesid)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
'''10-day course'''<br />
<br />
===Variant #5, 10-3-5, 1025/150/500, CI Ara-C {{#subobject:7ce6f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773224/ Mandelli et al. 2009 (EORTC-GIMEMA AML-10)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. AIE<br> 2. AME<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 25 mg/m<sup>2</sup>/day IV bolus once on day 1, then 100 mg/m<sup>2</sup>/day IV continuous infusion over 10 days (total dose: 1025 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 5 minutes once per day on days 1, 3, 5<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
'''10-day course'''<br />
<br />
===Variant #6, 10-3-5, 2000/150/500, intermittent Ara-C {{#subobject:77fe46|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/89/7/2311.long Hann et al. 1997 (UK MRC AML10)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[Acute_myeloid_leukemia_-_historical#DAT|DAT 3+10]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/93/12/4131.long Burnett et al. 1999 (UK MRC AML12)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
| style="background-color:#d3d3d3" |See note<br />
| style="background-color:#d3d3d3" |See note<br />
|-<br />
|[http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
| style="background-color:#d3d3d3" |See note<br />
| style="background-color:#d3d3d3" |See note<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ Gamis et al. 2014 (COG AAML0531)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
| style="background-color:#d3d3d3" |See note<br />
| style="background-color:#d3d3d3" |See note<br />
|-<br />
|}<br />
''Note: these trials have complicated treatment schemas; see papers for details.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV every 12 hours on days 1 to 10<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
'''10-day course'''<br />
====Subsequent treatment====<br />
<br />
*ADE 8-3-5<br />
<br />
===References===<br />
<br />
#Bishop JF, Matthews JP, Young GA, Szer J, Gillett A, Joshua D, Bradstock K, Enno A, Wolf MM, Fox R, Cobcroft R, Herrmann R, Van Der Weyden M, Lowenthal RM, Page F, Garson OM, Juneja S. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood. 1996 Mar 1;87(5):1710-7. [http://www.bloodjournal.org/content/87/5/1710.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8634416 PubMed]<br />
#'''UK MRC AML10:''' Hann IM, Stevens RF, Goldstone AH, Rees JK, Wheatley K, Gray RG, Burnett AK; Adult and Childhood Leukaemia Working Parties of the Medical Research Council. Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia: results of the Medical Research Council's 10th AML trial (MRC AML10). Blood. 1997 Apr 1;89(7):2311-8. [http://www.bloodjournal.org/content/89/7/2311.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9116274 PubMed]<br />
##'''Update:''' Burnett AK, Goldstone AH, Stevens RM, Hann IM, Rees JK, Gray RG, Wheatley K; UK Medical Research Council Adult and Children's Leukaemia Working Parties. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet. 1998 Mar 7;351(9104):700-8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)09214-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9504514 PubMed]<br />
#'''UK MRC AML12:''' Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the randomized MRC trial. Blood. 1999 Jun 15;93(12):4131-43. [http://www.bloodjournal.org/content/93/12/4131.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10361110 PubMed]<br />
##'''Update:''' Burnett AK, Hills RK, Milligan DW, Goldstone AH, Prentice AG, McMullin MF, Duncombe A, Gibson B, Wheatley K. Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial. J Clin Oncol. 2010 Feb 1;28(4):586-95. Epub 2009 Dec 28. [http://ascopubs.org/doi/full/10.1200/JCO.2009.22.9088 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20038732 PubMed]<br />
#'''CALGB 9720:''' Baer MR, George SL, Dodge RK, O'Loughlin KL, Minderman H, Caligiuri MA, Anastasi J, Powell BL, Kolitz JE, Schiffer CA, Bloomfield CD, Larson RA. Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720. Blood. 2002 Aug 15;100(4):1224-32. [http://www.bloodjournal.org/content/100/4/1224.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12149202 PubMed]<br />
##'''Update:''' Baer MR, George SL, Caligiuri MA, Sanford BL, Bothun SM, Mrózek K, Kolitz JE, Powell BL, Moore JO, Stone RM, Anastasi J, Bloomfield CD, Larson RA. Low-dose interleukin-2 immunotherapy does not improve outcome of patients age 60 years and older with acute myeloid leukemia in first complete remission: Cancer and Leukemia Group B Study 9720. J Clin Oncol. 2008 Oct 20;26(30):4934-9. Epub 2008 Jun 30. [http://ascopubs.org/doi/full/10.1200/JCO.2008.17.0472 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652081/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18591543 PubMed]<br />
#'''EORTC-GIMEMA AML-10:''' Mandelli F, Vignetti M, Suciu S, Stasi R, Petti MC, Meloni G, Muus P, Marmont F, Marie JP, Labar B, Thomas X, Di Raimondo F, Willemze R, Liso V, Ferrara F, Baila L, Fazi P, Zittoun R, Amadori S, de Witte T. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. J Clin Oncol. 2009 Nov 10;27(32):5397-403. Epub 2009 Oct 13. Erratum in: J Clin Oncol. 2010 Mar 10;28(8):1438. [http://ascopubs.org/doi/full/10.1200/JCO.2008.20.6490 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773224/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826132 PubMed]<br />
#'''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21172891 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [http://jco.ascopubs.org/content/31/27/3360.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23940227 PubMed]<br />
<!-- Presented at the 53rd American Society of Hematology Annual Meeting and Exposition, San Diego, CA, December 10-13, 2011. --><br />
#'''EORTC-GIMEMA AML-12:''' Willemze R, Suciu S, Meloni G, Labar B, Marie JP, Halkes CJ, Muus P, Mistrik M, Amadori S, Specchia G, Fabbiano F, Nobile F, Sborgia M, Camera A, Selleslag DL, Lefrère F Sr, Magro D, Sica S, Cantore N, Beksac M, Berneman Z, Thomas X, Melillo L, Guimaraes JE, Leoni P, Luppi M, Mitra ME, Bron D, Fillet G, Marijt EW, Venditti A, Hagemeijer A, Mancini M, Jansen J, Cilloni D, Meert L, Fazi P, Vignetti M, Trisolini SM, Mandelli F, de Witte T. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: Results of the EORTC-GIMEMA AML-12 trial. J Clin Oncol. 2014 Jan 20;32(3):219-28. Epub 2013 Dec 2. [http://jco.ascopubs.org/content/32/3/219.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24297940 PubMed]<br />
#'''COG AAML0531:''' Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. [http://ascopubs.org/doi/full/10.1200/JCO.2014.55.3628 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25092781 PubMed]<br />
<br />
==ADE (high-dose Ara-C) {{#subobject:c7eb71|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADE: '''<u>A</u>'''ra-C (Cytarabine), '''<u>D</u>'''aunorubicin, '''<u>E</u>'''toposide<br />
<br>HIDAC-3-5: '''<u>HI</u>'''gh-'''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine), '''<u>3</u>''' days of Daunorubicin, '''<u>5</u>''' days of Etoposide<br />
<br>HIDAC-3-7: '''<u>HI</u>'''gh-'''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine), '''<u>3</u>''' days of Daunorubicin, '''<u>7</u>''' days of Etoposide<br />
===Variant #1, HIDAC-3-5 {{#subobject:b1a101|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/32/3/219.full Willemze et al. 2013 (EORTC-GIMEMA AML-12)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#ADE_.28standard-dose_Ara-C.29|ADE (standard-dose Ara-C)]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 3, 5, 7 (8 doses per cycle)<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 5 minutes once per day on days 1, 3, 5<br />
*[[Etoposide (Vepesid)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
'''7-day course'''<br />
<br />
===Variant #2, HIDAC-3-7 {{#subobject:386df8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/87/5/1710.long Bishop et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#ADE_.28standard-dose_Ara-C.29|ADE (standard-dose Ara-C)]]<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV every 12 hours on days 1, 3, 5, 7 (8 doses per cycle)<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Etoposide (Vepesid)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 7<br />
<br />
'''7-day course, can be repeated up to 3 times if CR not achieved'''<br />
====Subsequent treatment====<br />
<br />
*5-2-5 consolidation x 2<br />
<br />
===References===<br />
<br />
#Bishop JF, Matthews JP, Young GA, Szer J, Gillett A, Joshua D, Bradstock K, Enno A, Wolf MM, Fox R, Cobcroft R, Herrmann R, Van Der Weyden M, Lowenthal RM, Page F, Garson OM, Juneja S. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood. 1996 Mar 1;87(5):1710-7. [http://www.bloodjournal.org/content/87/5/1710.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8634416 PubMed]<br />
<!-- Presented at the 53rd American Society of Hematology Annual Meeting and Exposition, San Diego, CA, December 10-13, 2011. --><br />
#'''EORTC-GIMEMA AML-12:''' Willemze R, Suciu S, Meloni G, Labar B, Marie JP, Halkes CJ, Muus P, Mistrik M, Amadori S, Specchia G, Fabbiano F, Nobile F, Sborgia M, Camera A, Selleslag DL, Lefrère F Sr, Magro D, Sica S, Cantore N, Beksac M, Berneman Z, Thomas X, Melillo L, Guimaraes JE, Leoni P, Luppi M, Mitra ME, Bron D, Fillet G, Marijt EW, Venditti A, Hagemeijer A, Mancini M, Jansen J, Cilloni D, Meert L, Fazi P, Vignetti M, Trisolini SM, Mandelli F, de Witte T. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: Results of the EORTC-GIMEMA AML-12 trial. J Clin Oncol. 2014 Jan 20;32(3):219-28. Epub 2013 Dec 2. [http://jco.ascopubs.org/content/32/3/219.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24297940 PubMed]<br />
<br />
==CIA {{#subobject:de6dec|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CIA: '''<u>C</u>'''lofarabine, '''<u>I</u>'''darubicin, '''<u>A</u>'''ra-C (Cytarabine)<br />
===Variant #1, 15/10/1000 {{#subobject:c6c8ec|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739034/ Jabbour et al. 2017]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|FIA<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given 4 hours before cytarabine'''<br />
*[[Idarubicin (Idamycin)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*Patients not achieving CR or CRp could undergo a second induction<br />
*Patients achieving CR or CRp: [[#CIA_2|CIA consolidation]]<br />
<br />
===Variant #2, 20/10/1000 {{#subobject:4a7d81|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110914/ Nazha et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
*[[Idarubicin (Idamycin)]] 10 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 3<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5<br />
<br />
====Supportive medications====<br />
<br />
*[[Levofloxacin (Levaquin)]]<br />
*[[Itraconazole (Sporanox)]]<br />
*[[Valacyclovir (Valtrex)]]<br />
*[[:Category:Granulocyte_colony-stimulating_factors|Granulocyte colony-stimulating factor]] neither mandated nor forbidden and given per physician discretion<br />
<br />
'''5-day course'''<br />
====Subsequent treatment====<br />
<br />
*Patients with PR: a second course with the same drugs, doses, and schedule.<br />
*Patients achieving CR or CRi: [[#CIA_2|CIA consolidation]]<br />
<br />
===References===<br />
<br />
#Nazha A, Kantarjian H, Ravandi F, Huang X, Choi S, Garcia-Manero G, Jabbour E, Borthakur G, Kadia T, Konopleva M, Cortes J, Ferrajoli A, Kornblau S, Daver N, Pemmaraju N, Andreeff M, Estrov Z, Du M, Brandt M, Faderl S. Clofarabine, idarubicin, and cytarabine (CIA) as frontline therapy for patients ≤60 years with newly diagnosed acute myeloid leukemia. Am J Hematol. 2013 Nov;88(11):961-6. Epub 2013 Sep 9. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110914/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23877926 PubMed]<br />
#Jabbour E, Short NJ, Ravandi F, Huang X, Xiao L, Garcia-Manero G, Plunkett W, Gandhi V, Sasaki K, Pemmaraju N, Daver NG, Borthakur G, Jain N, Konopleva M, Estrov Z, Kadia TM, Wierda WG, DiNardo CD, Brandt M, O'Brien SM, Cortes JE, Kantarjian H. A randomized phase 2 study of idarubicin and cytarabine with clofarabine or fludarabine in patients with newly diagnosed acute myeloid leukemia. Cancer. 2017 Nov 15;123(22):4430-4439. Epub 2017 Jul 14. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.30883/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739034/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28708931 PubMed]<br />
<br />
==DA 3 + 10, GO {{#subobject:e6f5bb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
DA 3 + 10, GO: '''<u>D</u>'''aunorubicin & '''<u>A</u>'''ra-C (Cytarabine), '''<u>3</u>''' days of daunorubicin '''<u>+ 10</u>''' days of cytarabine, '''<u>G</u>'''emtuzumab '''<u>O</u>'''zogamicin<br />
===Regimen {{#subobject:6a938e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|See note<br />
|See note<br />
|-<br />
|[http://jco.ascopubs.org/content/30/32/3924.long Burnett et al. 2012 (UK NCRI AML16)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#DA_3_.2B_10|DA 3 + 10]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Both trials have complicated treatment schemas; see papers for details.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV every 12 hours on days 1 to 10<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5<br />
*[[Gemtuzumab ozogamicin (Mylotarg)]] 3 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*See paper for details (to be completed).<br />
<br />
===References===<br />
<br />
#'''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21172891 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [http://jco.ascopubs.org/content/31/27/3360.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23940227 PubMed]<br />
#'''UK NCRI AML16:''' Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L, Hunter AE, Yin J, Craddock CF, Dufva IH, Wheatley K, Milligan D. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012 Nov 10;30(32):3924-31. Epub 2012 Jul 30. [http://jco.ascopubs.org/content/30/32/3924.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22851554 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, Yin J, McMullin MF, Ali S, Bowen D, Hills RK; UK National Cancer Research Institute AML Working Group. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013 Aug 22;122(8):1384-94. Epub 2013 Jul 9. [http://www.bloodjournal.org/content/122/8/1384.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23838349 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hills RK, Kell J, Nielsen OJ, Dennis M, Cahalin P, Pocock C, Ali S, Burns S, Freeman S, Milligan D, Clark RE. A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia. Leukemia. 2017 Feb;31(2):310-317. Epub 2016 Sep 2. [https://www.nature.com/leu/journal/v31/n2/fig_tab/leu2016225f1.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292678/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27624670 PubMed]<br />
<br />
==DA 3 + 10 {{#subobject:5c0062|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
DA 3 + 10: '''<u>D</u>'''aunorubicin & '''<u>A</u>'''ra-C (Cytarabine), '''<u>3</u>''' days of daunorubicin '''<u>+ 10</u>''' days of cytarabine<br />
===Variant #1, 50 mg/m<sup>2</sup> dauno {{#subobject:99321e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|See note<br />
|See note<br />
|-<br />
|[http://jco.ascopubs.org/content/30/32/3924.long Burnett et al. 2012 (UK NCRI AML16)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#DA_3_.2B_10.2C_GO|DA 3 + 10, GO]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: this regimen is very similar to [[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]; however, 1) there is slightly more cytarabine given, in an intermittent schedule, and 2) the daunorubicin is given intermittently over 5 days, not 3. Both trials have complicated treatment schemas; see papers for details.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV every 12 hours on days 1 to 10<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*See papers for details (to be completed).<br />
<br />
===Variant #2, 60 mg/m<sup>2</sup> dauno {{#subobject:211741|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505010/ Burnett et al. 2015 (UK NCRI AML17)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|DA 3 + 10 (high-dose)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: this regimen is very similar to [[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]]; however, 1) there is slightly more cytarabine given, in an intermittent schedule, and 2) the daunorubicin is given intermittently over 5 days, not 3.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV every 12 hours on days 1 to 10<br />
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 1, 3, 5<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*Complex randomization; see paper for details (to be completed).<br />
<br />
===References===<br />
<br />
#'''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21172891 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [http://jco.ascopubs.org/content/31/27/3360.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23940227 PubMed]<br />
#'''UK NCRI AML16:''' Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L, Hunter AE, Yin J, Craddock CF, Dufva IH, Wheatley K, Milligan D. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012 Nov 10;30(32):3924-31. Epub 2012 Jul 30. [http://jco.ascopubs.org/content/30/32/3924.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22851554 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, Yin J, McMullin MF, Ali S, Bowen D, Hills RK; UK National Cancer Research Institute AML Working Group. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013 Aug 22;122(8):1384-94. Epub 2013 Jul 9. [http://www.bloodjournal.org/content/122/8/1384.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23838349 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hills RK, Kell J, Nielsen OJ, Dennis M, Cahalin P, Pocock C, Ali S, Burns S, Freeman S, Milligan D, Clark RE. A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia. Leukemia. 2017 Feb;31(2):310-317. Epub 2016 Sep 2. [https://www.nature.com/leu/journal/v31/n2/fig_tab/leu2016225f1.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292678/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27624670 PubMed]<br />
#'''UK NCRI AML17:''' Burnett AK, Russell NH, Hills RK, Kell J, Cavenagh J, Kjeldsen L, McMullin MF, Cahalin P, Dennis M, Friis L, Thomas IF, Milligan D, Clark RE; UK NCRI AML Study Group. A randomized comparison of daunorubicin 90 mg/m<sup>2</sup> vs 60 mg/m<sup>2</sup> in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood. 2015 Jun 18;125(25):3878-85. Epub 2015 Apr 1. [http://www.bloodjournal.org/content/125/25/3878.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505010/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25833957 PubMed]<br />
<br />
==DAC {{#subobject:9b1553|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
DAC: '''<u>D</u>'''aunorubicin, '''<u>A</u>'''ra-C (Cytarabine), '''<u>C</u>'''ladribine<br />
===Regimen {{#subobject:f00b8a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v18/n5/full/2403336a.html Holowiecki et al. 2004 (PALG AML1/1999)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28intermediate-dose.29|DA]]<br />
| style="background-color:#1a9850" |Superior CR rate after first induction<br />
|-<br />
| rowspan="2" |[http://jco.ascopubs.org/content/30/20/2441.full Holowiecki et al. 2012 (PALG AML1/2004)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#7.2B3d_.28intermediate-dose.29|DA]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. DAF<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV over 5 minutes once per day on days 1 to 3<br />
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>)<br />
*[[Cladribine (Leustatin)]] 5 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 to 5<br />
<br />
====Supportive medications====<br />
<br />
*"According to commonly accepted guidelines with no prophylactic IV antibiotics"<br />
*[[:Category:Granulocyte_colony-stimulating_factors|Granulocyte colony-stimulating factor]] recommended only for patients older than 50 years old whose leukemic blasts were negative for CD114 expression<br />
<br />
'''7-day course'''<br />
====Subsequent treatment====<br />
<br />
*Patients with only partial remission in both studies underwent a second course with the same drugs, doses, and schedule.<br />
*Non-responders in PALG AML1/1999: [[#CLAG|CLAG salvage]]<br />
*Patients in remission in both studies: [[#HAM|HAM]], then [[#HiDAC|HiDAC]] consolidation<br />
<br />
===References===<br />
<br />
#'''PALG AML1/1999:''' Holowiecki J, Grosicki S, Robak T, Kyrcz-Krzemien S, Giebel S, Hellmann A, Skotnicki A, Jedrzejczak WW, Konopka L, Kuliczkowski K, Zdziarska B, Dmoszyńska A, Marianska B, Pluta A, Zawilska K, Komarnicki M, Kloczko J, Sulek K, Haus O, Stella-Holowiecka B, Baran W, Jakubas B, Paluszewska M, Wierzbowska A, Kielbinski M, Jagoda K; Polish Adult Leukemia Group (PALG). Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia: multicenter, phase III study. Leukemia. 2004 May;18(5):989-97. [https://www.nature.com/leu/journal/v18/n5/full/2403336a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14999298 PubMed]<br />
#'''PALG AML1/2004:''' Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszyńska A, Kloczko J, Jedrzejczak WW, Zdziarska B, Warzocha K, Zawilska K, Komarnicki M, Kielbinski M, Piatkowska-Jakubas B, Wierzbowska A, Wach M, Haus O. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012 Jul 10;30(20):2441-8. Epub 2012 Apr 16. [http://jco.ascopubs.org/content/30/20/2441.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22508825 PubMed]<br />
<br />
==FLAG-Ida {{#subobject:7fc219|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FLAG-Ida: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF (Lenograstim), '''<u>Ida</u>'''rubicin<br />
===Regimen {{#subobject:44e85e|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]<br />
| style="background-color:#1a9851" |Phase III (*)<br />
|-<br />
|}<br />
''This trial has a complex randomization; to be completed.''<br />
====Chemotherapy====<br />
<br />
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days 2 to 6<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 2 to 6, '''given 4 hours after fludarabine'''<br />
*[[Lenograstim (Granocyte)]] 263 mcg SC once per day on days 1 to 7<br />
*[[Idarubicin (Idamycin)]] 8 mg/m<sup>2</sup> IV once per day on days 4 to 6<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*See paper for details<br />
<br />
===References===<br />
<br />
#'''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [http://ascopubs.org/doi/10.1200/JCO.2010.31.4310 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21172891 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [http://jco.ascopubs.org/content/31/27/3360.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23940227 PubMed]<br />
<br />
==HAA {{#subobject:0788e0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
HAA: '''<u>H</u>'''omoharringtonine (Omacetaxine), '''<u>A</u>'''ra-C (Cytarabine), '''<u>A</u>'''clarubicin<br />
===Regimen {{#subobject:5c5c2e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70152-9/fulltext Jin et al. 2013]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#7.2B3d_.28standard-dose.29|DA]]<br />
| style="background-color:#1a9850" |Superior EFS<br />
|-<br />
|2. [[#HAD|HAD]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Unlikely to be completed since there were significantly more deaths in this arm, despite a superior primary efficacy endpoint.''<br />
====Chemotherapy====<br />
<br />
*[[Omacetaxine (Synribo)]]<br />
*[[Cytarabine (Ara-C)]]<br />
*[[Aclarubicin (Aclacinon)]]<br />
<br />
===References===<br />
<br />
#Jin J, Wang JX, Chen FF, Wu DP, Hu J, Zhou JF, Hu JD, Wang JM, Li JY, Huang XJ, Ma J, Ji CY, Xu XP, Yu K, Ren HY, Zhou YH, Tong Y, Lou YJ, Ni WM, Tong HY, Wang HF, Mi YC, Du X, Chen BA, Shen Y, Chen Z, Chen SJ. Homoharringtonine-based induction regimens for patients with de-novo acute myeloid leukaemia: a multicentre, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2013 Jun;14(7):599-608. Epub 2013 May 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70152-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23664707 PubMed]<br />
<br />
==HAD {{#subobject:30f8fa|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
HAD: '''<u>H</u>'''omoharringtonine (Omacetaxine), '''<u>A</u>'''ra-C (Cytarabine), '''<u>D</u>'''aunorubicin<br />
===Regimen {{#subobject:1d644a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70152-9/fulltext Jin et al. 2013]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#7.2B3d_.28standard-dose.29|DA]]<br />
| style="background-color:#d9ef8b" |Might have superior EFS<br />
|-<br />
|2. [[#HAA|HAA]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Unlikely to be completed since there were significantly more deaths in this arm, despite a trend towards a superior primary efficacy endpoint.''<br />
====Chemotherapy====<br />
<br />
*[[Omacetaxine (Synribo)]]<br />
*[[Cytarabine (Ara-C)]]<br />
*[[Daunorubicin (Cerubidine)]]<br />
<br />
===References===<br />
<br />
#Jin J, Wang JX, Chen FF, Wu DP, Hu J, Zhou JF, Hu JD, Wang JM, Li JY, Huang XJ, Ma J, Ji CY, Xu XP, Yu K, Ren HY, Zhou YH, Tong Y, Lou YJ, Ni WM, Tong HY, Wang HF, Mi YC, Du X, Chen BA, Shen Y, Chen Z, Chen SJ. Homoharringtonine-based induction regimens for patients with de-novo acute myeloid leukaemia: a multicentre, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2013 Jun;14(7):599-608. Epub 2013 May 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70152-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23664707 PubMed]<br />
<br />
==ICE (Idarubicin) {{#subobject:948b49|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ICE: '''<u>I</u>'''darubicin, '''<u>C</u>'''ytarabine, '''<u>E</u>'''toposide<br />
===Regimen {{#subobject:c7b35a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/105/2/481.long Bradstock et al. 2004 (ALLG M7)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nature.com/articles/2403528 Schlenk et al. 2004]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|A-ICE<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2005.05745.x Russo et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FLAI<br />
| style="background-color:#d73027" |Inferior CR rate<br />
|-<br />
|[https://www.nature.com/articles/2403932 Entz-Werle et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MCE<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948102/ de Witte et al. 2010 (CRIANT)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457212/ Bassan et al. 2019 (NILG AML 02/06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|sHD<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 3<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV over 30 minutes twice per day on days 1 to 7 (total dose: 1400 mg/m<sup>2</sup>)<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*ALLG M7: ICE versus IcE consolidation<br />
*NILG AML 02/06, early CR: IC consolidation<br />
<br />
===References===<br />
<br />
#'''ALLG M7:''' Bradstock KF, Matthews JP, Lowenthal RM, Baxter H, Catalano J, Brighton T, Gill D, Eliadis P, Joshua D, Cannell P, Schwarer AP, Durrant S, Gillett A, Koutts J, Taylor K, Bashford J, Arthur C, Enno A, Dunlop L, Szer J, Leahy M, Juneja S, Young GA; Australasian Leukaemia and Lymphoma Group. A randomized trial of high-versus conventional-dose cytarabine in consolidation chemotherapy for adult de novo acute myeloid leukemia in first remission after induction therapy containing high-dose cytarabine. Blood. 2005 Jan 15;105(2):481-8. Epub 2004 Jun 22. [http://www.bloodjournal.org/content/105/2/481.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15213095 PubMed]<br />
#Schlenk RF, Fröhling S, Hartmann F, Fischer JT, Glasmacher A, del Valle F, Grimminger W, Götze K, Waterhouse C, Schoch R, Pralle H, Mergenthaler HG, Hensel M, Koller E, Kirchen H, Preiss J, Salwender H, Biedermann HG, Kremers S, Griesinger F, Benner A, Addamo B, Döhner K, Haas R, Döhner H; AML Study Group Ulm. Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia. Leukemia. 2004 Nov;18(11):1798-803. [https://www.nature.com/articles/2403528 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15385923 PubMed]<br />
#Russo D, Malagola M, de Vivo A, Fiacchini M, Martinelli G, Piccaluga PP, Damiani D, Candoni A, Michielutti A, Castelli M, Testoni N, Ottaviani E, Rondoni M, Pricolo G, Mazza P, Zuffa E, Zaccaria A, Raspadori D, Bocchia M, Lauria F, Bonini A, Avanzini P, Gugliotta L, Visani G, Fanin R, Baccarani M. Multicentre phase III trial on fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukaemia patients. Br J Haematol. 2005 Oct;131(2):172-9. Erratum in: Br J Haematol. 2006 Mar;132(6):804. [https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2005.05745.x link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16197446 PubMed]<br />
#'''EORTC 58921:''' Entz-Werle N, Suciu S, van der Werff ten Bosch J, Vilmer E, Bertrand Y, Benoit Y, Margueritte G, Plouvier E, Boutard P, Vandecruys E, Ferster A, Lutz P, Uyttebroeck A, Hoyoux C, Thyss A, Rialland X, Norton L, Pages MP, Philippe N, Otten J, Behar C; EORTC Children Leukemia Group. Results of 58872 and 58921 trials in acute myeloblastic leukemia and relative value of chemotherapy vs allogeneic bone marrow transplantation in first complete remission: the EORTC Children Leukemia Group report. Leukemia. 2005 Dec;19(12):2072-81. [https://www.nature.com/articles/2403932 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16136166 PubMed]<br />
#'''CRIANT:''' de Witte T, Hagemeijer A, Suciu S, Belhabri A, Delforge M, Kobbe G, Selleslag D, Schouten HC, Ferrant A, Biersack H, Amadori S, Muus P, Jansen JH, Hellström-Lindberg E, Kovacsovics T, Wijermans P, Ossenkoppele G, Gratwohl A, Marie JP, Willemze R. Value of allogeneic versus autologous stem cell transplantation and chemotherapy in patients with myelodysplastic syndromes and secondary acute myeloid leukemia: final results of a prospective randomized European Intergroup Trial. Haematologica. 2010 Oct;95(10):1754-61. Epub 2010 May 21. [http://www.haematologica.org/content/95/10/1754.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948102/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20494931 PubMed]<br />
#'''NILG AML 02/06:''' Bassan R, Intermesoli T, Masciulli A, Pavoni C, Boschini C, Gianfaldoni G, Marmont F, Cavattoni I, Mattei D, Terruzzi E, De Paoli L, Cattaneo C, Borlenghi E, Ciceri F, Bernardi M, Scattolin AM, Todisco E, Campiotti L, Corradini P, Cortelezzi A, Ferrero D, Zanghì P, Oldani E, Spinelli O, Audisio E, Cortelazzo S, Bosi A, Falini B, Pogliani EM, Rambaldi A. Randomized trial comparing standard vs sequential high-dose chemotherapy for inducing early CR in adult AML. Blood Adv. 2019 Apr 9;3(7):1103-1117. [http://www.bloodadvances.org/content/3/7/1103.abstract link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457212/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30948365 PubMed]<br />
<br />
==ICL {{#subobject:a904d7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ICL: '''<u>I</u>'''darubicin, '''<u>C</u>'''ytarabine, '''<u>L</u>'''omustine<br />
===Regimen {{#subobject:909d7e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/10.1200/JCO.2018.78.7366 Pigneux et al. 2017 (LAM-SA 2007)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3i|IA]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Idarubicin (Idamycin)]] 8 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
*[[Lomustine (CCNU)]] 200 mg/m<sup>2</sup> PO once on day 1<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*[[Acute_myeloid_leukemia#IC_.26_Norethandrolone|IC and methotrexate/mercaptopurine with norethandrolone]]<br />
<br />
===References===<br />
<br />
#'''LAM-SA 2007:''' Pigneux A, Béné MC, Salmi LR, Dumas PY, Delaunay J, Bonmati C, Guièze R, Luquet I, Cornillet-Lefebvre P, Delabesse E, Ianotto JC, Ojeda-Uribe M, Hunault M, Banos A, Fornecker LM, Bernard M, Jourdan E, Vey N, Zerazhi H, Hishri Y, Mineur A, Asselineau J, Delepine R, Cahn JY, Ifrah N, Récher C; French Innovative Leukemia Organization. Improved survival by adding lomustine to conventional chemotherapy for elderly patients with aml without unfavorable cytogenetics: results of the LAM-SA 2007 FILO trial. J Clin Oncol. 2018 36:32, 3203-3210. Epub 2018 Sep 27. [http://ascopubs.org/doi/10.1200/JCO.2018.78.7366 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30260758 PubMed]<br />
<br />
==MEC {{#subobject:324735|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MEC: '''<u>M</u>'''itoxantrone, '''<u>E</u>'''toposide, '''<u>C</u>'''ytarabine<br />
<br>MICE: '''<u>MI</u>'''toxantrone, '''<u>C</u>'''ytarabine, '''<u>E</u>'''toposide<br />
===Regimen {{#subobject:33e408|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/2404356 Jehn et al. 2006 (EORTC/GIMEMA AML-13)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2013.49.0771 Amadori et al. 2013 (EORTC/GIMEMA AML-17)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GO, then MICE<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Mitoxantrone (Novantrone)]] 7 mg/m<sup>2</sup> IV once per day on days 1, 3, 5<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)<br />
<br />
'''One course'''<br />
<br />
===References===<br />
<br />
#'''EORTC/GIMEMA AML-13:''' Jehn U, Suciu S, Thomas X, Lefrère F, Muus P, Berneman Z, Marie JP, Adamo F, Fillet G, Nobile F, Ricciuti F, Leone G, Rizzoli V, Montanaro M, Beeldens F, Fazi P, Mandelli F, Willemze R, de Witte T, Amadori S. Non-infusional vs intravenous consolidation chemotherapy in elderly patients with acute myeloid leukemia: final results of the EORTC-GIMEMA AML-13 randomized phase III trial. Leukemia. 2006 Oct;20(10):1723-30. Epub 2006 Aug 17. [https://www.nature.com/articles/2404356 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16932345 PubMed]<br />
#'''EORTC/GIMEMA AML-17:''' Amadori S, Suciu S, Stasi R, Salih HR, Selleslag D, Muus P, De Fabritiis P, Venditti A, Ho AD, Lübbert M, Thomas X, Latagliata R, Halkes CJ, Falzetti F, Magro D, Guimaraes JE, Berneman Z, Specchia G, Karrasch M, Fazi P, Vignetti M, Willemze R, de Witte T, Marie JP. Sequential combination of gemtuzumab ozogamicin and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia: results of a randomized phase III trial by the EORTC and GIMEMA consortium (AML-17). J Clin Oncol. 2013 Dec 10;31(35):4424-30. Epub 2013 Oct 14. [http://ascopubs.org/doi/full/10.1200/JCO.2013.49.0771 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24127442 PubMed]<br />
<br />
=First-line induction therapy, older or "unfit" patients=<br />
''Note: these regimens are generally considered to be part of a non-curative line of treatment.''<br />
==Azacitidine monotherapy {{#subobject:791718|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7509ab|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.23.8329 Fenaux et al. 2009 (AZA PH GL 2003)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Investigator's choice of:<br> 1. Best supportive care<br> 2. [[#LoDAC|LoDAC]]<br> 3. Intensive chemotherapy<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ Dombret et al. 2015 (AZA-AML-001)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Investigator's choice of:<br> 1. [[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br> 2. [[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]]<br> 3. [[#7.2B3i|7+3i]]<br> 4. [[#Best_supportive_care|Best supportive care]]<br> 5. [[#LoDAC|LoDAC]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Azacitidine (Vidaza)]] 75 mg/m<sup>2</sup> SC once per day on days 1 to 7<br />
<br />
'''28-day cycle for at least 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''AZA PH GL 2003:''' Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010 Feb 1;28(4):562-9. Epub 2009 Dec 21. [http://ascopubs.org/doi/full/10.1200/JCO.2009.23.8329 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20026804 PubMed]<br />
#'''AZA-AML-001:''' Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/3/291.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25987659 PubMed]<br />
##'''Subgroup analysis:''' Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3803-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731212/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29241450 PubMed]<br />
<br />
==Azacitidine & Venetoclax {{#subobject:73ce92|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1ea50d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30010-X/fulltext DiNardo et al. 2018 (M14-358)]<br />
| style="background-color:#91cf61" |Phase Ib, >20 pts<br />
|-<br />
|}<br />
<br />
''Patients with WBC greater than 25 x 10<sup>9</sup>/L at presentation were pre-treated with hydroxyurea or leukapheresis.''<br />
<br />
====Chemotherapy, induction====<br />
<br />
*[[Azacitidine (Vidaza)]] 75 mg/m<sup>2</sup> IV or SC once per day on days 1 to 7<br />
*[[Venetoclax (Venclexta)]] 400, 800, or 1200 mg PO once per day<br />
<br />
===References===<br />
<br />
#'''M14-358:''' DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, Arellano M, Frattini MG, Kantarjian H, Popovic R, Chyla B, Xu T, Dunbar M, Agarwal SK, Humerickhouse R, Mabry M, Potluri J, Konopleva M, Pollyea DA. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018 Feb;19(2):216-228. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30010-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29339097 PubMed] [https://clinicaltrials.gov/ct2/show/NCT02203773 NCT02203773]<br />
##'''Update:''' DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, Frankfurt O, Konopleva M, Wei AH, Kantarjian HM, Xu T, Hong WJ, Chyla B, Potluri J, Pollyea DA, Letai A. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2018 Oct 25. [Epub ahead of print] [http://www.bloodjournal.org/content/133/1/7 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30361262 PubMed]<br />
<br />
==Azacitidine & Gemtuzumab ozogamicin {{#subobject:6f77be|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:188f5c|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.tandfonline.com/doi/full/10.1080/10428190802451254 Nand et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829116/ Nand et al. 2013 (SWOG S0703)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Patients with WBC greater than 10 x 10<sup>9</sup>/L at presentation were pre-treated with Hydrea. Leukapheresis was recommended for patients with WBC greater than x 10<sup>9</sup>/L. Nand et al. 2008 did not describe the maintenance portion of the regimen, and used only SC azacitidine.''<br />
<br />
====Supportive medications, pre-treatment phase====<br />
<br />
*[[Hydroxyurea (Hydrea)]] 1500 mg PO twice per day or in higher doses if necessary<br />
<br />
''Once WBC is less than 10 x 10<sup>9</sup>/L, stop Hydrea and proceed:''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Azacitidine (Vidaza)]] 75 mg/m<sup>2</sup> IV or SC once per day on days 1 to 7<br />
*[[Gemtuzumab ozogamicin (Mylotarg)]] 3 mg/m<sup>2</sup> IV once on day 8<br />
<br />
====Supportive medications====<br />
<br />
*"Appropriate premedications" which were not specified, for [[Gemtuzumab ozogamicin (Mylotarg)]]<br />
<br />
'''One cycle'''<br />
====Subsequent treatment====<br />
<br />
*If D14 bone marrow with 5% or more blasts, a second induction cycle identical to the first was administered<br />
*Patients achieving CR or CRi: [[#Azacitidine_.26_Gemtuzumab_ozogamicin_2|Azacitidine and gemtuzumab ozogamicin consolidation]], within 60 days<br />
<br />
===References===<br />
<br />
#Nand S, Godwin J, Smith S, Barton K, Michaelis L, Alkan S, Veerappan R, Rychlik K, Germano E, Stiff P. Hydroxyurea, azacitidine and gemtuzumab ozogamicin therapy in patients with previously untreated non-M3 acute myeloid leukemia and high-risk myelodysplastic syndromes in the elderly: results from a pilot trial. Leuk Lymphoma. 2008 Nov;49(11):2141-7. [https://www.tandfonline.com/doi/full/10.1080/10428190802451254 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19021057 PubMed]<br />
<!-- Presented in part at the American Society of Clinical Oncology annual meeting (Chicago, IL, June 1-5, 2012) and at the American Society of Hematology annual meeting (Atlanta, GA, December 8-11, 2012). --><br />
#'''SWOG S0703:''' Nand S, Othus M, Godwin JE, Willman CL, Norwood TH, Howard DS, Coutre SE, Erba HP, Appelbaum FR. A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood. 2013 Nov 14;122(20):3432-9. Epub 2013 Oct 3. [http://www.bloodjournal.org/content/122/20/3432.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829116/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24092933 PubMed]<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/abs/10.1200/JCO.1989.7.9.1268 Löwenberg et al. 1989]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Acute_myeloid_leukemia_-_historical#Cytarabine.2C_Daunorubicin.2C_Vincristine|Cytarabine, Daunorubicin, Vincristine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://www.bloodjournal.org/content/114/6/1166.long Harousseau et al. 2009 (FIGHT-AML-301)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Tipifarnib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874148/ Kantarjian et al. 2012 (DACO-016)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Decitabine_monotherapy|Decitabine]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ Dombret et al. 2015 (AZA-AML-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Azacitidine_monotherapy|Azacitidine]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/34/9/972.full Amadori et al. 2016 (EORTC/GIMEMA AML-19)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemtuzumab_ozogamicin_monotherapy|Gemtuzumab ozogamicin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment, although some trials consider [[Hydroxyurea (Hydrea)]] to be a component of best supportive care.''<br />
<br />
===References===<br />
<br />
#Löwenberg B, Zittoun R, Kerkhofs H, Jehn U, Abels J, Debusscher L, Cauchie C, Peetermans M, Solbu G, Suciu S, Stryckmans P. On the value of intensive remission-induction chemotherapy in elderly patients of 65+ years with acute myeloid leukemia: a randomized phase III study of the European Organization for Research and Treatment of Cancer Leukemia Group. J Clin Oncol. 1989 Sep;7(9):1268-74. [http://ascopubs.org/doi/abs/10.1200/JCO.1989.7.9.1268 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2475589 PubMed]<br />
#'''FIGHT-AML-301:''' Harousseau JL, Martinelli G, Jedrzejczak WW, Brandwein JM, Bordessoule D, Masszi T, Ossenkoppele GJ, Alexeeva JA, Beutel G, Maertens J, Vidriales MB, Dombret H, Thomas X, Burnett AK, Robak T, Khuageva NK, Golenkov AK, Tothova E, Mollgard L, Park YC, Bessems A, De Porre P, Howes AJ; FIGHT-AML-301 Investigators. A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood. 2009 Aug 6;114(6):1166-73. Epub 2009 May 21. [http://www.bloodjournal.org/content/114/6/1166.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19470696 PubMed]<br />
<!-- Presented in part at the 47th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2011. --><br />
#'''DACO-016:''' Kantarjian HM, Thomas XG, Dmoszyńska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysák D, Minden M, Arthur C. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012 Jul 20;30(21):2670-7. Epub 2012 Jun 11. [http://jco.ascopubs.org/content/30/21/2670.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874148/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22689805 PubMed]<br />
##'''Subgroup analysis:''' Wierzbowska A, Wawrzyniak E, Pluta A, Robak T, Mazur GJ, Dmoszynska A, Cermak J, Oriol A, Lysak D, Arthur C, Doyle M, Xiu L, Ravandi F, Kantarjian HM. Decitabine improves response rate and prolongs progression-free survival in older patients with newly diagnosed acute myeloid leukemia and with monosomal karyotype: A subgroup analysis of the DACO-016 trial. Am J Hematol. 2018 May;93(5):E125-E127. Epub 2018 Feb 24. [https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.25062 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29417613 PubMed]<br />
#'''AZA-AML-001:''' Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/3/291.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25987659 PubMed]<br />
##'''Subgroup analysis:''' Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3803-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731212/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29241450 PubMed]<br />
<!-- Presented in part at the 56th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 6-9, 2014. --><br />
#'''EORTC/GIMEMA AML-19:''' Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M, Annino L, Venditti A, Voso MT, Mazzone C, Magro D, De Fabritiis P, Muus P, Alimena G, Mancini M, Hagemeijer A, Paoloni F, Vignetti M, Fazi P, Meert L, Ramadan SM, Willemze R, de Witte T, Baron F. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016 Mar 20;34(9):972-9. Epub 2016 Jan 25. [http://jco.ascopubs.org/content/34/9/972.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26811524 PubMed]<br />
<br />
==Clofarabine monotherapy {{#subobject:18ac50|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 20 mg/m<sup>2</sup> {{#subobject:42be8e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/30/32/3924.long Burnett et al. 2012 (UK NCRI AML16)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#LoDAC|LoDAC]]<br />
| style="background-color:#ffffbf" |Seems not superior (*)<br />
|-<br />
|}<br />
''Note: reported efficacy is based on the 2013 update.''<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
'''4- to 6-week cycle for 4 cycles'''<br />
<br />
===Variant #2, 30 mg/m<sup>2</sup> {{#subobject:f9ef00|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081352/ Faderl et al. 2008]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#Clofarabine_.26_LoDAC|Clofarabine & LoDAC]]<br />
| style="background-color:#fc8d59" |Seems to have inferior EFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.26.4242 Burnett et al. 2010 (UWCM-001 and BIOV-121)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 30 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*A second induction was permitted for SD or better.<br />
*Faderl et al. 2008: Responders proceeded to clofarabine & cytarabine consolidation<br />
<br />
===References===<br />
<br />
#Faderl S, Ravandi F, Huang X, Garcia-Manero G, Ferrajoli A, Estrov Z, Borthakur G, Verstovsek S, Thomas DA, Kwari M, Kantarjian HM. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2008 Sep 1;112(5):1638-45. Epub 2008 Jun 18. [http://www.bloodjournal.org/content/112/5/1638.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081352/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18565853 PubMed]<br />
#Burnett AK, Russell NH, Kell J, Dennis M, Milligan D, Paolini S, Yin J, Culligan D, Johnston P, Murphy J, McMullin MF, Hunter A, Das-Gupta E, Clark R, Carr R, Hills RK. European development of clofarabine as treatment for older patients with acute myeloid leukemia considered unsuitable for intensive chemotherapy. J Clin Oncol. 2010 May 10;28(14):2389-95. Epub 2010 Apr 12. [http://ascopubs.org/doi/full/10.1200/JCO.2009.26.4242 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20385984 PubMed]<br />
#'''UK NCRI AML16:''' Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L, Hunter AE, Yin J, Craddock CF, Dufva IH, Wheatley K, Milligan D. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012 Nov 10;30(32):3924-31. Epub 2012 Jul 30. [http://jco.ascopubs.org/content/30/32/3924.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22851554 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, Yin J, McMullin MF, Ali S, Bowen D, Hills RK; UK National Cancer Research Institute AML Working Group. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013 Aug 22;122(8):1384-94. Epub 2013 Jul 9. [http://www.bloodjournal.org/content/122/8/1384.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23838349 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hills RK, Kell J, Nielsen OJ, Dennis M, Cahalin P, Pocock C, Ali S, Burns S, Freeman S, Milligan D, Clark RE. A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia. Leukemia. 2017 Feb;31(2):310-317. Epub 2016 Sep 2. [https://www.nature.com/leu/journal/v31/n2/fig_tab/leu2016225f1.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292678/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27624670 PubMed]<br />
<br />
==Clofarabine & LoDAC {{#subobject:7a3edd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Clofarabine & LoDAC: Clofarabine & '''<u>Lo</u>'''w '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
===Variant #1 {{#subobject:12351c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081352/ Faderl et al. 2008]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#Clofarabine_monotherapy|Clofarabine]]<br />
| style="background-color:#91cf60" |Seems to have superior EFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 30 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, '''given first'''<br />
*[[Cytarabine (Ara-C)]] 20 mg SC once per day on days 1 to 14, '''given 4 hours after clofarabine on days 1 to 5'''<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*A second induction was permitted for SD or better<br />
*Responders proceeded to clofarabine & cytarabine consolidation<br />
<br />
===Variant #2 {{#subobject:7d207f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907176/ Faderl et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
*[[Cytarabine (Ara-C)]] 20 mg SC twice per day on days 1 to 10<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*Patients not achieving CR could undergo an identical second induction after at least 28 days. <br />
**Patients not achieving CR after the second induction were given [[#Decitabine_monotherapy_3|salvage decitabine]]<br />
*Patients achieving CR: [[#Clofarabine_.26_LoDAC.2FDecitabine|Clofarabine & low-dose cytarabine alternating with decitabine consolidation]]<br />
<br />
===References===<br />
<br />
#Faderl S, Ravandi F, Huang X, Garcia-Manero G, Ferrajoli A, Estrov Z, Borthakur G, Verstovsek S, Thomas DA, Kwari M, Kantarjian HM. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2008 Sep 1;112(5):1638-45. Epub 2008 Jun 18. [http://www.bloodjournal.org/content/112/5/1638.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081352/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18565853 PubMed]<br />
#Faderl S, Ravandi F, Huang X, Wang X, Jabbour E, Garcia-Manero G, Kadia T, Ferrajoli A, Konopleva M, Borthakur G, Burger J, Feliu J, Kantarjian HM. Clofarabine plus low-dose cytarabine followed by clofarabine plus low-dose cytarabine alternating with decitabine in acute myeloid leukemia frontline therapy for older patients. Cancer. 2012 Sep 15;118(18):4471-7. Epub 2012 Jan 26. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.27429/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907176/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22282348 PubMed]<br />
##'''Update:''' Kadia TM, Faderl S, Ravandi F, Jabbour E, Garcia-Manero G, Borthakur G, Ferrajoli A, Konopleva M, Burger J, Huang X, Wang X, Pierce S, Brandt M, Feliu J, Cortes J, Kantarjian H. Final results of a phase 2 trial of clofarabine and low-dose cytarabine alternating with decitabine in older patients with newly diagnosed acute myeloid leukemia. Cancer. 2015 Jul 15;121(14):2375-82. Epub 2015 Mar 25. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.29367/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436272/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25809968 PubMed]<br />
<br />
==CPX-351 monotherapy {{#subobject:03f404|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CPX-351: Liposomal Cytarabine and Daunorubicin<br />
===Regimen {{#subobject:0b4cdf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624448/ Lancet et al. 2014 (CLTR0308-204)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]]<br />
| style="background-color:#d9ef8b" |Might have superior ORR<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6112 Lancet et al. 2018 (CLTR0310-301)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]]<br />
| style="background-color:#1a9851" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine and daunorubicin liposomal (Vyxeos)|CPX-351 (Vyxeos)]] as follows:<br />
**First induction: 100 units/m<sup>2</sup> IV over 90 minutes once per day on days 1, 3, 5<br />
**Second induction (if needed): 100 units/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 3<br />
<br />
'''One or two courses'''<br />
====Subsequent treatment====<br />
<br />
*CR/CRi: [[#CPX-351_monotherapy_2|CPX-351 monotherapy consolidation]]<br />
<br />
===References===<br />
<!-- Presented in part in abstract form at the 52nd annual meeting of the American Society of Hematology, Orlando, FL December 4-7, 2010. --><br />
<br />
#'''CLTR0308-204:''' Lancet JE, Cortes JE, Hogge DE, Tallman MS, Kovacsovics TJ, Damon LE, Komrokji R, Solomon SR, Kolitz JE, Cooper M, Yeager AM, Louie AC, Feldman EJ. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014 May 22;123(21):3239-46. Epub 2014 Mar 31. [http://bloodjournal.hematologylibrary.org/content/123/21/3239.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624448/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24687088 PubMed]<br />
<!-- # '''Abstract:''' Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Chiarella M, Louie AC, Medeiros BC. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol. 2016 34:15_suppl, 7000-7000 [http://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.7000 link to abstract] '''contains partial protocol''' [https://clinicaltrials.gov/ct2/show/NCT01696084 ClinicalTrials.gov] --><br />
#'''CLTR0310-301:''' Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018 Sep 10;36(26):2684-2692. Epub 2018 Jul 19. [http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6112 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30024784 PubMed]<br />
<br />
==Decitabine monotherapy {{#subobject:2d1dad|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1 {{#subobject:b60a91|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320000/ Issa et al. 2014]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[Acute_myeloid_leukemia_-_historical#Decitabine_.26_Valproate|Decitabine & Valproate]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Decitabine (Dacogen)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
'''4- to 6-week cycles'''<br />
<br />
===Variant #2 {{#subobject:22a24e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874148/ Kantarjian et al. 2012 (DACO-016)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#LoDAC|LoDAC]]<br> 2. [[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Decitabine (Dacogen)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
====Supportive medications====<br />
<br />
*[[Hydroxyurea (Hydrea)]] (dose not specified) could be used up until cycle 1 day 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:c6ffdd|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867720/ Blum et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1605949 Welch et al. 2016]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Decitabine (Dacogen)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
<br />
*[[Hydroxyurea (Hydrea)]] (dose not specified) allowed during and prior to cycle 1<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
<br />
*Blum et al. 2010, persistent AML (greater than or equal to 5% blasts): repeated cycles with 10 days of decitabine as described above<br />
*Blum et al. 2010, no morphologic evidence of AML (less than 5% blasts): received 5 days of decitabine as described by [[#Decitabine_monotherapy_2|decitabine maintenance]]<br />
<br />
===References===<br />
<br />
#Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, Liu S, Havelange V, Becker H, Schaaf L, Mickle J, Devine H, Kefauver C, Devine SM, Chan KK, Heerema NA, Bloomfield CD, Grever MR, Byrd JC, Villalona-Calero M, Croce CM, Marcucci G. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7473-8. Epub 2010 Apr 5. [http://www.pnas.org/content/107/16/7473.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867720/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20368434 PubMed]<br />
<!-- Presented in part at the 47th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2011. --><br />
#'''DACO-016:''' Kantarjian HM, Thomas XG, Dmoszyńska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysák D, Minden M, Arthur C. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012 Jul 20;30(21):2670-7. Epub 2012 Jun 11. [http://jco.ascopubs.org/content/30/21/2670.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874148/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22689805 PubMed]<br />
##'''Subgroup analysis:''' Wierzbowska A, Wawrzyniak E, Pluta A, Robak T, Mazur GJ, Dmoszynska A, Cermak J, Oriol A, Lysak D, Arthur C, Doyle M, Xiu L, Ravandi F, Kantarjian HM. Decitabine improves response rate and prolongs progression-free survival in older patients with newly diagnosed acute myeloid leukemia and with monosomal karyotype: A subgroup analysis of the DACO-016 trial. Am J Hematol. 2018 May;93(5):E125-E127. Epub 2018 Feb 24. [https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.25062 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29417613 PubMed]<br />
#Issa JP, Garcia-Manero G, Huang X, Cortes J, Ravandi F, Jabbour E, Borthakur G, Brandt M, Pierce S, Kantarjian HM. Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer. 2015 Feb 15;121(4):556-61. Epub 2014 Oct 21. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.29085/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320000/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25336333 PubMed]<br />
#Welch JS, Petti AA, Miller CA, Fronick CC, O'Laughlin M, Fulton RS, Wilson RK, Baty JD, Duncavage EJ, Tandon D, Lee Y, Wartman LD, Uy GL, Ghobadi A, Tomasson MH, Pusic I, Romee R, Fehniger TA, Stockerl-Goldstein KE, Vij R, Oh ST, Abboud CN, Cashen AF, Schroeder MA, Jacoby MA, Heath SE, Luber K, Janke MR, Hantel A, Khan N, Sukhanova MJ, Knoebel RW, Stock W, Graubert TA, Walter MJ, Westervelt P, Link DC, DiPersio JF, Ley TJ. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016 Nov 24;375(21):2023-2036. [https://www.nejm.org/doi/full/10.1056/NEJMoa1605949#article_supplementary_material link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217532/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27959731 PubMed]<br />
<br />
==Decitabine & Venetoclax {{#subobject:30c499|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 5 days of decitabine {{#subobject:2aab30|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30010-X/fulltext DiNardo et al. 2018 (M14-358)]<br />
| style="background-color:#91cf61" |Phase Ib, >20 pts<br />
|-<br />
|}<br />
<br />
''Patients with WBC greater than 25 x 10<sup>9</sup>/L at presentation were pre-treated with hydroxyurea or leukapheresis.''<br />
<br />
====Chemotherapy, induction====<br />
<br />
*[[Decitabine (Dacogen)]] 20 mg/m<sup>2</sup> IV or SC once per day on days 1 to 5<br />
*[[Venetoclax (Venclexta)]] 400, 800, or 1200 mg PO once per day<br />
<br />
===Variant #2, 10 days of decitabine {{#subobject:08cde2|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/132/Suppl_1/286 Maiti et al. 2018 (DEC10-VEN)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Therapy with hydroxyurea or one dose of cytarabine up to 2g/m<sup>2</sup> was allowed during cycle 1.''<br />
<br />
====Chemotherapy, induction====<br />
<br />
*[[Decitabine (Dacogen)]] 20 mg/m<sup>2</sup> IV or SC once per day on days 1 to 10<br />
*[[Venetoclax (Venclexta)]] 400, 800, or 1200 mg PO once per day<br />
<br />
===References===<br />
<br />
#'''M14-358:''' DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, Arellano M, Frattini MG, Kantarjian H, Popovic R, Chyla B, Xu T, Dunbar M, Agarwal SK, Humerickhouse R, Mabry M, Potluri J, Konopleva M, Pollyea DA. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018 Feb;19(2):216-228. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30010-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29339097 PubMed] [https://clinicaltrials.gov/ct2/show/NCT02203773 NCT02203773]<br />
##'''Update:''' DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, Frankfurt O, Konopleva M, Wei AH, Kantarjian HM, Xu T, Hong WJ, Chyla B, Potluri J, Pollyea DA, Letai A. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019 Jan 3;133(1):7-17. Epub 2018 Oct 25. [http://www.bloodjournal.org/content/133/1/7 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30361262 PubMed]<br />
#'''Abstract:''' Maiti A, DiNardo CD, Cortes JE, Borthakur G, Pemmaraju,N, Benton CB, Kadia TM, Takahashi K, Naqvi K, Ravandi F, Alvarado Y, Short NJ, Daver NG, Sasaki K, Ohanian MN, Garcia-Manero G, Thompson PA, Kornblau SM, Masarova L, Jain N, Jabbour EJ, Andreeff M, Maduike R, Guerrero JA, Zhang Q, Cavazos A, Ma H, Rausch CR, Bivins CA, Vaughan K, Pierce SA, Ning J, Qiao W, Welch JS, Kantarjian HM, Konopleva MY. Interim Analysis of Phase II Study of Venetoclax with 10-Day Decitabine (DEC10-VEN) in Acute Myeloid Leukemia and Myelodysplastic Syndrome. Blood, 132(Suppl 1), 286. [http://www.bloodjournal.org/content/132/Suppl_1/286 link to original abstract] [https://clinicaltrials.gov/ct2/show/NCT03404193 NCT03404193]<br />
<br />
==Gemtuzumab ozogamicin monotherapy {{#subobject:4e3c9a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e01685|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/34/9/972.full Amadori et al. 2016 (EORTC/GIMEMA AML-19)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Gemtuzumab ozogamicin (Mylotarg)]] 6 mg/m<sup>2</sup> IV once on day 1, then 3 mg/m<sup>2</sup> IV once on day 8<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*Patients with benefit: [[#Gemtuzumab_ozogamicin_monotherapy_2|Gemtuzumab ozogamicin maintenance]]<br />
<br />
===References===<br />
<!-- Presented in part at the 56th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 6-9, 2014. --><br />
<br />
#'''EORTC/GIMEMA AML-19:''' Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M, Annino L, Venditti A, Voso MT, Mazzone C, Magro D, De Fabritiis P, Muus P, Alimena G, Mancini M, Hagemeijer A, Paoloni F, Vignetti M, Fazi P, Meert L, Ramadan SM, Willemze R, de Witte T, Baron F. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016 Mar 20;34(9):972-9. Epub 2016 Jan 25. [http://jco.ascopubs.org/content/34/9/972.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26811524 PubMed]<br />
<br />
==Glasdegib & LoDAC {{#subobject:ba44c2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Glasdegib & LoDAC: Glasdegib & '''<u>Lo</u>'''w '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
===Regimen {{#subobject:e4c7c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365492/ Cortes et al. 2018 (BRIGHT AML 1003)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#LoDAC|LoDAC]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Glasdegib (Daurismo)]] 100 mg PO once per day<br />
*[[Cytarabine (Ara-C)]] 20 mg SC twice per day on days 1 to 10<br />
<br />
'''28-day cycles'''<br />
===References===<br />
<!-- # '''Abstract:''' Cortes JE, Heidel FH, Heuser M, Fiedler W, Smith BD, Robak T. Montesinos Fernandez P, Ma WW, Shaik MN, Zeremski M, O'Connell A, Chan, G. A Phase 2 Randomized Study of Low Dose Ara-C with or without Glasdegib (PF-04449913) in Untreated Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome. Blood 2016, 128(22), 99. [http://www.bloodjournal.org/content/128/22/99 link to original article] '''contains verified protocol''' --><br />
<br />
#'''BRIGHT AML 1003:''' Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, Montesinos P, Pollyea DA, DesJardins P, Ottmann O, Ma WW, Shaik MN, Laird AD, Zeremski M, O'Connell A, Chan G, Heuser M. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019 Feb;33(2):379-389. Epub 2018 Dec 16. [https://www.nature.com/articles/s41375-018-0312-9 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365492/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30555165 PubMed]<br />
<br />
==LoDAC {{#subobject:25e1c6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
LoDAC: '''<u>Lo</u>'''w '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
<br>LDAC: '''<u>L</u>'''ow-dose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
===Variant #1, 20 mg twice per day, indefinite duration {{#subobject:a3d4fb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132839/ Kantarjian et al. 2013 (SPARK-AML1)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Barasertib & LoDAC<br />
| style="background-color:#fc8d59" |Seems to have inferior OCRR<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148765/ Döhner et al. 2014 (BI 1230.4)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|LoDAC & Volasertib<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365492/ Cortes et al. 2018 (BRIGHT AML 1003)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Glasdegib_.26_LoDAC|Glasdegib & LoDAC]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 20 mg SC twice per day on days 1 to 10<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 20 mg/m<sup>2</sup> twice per day, limited duration {{#subobject:d5c6f7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533673/ Sekeres et al. 2012 (SG033-0003)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|LDAC & Lintuzumab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/30/32/3924.long Burnett et al. 2012 (UK NCRI AML16)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Clofarabine_monotherapy|Clofarabine]]<br />
| style="background-color:#ffffbf" |Seems not superior (*)<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536889/ Dennis et al. 2015]<br />
| rowspan="2" style="background-color:#1a9851" |Randomized (C)<br />
|1. LDAC & Vosaroxin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. Vosaroxin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nature.com/leu/journal/v29/n6/full/leu201538a.html Burnett et al. 2015]<br />
| style="background-color:#1a9851" |Randomized (C)<br />
|Sapacitabine<br />
| style="background-color:#fee08b" |Might have inferior CR rate<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ Dombret et al. 2015 (AZA-AML-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Azacitidine_monotherapy|Azacitidine]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
''Note: reported efficacy for UK NCRI AML16 is based on the 2016 update.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 20 mg/m<sup>2</sup> SC twice per day on days 1 to 10<br />
<br />
'''4- to 6-week cycle for up to 4 cycles'''<br />
<br />
===Variant #3, 20 mg/m<sup>2</sup> once per day, indefinite duration {{#subobject:fd61d0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874148/ Kantarjian et al. 2012 (DACO-016)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Decitabine_monotherapy|Decitabine]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 20 mg/m<sup>2</sup> SC once per day on days 1 to 10<br />
<br />
'''28-day cycles until progression or intolerance'''<br />
<br />
===References===<br />
<!-- Presented in part at the 47th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2011. --><br />
<br />
#'''DACO-016:''' Kantarjian HM, Thomas XG, Dmoszyńska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysák D, Minden M, Arthur C. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012 Jul 20;30(21):2670-7. Epub 2012 Jun 11. [http://jco.ascopubs.org/content/30/21/2670.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874148/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22689805 PubMed]<br />
##'''Subgroup analysis:''' Wierzbowska A, Wawrzyniak E, Pluta A, Robak T, Mazur GJ, Dmoszynska A, Cermak J, Oriol A, Lysak D, Arthur C, Doyle M, Xiu L, Ravandi F, Kantarjian HM. Decitabine improves response rate and prolongs progression-free survival in older patients with newly diagnosed acute myeloid leukemia and with monosomal karyotype: A subgroup analysis of the DACO-016 trial. Am J Hematol. 2018 May;93(5):E125-E127. Epub 2018 Feb 24. [https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.25062 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29417613 PubMed]<br />
#'''SG033-0003:''' Sekeres MA, Lancet JE, Wood BL, Grove LE, Sandalic L, Sievers EL, Jurcic JG. Randomized phase IIb study of low-dose cytarabine and lintuzumab versus low-dose cytarabine and placebo in older adults with untreated acute myeloid leukemia. Haematologica. 2013 Jan;98(1):119-28. Epub 2012 Jul 16. [http://www.haematologica.org/content/98/1/119.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533673/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22801961 PubMed]<br />
#'''UK NCRI AML16:''' Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L, Hunter AE, Yin J, Craddock CF, Dufva IH, Wheatley K, Milligan D. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012 Nov 10;30(32):3924-31. Epub 2012 Jul 30. [http://jco.ascopubs.org/content/30/32/3924.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22851554 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, Yin J, McMullin MF, Ali S, Bowen D, Hills RK; UK National Cancer Research Institute AML Working Group. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013 Aug 22;122(8):1384-94. Epub 2013 Jul 9. [http://www.bloodjournal.org/content/122/8/1384.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23838349 PubMed]<br />
##'''Update:''' Burnett AK, Russell NH, Hills RK, Kell J, Nielsen OJ, Dennis M, Cahalin P, Pocock C, Ali S, Burns S, Freeman S, Milligan D, Clark RE. A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia. Leukemia. 2017 Feb;31(2):310-317. Epub 2016 Sep 2. [https://www.nature.com/leu/journal/v31/n2/fig_tab/leu2016225f1.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292678/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27624670 PubMed]<br />
#'''SPARK-AML1:''' Kantarjian HM, Martinelli G, Jabbour EJ, Quintás-Cardama A, Ando K, Bay JO, Wei A, Gröpper S, Papayannidis C, Owen K, Pike L, Schmitt N, Stockman PK, Giagounidis A; SPARK-AML1 Investigators. Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia. Cancer. 2013 Jul 15;119(14):2611-9. Epub 2013 Apr 19. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.28113 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132839/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23605952 PubMed]<br />
#'''BI 1230.4:''' Döhner H, Lübbert M, Fiedler W, Fouillard L, Haaland A, Brandwein JM, Lepretre S, Reman O, Turlure P, Ottmann OG, Müller-Tidow C, Krämer A, Raffoux E, Döhner K, Schlenk RF, Voss F, Taube T, Fritsch H, Maertens J. Randomized, phase 2 trial comparing low-dose cytarabine with or without volasertib in AML patients not suitable for intensive induction therapy. Blood. 2014 Aug 28;124(9):1426-33. Epub 2014 Jul 8. [http://www.bloodjournal.org/content/124/9/1426.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148765/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25006120 PubMed]<br />
#Dennis M, Russell N, Hills RK, Hemmaway C, Panoskaltsis N, McMullin MF, Kjeldsen L, Dignum H, Thomas IF, Clark RE, Milligan D, Burnett AK. Vosaroxin and vosaroxin plus low-dose Ara-C (LDAC) vs low-dose Ara-C alone in older patients with acute myeloid leukemia. Blood. 2015 May 7;125(19):2923-32. Epub 2015 Mar 24. [http://www.bloodjournal.org/content/125/19/2923.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536889/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25805811 PubMed]<br />
#Burnett AK, Russell N, Hills RK, Panoskaltsis N, Khwaja A, Hemmaway C, Cahalin P, Clark RE, Milligan D. A randomised comparison of the novel nucleoside analogue sapacitabine with low-dose cytarabine in older patients with acute myeloid leukaemia. Leukemia. 2015 Jun;29(6):1312-9. Epub 2015 Feb 13. [https://www.nature.com/leu/journal/v29/n6/full/leu201538a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25676423 PubMed]<br />
#'''AZA-AML-001:''' Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/3/291.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504945/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25987659 PubMed]<br />
##'''Subgroup analysis:''' Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3803-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731212/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29241450 PubMed]<br />
#'''BRIGHT AML 1003:''' Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, Montesinos P, Pollyea DA, DesJardins P, Ottmann O, Ma WW, Shaik MN, Laird AD, Zeremski M, O'Connell A, Chan G, Heuser M. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019 Feb;33(2):379-389. Epub 2018 Dec 16. [https://www.nature.com/articles/s41375-018-0312-9 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365492/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30555165 PubMed]<br />
<br />
==LoDAC & Venetoclax {{#subobject:b84441|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
LoDAC & Venetoclax: '''<u>Lo</u>'''w '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine) & Venetoclax<br />
===Regimen {{#subobject:e84ab4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.18.01600?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed Wei et. al. 2019 (M14-387)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br /><br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 20 mg/m<sup>2</sup> SC once per day on days 1 to 10<br />
*[[Venetoclax (Venclexta)]] 600 mg PO once per day (dose reduction indicated when used when with CYP3A inhibitors) <br />
<br />
'''28-day cycles'''<br />
===References===<br />
===1. Wei AH, Strickland Jr SA, Hou JZ, Fiedler W, Lin TL, Walter RB, Enjeti A, Tiong IS, Savona M, Lee S, Chyla B. Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study. Journal of Clinical Oncology. 2019 Mar 20:JCO-18. [https://ascopubs.org/doi/full/10.1200/JCO.18.01600?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed link to abstract] '''contains protocol'''===<br />
<br />
#[https://clinicaltrials.gov/ct2/show/NCT02287233 NCT02287233] '''contains protocol'''<br />
<br />
==Temozolomide monotherapy {{#subobject:261bcb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:fb4aeb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13094/full Brandwein et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Patient selection was based on MGMT expression by Western blot. See article for details.''<br />
====Chemotherapy====<br />
<br />
*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup>/day PO on days 1 to 7<br />
**Complete responders could receive: 200 mg/m<sup>2</sup>/day PO on days 1 to 5<br />
<br />
'''28-day cycle for up to 12 cycles'''<br />
<br />
===References===<br />
<br />
#Brandwein JM, Kassis J, Leber B, Hogge D, Howson-Jan K, Minden MD, Galarneau A, Pouliot JF. Phase II study of targeted therapy with temozolomide in acute myeloid leukaemia and high-risk myelodysplastic syndrome patients pre-screened for low O(6) -methylguanine DNA methyltransferase expression. Br J Haematol. 2014 Dec;167(5):664-70. Epub 2014 Aug 27. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13094/full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25160658 PubMed]<br />
<br />
=Consolidation after upfront therapy=<br />
==5+2d {{#subobject:b409f7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a67da7|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6112 Lancet et al. 2018 (CLTR0310-301)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose: 500 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
<br />
'''5-day course'''<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Chiarella M, Louie AC, Medeiros BC. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol. 2016 34:15_suppl, 7000-7000 [http://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.7000 link to abstract] '''contains partial protocol''' [https://clinicaltrials.gov/ct2/show/NCT01696084 ClinicalTrials.gov] --><br />
<br />
#'''CLTR0310-301:''' Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018 Sep 10;36(26):2684-2692. Epub 2018 Jul 19. [http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6112 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30024784 PubMed]<br />
<br />
==HiDAC {{#subobject:caa3a2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
HiDAC: '''<u>Hi</u>'''gh '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
<br>HDAC: '''<u>H</u>'''igh '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
<br>HDAraC: '''<u>H</u>'''igh '''<u>D</u>'''ose '''<u>AraC</u>''' (Cytarabine)<br />
===Variant #1, 2000 mg/m<sup>2</sup> every 12 hours x 6 {{#subobject:4e73ae|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/30/20/2441.full Holowiecki et al. 2012 (PALG AML1/2004)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Details in the text are scant.''<br />
====Preceding treatment====<br />
<br />
*[[#Cytarabine_.26_Mitoxantrone|Cytarabine & Mitoxantrone consolidation]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV every 12 hours on days 1, 3, 5 (6 total doses)<br />
<br />
===Variant #2, 2 cycles of 2000 mg/m<sup>2</sup> every 12 hours x 10 {{#subobject:2a4b32|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ar.iiarjournals.org/content/32/2/643.long Fukushima et al. 2012]<br />
| style="background-color:#91cf61" |Randomized, <20 pts in this arm (C)<br />
|[[#IDAC|mIDAC]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*BHAC-MMV<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 60 minutes every 12 hours on days 1 to 5 (10 total doses)<br />
<br />
'''2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*A-VVV<br />
<br />
===Variant #3, 1 cycle of 3000 mg/m<sup>2</sup> every 12 hours x 12 {{#subobject:a0e7d9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJM199812033392301 Cassileth et al. 1998]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#BuCy.2C_then_auto_HSCT|BuCy, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*5+2i<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1 to 6 (12 total doses)<br />
<br />
'''One course'''<br />
<br />
===Variant #4, 3 cycles of 3000 mg/m<sup>2</sup> every 12 hours x 6 {{#subobject:746f61|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895015/ Moore et al. 2004 (CALGB 9222)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|HiDAC, then CYVE, then AZQ & Mitoxantrone<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682338/ Petersdorf et al. 2013 (SWOG S0106)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2012.46.4743 Schaich et al. 2013 (AML2003)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MAC/MAMAC/MAC<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/33/11/1252.full Stone et al. 2015 (ACCEDE)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00362-9/fulltext Röllig et al. 2015 (SORAML)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|HiDAC & Sorafenib<br />
| style="background-color:#fc8d59" |Seems to have inferior EFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 Stone et al. 2015 (COSAH C-022)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: CALGB 9222 specified that each cycle begins within 2 weeks after hematopoietic recovery from the preceding cycle. SORAML specified a 28-day (minimum) cycle or 1 week after marrow recovery, whichever comes later.''<br />
====Preceding treatment====<br />
<br />
*CALGB 9222: [[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br />
*SWOG S0106: [[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]] versus [[#7.2B3d_.26_GO|7+3d & GO]]<br />
*AML2003: [[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]] x 2<br />
*ACCEDE: Amonafide & Cytarabine versus [[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br />
*SORAML: [[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]] versus 7+3d & Sorafenib<br />
*COSAH C-022: [[#7.2B3d_.28high-dose.29|7+3d (high-dose)]] versus [[#7.2B3i|7+3i]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 3, 5 (6 total doses)<br />
<br />
'''3 cycles of varying durations'''<br />
====Subsequent treatment====<br />
<br />
*SWOG S0106: GO maintenance versus [[#Observation|no further treatment]]<br />
<br />
===Variant #5, 3 cycles of 2000 mg/m<sup>2</sup> every 12 hours x 10 {{#subobject:8887b8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/117/8/2358 Ohtake et al. 2010 (JALSG AML201)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Multiagent chemotherapy<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: this was considered an experimental arm in Japan, given the timing of HiDAC approval. Reported efficacy is based on the 2010 update by Miyawaki et al.''<br />
====Preceding treatment====<br />
<br />
*7+5d or [[#7.2B3i|7+3i]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1 to 5 (10 total doses)<br />
<br />
'''3 cycles, started 1 week after neutrophils, WBCs, and platelets recovered to more than 1500/uL, 3 × 10<sup>9</sup>/L, and 100 × 10<sup>9</sup>/L'''<br />
<br />
===Variant #6, 4 cycles of 3000 mg/m<sup>2</sup> every 12 hours x 6 {{#subobject:0c2779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199410063311402 Mayer et al. 1994 (CALGB 8525)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Low-dose continuous infusion cytarabine<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://www.bloodjournal.org/content/118/7/1754.long Thomas et al. 2011 (ALFA-9802)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Timed sequential chemotherapy (TSC)<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 Lee et al. 2017 (COSAH C-022)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*ALFA-9802: Timed sequential therapy +/- GM-CSF priming<br />
*COSAH C-022: [[#7.2B3d_.28high-dose.29|7+3d (high-dose)]] versus [[#7.2B3i|7+3i]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 3, 5 (6 total doses)<br />
<br />
'''Up to 4 cycles'''<br />
====Subsequent treatment====<br />
<br />
*ALFA-9802: Cytarabine & Daunorubicin maintenance<br />
<br />
===References===<br />
<br />
#'''CALGB 8525:''' Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, Omura GA, Moore JO, McIntyre OR, Frei E 3rd; Cancer and Leukemia Group B. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med. 1994 Oct 6;331(14):896-903. [https://www.nejm.org/doi/full/10.1056/NEJM199410063311402 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8078551 PubMed]<br />
#Cassileth PA, Harrington DP, Appelbaum FR, Lazarus HM, Rowe JM, Paietta E, Willman C, Hurd DD, Bennett JM, Blume KG, Head DR, Wiernik PH. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med. 1998 Dec 3;339(23):1649-56. [https://www.nejm.org/doi/10.1056/NEJM199812033392301 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9834301 PubMed]<br />
#'''CALGB 9222:''' Moore JO, George SL, Dodge RK, Amrein PC, Powell BL, Kolitz JE, Baer MR, Davey FR, Bloomfield CD, Larson RA, Schiffer CA. Sequential multiagent chemotherapy is not superior to high-dose cytarabine alone as postremission intensification therapy for acute myeloid leukemia in adults under 60 years of age: Cancer and Leukemia Group B Study 9222. Blood. 2005 May 1;105(9):3420-7. Epub 2004 Nov 30. [http://www.bloodjournal.org/content/105/9/3420.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895015/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15572587 PubMed]<br />
#'''JALSG AML201:''' Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N, Okumura H, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R. Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood. 2011 Feb 24;117(8):2358-65. Epub 2010 Aug 6. [http://www.bloodjournal.org/content/117/8/2358 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20693429 PubMed]<br />
##'''Update:''' Miyawaki S, Ohtake S, Fujisawa S, Kiyoi H, Shinagawa K, Usui N, Sakura T, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R. A randomized comparison of 4 courses of standard-dose multiagent chemotherapy versus 3 courses of high-dose cytarabine alone in postremission therapy for acute myeloid leukemia in adults: the JALSG AML201 Study. Blood. 2011 Feb 24;117(8):2366-72. Epub 2010 Dec 29. [http://www.bloodjournal.org/content/117/8/2366.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21190996 PubMed]<br />
#'''ALFA-9802:''' Thomas X, Elhamri M, Raffoux E, Renneville A, Pautas C, de Botton S, de Revel T, Reman O, Terré C, Gardin C, Chelghoum Y, Boissel N, Quesnel B, Hicheri Y, Bourhis JH, Fenaux P, Preudhomme C, Michallet M, Castaigne S, Dombret H. Comparison of high-dose cytarabine and timed-sequential chemotherapy as consolidation for younger adults with AML in first remission: the ALFA-9802 study. Blood. 2011 Aug 18;118(7):1754-62. Epub 2011 Jun 20. [http://www.bloodjournal.org/content/118/7/1754.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21690555 PubMed]<br />
#Fukushima T, Urasaki Y, Yamaguchi M, Ueda M, Morinaga K, Haba T, Sugiyama T, Nakao S, Origasa H, Umehara H, Ueda T. A randomized comparison of modified intermediate-dose Ara-C versus high-dose ara-c in post-remission therapy for acute myeloid leukemia. Anticancer Res. 2012 Feb;32(2):643-7. [http://ar.iiarjournals.org/content/32/2/643.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22287757 PubMed]<br />
#'''SWOG S0106:''' Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013 Jun 13;121(24):4854-60. Epub 2013 Apr 16. [http://bloodjournal.hematologylibrary.org/content/121/24/4854.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682338/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23591789 PubMed]<br />
#'''AML2003:''' Schaich M, Parmentier S, Kramer M, Illmer T, Stölzel F, Röllig C, Thiede C, Hänel M, Schäfer-Eckart K, Aulitzky W, Einsele H, Ho AD, Serve H, Berdel WE, Mayer J, Schmitz N, Krause SW, Neubauer A, Baldus CD, Schetelig J, Bornhäuser M, Ehninger G. High-dose cytarabine consolidation with or without additional amsacrine and mitoxantrone in acute myeloid leukemia: results of the prospective randomized AML2003 trial. J Clin Oncol. 2013 Jun 10;31(17):2094-102. Epub 2013 Apr 29. [http://ascopubs.org/doi/full/10.1200/JCO.2012.46.4743 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23630210 PubMed]<br />
#'''ACCEDE:''' Stone RM, Mazzola E, Neuberg D, Allen SL, Pigneux A, Stuart RK, Wetzler M, Rizzieri D, Erba HP, Damon L, Jang JH, Tallman MS, Warzocha K, Masszi T, Sekeres MA, Egyed M, Horst HA, Selleslag D, Solomon SR, Venugopal P, Lundberg AS, Powell B. Phase III open-label randomized study of cytarabine in combination with amonafide l-malate or daunorubicin as induction therapy for patients with secondary acute myeloid leukemia. J Clin Oncol. 2015 Apr 10;33(11):1252-7. Epub 2015 Mar 2. [http://jco.ascopubs.org/content/33/11/1252.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25732165 PubMed]<br />
#'''PALG AML1/2004:''' Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszyńska A, Kloczko J, Jedrzejczak WW, Zdziarska B, Warzocha K, Zawilska K, Komarnicki M, Kielbinski M, Piatkowska-Jakubas B, Wierzbowska A, Wach M, Haus O. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012 Jul 10;30(20):2441-8. Epub 2012 Apr 16. [http://jco.ascopubs.org/content/30/20/2441.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22508825 PubMed]<br />
#'''SORAML:''' Röllig C, Serve H, Hüttmann A, Noppeney R, Müller-Tidow C, Krug U, Baldus CD, Brandts CH, Kunzmann V, Einsele H, Krämer A, Schäfer-Eckart K, Neubauer A, Burchert A, Giagounidis A, Krause SW, Mackensen A, Aulitzky W, Herbst R, Hänel M, Kiani A, Frickhofen N, Kullmer J, Kaiser U, Link H, Geer T, Reichle A, Junghanß C, Repp R, Heits F, Dürk H, Hase J, Klut IM, Illmer T, Bornhäuser M, Schaich M, Parmentier S, Görner M, Thiede C, von Bonin M, Schetelig J, Kramer M, Berdel WE, Ehninger G; Study Alliance Leukaemia. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015 Dec;16(16):1691-9. Epub 2015 Nov 6. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00362-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26549589 PubMed]<br />
#'''COSAH C-022:''' Lee JH, Kim H, Joo YD, Lee WS, Bae SH, Zang DY, Kwon J, Kim MK, Lee J, Lee GW, Lee JH, Choi Y, Kim DY, Hur EH, Lim SN, Lee SM, Ryoo HM, Kim HJ, Hyun MS, Lee KH; Cooperative Study Group A for Hematology. Prospective randomized comparison of idarubicin and high-dose daunorubicin in induction chemotherapy for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2017 Aug 20;35(24):2754-2763. Epub 2017 Jun 20. [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28632487 PubMed]<br />
<br />
==IDAC {{#subobject:f5cd74|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
IDAC: '''<u>I</u>'''ntermediate '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
<br>mIDAC: '''<u>m</u>'''odified '''<u>I</u>'''ntermediate '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
<br />
===Variant #1, 1000 mg/m<sup>2</sup> x 3 {{#subobject:0340ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/11/1252.full Stone et al. 2015 (ACCEDE)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Amonafide & Cytarabine versus [[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]<br />
*7+3d & Glasdegib<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 3 hours once per day on days 1, 3, 5 (3 total doses)<br />
<br />
===Variant #2, 1000 mg/m<sup>2</sup> x 10 {{#subobject:cbba35|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ar.iiarjournals.org/content/32/2/643.long Fukushima et al. 2012]<br />
| style="background-color:#91cf61" |Randomized, <20 pts in this arm (E)<br />
|[[#HiDAC|HDAC]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*BHAC-MMV<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 60 minutes every 12 hours on days 1 to 5 (10 total doses)<br />
<br />
'''Two cycles'''<br />
====Subsequent treatment====<br />
<br />
*A-VVV<br />
<br />
===Variant #3, 1000 mg/m<sup>2</sup> x 12 {{#subobject:22eda3|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0901409 Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]] versus [[#7.2B3d_.28high-dose.29|7+3d (high-dose)]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 6 hours every 12 hours on days 1 to 6 (12 total doses)<br />
<br />
'''One cycle'''<br />
====Subsequent treatment====<br />
<br />
*Transplant eligible patients: [[#Allogeneic_hematopoietic_stem_cell_transplant|allogeneic HSCT]]<br />
*Transplant ineligible patients: Gemtuzumab ozogamicin maintenance versus [[#Observation|no further treatment]]<br />
<br />
===References===<br />
<br />
#'''HOVON 43 AML/SAKK 30/01:''' Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Döhner H, Gratwohl A, Pabst T, Verhoef G; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. [https://www.nejm.org/doi/full/10.1056/NEJMoa0901409 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19776405 PubMed]<br />
#Fukushima T, Urasaki Y, Yamaguchi M, Ueda M, Morinaga K, Haba T, Sugiyama T, Nakao S, Origasa H, Umehara H, Ueda T. A randomized comparison of modified intermediate-dose Ara-C versus high-dose ara-c in post-remission therapy for acute myeloid leukemia. Anticancer Res. 2012 Feb;32(2):643-7. [http://ar.iiarjournals.org/content/32/2/643.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22287757 PubMed]<br />
#'''ACCEDE:''' Stone RM, Mazzola E, Neuberg D, Allen SL, Pigneux A, Stuart RK, Wetzler M, Rizzieri D, Erba HP, Damon L, Jang JH, Tallman MS, Warzocha K, Masszi T, Sekeres MA, Egyed M, Horst HA, Selleslag D, Solomon SR, Venugopal P, Lundberg AS, Powell B. Phase III open-label randomized study of cytarabine in combination with amonafide l-malate or daunorubicin as induction therapy for patients with secondary acute myeloid leukemia. J Clin Oncol. 2015 Apr 10;33(11):1252-7. Epub 2015 Mar 2. [http://jco.ascopubs.org/content/33/11/1252.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25732165 PubMed]<br />
<br />
==HDAC & G-CSF {{#subobject:e0396d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
HDAC & G-CSF: '''<u>H</u>'''igh '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine) & '''<u>G</u>'''ranulocyte '''<u>C</u>'''olony '''<u>S</u>'''timulating '''<u>F</u>'''actor<br />
<br />
===Regimen {{#subobject:d8edc4|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2016.70.4551 Thomas et al. 2017 (ALFA-0702)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#CLARA|CLARA]]<br />
| style="background-color:#fc8d59" |Seems to have inferior RFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Cytarabine, Daunorubicin, G-CSF induction<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 3, 5 (6 total doses)<br />
*[[Filgrastim (Neupogen)]] 5 mcg/kg IV once per day on days 1 to 5<br />
<br />
'''35-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''ALFA-0702:''' Thomas X, de Botton S, Chevret S, Caillot D, Raffoux E, Lemasle E, Marolleau JP, Berthon C, Pigneux A, Vey N, Reman O, Simon M, Recher C, Cahn JY, Hermine O, Castaigne S, Celli-Lebras K, Ifrah N, Preudhomme C, Terré C, Dombret H. Randomized phase II study of clofarabine-based consolidation for younger adults with acute myeloid leukemia in first remission. J Clin Oncol. 2017 Apr 10;35(11):1223-1230. Epub 2017 Feb 21. [http://ascopubs.org/doi/full/10.1200/JCO.2016.70.4551 link to original article] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/28221862 PubMed]<br />
<br />
==Azacitidine monotherapy {{#subobject:7abfd6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f7e3f6|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829116/ Nand et al. 2013 (SWOG S0703)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Azacitidine_.26_Gemtuzumab_ozogamicin_2|Azacitidine & Gemtuzumab ozogamicin consolidation]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Azacitidine (Vidaza)]] 75 mg/m<sup>2</sup> SC once on day 1<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<!-- Presented in part at the American Society of Clinical Oncology annual meeting (Chicago, IL, June 1-5, 2012) and at the American Society of Hematology annual meeting (Atlanta, GA, December 8-11, 2012). --><br />
<br />
#'''SWOG S0703:''' Nand S, Othus M, Godwin JE, Willman CL, Norwood TH, Howard DS, Coutre SE, Erba HP, Appelbaum FR. A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood. 2013 Nov 14;122(20):3432-9. Epub 2013 Oct 3. [http://www.bloodjournal.org/content/122/20/3432.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829116/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24092933 PubMed]<br />
<br />
==Azacitidine & Gemtuzumab ozogamicin {{#subobject:e5ff95|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:eb3f69|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829116/ Nand et al. 2013 (SWOG S0703)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Azacitidine_.26_Gemtuzumab_ozogamicin|Azacitidine & Gemtuzumab ozogamicin induction]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Azacitidine (Vidaza)]] 75 mg/m<sup>2</sup> IV or SC once per day on days 1 to 7<br />
*[[Gemtuzumab ozogamicin (Mylotarg)]] 3 mg/m<sup>2</sup> IV once on day 8<br />
<br />
====Supportive medications====<br />
<br />
*"Appropriate premedications" which were not specified, for [[Gemtuzumab ozogamicin (Mylotarg)]]<br />
*Growth factors per physician discretion<br />
<br />
'''1 cycle'''<br />
====Subsequent treatment====<br />
<br />
*[[#Azacitidine_monotherapy_2|Azacitidine maintenance]], within 42 days of completion of consolidation<br />
<br />
===References===<br />
<!-- Presented in part at the American Society of Clinical Oncology annual meeting (Chicago, IL, June 1-5, 2012) and at the American Society of Hematology annual meeting (Atlanta, GA, December 8-11, 2012). --><br />
<br />
#'''SWOG S0703:''' Nand S, Othus M, Godwin JE, Willman CL, Norwood TH, Howard DS, Coutre SE, Erba HP, Appelbaum FR. A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood. 2013 Nov 14;122(20):3432-9. Epub 2013 Oct 3. [http://www.bloodjournal.org/content/122/20/3432.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829116/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24092933 PubMed]<br />
<br />
==BuCy, then auto HSCT {{#subobject:9acbe9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
BuCy: '''<u>Bu</u>'''sulfan & '''<u>Cy</u>'''clophosphamide<br />
===Variant #1, 16/120 {{#subobject:6ccf66|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/23/6037.long Vellenga et al. 2011 (HOVON-SAKK AML-29/AML-42)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Etoposide_.26_Mitoxantrone|Etoposide & Mitoxantrone]]<br />
| style="background-color:#d9ef8b" |Might have superior RFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3i|7+3i]], then amsacrine & cytarabine<br />
{{#lst:Autologous HSCT|6ccf66}}<br />
===Variant #2, 16/200 {{#subobject:5d4efb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJM199605303342203 Ravindranath et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Intensive chemotherapy<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3d_.28standard-dose.29|7+3d]], then [[#HiDAC|HiDAC]]<br />
{{#lst:Autologous HSCT|5d4efb}}<br />
===References===<br />
<br />
#Ravindranath Y, Yeager AM, Chang MN, Steuber CP, Krischer J, Graham-Pole J, Carroll A, Inoue S, Camitta B, Weinstein HJ; Pediatric Oncology Group. Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. N Engl J Med. 1996 May 30;334(22):1428-34. [https://www.nejm.org/doi/10.1056/NEJM199605303342203 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8618581 PubMed]<br />
#'''HOVON-SAKK AML-29/AML-42:''' Vellenga E, van Putten W, Ossenkoppele GJ, Verdonck LF, Theobald M, Cornelissen JJ, Huijgens PC, Maertens J, Gratwohl A, Schaafsma R, Schanz U, Graux C, Schouten HC, Ferrant A, Bargetzi M, Fey MF, Löwenberg B; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON); Swiss Group for Clinical Cancer Research Collaborative Group (SAKK). Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood. 2011 Dec 1;118(23):6037-42. Epub 2011 Sep 27. [http://www.bloodjournal.org/content/118/23/6037.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21951683 PubMed]<br />
<br />
==BuFlu, then allo HSCT {{#subobject:3fe0f0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
BuFlu: '''<u>Bu</u>'''sulfan & '''<u>Flu</u>'''darabine<br />
===Regimen {{#subobject:a7e574|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658453/ Devine et al. 2015 (CALGB 100103)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts in subgroup<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|a7e574}}<br />
===References===<br />
<!-- Presented in part as an oral presentation at the 54th American Society of Hematology Annual Meeting and Exposition, Atlanta, GA, December 8-11, 2012. --><br />
<br />
#Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, Champlin RE, Chen YB, Vij R, Slack J, Soiffer RJ, Larson RA, Shea TC, Hars V, Sibley AB, Giralt S, Carter S, Horowitz MM, Linker C, Alyea EP. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. 2015 Dec 10;33(35):4167-75. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/35/4167.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658453/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527780 PubMed]<br />
<br />
==CIA {{#subobject:db5c09|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CIA: '''<u>C</u>'''lofarabine, '''<u>I</u>'''darubicin, '''<u>A</u>'''ra-C (Cytarabine)<br />
===Regimen {{#subobject:1bbed8|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/ajh.23544/references Nazha et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#CIA|CIA induction]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Idarubicin (Idamycin)]] 8 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Cytarabine (Ara-C)]] 750 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''3-day course; repeated every 3 to 4 weeks depending on disease response and recovery from regimen toxicity for up to six cycles'''<br />
<br />
===References===<br />
<br />
#Nazha A, Kantarjian H, Ravandi F, Huang X, Choi S, Garcia-Manero G, Jabbour E, Borthakur G, Kadia T, Konopleva M, Cortes J, Ferrajoli A, Kornblau S, Daver N, Pemmaraju N, Andreeff M, Estrov Z, Du M, Brandt M, Faderl S. Clofarabine, idarubicin, and cytarabine (CIA) as frontline therapy for patients ≤60 years with newly diagnosed acute myeloid leukemia. Am J Hematol. 2013 Nov;88(11):961-6. Epub 2013 Sep 9. [https://onlinelibrary.wiley.com/doi/10.1002/ajh.23544/references long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110914/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23877926 PubMed]<br />
<br />
==CLARA {{#subobject:6160cf|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CLARA: '''<u>CL</u>'''ofarabine and '''<u>ARA</u>'''-C (Cytarabine)<br />
===Regimen {{#subobject:6ed739|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2016.70.4551 Thomas et al. 2017 (ALFA-0702)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#HDAC_.26_G-CSF|HDAC & G-CSF]]<br />
| style="background-color:#91cf60" |Seems to have superior RFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Cytarabine, Daunorubicin, G-CSF induction<br />
<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 30 mg/m<sup>2</sup> IV over 2 hours once per day on days 2 to 6, '''given first'''<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given second, 4 hours after clofarabine, on days 2 to 5'''<br />
*[[Filgrastim (Neupogen)]] 5 mcg/kg IV once per day on days 1 to 6<br />
<br />
'''35-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''ALFA-0702:''' Thomas X, de Botton S, Chevret S, Caillot D, Raffoux E, Lemasle E, Marolleau JP, Berthon C, Pigneux A, Vey N, Reman O, Simon M, Recher C, Cahn JY, Hermine O, Castaigne S, Celli-Lebras K, Ifrah N, Preudhomme C, Terré C, Dombret H. Randomized phase II study of clofarabine-based consolidation for younger adults with acute myeloid leukemia in first remission. J Clin Oncol. 2017 Apr 10;35(11):1223-1230. Epub 2017 Feb 21. [http://ascopubs.org/doi/full/10.1200/JCO.2016.70.4551 link to original article] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/28221862 PubMed]<br />
<br />
==Clofarabine & LoDAC/Decitabine {{#subobject:756e06|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Clofarabine & LoDAC/Decitabine: Clofarabine & '''<u>Lo</u>'''w '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine) alternating with Decitabine<br />
===Regimen {{#subobject:0ac883|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907176/ Faderl et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Clofarabine_.26_LoDAC|Clofarabine & LoDAC]], which is counted as "Cycle 1". Cycles are given every 4 to 7 weeks pending hematologic recovery and resolution of other toxicities.<br />
<br />
====Chemotherapy, clofarabine & LoDAC portion====<br />
<br />
*[[Clofarabine (Clolar)]] as follows:<br />
**Cycles 2, 3, 7 to 9, 13 to 15: 20 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Cytarabine (Ara-C)]] as follows:<br />
**Cycles 2, 3, 7 to 9, 13 to 15: 20 mg SC twice per day on days 1 to 7<br />
<br />
'''4- to 7-week cycles, depending on count recovery'''<br />
<br />
====Chemotherapy, decitabine portion====<br />
<br />
*[[Decitabine (Dacogen)]] as follows:<br />
**Cycles 4 to 6, 10 to 12, 16 to 18: 20 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''4- to 7-week cycles, depending on count recovery'''<br />
<br />
===References===<br />
<br />
#Faderl S, Ravandi F, Huang X, Wang X, Jabbour E, Garcia-Manero G, Kadia T, Ferrajoli A, Konopleva M, Borthakur G, Burger J, Feliu J, Kantarjian HM. Clofarabine plus low-dose cytarabine followed by clofarabine plus low-dose cytarabine alternating with decitabine in acute myeloid leukemia frontline therapy for older patients. Cancer. 2012 Sep 15;118(18):4471-7. Epub 2012 Jan 26. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.27429/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907176/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22282348 PubMed]<br />
##'''Update:''' Kadia TM, Faderl S, Ravandi F, Jabbour E, Garcia-Manero G, Borthakur G, Ferrajoli A, Konopleva M, Burger J, Huang X, Wang X, Pierce S, Brandt M, Feliu J, Cortes J, Kantarjian H. Final results of a phase 2 trial of clofarabine and low-dose cytarabine alternating with decitabine in older patients with newly diagnosed acute myeloid leukemia. Cancer. 2015 Jul 15;121(14):2375-82. Epub 2015 Mar 25. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.29367/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436272/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25809968 PubMed]<br />
<br />
==CPX-351 monotherapy {{#subobject:6a5fb5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CPX-351: Liposomal Cytarabine and Daunorubicin<br />
===Regimen {{#subobject:896083|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6112 Lancet et al. 2018 (CLTR0310-301)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#CPX-351_monotherapy|CPX-351 monotherapy induction]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine and daunorubicin liposomal (Vyxeos)|CPX-351 (Vyxeos)]] 65 units/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 3<br />
<br />
'''Up to two courses'''<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Chiarella M, Louie AC, Medeiros BC. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol. 2016 34:15_suppl, 7000-7000 [http://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.7000 link to abstract] '''contains partial protocol''' [https://clinicaltrials.gov/ct2/show/NCT01696084 ClinicalTrials.gov] --><br />
<br />
#'''CLTR0310-301:''' Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018 Sep 10;36(26):2684-2692. Epub 2018 Jul 19. [http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6112 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30024784 PubMed]<br />
<br />
==Cytarabine & Daunorubicin {{#subobject:d6f810|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:c39b55|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60485-1/fulltext Castaigne et al. 2012 (ALFA-0701)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: the preceding treatment is not a true randomization because only patients in the gemtuzumab ozogamicin arm with platelet count less than 100 x 10<sup>9</sup> at day 45 from initiation of chemotherapy were assigned to this regimen. Length of courses is not specified.''<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]] or [[#7.2B3d_.26_GO|7+3d & GO]] induction<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 4 (8 total doses)<br />
*[[Daunorubicin (Cerubidine)]] as follows:<br />
**Course 1: 60 mg/m<sup>2</sup> IV once on day 1<br />
**Course 2: 60 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
<br />
'''2 courses'''<br />
<br />
===Variant #2 {{#subobject:59874e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/12/5129.full Gardin et al. 2007 (ALFA 9803)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|4 + 7 with daunorubicin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*4d + 7 induction<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 60 mg/m<sup>2</sup> SC every 12 hours on days 1 to 5 (10 total doses)<br />
*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''1-month cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Gardin C, Turlure P, Fagot T, Thomas X, Terre C, Contentin N, Raffoux E, de Botton S, Pautas C, Reman O, Bourhis JH, Fenaux P, Castaigne S, Michallet M, Preudhomme C, de Revel T, Bordessoule D, Dombret H. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood. 2007 Jun 15;109(12):5129-35. Epub 2007 Mar 6. [http://www.bloodjournal.org/content/109/12/5129.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17341661 PubMed]<br />
#'''ALFA-0701:''' Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60485-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22482940 PubMed]<br />
##'''Update:''' Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019 Jan;104(1):113-119. Epub 2018 Aug 3. [http://www.haematologica.org/content/104/1/113 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312010/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30076173 PubMed]<br />
<br />
==Cytarabine, Daunorubicin, Gemtuzumab ozogamicin {{#subobject:0f7f87|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c56261|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60485-1/fulltext Castaigne et al. 2012 (ALFA-0701)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: length of courses is not specified.''<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3d_.26_GO|7+3d & GO]] induction<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 4 (8 total doses)<br />
*[[Daunorubicin (Cerubidine)]] as follows:<br />
**Course 1: 60 mg/m<sup>2</sup> IV once on day 1<br />
**Course 2: 60 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Gemtuzumab ozogamicin (Mylotarg)]] 3 mg/m<sup>2</sup> (maximum dose of 5 mg) IV once on day 1<br />
<br />
'''2 courses'''<br />
<br />
===References===<br />
<br />
#'''ALFA-0701:''' Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60485-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22482940 PubMed]<br />
##'''Update:''' Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019 Jan;104(1):113-119. Epub 2018 Aug 3. [http://www.haematologica.org/content/104/1/113 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312010/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30076173 PubMed]<br />
<br />
==CYVE {{#subobject:f8d436|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CYVE: '''<u>CY</u>'''tarabine & '''<u>VE</u>'''pesid (Etoposide)<br />
===Regimen {{#subobject:79438d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 Lee et al. 2017 (COSAH C-022)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this consolidation regimen was for patients with high-risk cytogenetics.''<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3d_.28high-dose.29|7+3d (high-dose)]] versus [[#7.2B3i|7+3i]]<br />
<div class="toccolours" style="width:100%; overflow:auto;"><br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 6<br />
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''4 courses'''<br />
</div><br />
====Subsequent treatment====<br />
<br />
*Transplant eligible patients with available donors usually proceeded to [[#Allogeneic_hematopoietic_stem_cell_transplant|allogeneic HSCT]] after 2 courses (details not specified)<br />
<br />
===References===<br />
<br />
#'''COSAH C-022:''' Lee JH, Kim H, Joo YD, Lee WS, Bae SH, Zang DY, Kwon J, Kim MK, Lee J, Lee GW, Lee JH, Choi Y, Kim DY, Hur EH, Lim SN, Lee SM, Ryoo HM, Kim HJ, Hyun MS, Lee KH; Cooperative Study Group A for Hematology. Prospective randomized comparison of idarubicin and high-dose daunorubicin in induction chemotherapy for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2017 Aug 20;35(24):2754-2763. Epub 2017 Jun 20. [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.8618 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28632487 PubMed]<br />
<br />
==Cytarabine & Idarubicin {{#subobject:f8c456|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:099908|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/12/5129.full Gardin et al. 2007 (ALFA 9803)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|4 + 7 with idarubicin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*4i + 7 induction<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 60 mg/m<sup>2</sup> SC every 12 hours on days 1 to 5 (10 total doses)<br />
*[[Idarubicin (Idamycin)]] 9 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''1-month cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Gardin C, Turlure P, Fagot T, Thomas X, Terre C, Contentin N, Raffoux E, de Botton S, Pautas C, Reman O, Bourhis JH, Fenaux P, Castaigne S, Michallet M, Preudhomme C, de Revel T, Bordessoule D, Dombret H. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood. 2007 Jun 15;109(12):5129-35. Epub 2007 Mar 6. [http://www.bloodjournal.org/content/109/12/5129.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17341661 PubMed]<br />
<br />
==Cytarabine, Idarubicin, Sorafenib {{#subobject:8c0061|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:97a478|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930809/ Ravandi et al. 2010<sub>AML</sub>]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Regimen details are from the phase II part of the published phase I/II trial. This trial should not be confused for the one by the same name in Ph+ B-ALL.''<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3i_.26_Sorafenib|7+3i & Sorafenib induction]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 750 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 2250 mg/m<sup>2</sup>)<br />
*[[Idarubicin (Idamycin)]] 8 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 2<br />
*[[Sorafenib (Nexavar)]] 400 mg PO twice per day for up to 28 days<br />
<br />
'''4 to 6-week cycle for up to 5 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[#Sorafenib_monotherapy|Sorafenib maintenance]]<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
<br />
#Ravandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce SR, Brandt M, Byrd A, Bekele BN, Pratz K, Luthra R, Levis M, Andreeff M, Kantarjian HM. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010 Apr 10;28(11):1856-62. Epub 2010 Mar 8. [http://jco.ascopubs.org/content/28/11/1856.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930809/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20212254 PubMed]<br />
##'''Update:''' Ravandi F, Arana Yi C, Cortes JE, Levis M, Faderl S, Garcia-Manero G, Jabbour E, Konopleva M, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce S, Brandt M, Pratz K, Luthra R, Andreeff M, Kantarjian H. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia. 2014 Jul;28(7):1543-5. Epub 2014 Feb 3. [https://www.nature.com/leu/journal/v28/n7/full/leu201454a.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091714/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24487412 PubMed]<br />
<br />
==Cyclophosphamide & TBI, then allo HSCT {{#subobject:a9f7e8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Cy/TBI: '''<u>Cy</u>'''clophosphamide & '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation<br />
===Regimen {{#subobject:6ca28d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Non-relapse mortality]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM198005083021901 Blume et al. 1980]<br />
| style="background-color:#ffffbe" |Non-randomized, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM198712243172602 Brochstein et al. 1987]<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199501263320403 Zittoun et al. 1995]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Intensive chemotherapy<br />
| style="background-color:#1a9850" |Superior DFS<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70349-2/fulltext Bornhäuser et al. 2012]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fludarabine_.26_TBI.2C_then_allo_HSCT|Fludarabine & TBI, then allo HSCT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Zittoun et al. 1995: [[#7.2B3d_.28standard-dose.29|7+3d]] with CR, then amsacrine & IDAC<br />
{{#lst:Allogeneic HSCT|6ca28d}}<br />
===References===<br />
<br />
#Blume KG, Beutler E, Bross KJ, Chillar RK, Ellington OB, Fahey JL, Farbstein MJ, Forman SJ, Schmidt GM, Scott EP, Spruce WE, Turner MA, Wolf JL. Bone-marrow ablation and allogeneic marrow transplantation in acute leukemia. N Engl J Med. 1980 May 8;302(19):1041-6. [https://www.nejm.org/doi/full/10.1056/NEJM198005083021901 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6245359 PubMed]<br />
#Brochstein JA, Kernan NA, Groshen S, Cirrincione C, Shank B, Emanuel D, Laver J, O'Reilly RJ. Allogeneic bone marrow transplantation after hyperfractionated total-body irradiation and cyclophosphamide in children with acute leukemia. N Engl J Med. 1987 Dec 24;317(26):1618-24. [https://www.nejm.org/doi/full/10.1056/NEJM198712243172602 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3317056 PubMed]<br />
#Zittoun RA, Mandelli F, Willemze R, de Witte T, Labar B, Resegotti L, Leoni F, Damasio E, Visani G, Papa G, Caronia F, Hayat M, Stryckmans P, Rotoli B, Leoni P, Peetermans ME, Dardenne M, Vegna ML, Petti MC, Solbu G, Suciu S; European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med. 1995 Jan 26;332(4):217-23. [https://www.nejm.org/doi/full/10.1056/NEJM199501263320403 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7808487 PubMed]<br />
#Bornhäuser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, Baurmann H, Schäfer-Eckart K, Holler E, Kröger N, Schmid C, Einsele H, Kiehl MG, Hiddemann W, Schwerdtfeger R, Buchholz S, Dreger P, Neubauer A, Berdel WE, Ehninger G, Beelen DW, Schetelig J, Stelljes M. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012 Oct;13(10):1035-44. Epub 2012 Sep 7. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70349-2/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22959335 PubMed]<br />
#'''Retrospective:''' Copelan EA, Hamilton BK, Avalos B, Ahn KW, Bolwell BJ, Zhu X, Aljurf M, van Besien K, Bredeson C, Cahn JY, Costa LJ, de Lima M, Gale RP, Hale GA, Halter J, Hamadani M, Inamoto Y, Kamble RT, Litzow MR, Loren AW, Marks DI, Olavarria E, Roy V, Sabloff M, Savani BN, Seftel M, Schouten HC, Ustun C, Waller EK, Weisdorf DJ, Wirk B, Horowitz MM, Arora M, Szer J, Cortes J, Kalaycio ME, Maziarz RT, Saber W. Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood. 2013 Dec 5;122(24):3863-70. Epub 2013 Sep 24. [http://www.bloodjournal.org/content/122/24/3863.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854108/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24065243 PubMed]<br />
<br />
==Etoposide & Mitoxantrone {{#subobject:ab1766|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:780933|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/23/6037.long Vellenga et al. 2011 (HOVON-SAKK AML-29/AML-42)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#BuCy.2C_then_auto_HSCT|Bu/Cy, then auto HSCT]]<br />
| style="background-color:#fee08b" |Might have inferior RFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3i|7+3i]], then Amsacrine & Cytarabine<br />
<br />
====Chemotherapy====<br />
<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
===References===<br />
<br />
#'''HOVON-SAKK AML-29/AML-42:''' Vellenga E, van Putten W, Ossenkoppele GJ, Verdonck LF, Theobald M, Cornelissen JJ, Huijgens PC, Maertens J, Gratwohl A, Schaafsma R, Schanz U, Graux C, Schouten HC, Ferrant A, Bargetzi M, Fey MF, Löwenberg B; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON).; Swiss Group for Clinical Cancer Research Collaborative Group (SAKK). Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood. 2011 Dec 1;118(23):6037-42. Epub 2011 Sep 27. [http://www.bloodjournal.org/content/118/23/6037.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21951683 PubMed]<br />
<br />
==Fludarabine & TBI, then allo HSCT {{#subobject:53c6af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:be3609|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Non-relapse mortality]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70349-2/fulltext Bornhäuser et al. 2012]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Cyclophosphamide_.26_TBI.2C_then_allo_HSCT|Cyclophosphamide & TBI, then allo HSCT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|be3609}}<br />
===Variant #2, low-dose TBI{{#subobject:7fa6ce|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903320/ Gyukocza et al. 2010]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|7fa6ce}}<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
<br />
#Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA, Langston AA, Pulsipher MA, Bredeson CN, Maziarz RT, Bruno B, Petersen FB, Maris MB, Agura E, Yeager A, Bethge W, Sahebi F, Appelbaum FR, Maloney DG, Sandmaier BM. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010 Jun 10;28(17):2859-67. Epub 2010 May 3. [http://jco.ascopubs.org/content/28/17/2859.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903320/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20439626 PubMed]<br />
#Bornhäuser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, Baurmann H, Schäfer-Eckart K, Holler E, Kröger N, Schmid C, Einsele H, Kiehl MG, Hiddemann W, Schwerdtfeger R, Buchholz S, Dreger P, Neubauer A, Berdel WE, Ehninger G, Beelen DW, Schetelig J, Stelljes M. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012 Oct;13(10):1035-44. Epub 2012 Sep 7. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70349-2/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22959335 PubMed]<br />
<br />
==Fludarabine, Busulfan, ATG, then allo HSCT {{#subobject:ed545b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dd1486|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658453/ Devine et al. 2015 (CALGB 100103)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|dd1486}}<br />
===References===<br />
<!-- Presented in part as an oral presentation at the 54th American Society of Hematology Annual Meeting and Exposition, Atlanta, GA, December 8-11, 2012. --><br />
<br />
#'''CALGB 100103:''' Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, Champlin RE, Chen YB, Vij R, Slack J, Soiffer RJ, Larson RA, Shea TC, Hars V, Sibley AB, Giralt S, Carter S, Horowitz MM, Linker C, Alyea EP. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. 2015 Dec 10;33(35):4167-75. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/35/4167.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658453/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527780 PubMed]<br />
<br />
==HAM {{#subobject:1da5a5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
HAM: '''<u>H</u>'''igh-dose '''<u>A</u>'''ra-C (Cytarabine), '''<u>M</u>'''itoxantrone<br />
<br />
===Regimen {{#subobject:eb86c6|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0609.2007.00988.x/abstract Wierzbowksa et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[http://jco.ascopubs.org/content/30/20/2441.full Holowiecki et al. 2012 (PALG AML1/2004)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Wierzbowska et al. 2007: [[#CLAG-M|CLAG-M]]<br />
*PALG AML1/2004: [[#7.2B3d_.28intermediate-dose.29|DA]] versus [[#DAC|DAC]] versus DAF<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1500 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 3 to 5<br />
<br />
====Subsequent treatment====<br />
<br />
*[[#HiDAC|HiDAC consolidation]]<br />
<br />
===References===<br />
<br />
#Wierzbowska A, Robak T, Pluta A, Wawrzyniak E, Cebula B, Holowiecki J, Kyrcz-Krzemien S, Grosicki S, Giebel S, Skotnicki AB, Piatkowska-Jakubas B, Kuliczkowski K, Kielbinski M, Zawilska K, Kloczko J, Wrzesień-Kuś A; Polish Adult Leukemia Group. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol. 2008 Feb;80(2):115-26. Epub 2007 Dec 11. [https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0609.2007.00988.x/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18076637 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
#'''PALG AML1/2004:''' Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszyńska A, Kloczko J, Jedrzejczak WW, Zdziarska B, Warzocha K, Zawilska K, Komarnicki M, Kielbinski M, Piatkowska-Jakubas B, Wierzbowska A, Wach M, Haus O. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012 Jul 10;30(20):2441-8. Epub 2012 Apr 16. [http://jco.ascopubs.org/content/30/20/2441.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22508825 PubMed]<br />
<br />
==IC & Norethandrolone/6-MP, MTX, Norethandrolone {{#subobject:2034a1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
IC & Norethandrolone: '''<u>I</u>'''darubicin, '''<u>C</u>'''ytarabine, Norethandrolone<br />
===Regimen {{#subobject:0849b9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2016.67.6213 Pigneux et al. 2016 (GOELAMS LAM-SA2002)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|IC/6-MP & MTX<br />
| style="background-color:#1a9850" |Superior OS<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#ICL|7+3i & Lomustine]]<br />
<br />
====Chemotherapy, reinduction====<br />
<br />
*[[Idarubicin (Idamycin)]] 8 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 500 mg/m<sup>2</sup>)<br />
<br />
====Hormonotherapy, reinduction====<br />
<br />
*[[Norethandrolone (Nilevar)]] as follows:<br />
**If less than 60 kg: 10 mg PO once per day<br />
**If greater than 60 kg: 20 mg PO once per day<br />
<br />
'''3-month cycle for 6 cycles, alternating with maintenance'''<br />
====Chemotherapy, maintenance====<br />
<br />
*[[Methotrexate (MTX)]] as follows:<br />
**If less than 60 kg: 20 mg PO twice per week in weeks 1 & 2<br />
**If greater than 60 kg: 25 mg PO twice per week in weeks 1 & 2<br />
*[[Mercaptopurine (6-MP)]] as follows:<br />
**If less than 60 kg: 100 mg PO once per day on days 15 to 30<br />
**If greater than 60 kg: 150 mg PO once per day on days 15 to 30<br />
<br />
====Hormonotherapy, maintenance====<br />
<br />
*[[Norethandrolone (Nilevar)]] as follows:<br />
**If less than 60 kg: 10 mg PO once per day<br />
**If greater than 60 kg: 20 mg PO once per day<br />
<br />
'''3-month cycle for 6 cycles, alternating with re-induction courses'''<br />
<br />
===References===<br />
<br />
#'''GOELAMS LAM-SA2002:''' Pigneux A, Béné MC, Guardiola P, Recher C, Hamel JF, Sauvezie M, Harousseau JL, Tournilhac O, Witz F, Berthou C, Escoffre-Barbe M, Guyotat D, Fegueux N, Himberlin C, Hunault M, Delain M, Lioure B, Jourdan E, Bauduer F, Dreyfus F, Cahn JY, Sotto JJ, Ifrah N. Addition of androgens improves survival in elderly patients with acute myeloid leukemia: a GOELAMS study. J Clin Oncol. 2017 Feb;35(4):387-393. Epub 2016 Oct 24. [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.6213 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129526 PubMed]<br />
<br />
==Low-dose TBI, then allo HSCT {{#subobject:529ee7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TBI: '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation<br />
===Regimen {{#subobject:174a8e|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903320/ Gyukocza et al. 2010]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|174a8e}}<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
<br />
#Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA, Langston AA, Pulsipher MA, Bredeson CN, Maziarz RT, Bruno B, Petersen FB, Maris MB, Agura E, Yeager A, Bethge W, Sahebi F, Appelbaum FR, Maloney DG, Sandmaier BM. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010 Jun 10;28(17):2859-67. Epub 2010 May 3. [http://jco.ascopubs.org/content/28/17/2859.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903320/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20439626 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
''Note: with a few exceptions, these regimens are given as part of a non-curative line of therapy.''<br />
==Azacitidine monotherapy {{#subobject:887fd6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:482f11|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2010.08235.x/full Grövdal et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Intended to be used for transformed MDS patients in remission after AML induction therapy.''<br />
====Preceding treatment====<br />
<br />
*7+2d<br />
<br />
====Chemotherapy====<br />
<br />
*[[Azacitidine (Vidaza)]] 60 mg/m<sup>2</sup> SC once per day on days 1 to 5<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Grövdal M, Karimi M, Khan R, Aggerholm A, Antunovic P, Astermark J, Bernell P, Engström LM, Kjeldsen L, Linder O, Nilsson L, Olsson A, Holm MS, Tangen JM, Wallvik J, Oberg G, Hokland P, Jacobsen SE, Porwit A, Hellström-Lindberg E. Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy. Br J Haematol. 2010 Aug;150(3):293-302. Epub 2010 May 20. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2010.08235.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20497178 PubMed]<br />
<br />
==Decitabine monotherapy {{#subobject:d8250a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:4726aa|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867720/ Blum et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Blum et al. 2010 did not clearly state whether decitabine maintenance is at the same dosage/frequency as induction therapy. This is the inferred dosage from the paper.''<br />
====Preceding treatment====<br />
<br />
*[[#Decitabine_monotherapy|Decitabine induction]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Decitabine (Dacogen)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
**Patients with no evidence of residual disease by flow cytometry or cytogenetics who had grade 4 neutropenia (ANC less than 500/uL) persisting greater than or equal to 14 days received 4 days instead of 5 days of decitabine starting with the following cycle. If neutropenia occurred again as above with 4 days of decitabine, patients received 3 days instead of 4 days of decitabine starting with the following cycle.<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, Liu S, Havelange V, Becker H, Schaaf L, Mickle J, Devine H, Kefauver C, Devine SM, Chan KK, Heerema NA, Bloomfield CD, Grever MR, Byrd JC, Villalona-Calero M, Croce CM, Marcucci G. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7473-8. Epub 2010 Apr 5. [http://www.pnas.org/content/107/16/7473.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867720/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20368434 PubMed]<br />
<br />
==Gemtuzumab ozogamicin monotherapy {{#subobject:39de3d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b7c813|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/34/9/972.full Amadori et al. 2016 (EORTC/GIMEMA AML-19)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Gemtuzumab_ozogamicin_monotherapy|Gemtuzumab ozogamicin induction]], with clinical benefit<br />
<br />
====Chemotherapy====<br />
<br />
*[[Gemtuzumab ozogamicin (Mylotarg)]] 2 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''1-month cycle for up to 8 cycles'''<br />
<br />
===References===<br />
<!-- Presented in part at the 56th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 6-9, 2014. --><br />
<br />
#'''EORTC/GIMEMA AML-19:''' Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M, Annino L, Venditti A, Voso MT, Mazzone C, Magro D, De Fabritiis P, Muus P, Alimena G, Mancini M, Hagemeijer A, Paoloni F, Vignetti M, Fazi P, Meert L, Ramadan SM, Willemze R, de Witte T, Baron F. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016 Mar 20;34(9):972-9. Epub 2016 Jan 25. [http://jco.ascopubs.org/content/34/9/972.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26811524 PubMed]<br />
<br />
==LoDAC {{#subobject:4c65c8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
LoDAC: '''<u>Lo</u>'''w '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (cytarabine)<br />
<br>LDAC: '''<u>L</u>'''ow '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (cytarabine)<br />
<br />
===Regimen {{#subobject:2f5aa0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/2401850 Robles et al. 2000 (ECOG E5483)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#d9ef8b" |Might have superior DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*HiDAC, then amsacrine induction<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 10 mg/m<sup>2</sup> SC twice per day on days 1 to 21<br />
<br />
'''8-week cycles'''<br />
<br />
===References===<br />
<br />
#'''ECOG E5483:''' Robles C, Kim KM, Oken MM, Bennett JM, Letendre L, Wiernik PH, O'Connell MJ, Cassileth PA. Low-dose cytarabine maintenance therapy vs observation after remission induction in advanced acute myeloid leukemia: an Eastern Cooperative Oncology Group Trial (E5483). Leukemia. 2000 Aug;14(8):1349-53. [https://www.nature.com/articles/2401850 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10942228 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(84)90424-0/fulltext Sauter et al. 1984]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Maintenance chemotherapy<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nature.com/articles/2401850 Robles et al. 2000 (ECOG E5483)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#LoDAC_2|LoDAC]]<br />
| style="background-color:#fee08b" |Might have inferior DFS<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2004.05282.x Breems et al. 2005 (HOVON/SAKK AML4)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Auto HSCT<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.bloodjournal.org/content/108/1/88.long Brune et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|HDC/IL-2<br />
| style="background-color:#d73027" |Inferior DFS<br />
|-<br />
|[http://www.bloodjournal.org/content/100/4/1224.long Baer et al. 2002 (CALGB 9720)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Low-dose IL-2<br />
| style="background-color:#ffffbf" |Seems not superior (*)<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0901409 Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemtuzumab_ozogamicin_monotherapy_2|Gemtuzumab ozogamicin]]<br />
| style="background-color:#ffffbf" |Seems not superior (*)<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682338/ Petersdorf et al. 2013 (SWOG S0106)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemtuzumab_ozogamicin_monotherapy_2|Gemtuzumab ozogamicin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139069/ Kolitz et al. 2013 (CALGB 19808)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Low-dose IL-2<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''No further antineoplastic treatment. Reported efficacy for CALGB 9720 is based on the 2008 update. Reported efficacy for HOVON 43 AML/SAKK 30/01 is based on the 2010 update.''<br />
====Preceding treatment====<br />
<br />
*ECOG E5483: HiDAC, then amsacrine induction<br />
*HOVON 43 AML/SAKK 30/01: [[#IDAC|IDAC consolidation]] x 1<br />
*SWOG S0106: [[#HiDAC|HiDAC consolidation]] x 3<br />
<br />
===References===<br />
<br />
#Sauter C, Berchtold W, Fopp M, Gratwohl A, Imbach P, Maurice P, Tschopp L, von Fliedner V, Cavalli F. Acute myelogenous leukaemia: maintenance chemotherapy after early consolidation treatment does not prolong survival. Lancet. 1984 Feb 18;1(8373):379-82. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(84)90424-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6141436 PubMed]<br />
#'''ECOG E5483:''' Robles C, Kim KM, Oken MM, Bennett JM, Letendre L, Wiernik PH, O'Connell MJ, Cassileth PA. Low-dose cytarabine maintenance therapy vs observation after remission induction in advanced acute myeloid leukemia: an Eastern Cooperative Oncology Group Trial (E5483). Leukemia. 2000 Aug;14(8):1349-53. [https://www.nature.com/articles/2401850 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10942228 PubMed]<br />
#'''HOVON/SAKK AML4:''' Breems DA, Boogaerts MA, Dekker AW, Van Putten WL, Sonneveld P, Huijgens PC, Van der Lelie J, Vellenga E, Gratwohl A, Verhoef GE, Verdonck LF, Löwenberg B. Autologous bone marrow transplantation as consolidation therapy in the treatment of adult patients under 60 years with acute myeloid leukaemia in first complete remission: a prospective randomized Dutch-Belgian Haemato-Oncology Co-operative Group (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) trial. Br J Haematol. 2005 Jan;128(1):59-65. [https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2004.05282.x link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15606550 PubMed]<br />
#Brune M, Castaigne S, Catalano J, Gehlsen K, Ho AD, Hofmann WK, Hogge DE, Nilsson B, Or R, Romero AI, Rowe JM, Simonsson B, Spearing R, Stadtmauer EA, Szer J, Wallhult E, Hellstrand K. Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trial. Blood. 2006 Jul 1;108(1):88-96. Epub 2006 Mar 23. [http://www.bloodjournal.org/content/108/1/88.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16556892 PubMed]<br />
#'''CALGB 9720:''' Baer MR, George SL, Dodge RK, O'Loughlin KL, Minderman H, Caligiuri MA, Anastasi J, Powell BL, Kolitz JE, Schiffer CA, Bloomfield CD, Larson RA. Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720. Blood. 2002 Aug 15;100(4):1224-32. [http://www.bloodjournal.org/content/100/4/1224.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12149202 PubMed]<br />
##'''Update:''' Baer MR, George SL, Caligiuri MA, Sanford BL, Bothun SM, Mrózek K, Kolitz JE, Powell BL, Moore JO, Stone RM, Anastasi J, Bloomfield CD, Larson RA. Low-dose interleukin-2 immunotherapy does not improve outcome of patients age 60 years and older with acute myeloid leukemia in first complete remission: Cancer and Leukemia Group B Study 9720. J Clin Oncol. 2008 Oct 20;26(30):4934-9. Epub 2008 Jun 30. [http://ascopubs.org/doi/full/10.1200/JCO.2008.17.0472 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652081/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18591543 PubMed]<br />
#'''HOVON 43 AML/SAKK 30/01:''' Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Döhner H, Gratwohl A, Pabst T, Verhoef G; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. [https://www.nejm.org/doi/full/10.1056/NEJMoa0901409 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19776405 PubMed]<br />
##'''Update:''' Löwenberg B, Beck J, Graux C, van Putten W, Schouten HC, Verdonck LF, Ferrant A, Sonneveld P, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, Breems D, de Muijnck H, Schaafsma R, Verhoef G, Döhner H, Gratwohl A, Pabst T, Ossenkoppele GJ, Maertens J; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON); German Austrian AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research Collaborative Group (SAKK). Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study. Blood. 2010 Apr 1;115(13):2586-91. Epub 2010 Jan 26. [http://www.bloodjournal.org/content/115/13/2586.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20103782 PubMed]<br />
#'''SWOG S0106:''' Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013 Jun 13;121(24):4854-60. Epub 2013 Apr 16. [http://bloodjournal.hematologylibrary.org/content/121/24/4854.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682338/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23591789 PubMed]<br />
#'''CALGB 19808:''' Kolitz JE, George SL, Benson DM Jr, Maharry K, Marcucci G, Vij R, Powell BL, Allen SL, Deangelo DJ, Shea TC, Stock W, Bakan CE, Hars V, Hoke E, Bloomfield CD, Caligiuri MA, Larson RA; Alliance for Clinical Trials in Oncology. Recombinant interleukin-2 in patients aged younger than 60 years with acute myeloid leukemia in first complete remission: results from Cancer and Leukemia Group B 19808. Cancer. 2014 Apr 1;120(7):1010-7. Epub 2013 Dec 31. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.28516 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139069/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24382782 PubMed]<br />
<br />
==Sorafenib monotherapy {{#subobject:23822e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:b50325|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930809/ Ravandi et al. 2010<sub>AML</sub>]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Note: This trial should not be confused for the one by the same name in Ph+ B-ALL.''<br />
====Preceding treatment====<br />
<br />
*[[#Cytarabine.2C_Idarubicin.2C_Sorafenib|Cytarabine, Idarubicin, Sorafenib consolidation]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Sorafenib (Nexavar)]] 400 mg PO twice per day<br />
<br />
'''Up to one year of sorafenib therapy, including consolidation course(s)'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
<br />
#Ravandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce SR, Brandt M, Byrd A, Bekele BN, Pratz K, Luthra R, Levis M, Andreeff M, Kantarjian HM. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010 Apr 10;28(11):1856-62. Epub 2010 Mar 8. [http://jco.ascopubs.org/content/28/11/1856.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930809/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20212254 PubMed]<br />
##'''Update:''' Ravandi F, Arana Yi C, Cortes JE, Levis M, Faderl S, Garcia-Manero G, Jabbour E, Konopleva M, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce S, Brandt M, Pratz K, Luthra R, Andreeff M, Kantarjian H. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia. 2014 Jul;28(7):1543-5. Epub 2014 Feb 3. [https://www.nature.com/leu/journal/v28/n7/full/leu201454a.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091714/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24487412 PubMed]<br />
<br />
=Relapsed or refractory, salvage therapy=<br />
''Note: these are generally aggressive regimens intended to induce a second remission as part of a path towards pre-planned allogeneic HSCT.''<br />
==5+2d {{#subobject:df9bab|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c9d569|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800702/ Zeidner et al. 2015 (JHOC-J1101)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#7.2B3d_.28high-dose.29|7+3d (high-dose)]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose: 500 mg/m<sup>2</sup>)<br />
*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
<br />
'''5-day course'''<br />
<br />
===References===<br />
<br />
#'''JHOC-J1101:''' Zeidner JF, Foster MC, Blackford AL, Litzow MR, Morris LE, Strickland SA, Lancet JE, Bose P, Levy MY, Tibes R, Gojo I, Gocke CD, Rosner GL, Little RF, Wright JJ, Doyle LA, Smith BD, Karp JE. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015 Sep;100(9):1172-9. Epub 2015 May 28. [http://www.haematologica.org/content/100/9/1172 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800702/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26022709 PubMed]<br />
<br />
==ADE (standard-dose Ara-C) {{#subobject:d16134|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ADE: '''<u>A</u>'''ra-C (Cytarabine), '''<u>D</u>'''aunorubicin, '''<u>E</u>'''toposide <br />
<br />
===Regimen {{#subobject:a99e51|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/107/12/4614.long Milligan et al. 2006 (MRC AML-HR)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FLA<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
<br />
====Chemotherapy, Course 1====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV push every 12 hours on days 1 to 10 (20 total doses)<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV slow push once per day on days 1, 3, 5<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
====Chemotherapy, Course 2====<br />
<br />
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV push every 12 hours on days 1 to 8 (16 total doses)<br />
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV slow push once per day on days 1, 3, 5<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
<br />
===References===<br />
<br />
#'''MRC AML-HR:''' Milligan DW, Wheatley K, Littlewood T, Craig JI, Burnett AK; NCRI Haematological Oncology Clinical Studies Group. Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial. Blood. 2006 Jun 15;107(12):4614-22. Epub 2006 Feb 16. [http://www.bloodjournal.org/content/107/12/4614.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16484584 PubMed]<br />
<br />
==CLAG {{#subobject:702383|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CLAG: '''<u>CL</u>'''adribine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF<br />
<br />
===Regimen {{#subobject:12d1bb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.tandfonline.com/doi/full/10.3109/10428190009053545 Robak et al. 2000]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cladribine (Leustatin)]] 5 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given first'''<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 5, '''given second, 2 hours after cladribine'''<br />
*[[Filgrastim (Neupogen)]] 300 mcg SC once per day on days -1 to 5 (first dose is given 24 hours before first dose of cladribine)<br />
<br />
===References===<br />
<br />
#Robak T, Wrzesień-Kuś A, Lech-Marańda E, Kowal M, Dmoszyńska A. Combination regimen of cladribine (2-chlorodeoxyadenosine), cytarabine and G-CSF (CLAG) as induction therapy for patients with relapsed or refractory acute myeloid leukemia. Leuk Lymphoma. 2000 Sep;39(1-2):121-9. [https://www.tandfonline.com/doi/full/10.3109/10428190009053545 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10975390 PubMed]<br />
#'''Retrospective:''' Martin MG, Welch JS, Augustin K, Hladnik L, DiPersio JF, Abboud CN. Cladribine in the treatment of acute myeloid leukemia: a single-institution experience. Clin Lymphoma Myeloma. 2009 Aug;9(4):298-301. [https://www.ncbi.nlm.nih.gov/pubmed/19717379 PubMed]<br />
<br />
==CLAG-M {{#subobject:51b417|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CLAG-M: '''<u>CL</u>'''adribine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF, '''<u>M</u>'''itoxantrone <br />
===Regimen {{#subobject:e0b308|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0609.2007.00988.x/abstract Wierzbowksa et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cladribine (Leustatin)]] 5 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given first'''<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 5, '''given second, 2 hours after cladribine'''<br />
*[[Filgrastim (Neupogen)]] based on WBC count:<br />
**WBC count less than or equal to 20 x 10<sup>9</sup>/L: 300 mcg SC once per day on days 0 to 5, '''started 24 hours prior to chemotherapy'''<br />
**WBC count greater than 20 x 10<sup>9</sup>/L: 300 mcg SC once per day on days 1 to 5, '''started simultaneously to cladribine'''<br />
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
<br />
*Patients with PR were recommended to undergo a second course of CLAG-M. <br />
**Primary refractory patients achieving CR after 2nd CLAG-M: [[#HAM|HAM consolidation]]<br />
*Others could receive another course of CLAG-M or [[#HAM|HAM consolidation]] per investigator discretion<br />
<br />
===References===<br />
<br />
#Wierzbowska A, Robak T, Pluta A, Wawrzyniak E, Cebula B, Holowiecki J, Kyrcz-Krzemien S, Grosicki S, Giebel S, Skotnicki AB, Piatkowska-Jakubas B, Kuliczkowski K, Kielbinski M, Zawilska K, Kloczko J, Wrzesień-Kuś A; Polish Adult Leukemia Group. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol. 2008 Feb;80(2):115-26. Epub 2007 Dec 11. [https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0609.2007.00988.x/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18076637 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
#'''Retrospective:''' Martin MG, Welch JS, Augustin K, Hladnik L, DiPersio JF, Abboud CN. Cladribine in the treatment of acute myeloid leukemia: a single-institution experience. Clin Lymphoma Myeloma. 2009 Aug;9(4):298-301. [https://www.ncbi.nlm.nih.gov/pubmed/19717379 PubMed]<br />
<br />
==CLARA {{#subobject:48978a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CLARA: '''<u>CL</u>'''ofarabine and '''<u>ARA</u>'''-C (Cytarabine)<br />
<br>GCLAC: '''<u>G</u>'''-CSF, '''<u>C</u>'''lofarabine, '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
===Regimen {{#subobject:b8a3a2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834701/ Becker et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 25 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, '''given first'''<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 5, '''given second, 4 hours after start of clofarabine infusion'''<br />
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting day -1, continuing until ANC at least 2000/uL for 2 consecutive days<br />
<br />
'''One course with one re-induction allowed for patients with greater than 5% blasts at day 21''' <br />
====Subsequent treatment====<br />
<br />
*Patients achieving CR could receive consolidation with clofarabine reduced to 20 mg/m<sup>2</sup>, and cytarabine reduced to 1000 mg/m<sup>2</sup>, up to 2 cycles<br />
<br />
===References===<br />
<br />
#Becker PS, Kantarjian HM, Appelbaum FR, Petersdorf SH, Storer B, Pierce S, Shan J, Hendrie PC, Pagel JM, Shustov AR, Stirewalt DL, Faderl S, Harrington E, Estey EH. Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia. Br J Haematol. 2011 Oct;155(2):182-9. Epub 2011 Aug 18. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2011.08831.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834701/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21848522 PubMed]<br />
<br />
==Clofarabine & Cytarabine {{#subobject:23e3f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 20/20 {{#subobject:d4a73c|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13437/full Buckley et al. 2015]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''The dose of clofarabine is the one reported as the MTD. Note that the doses of both drugs are much lower than the other variants here.''<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 20 mg PO once per day on days 1 to 5<br />
*[[Cytarabine (Ara-C)]] as follows (per physician choice):<br />
**20 mg/m<sup>2</sup> SC twice per day on days 1 to 10<br />
**20 mg/m<sup>2</sup> SC once per day on days 1 to 14<br />
<br />
'''Cycle duration not explicitly defined; presumably 28 days'''<br />
<br />
===Variant #2, 30/1000 {{#subobject:f6ada8|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v30/n2/full/leu2015226a.html Middeke et al. 2015 (BRIDGE)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''At least one cycle'''<br />
====Subsequent treatment====<br />
<br />
*Chemo-responsive patients: [[#Clofarabine_.26_Melphalan.2C_then_allo_HSCT|Clofarabine & Melphalan, then allo HSCT]]<br />
<br />
===Variant #3, 40/1000 {{#subobject:d95457|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/105/3/940.long Faderl et al. 2004]<br />
| style="background-color:#91cf61" |Phase I/II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228084/ Agura et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874149/ Faderl et al. 2012 (CLASSIC I)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[Acute_myeloid_leukemia_-_historical#IDAC|IDAC]]<br />
| style="background-color:#1a9850" |Superior EFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Clofarabine (Clolar)]] 40 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, '''given first'''<br />
**Note: in Faderl et al. 2004, clofarabine was given on days 2 to 6<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given second, 3 to 4 hours after completion of clofarabine infusion'''<br />
<br />
====Supportive medications====<br />
<br />
*Best described in Agura et al. 2011<br />
*[[Dexamethasone (Decadron)]] 10 mg IV once per day<br />
*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonists]] on each day of chemotherapy<br />
*Hydration at 150 mL/m<sup>2</sup>/H "to prevent tumor lysis syndrome" during chemotherapy<br />
*[[Bumetanide (Bumex)]] 2 to 4 mg IV push once to twice per day as needed to keep weight within 1 kg of patient's initial weight<br />
*[[Levofloxacin (Levaquin)]] 500 mg IV or PO once per day<br />
*[[Acyclovir (Zovirax)]] 500 mg IV Q12H<br />
*One of the following antifungals:<br />
**[[Caspofungin (Cancidas)]] 50 mg IV once per day<br />
**[[Voriconazole (Vfend)]] 200 mg (route not specified) twice per day<br />
*Parenteral nutrition allowed<br />
*No routine use of growth factors<br />
<br />
'''1 to 4 cycles''' <br />
====Subsequent treatment====<br />
<br />
*See individual papers for details<br />
<br />
===References===<br />
<br />
#Faderl S, Gandhi V, O'Brien S, Bonate P, Cortes J, Estey E, Beran M, Wierda W, Garcia-Manero G, Ferrajoli A, Estrov Z, Giles FJ, Du M, Kwari M, Keating M, Plunkett W, Kantarjian H. Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood. 2005 Feb 1;105(3):940-7. Epub 2004 Oct 14. [http://www.bloodjournal.org/content/105/3/940.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15486072 PubMed]<br />
#Agura E, Cooper B, Holmes H, Vance E, Berryman RB, Maisel C, Li S, Saracino G, Tadic-Ovcina M, Fay J. Report of a phase II study of clofarabine and cytarabine in de novo and relapsed and refractory AML patients and in selected elderly patients at high risk for anthracycline toxicity. Oncologist. 2011;16(2):197-206. Epub 2011 Jan 27. [http://theoncologist.alphamedpress.org/content/16/2/197.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228084/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21273514 PubMed]<br />
<!-- Presented in part at the 53rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2011, and at the 16th Congress of the European Hematology Association, London, United Kingdom, June 9-12, 2011. --><br />
#'''CLASSIC I:''' Faderl S, Wetzler M, Rizzieri D, Schiller G, Jagasia M, Stuart R, Ganguly S, Avigan D, Craig M, Collins R, Maris M, Kovacsovics T, Goldberg S, Seiter K, Hari P, Greiner J, Vey N, Recher C, Ravandi F, Wang ES, Vasconcelles M, Huebner D, Kantarjian HM. Clofarabine plus cytarabine compared with cytarabine alone in older patients with relapsed or refractory acute myelogenous leukemia: results from the CLASSIC I Trial. J Clin Oncol. 2012 Jul 10;30(20):2492-9. Epub 2012 May 14. [http://jco.ascopubs.org/content/30/20/2492.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874149/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22585697 PubMed]<br />
#Buckley SA, Mawad R, Gooley TA, Becker PS, Sandhu V, Hendrie P, Scott BL, Wood BL, Walter RB, Smith K, Dean C, Estey EH, Pagel JM. A phase I/II study of oral clofarabine plus low-dose cytarabine in previously treated acute myeloid leukaemia and high-risk myelodysplastic syndrome patients at least 60 years of age. Br J Haematol. 2015 Aug;170(3):349-55. Epub 2015 Apr 8. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13437/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25854284 PubMed]<br />
#'''BRIDGE:''' Middeke JM, Herbst R, Parmentier S, Bug G, Hänel M, Stuhler G, Schäfer-Eckart K, Rösler W, Klein S, Bethge W, Bitz U, Büttner B, Knoth H, Alakel N, Schaich M, Morgner A, Kramer M, Sockel K, von Bonin M, Stölzel F, Platzbecker U, Röllig C, Thiede C, Ehninger G, Bornhäuser M, Schetelig J. Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial. Leukemia. 2016 Feb;30(2):261-7. Epub 2015 Aug 18. [https://www.nature.com/leu/journal/v30/n2/full/leu2015226a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26283567 PubMed]<br />
<br />
==Cytarabine & Mitoxantrone {{#subobject:fba448|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MIDAC: '''<u>M</u>'''itoxantrone & '''<u>I</u>'''ntermediate-'''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
===Variant #1, 6000/25 {{#subobject:5bf868|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/%28SICI%291097-0142%2820000501%2988:9%3C2037::AID-CNCR8%3E3.0.CO;2-K/full Sternberg et al. 2000]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 500 mg/m<sup>2</sup> IV over 90 minutes every 12 hours on days 1 to 6 (12 total doses)<br />
*[[Mitoxantrone (Novantrone)]] 5 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
<br />
'''One course'''<br />
<br />
===Variant #2, 10,000/48 {{#subobject:4a2f44|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/88/4/1198.long Solary et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cytarabine, Mitoxantrone, Quinine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once every 12 hours on days 1 to 5 (10 total doses)<br />
*[[Mitoxantrone (Novantrone)]] 12 mg/m<sup>2</sup> IV bolus once per day on days 2 to 5<br />
<br />
'''One course'''<br />
===References===<br />
<br />
#Solary E, Witz B, Caillot D, Moreau P, Desablens B, Cahn JY, Sadoun A, Pignon B, Berthou C, Maloisel F, Guyotat D, Casassus P, Ifrah N, Lamy Y, Audhuy B, Colombat P, Harousseau JL. Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study. Blood. 1996 Aug 15;88(4):1198-205. [http://www.bloodjournal.org/content/88/4/1198.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8695837 PubMed]<br />
#Sternberg DW, Aird W, Neuberg D, Thompson L, MacNeill K, Amrein P, Shulman LN. Treatment of patients with recurrent and primary refractory acute myelogenous leukemia using mitoxantrone and intermediate-dose cytarabine: a pharmacologically based regimen. Cancer. 2000 May 1;88(9):2037-41. [https://onlinelibrary.wiley.com/doi/10.1002/%28SICI%291097-0142%2820000501%2988:9%3C2037::AID-CNCR8%3E3.0.CO;2-K/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10813714 PubMed]<br />
<br />
==Etoposide & Mitoxantrone {{#subobject:3f0d63|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7683cc|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
! style="width: 33%" |Study<br />
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/6/2/213.abstract Ho et al. 1988]<br />
| style="background-color:#91cf61" |Phase II<br />
|ORR: 54%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5<br />
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV over 15 minutes once per day on days 1 to 5<br />
<br />
===References===<br />
<br />
#Ho AD, Lipp T, Ehninger G, Illiger HJ, Meyer P, Freund M, Hunstein W. Combination of mitoxantrone and etoposide in refractory acute myelogenous leukemia--an active and well-tolerated regimen. J Clin Oncol. 1988 Feb;6(2):213-7. [http://jco.ascopubs.org/content/6/2/213.abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3422260 PubMed]<br />
<br />
==FLAG {{#subobject:551761|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FLAG: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF<br />
===Variant #1, weight-based G-CSF {{#subobject:9501d2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/%28SICI%291096-8652%28199806%2958:2%3C105::AID-AJH3%3E3.0.CO;2-W/abstract Montillo et al. 1998]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first'''<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 5, '''given second, 4 hours after the start of fludarabine'''<br />
*G-CSF with one of the following:<br />
**[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day -1 (the paper described this as day 0), first dose given 24 hours before first dose of chemotherapy, to continue until neutrophil recovery<br />
**[[Lenograstim (Granocyte)]] 5 mcg/kg SC once per day, starting on day -1 (the paper described this as day 0), first dose given 24 hours before first dose of chemotherapy, to continue until neutrophil recovery<br />
<br />
'''One course'''<br />
<br />
===Variant #2, BSA-based G-CSF {{#subobject:bdc7e4|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;"<br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.7384 Kaspers et al. 2013 (I-BFM-SG 2001/01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Acute_myeloid_leukemia_-_historical#FLAG-DNX|FLAG-DNX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior CR rate<br />
|-<br />
|}<br />
''Note: this regimen was studied in patients up to 21 years of age.''<br />
====Chemotherapy====<br />
<br />
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second'''<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given third, 4 hours after the start of fludarabine'''<br />
*[[Filgrastim (Neupogen)]] 200 mcg/m<sup>2</sup> (route not specified) once per day on days 0 to 5, '''given first'''<br />
<br />
'''Two cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[#CYVE_2|CYVE]] or [[#Cytarabine_.26_Thioguanine|Cytarabine & Thioguanine]] consolidation, as a bridge to [[#Allogeneic_hematopoietic_stem_cell_transplant_2|allogeneic HSCT]]<br />
<br />
===References===<br />
<br />
#Montillo M, Mirto S, Petti MC, Latagliata R, Magrin S, Pinto A, Zagonel V, Mele G, Tedeschi A, Ferrara F. Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of poor risk acute myeloid leukemia. Am J Hematol. 1998 Jun;58(2):105-9. [https://onlinelibrary.wiley.com/doi/10.1002/%28SICI%291096-8652%28199806%2958:2%3C105::AID-AJH3%3E3.0.CO;2-W/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9625576 PubMed]<br />
#'''I-BFM-SG 2001/01:''' Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.7384 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23319696 PubMed]<br />
<br />
==FLAG-Ida {{#subobject:d8c75b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FLAG-Ida: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF (Filgrastim), '''<u>Ida</u>'''rubicin<br />
===Regimen {{#subobject:5fa1bb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/9432047 Parker et al. 1997]<br />
| style="background-color:#ffffbe" |Phase II, <20 patients<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00277-003-0624-2 Pastore et al. 2003]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first'''<br />
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 5, '''given second, 4 hours after fludarabine'''<br />
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 6, to continue until neutrophil recovery<br />
*[[Idarubicin (Idamycin)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
<br />
===References===<br />
<br />
#Parker JE, Pagliuca A, Mijovic A, Cullis JO, Czepulkowski B, Rassam SM, Samaratunga IR, Grace R, Gover PA, Mufti GJ. Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia. Br J Haematol. 1997 Dec;99(4):939-44. [https://www.ncbi.nlm.nih.gov/pubmed/9432047 PubMed]<br />
#Pastore D, Specchia G, Carluccio P, Liso A, Mestice A, Rizzi R, Greco G, Buquicchio C, Liso V. FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience. Ann Hematol. 2003 Apr;82(4):231-5. Epub 2003 Mar 15. [https://link.springer.com/article/10.1007%2Fs00277-003-0624-2 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12707726 PubMed]<br />
<br />
==F-SHAI {{#subobject:9e1c5f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
F-SHAI: '''<u>F</u>'''ludarabine, '''<u>S</u>'''equential '''<u>H</u>'''igh-dose '''<u>A</u>'''ra-C (cytarabine), '''<u>I</u>'''darubicin<br />
<br />
===Regimen {{#subobject:b50224|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v28/n5/full/leu2013297a.html Fiegl et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[Acute_myeloid_leukemia_-_historical#SHAI|SHAI]]<br />
| style="background-color:#91cf60" |Seems to have superior TTTF<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fludarabine (Fludara)]] 15 mg/m<sup>2</sup> IV twice per day on days 1, 2, 8, 9, '''given 4 hours prior to each cytarabine dose'''<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV twice per day on days 1, 2, 8, 9<br />
**Dose increased to 3000 mg/m<sup>2</sup> for patients 60 or younger with refractory AML or greater than or equal to 2nd relapse<br />
*[[Idarubicin (Idamycin)]] 10 mg/m<sup>2</sup> IV once per day on days 3, 4, 10, 11<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] 5 mcg/kg SC once per day from day 14 until ANC greater than 1500/uL<br />
**Discontinued if the post-treatment bmbx had greater than 5% bone marrow blasts<br />
<br />
'''One course'''<br />
<br />
===References===<br />
<br />
#Fiegl M, Unterhalt M, Kern W, Braess J, Spiekermann K, Staib P, Grüneisen A, Wörmann B, Schöndube D, Serve H, Reichle A, Hentrich M, Schiel X, Sauerland C, Heinecke A, Rieger C, Beelen D, Berdel WE, Büchner T, Hiddemann W. Chemomodulation of sequential high-dose cytarabine by fludarabine in relapsed or refractory acute myeloid leukemia: a randomized trial of the AMLCG. Leukemia. 2014 May;28(5):1001-7. Epub 2013 Oct 22. [https://www.nature.com/leu/journal/v28/n5/full/leu2013297a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24150216 PubMed]<br />
<br />
==HiDAC {{#subobject:1dddf5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
HiDAC: '''<u>Hi</u>'''gh '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)<br />
===Variant #1, CI {{#subobject:e8a7af|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/114/19/4027.long Giles et al. 2009 (VION-CLI-037)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|HiDAC & Laromustine<br />
| style="background-color:#ffffbf" |Mixed response (see note)<br />
|-<br />
|}<br />
''Note: while the experimental arm of this trial met the primary endpoint of ORR, the control arm had superior PFS.''<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 1500 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose: 7500 mg/m<sup>2</sup>)<br />
<br />
'''One course'''<br />
<br />
===Variant #2, intermittent {{#subobject:ab6f08|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0145212699000879 Karanes et al. 1999]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|HiDAC & Mitoxantrone<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 6<br />
<br />
'''One course'''<br />
===References===<br />
<br />
#Karanes C, Kopecky KJ, Head DR, Grever MR, Hynes HE, Kraut EH, Vial RH, Lichtin A, Nand S, Samlowski WE, Appelbaum FR. A phase III comparison of high dose ARA-C (HIDAC) versus HIDAC plus mitoxantrone in the treatment of first relapsed or refractory acute myeloid leukemia Southwest Oncology Group Study. Leuk Res. 1999 Sep;23(9):787-94. [https://www.sciencedirect.com/science/article/pii/S0145212699000879 link to SD article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10475617 PubMed]<br />
#'''VION-CLI-037:''' Giles F, Vey N, DeAngelo D, Seiter K, Stock W, Stuart R, Boskovic D, Pigneux A, Tallman M, Brandwein J, Kell J, Robak T, Staib P, Thomas X, Cahill A, Albitar M, O'Brien S. Phase 3 randomized, placebo-controlled, double-blind study of high-dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse. Blood. 2009 Nov 5;114(19):4027-33. Epub 2009 Aug 26. [http://www.bloodjournal.org/content/114/19/4027.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19710500 PubMed]<br />
<br />
==MEC {{#subobject:48e49b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MEC: '''<u>M</u>'''itoxantrone, '''<u>E</u>'''toposide, '''<u>C</u>'''ytarabine<br />
===Variant #1, 6/80/1000 {{#subobject:ac3985|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/9/7/1210.long Amadori et al. 1991]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Mitoxantrone (Novantrone)]] 6 mg/m<sup>2</sup> IV bolus once per day on days 1 to 6<br />
*[[Etoposide (Vepesid)]] 80 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 6<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 6 hours once per day on days 1 to 6<br />
<br />
'''One course'''<br />
<br />
===Variant #2, 8/80/1000 {{#subobject:9ad362|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/18/4110.long Feldman et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MEC & Lintuzumab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Mitoxantrone (Novantrone)]] 8 mg/m<sup>2</sup> IV once per day on days 1 to 6<br />
*[[Etoposide (Vepesid)]] 80 mg/m<sup>2</sup> IV once per day on days 1 to 6<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 6<br />
<br />
'''One course'''<br />
<br />
===Variant #3, 8/100/1000 {{#subobject:bd7f87|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457168/ Greenberg et al. 2004 (ECOG E2995)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MEC & Valspodar<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542857/ Cortes et al. 2014 (CLTR0308-205)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|CPX-351<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: this was the most commonly used salvage regimen in the control arm of CLTR0308-205; exact dosing details were not described in the paper.''<br />
====Chemotherapy====<br />
<br />
*[[Mitoxantrone (Novantrone)]] 8 mg/m<sup>2</sup> IV push once per day on days 1 to 5, '''given third'''<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given first'''<br />
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second'''<br />
<br />
'''One course'''<br />
===References===<br />
<br />
#Amadori S, Arcese W, Isacchi G, Meloni G, Petti MC, Monarca B, Testi AM, Mandelli F. Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. J Clin Oncol. 1991 Jul;9(7):1210-4. [http://jco.ascopubs.org/content/9/7/1210.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2045861 PubMed]<br />
#'''ECOG E2995:''' Greenberg PL, Lee SJ, Advani R, Tallman MS, Sikic BI, Letendre L, Dugan K, Lum B, Chin DL, Dewald G, Paietta E, Bennett JM, Rowe JM. Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). J Clin Oncol. 2004 Mar 15;22(6):1078-86. Erratum in: J Clin Oncol. 2004 Jul 1;22(13):2747. [http://ascopubs.org/doi/full/10.1200/JCO.2004.07.048 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457168/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15020609 PubMed]<br />
#Feldman EJ, Brandwein J, Stone R, Kalaycio M, Moore J, O'Connor J, Wedel N, Roboz GJ, Miller C, Chopra R, Jurcic JC, Brown R, Ehmann WC, Schulman P, Frankel SR, De Angelo D, Scheinberg D. Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia. J Clin Oncol. 2005 Jun 20;23(18):4110-6. [http://jco.ascopubs.org/content/23/18/4110.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15961759 PubMed]<br />
#'''CLTR0308-205:''' Cortes JE, Goldberg SL, Feldman EJ, Rizzeri DA, Hogge DE, Larson M, Pigneux A, Recher C, Schiller G, Warzocha K, Kantarjian H, Louie AC, Kolitz JE. Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML. Cancer. 2015 Jan 15;121(2):234-42. Epub 2014 Sep 15. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.28974/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542857/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25223583 PubMed]<br />
<br />
=Consolidation after salvage therapy=<br />
==BuCy, then allo HSCT {{#subobject:83e07a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
BuCy: '''<u>Bu</u>'''sulfan & '''<u>Cy</u>'''clophosphamide<br />
===Variant #1, 12.8/120 {{#subobject:eeaff3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00200-4/abstract Rambaldi et al. 2015]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#BuFlu.2C_then_allo_HSCT|BuFlu, then allo HSCT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior 1-year non-relapse mortality<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455603/ Scott et al. 2017 (BMT CTN 0901)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|RIC allo HSCT<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|eeaff3}}<br />
===Variant #2, 16/200 {{#subobject:334af6|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM198312013092202 Santos et al. 1983]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|334af6}}<br />
===References===<br />
<br />
#Santos GW, Tutschka PJ, Brookmeyer R, Saral R, Beschorner WE, Bias WB, Braine HG, Burns WH, Elfenbein GJ, Kaizer H, Mellits D, Sensenbrenner LL, Stuart RK, Yeager AM. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med. 1983 Dec 1;309(22):1347-53. [https://www.nejm.org/doi/full/10.1056/NEJM198312013092202 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/6355849 PubMed]<br />
#Rambaldi A, Grassi A, Masciulli A, Boschini C, Micò MC, Busca A, Bruno B, Cavattoni I, Santarone S, Raimondi R, Montanari M, Milone G, Chiusolo P, Pastore D, Guidi S, Patriarca F, Risitano AM, Saporiti G, Pini M, Terruzzi E, Arcese W, Marotta G, Carella AM, Nagler A, Russo D, Corradini P, Alessandrino EP, Torelli GF, Scimè R, Mordini N, Oldani E, Marfisi RM, Bacigalupo A, Bosi A. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1525-36. Epub 2015 Sep 28. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00200-4/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26429297 PubMed]<br />
#'''BMT CTN 0901:''' Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, Maziarz RT, Warlick ED, Fernandez HF, Alyea EP, Hamadani M, Bashey A, Giralt S, Geller NL, Leifer E, Le-Rademacher J, Mendizabal AM, Horowitz MM, Deeg HJ, Horwitz ME. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol. 2017 Apr 10;35(11):1154-1161. Epub 2017 Feb 13. [http://ascopubs.org/doi/full/10.1200/JCO.2016.70.7091 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455603/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28380315 PubMed]<br />
<br />
==BuFlu, then allo HSCT {{#subobject:576283|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
BuFlu: '''<u>Bu</u>'''sulfan & '''<u>Flu</u>'''darabine<br />
<br>Flu/Bu: '''<u>Flu</u>'''darabine & '''<u>Bu</u>'''sulfan<br />
===Variant #1 {{#subobject:d415a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00200-4/abstract Rambaldi et al. 2015]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#BuCy.2C_then_allo_HSCT|BuCy, then allo HSCT]]<br />
| style="background-color:#fc8d59" |Seems to improve 1 & 2 year NRM, similar OS<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|d415a}}<br />
===Variant #2 {{#subobject:d415b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230823/ Andersson et al. 2008]<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#fc8d59" |Suggested improved outcomes, but shorter follow up<br />
|}<br />
{{#lst:Allogeneic HSCT|d415b}}<br />
===Variant #3 {{#subobject:d415c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/31/6/701.full Lee et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#BuCy.2C_then_allo_HSCT|BuCy, then allo HSCT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
{{#lst:Allogeneic HSCT|d415c}}<br />
===References===<br />
<br />
#Andersson BS, de Lima M, Thall PF, Wang X, Couriel D, Korbling M, Roberson S, Giralt S, Pierre B, Russell JA, Shpall EJ, Jones RB, Champlin RE. Once daily IV busulfan and fludarabine (IV Bu-Flu) compares favorably with IV busulfan and cyclophosphamide (IV BuCy2) as pretransplant conditioning therapy in AML/MDS. Biol Blood Marrow Transplant. 2008;14(6):672-84. [http://www.bbmt.org/article/S1083-8791(08)00118-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230823/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18489993 Pubmed]<br />
#Lee JH, Joo YD, Kim H, Ryoo HM, Kim MK, Lee GW, Lee JH, Lee WS, Park JH, Bae SH, Hyun MS, Kim DY, Kim SD, Min YJ, Lee KH. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol. 2013 Feb 20;31(6):701-9. Epub 2012 Nov 5. [http://jco.ascopubs.org/content/31/6/701.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23129746 PubMed]<br />
#Rambaldi A, Grassi A, Masciulli A, Boschini C, Micò MC, Busca A, Bruno B, Cavattoni I, Santarone S, Raimondi R, Montanari M, Milone G, Chiusolo P, Pastore D, Guidi S, Patriarca F, Risitano AM, Saporiti G, Pini M, Terruzzi E, Arcese W, Marotta G, Carella AM, Nagler A, Russo D, Corradini P, Alessandrino EP, Torelli GF, Scimè R, Mordini N, Oldani E, Marfisi RM, Bacigalupo A, Bosi A. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1525-36. Epub 2015 Sep 28. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00200-4/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26429297 PubMed]<br />
<br />
==Clofarabine & Melphalan, then allo HSCT {{#subobject:08947a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a408ed|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v30/n2/full/leu2015226a.html Middeke et al. 2015 (BRIDGE)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Limited details are available in the abstract. Treatment is meant to be given during aplasia.''<br />
====Preceding treatment====<br />
<br />
*[[#Clofarabine_.26_Cytarabine|Clofarabine & Cytarabine salvage]]<br />
{{#lst:Allogeneic HSCT|a408ed}}<br />
===References===<br />
<br />
#'''BRIDGE:''' Middeke JM, Herbst R, Parmentier S, Bug G, Hänel M, Stuhler G, Schäfer-Eckart K, Rösler W, Klein S, Bethge W, Bitz U, Büttner B, Knoth H, Alakel N, Schaich M, Morgner A, Kramer M, Sockel K, von Bonin M, Stölzel F, Platzbecker U, Röllig C, Thiede C, Ehninger G, Bornhäuser M, Schetelig J. Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial. Leukemia. 2016 Feb;30(2):261-7. Epub 2015 Aug 18. [https://www.nature.com/leu/journal/v30/n2/full/leu2015226a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26283567 PubMed]<br />
<br />
==Cytarabine & Thioguanine {{#subobject:3c38bc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f2728e|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.7384 Kaspers et al. 2013 (I-BFM-SG 2001/01)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this regimen was studied in patients up to 21 years of age, and was intended for use when the time to transplant would be relatively short or for patients in "poor condition".''<br />
====Preceding treatment====<br />
<br />
*[[#FLAG|FLAG]] versus [[Acute_myeloid_leukemia_-_historical#FLAG-DNX|FLAG-DNX]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC once per day on days 1 to 4, every other week<br />
*[[Thioguanine (Tabloid)]] 100 mg/m<sup>2</sup> PO once per day for up to 4 weeks maximum<br />
<br />
====Subsequent treatment====<br />
<br />
*Allogeneic HSCT<br />
<br />
===References===<br />
<br />
#'''I-BFM-SG 2001/01:''' Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.7384 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23319696 PubMed]<br />
<br />
==CYVE {{#subobject:4bd791|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CYVE: '''<u>CY</u>'''tarabine & '''<u>VE</u>'''pesid (Etoposide)<br />
===Regimen {{#subobject:a16529|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.7384 Kaspers et al. 2013 (I-BFM-SG 2001/01)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this regimen was studied in patients up to 21 years of age. It is unclear if the course is repeated more than once.''<br />
====Preceding treatment====<br />
<br />
*[[#FLAG|FLAG]] versus [[Acute_myeloid_leukemia_-_historical#FLAG-DNX|FLAG-DNX]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cytarabine (Ara-C)]] 500 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose: 2000 mg/m<sup>2</sup>)<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV twice per day on days 1 to 4<br />
<br />
====Subsequent treatment====<br />
<br />
*[[#Allogeneic_hematopoietic_stem_cell_transplant_2|allogeneic HSCT]]<br />
<br />
===References===<br />
<br />
#'''I-BFM-SG 2001/01:''' Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.7384 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23319696 PubMed]<br />
<br />
=Relapsed or refractory, subsequent lines of therapy=<br />
''Note: these regimens are generally intended to delay progression of disease and are of non-curative intent.''<br />
<br />
==Azacitidine monotherapy {{#subobject:531b70|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:39f96a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/19/3735.long Thepot et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Azacitidine (Vidaza)]] 75 mg/m<sup>2</sup> SC once per day on days 1 to 7<br />
<br />
'''28-day cycle for at least 4 to 6 cycles'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
<br />
#Thepot S, Itzykson R, Seegers V, Raffoux E, Quesnel B, Chait Y, Sorin L, Dreyfus F, Cluzeau T, Delaunay J, Sanhes L, Eclache V, Dartigeas C, Turlure P, Harel S, Salanoubat C, Kiladjian JJ, Fenaux P, Adès L; Groupe Francophone des Myelodysplasies (GFM). Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM). Blood. 2010 Nov 11;116(19):3735-42. Epub 2010 Jul 27. [http://www.bloodjournal.org/content/116/19/3735.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20664061 PubMed]<br />
<br />
==Ruxolitinib monotherapy {{#subobject:ad5c7c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:596d8b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081383/ Eghtedar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Ruxolitinib (Jakafi)]] 25 mg PO twice per day<br />
<br />
'''28-day cycles'''<br />
<br />
''Patients with progression were allowed to increase the dose to 50 mg PO twice per day''<br />
<br />
===References===<br />
<!-- This study was presented in part at the American Society of Hematology annual meeting, December 2010, Orlando, FL. --><br />
<br />
#Eghtedar A, Verstovsek S, Estrov Z, Burger J, Cortes J, Bivins C, Faderl S, Ferrajoli A, Borthakur G, George S, Scherle PA, Newton RC, Kantarjian HM, Ravandi F. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood. 2012 May 17;119(20):4614-8. Epub 2012 Mar 15. [http://www.bloodjournal.org/content/119/20/4614.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081383/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22422826 PubMed]<br />
<br />
=Response criteria=<br />
==NCI-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia (1990)==<br />
<br />
#Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD, Brunning R, Gale RP, Grever MR, Keating MJ, et al. Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol. 1990 May;8(5):813-9. Review. [http://jco.ascopubs.org/content/8/5/813.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2185339 PubMed]<br />
<br />
==Revised International Working Group recommendations (2003)==<br />
<br />
#Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Löwenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-9. Erratum in: J Clin Oncol. 2004 Feb 1;22(3):576. LoCocco, Francesco [corrected to Lo-Coco, Francesco]. [http://jco.ascopubs.org/content/21/24/4642.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14673054 PubMed]<br />
<br />
=Prognosis=<br />
<br />
==Prognostic Index for Adult Patients With Acute Myeloid Leukemia in First Relapse (2005)==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
*Relapse-free interval from first complete remission<br />
**Greater than 18 months (0 points)<br />
**7 to 18 months ('''3 points''')<br />
**Less than or equal to 6 months ('''5 points''')<br />
*Cytogenetics at diagnosis<br />
**t(16;16) or inv(16) with or without additional cytogenetic abnormalities (0 points)<br />
**t(8;21) with or without additional cytogenetic abnormalities ('''3 points''')<br />
**Normal, intermediate, unfavorable, or unknown cytogenetics ('''5 points''')<br />
*Age at time of first relapse<br />
**Less than or equal to 35 years (0 points)<br />
**36 to 45 years ('''1 point''')<br />
**Greater than 45 years ('''2 points''')<br />
*Stem cell transplantation performed before first relapse<br />
**No (0 points)<br />
**Yes, autologous or allogeneic ('''2 points''')<br />
<br />
Risk stratification:<br />
<br />
*'''1 to 6 points''': Favorable risk (1-year OS of 70%; 5-year OS of 46%)<br />
*'''7 to 9 points''': Intermediate risk (1-year OS of 49%; 5-year OS of 18%)<br />
*'''10 to 14 points''': Poor risk (1-year OS of 16%; 5-year OS of 4%)<br />
<br />
===References===<br />
<br />
#Breems DA, Van Putten WL, Huijgens PC, Ossenkoppele GJ, Verhoef GE, Verdonck LF, Vellenga E, De Greef GE, Jacky E, Van der Lelie J, Boogaerts MA, Löwenberg B. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol. 2005 Mar 20;23(9):1969-78. Epub 2005 Jan 4. [http://jco.ascopubs.org/content/23/9/1969.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15632409 PubMed]<br />
<br />
==Prognosis in cytogenetically normal AML==<br />
<br />
#''Seminal paper comparing the mutational status of NPM1, FLT3, CEBPA, MLL, and NRAS with clinical outcome:'' Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H; German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008 May 1;358(18):1909-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa074306 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18450602 PubMed]<br />
<br />
=Investigational agents=<br />
<br />
''These are drugs under study with at least some promising results for this disease.''<br />
<br />
*[[Alvocidib (Flavopiridol)]]<br />
*[[Vadastuximab talirine (SGN-CD33A)]]<br />
*[[Volasertib (BI 6727)]]<br />
*[[Vosaroxin (SNS 595)]]<br />
<br />
=Additional information=<br />
<br />
==Antifungal prophylaxis==<br />
<br />
#'''Review:''' Halpern AB, Lyman GH, Walsh TJ, Kontoyiannis DP, Walter RB. Primary antifungal prophylaxis during curative-intent therapy for acute myeloid leukemia. Blood. 2015 Dec 24;126(26):2790-7. Epub 2015 Oct 26. [http://www.bloodjournal.org/content/126/26/2790.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26504183 PubMed]<br />
<br />
[[Category:Acute myeloid leukemia regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Acute leukemias]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=37582Antiemesis2019-05-19T23:08:26Z<p>Karine: Melphalan antiemesis with citation</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2019)<br />
!ASCO emetogenic potential<br />
(2017)<br />
!MASCC/ESMO emetogenic potential (2016)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|High/Moderate<br />
|High<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Atezolizumab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Blinatumomab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
|Ceritinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
|Daratumumab<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then +APR days 2-3)''<br />
|-<br />
|MASCC 2016<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
<br />
''(if APR on day 1, then +APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.7859 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2016 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://www.ncbi.nlm.nih.gov/pubmed/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://www.ncbi.nlm.nih.gov/pubmed/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
''Note: Day 0 is the day of BMT, days with "-" in front are days prior to transplant, days with "+" afterwards are days after transplant'' <br />
<br />
=Allogeneic BMT conditioning regimens=<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<ref>Schmitt T, Goldschmidt H, Neben K, et al: Aprepitant, granisetron, and dexamethasone for prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan in autologous transplantation for multiple myeloma: Results of a randomized, placebo-controlled phase III trial. J Clin Oncol 32:3413-3420, 2014 <br />
<br />
https://www.ncbi.nlm.nih.gov/pubmed/?term=schmitt+aprepitant+melphalan</ref><br />
| - NK1 on days -3 to 0<br />
<br />
- 5-HT3 on days -3 to 0<br />
<br />
- DEX on days -3 to -1<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br /><br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=37581Antiemesis2019-05-19T22:00:10Z<p>Karine: BMT allo antiemesis</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2019)<br />
!ASCO emetogenic potential<br />
(2017)<br />
!MASCC/ESMO emetogenic potential (2016)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|High/Moderate<br />
|High<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Atezolizumab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Blinatumomab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
|Ceritinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
|Daratumumab<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then +APR days 2-3)''<br />
|-<br />
|MASCC 2016<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
<br />
''(if APR on day 1, then +APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.7859 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2016 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://www.ncbi.nlm.nih.gov/pubmed/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://www.ncbi.nlm.nih.gov/pubmed/27176138</ref>. One of them was conducted in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
<br />
==Allogeneic BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
| - NK1 on day -7<br />
<br />
- 5-HT3 on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - NK1 on day -2<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
| - NK1 on day -6<br />
<br />
- 5-HT3 on days -6 to -1<br />
<br />
- DEX on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<br />
|<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]</div>Karinehttps://hemonc.org/w/index.php?title=Antiemesis&diff=37580Antiemesis2019-05-19T18:17:55Z<p>Karine: Allogeneic BMT conditioning</p>
<hr />
<div>Adapted from the NCCN<ref>[http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf NCCN antiemesis guidelines]</ref>, ASCO<ref>Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update<br />
</ref> and MASCC/ESMO<ref>MASCC antiemetic guidlines https://www.mascc.org/antiemetic-guidelines</ref><br />
<br />
=Emetic risk of chemotherapy, immunotherapy, TKIs and other agents=<br />
'''Hint: You can sort the table by clicking on the boxes containing arrows at the top of each column.'''<br><br />
''All drugs are IV route unless otherwise specified.''<br />
<br />
NCCN, ASCO and MASCC categories of emetic risk in the absence of prophylaxis:<br />
<br />
*High: >90% frequency of emesis (HEC)<br />
*Moderate: 30-90% frequency of emesis (MEC)<br />
*Low: 10-30% frequency of emesis<br />
*Minimal: <10% frequency of emesis<br />
<br />
ASCO guidelines say that in cases of combination chemotherapy regimens, patients should be given antiemetics that are recommended for the individual medication with the highest emetic risk. The exception is with anthracycline and [[Cyclophosphamide (Cytoxan)]] combinations as described below.<br />
<br />
{| class="wikitable sortable" border="1" style="text-align:center;"<br />
!Drug<br />
!NCCN emetogenic potential (2019)<br />
!ASCO emetogenic potential<br />
(2017)<br />
!MASCC/ESMO emetogenic potential (2016)<br />
!Comment<br />
|-<br />
| align="left" |[[Ado-trastuzumab emtansine (Kadcyla)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |Anthracycline (see differences between NCCN & ASCO) & [[Cyclophosphamide (Cytoxan)]] combination chemotherapy<br />
|High ([[Doxorubicin (Adriamycin)]] or [[Epirubicin (Ellence)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High ([[Daunorubicin (Cerubidine)]], [[Doxorubicin (Adriamycin)]], [[Epirubicin (Ellence)]], or [[Idarubicin (Idamycin)]] with [[Cyclophosphamide (Cytoxan)]])<br />
|High<br />
|MASCC comment - in patients with breast cancer<br />
|-<br />
| align="left" |[[Aldesleukin (Proleukin)]]<br />
|Moderate: >12 to 15 million international units/m<sup>2</sup><br>Low: ≤12 million international units/m<sup>2</sup><br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Alemtuzumab (Campath)]]<br />
|Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Altretamine (Hexalen)]] or Hexamethylmelamine (oral)<br />
|High/Moderate<br />
|High<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Amifostine (Ethyol)]]<br />
|Moderate: >300 mg/m<sup>2</sup><br>Low: ≤300 mg<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Arsenic trioxide (Trisenox)]]<br />
|Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Asparaginase (Elspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
|Atezolizumab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Axitinib (Inlyta)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Azacitidine (Vidaza)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bendamustine]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Bevacizumab (Avastin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Bexarotene (Targretin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Bleomycin (Blenoxane)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Blinatumomab<br />
|<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Bortezomib (Velcade)]]<br />
|Minimal<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Bosutinib (Bosulif)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Brentuximab vedotin (Adcetris)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]]<br />
|High/Moderate: ≥4 mg/day <br> Low/Minimal: <4 mg/day<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Busulfan (Myleran)]] (oral)<br />
|High/Moderate: ≥4 mg/day<br>Low/Minimal: <4 mg/day<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cabazitaxel (Jevtana)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cabozantinib (Cometriq)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Capecitabine (Xeloda)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Carboplatin (Paraplatin)]]<br />
|High: AUC ≥4<br />
Moderate: AUC <4<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and Dex if AUC ≥4)<br />
|Moderate (but recommended triplet combination of NK1, 5-HT3, and dexamethasone)<br />
|MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Carfilzomib (Kyprolis)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Carmustine (BCNU)]]<br />
|High: >250 mg/m<sup>2</sup><br>Moderate: ≤250 mg/m<sup>2</sup><br />
|High<br />
|High<br />
|ASCO and MASCC/ESMO did not subclassify based on dose<br />
|-<br />
| align="left" |[[Catumaxomab (Removab)]]<br />
|<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Cetuximab (Erbitux)]]<br />
|Minimal<br />
|Minimal<br />
|Low<br />
|<br />
|-<br />
|Ceritinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Chlorambucil (Leukeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cisplatin (Platinol)]]<br />
|High<br />
|High<br />
|High<br />
|Some only consider emetogenic potential high when dose ≥70 mg/m<sup>2</sup><br />
|-<br />
| align="left" |[[Cladribine (Leustatin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Clofarabine (Clolar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Crizotinib (Xalkori)]] (oral)<br />
|High/Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]]<br />
|High: >1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with certain anthracyclines]]<br>Moderate: ≤1500 mg/m<sup>2</sup><br />
|High: ≥1500 mg/m<sup>2</sup> or [[#Emetic_risk_of_chemotherapy|when given with anthracyclines]]<br>Moderate: <1500 mg/m<sup>2</sup><br />
|High: > 1500 mg/m2 or when combined with anthracyclines (in breast cancer patients)<br />
Moderate: < 1500 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Cyclophosphamide (Cytoxan)]] (oral)<br />
|High/Moderate: ≥100 mg/m<sup>2</sup>/day<br>Low/Minimal: <100 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Cytarabine (Ara-C)]]<br />
|Moderate: >200 mg/m<sup>2</sup><br>Low: 100 to 200 mg/m<sup>2</sup><br>Minimal: <100 mg/m<sup>2</sup><br />
|Moderate: >1000 mg/m<sup>2</sup><br>Low: ≤1000 mg/m<sup>2</sup><br />
|Moderate: > 1000 mg/m2 <br />
Low: < 1000 mg/m2<br />
|<br />
|-<br />
| align="left" |[[Dabrafenib (Tafinlar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Dacarbazine (DTIC)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
|Daratumumab<br />
|<br />
|Minimal<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dactinomycin (Cosmegen)]]<br />
|Moderate<br />
|High<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dasatinib (Sprycel)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Daunorubicin (Cerubidine)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Decitabine (Dacogen)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Denileukin diftitox (Ontak)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Dexrazoxane (Zinecard)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Docetaxel (Taxotere)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Doxorubicin (Adriamycin)]]<br />
|High: ≥60 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: <60 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when given with combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Pegylated liposomal doxorubicin (Doxil)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Epirubicin (Ellence)]]<br />
|High: >90 mg/m<sup>2</sup> or when given at any dose with [[Cyclophosphamide (Cytoxan)]]<br>Moderate: ≤90 mg/m<sup>2</sup><br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients)<br />
<br />
Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Eribulin (Halaven)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Erlotinib (Tarceva)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Estramustine (Emcyt)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Etoposide (Vepesid)]] (oral)<br />
|High/Moderate<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Everolimus (Afinitor)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Floxuridine (FUDR)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Fludarabine (Fludara)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Fluorouracil (5-FU)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Gefitinib (Iressa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Gemcitabine (Gemzar)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Hydroxyurea (Hydrea)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Idarubicin (Idamycin)]]<br />
|Moderate<br />
|High when given with [[Cyclophosphamide (Cytoxan)]]<br>Moderate when used alone<br />
|High: when combined with cyclophosphamide (in breast cancer patients) Moderate: when used alone<br />
|<br />
|-<br />
| align="left" |[[Ifosfamide (Ifex)]]<br />
|High: ≥2 g/m<sup>2</sup> per dose <br> Moderate: <2 g/m<sup>2</sup> per dose<br />
|Moderate<br />
|Moderate<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Imatinib (Gleevec)]] (oral)<br />
|Low/Minimal<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Interferon alfa-2a (Roferon-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Interferon alfa-2b (Intron-A)]]<br />
|Moderate: ≥10 million international units/m<sup>2</sup><br>Low: >5, <10 million international units/m<sup>2</sup><br>Minimal: ≤5 million international units/m<sup>2</sup><br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Ipilimumab (Yervoy)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Irinotecan (Camptosar)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ixabepilone (Ixempra)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Lapatinib (Tykerb)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Lenalidomide (Revlimid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
|Lenvatinib<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Lomustine (CCNU)]] (oral)<br />
|High/Moderate (single day)<br />
|<br />
|<br />
|single day; NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mechlorethamine (Mustargen)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]]<br />
|Moderate<br />
|<br />
|<br />
|ASCO and MASCC recommend combination of NK1+5-HT3+DEX when melphalan is used at high dose for BMT conditioning.<br />
|-<br />
| align="left" |[[Melphalan (Alkeran)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mercaptopurine (6-MP)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]]<br />
|Moderate: ≥250 mg/m<sup>2</sup><br>Low: >50, <250 mg/m<sup>2</sup><br>Minimal: ≤50 mg/m<sup>2</sup><br />
|Low<br />
|Low<br />
|ASCO and MASCC did not subclassify based on dose<br />
|-<br />
| align="left" |[[Methotrexate (MTX)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Mitomycin (Mutamycin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Mitotane (Lysodren)]] (oral)<br />
|High/Moderate<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Mitoxantrone (Novantrone)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Nelarabine (Arranon)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Nilotinib (Tasigna)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ofatumumab (Arzzera)]]<br />
|Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Omacetaxine (Synribo)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Oxaliplatin (Eloxatin)]]<br />
|Moderate<br />
|Moderate<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel (Taxol)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]]<br />
|Low<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Panitumumab (Vectibix)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pazopanib (Votrient)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Peg-asparginase (Oncaspar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Peginterferon alfa-2a (Pegasys)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Peginterferon alfa-2b (PegIntron)]]<br />
|Minimal<br />
|<br />
|<br />
|NCCN did not specify interferon alfa-2a vs. 2b<br />
|-<br />
| align="left" |[[Pemetrexed (Alimta)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pentostatin (Nipent)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Pertuzumab (Perjeta)]]<br />
|Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pomalidomide (Pomalyst)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Ponatinib (Iclusig)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Pralatrexate (Folotyn)]]<br />
|Low<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Procarbazine (Matulane)]] (oral)<br />
|High/Moderate<br />
|High<br />
|High<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Regorafenib (Stivarga)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Rituximab (Rituxan)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Romidepsin (Istodax)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Ruxolitinib (Jakafi)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Sorafenib (Nexavar)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Streptozocin (Zanosar)]]<br />
|High<br />
|High<br />
|High<br />
|<br />
|-<br />
| align="left" |[[Sunitinib (Sutent)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]]<br />
|Moderate<br />
|<br />
|Moderate<br />
|MASCC remark: No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a<br />
similar safety profile<br />
|-<br />
| align="left" |[[Temozolmide (Temodar)]] (oral)<br />
|High/Moderate: >75 mg/m<sup>2</sup>/day<br>Low/Minimal: ≤75 mg/m<sup>2</sup>/day<br />
|Moderate<br />
|Moderate<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Temsirolimus (Torisel)]]<br />
|Minimal<br />
|Low<br />
|<br />
|<br />
|-<br />
| align="left" |[[Thalidomide (Thalomid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thioguanine (Tabloid)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Minimal<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Thiotepa (Thioplex)]]<br />
|Low<br />
|<br />
|Moderate<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]]<br />
|Low<br />
|Low<br />
|Low<br />
|<br />
|-<br />
| align="left" |[[Topotecan (Hycamtin)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Trametinib (Mekinist)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Trastuzumab (Herceptin)]]<br />
|Minimal<br />
|Low<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[All-trans retinoic acid (ATRA)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Valrubicin (Valstar)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vandetanib (Caprelsa)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Vemurafenib (Zelboraf)]] (oral)<br />
|Low/Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinblastine (Velban)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine (Oncovin)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vincristine liposomal (Marqibo)]]<br />
|Minimal<br />
|<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vinorelbine (Navelbine)]]<br />
|Minimal<br />
|Minimal<br />
|Minimal<br />
|<br />
|-<br />
|Vinorelbine (oral)<br />
|<br />
|Moderate<br />
|<br />
|<br />
|-<br />
| align="left" |[[Vismodegib (Erivedge)]] (oral)<br />
|High/Moderate<br />
|<br />
|Minimal<br />
|<br />
|-<br />
| align="left" |[[Vorinostat (Zolinza)]] (oral)<br />
|Low/Minimal<br />
|<br />
|Low<br />
|NCCN did not further delineate between degrees of emetic potential<br />
|-<br />
| align="left" |[[Ziv-aflibercept (Zaltrap)]]<br />
|Low<br />
|<br />
|<br />
|<br />
|}<br />
<br />
=Highly emetogenic IV chemotherapy (HEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|NK1 + 5-HT3 + DEX + OLN<br />
|DEX + OLN<br />
<br />
''(if APR on day 1, then +APR days 2-3)''<br />
|-<br />
|MASCC 2016<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
<br />
''(if APR on day 1, then +APR days 2-3)''<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- NK1 + 5-HT3 + DEX + OLN</nowiki><br />
|DEX + OLN<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX</nowiki><br />
|DEX<br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
==Neurokinin-1 (NK1) antagonist-containing regimen (except netupitant)==<br />
===Neurokinin 1 (NK1) antagonist===<br />
<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3<br />
*[[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Rolapitant (Varubi)]] 180 mg PO once on day 1<br />
<br />
''Note: All of the above NK1 antagonists are equally effective in IV and PO formulations at recommended doses <ref>Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. [http://ascopubs.org/doi/full/10.1200/JCO.2010.31.7859 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21383291 PubMed]</ref>''<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
''Note: When given at biologically equivalent doses, all of the above 5-HT3 antagonists are equally efficacious and appear to be interchangeable''<ref>Karin Jordan et al. "Comparative activity of antiemetic drugs"<br />
<br />
https://www-sciencedirect-com.elibrary.einstein.yu.edu/science/article/pii/S1040842806001661#tbl2<br />
</ref><br />
<br />
''Note: Ramosetron is another available 5-HT3, but not approved by FDA''<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1">Ronald CHow et Al. "Efficacy and safety of 1-day versus 3-day dexamethasone for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials"<br />
<br />
http://jhmhp.amegroups.com/article/view/4296<br />
</ref> <br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Moderately emetogenic IV chemotherapy (MEC)=<br />
{| class="wikitable"<br />
|<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017<br />
|5-HT3 + DEX<br />
|DEX maybe offered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
|MASCC 2016<br />
|5-HT3 + DEX<br />
|DEX can be considered for: oxaliplatin, or anthracycline, or cyclophosphamide<br />
|-<br />
| rowspan="3" |NCCN 2019<br />
|<nowiki>- 5-HT3 + DEX</nowiki><br />
|DEX or 5-HT3<br />
|-<br />
|<nowiki>- NK1 + 5-HT3 + DEX </nowiki><br />
<br />
(for selected patients with additional risk factors or previous Rx failure)<br />
|<nowiki>+/- DEX</nowiki><br />
|-<br />
|<nowiki>- OLN + 5-HT3 + DEX</nowiki><br />
|OLN<br />
|}<br />
<br />
===Serotonin (5-HT3) antagonist===<br />
<br />
*[[Dolasetron (Anzemet)]] 100 mg PO once on day 1<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once on day 1<br />
**0.01 mg/kg (maximum dose 1 mg) IV once on day 1<br />
**transdermal patch as 3.1 mg/24H patch (containing 34.3 mg granisetron total dose) placed ~24 to 48 hours before the first dose of chemotherapy. May use patch up to 7 days.<br />
*[[Ondansetron (Zofran)]] (choose one of the options below):<br />
**8 to 16 mg IV<ref name="ondansetron QTc">As of 6/28/2012, the once daily dose of ondansetron (Zofran) 32 mg is no longer recommended due to dose-dependent QTc prolongation. The [http://us.gsk.com/products/assets/us_zofran.pdf Ondansetron (Zofran) package insert] recommends only a maximum of 16 mg per dose, which can be given as often as every 4 hours x up to 3 doses, as detailed in the 6/29/2012 [http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm FDA Drug Safety Communication].</ref> once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1<br />
*[[Tropisetron (Navoban)]] 5 mg IV or PO day 1<br />
<br />
===Dexamethasone (DEX)===<br />
''Steroids contraindicated for use with interleukin-2 and interferon.''<br />
<br />
*If [[Aprepitant (Emend)]] used: <br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Fosaprepitant (Emend for Injection)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO once per day on days 2 to 4<br />
*If [[Rolapitant (Varubi)]] used:<br />
**[[Dexamethasone (Decadron)]] 12 mg IV or PO once on day 1, then 8 mg PO twice per day on days 2 to 4<br />
<br />
''Dexamethasone use beyond day 1 might be revised based on the 2018 meta analysis results''<ref name=":1" /><br />
<br />
==Netupitant-containing regimen==<br />
<br />
*[[Netupitant and palonosetron (Akynzeo)]] 300/0.5 mg PO once on day 1 as a fixed oral formulation<br />
*[[Dexamethasone (Decadron)]] 12 mg PO or IV once on day 1, then 8 mg PO or IV once per day on days 2 to 4<br />
<br />
==Olanzapine (OLN) containing regimen==<br />
''Note: a 4-drug regimen based on [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 Navari et al. 2016]<ref>Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M, Dietrich L, Biggs D, Lafky JM, Loprinzi CL. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa1515725 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27410922 PubMed]</ref>''<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO once per day on days 1 to 4<br />
*[[Aprepitant (Emend)]] 125 mg PO once on day 1, then 80 mg PO once per day on days 2 & 3, '''OR''' [[Fosaprepitant (Emend for Injection)]] 150 mg IV once on day 1<br />
*[[Palonosetron (Aloxi)]] 0.25 mg IV once on day 1, '''OR''' Granisetron 1mg IV or 2mg PO, '''OR''' Ondansetron 8 mg PO or IV<br />
*[[Dexamethasone (Decadron)]] 12 mg PO on day 1, and 8 mg PO on days 2, 3, and 4<br />
<br />
=Carboplatin based chemotherapy=<br />
{| class="wikitable"<br />
|'''Guideline and emetic risk'''<br />
|'''Day 1 CINV prophylaxis'''<br />
|'''Day 2-4 CINV prophylaxis'''<br />
|-<br />
|ASCO 2017 (MEC)<br />
<br />
AUC ≥ 4<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
|MASCC 2016 (MEC)<br />
<br />
(doesn’t specify AUC)<br />
|NK1 + 5-HT3 + DEX<br />
|NONE<br />
<br />
(if APR on day 1, then +APR days 2-3)<br />
|-<br />
| rowspan="2" |NCCN 2019<br />
<br />
AUC ≥ 4 (HEC)<br />
<br />
AUC < 4 (MEC)<br />
|NK1 + 5-HT3 + DEX<br />
|DEX<br />
|-<br />
|5-HT3 + DEX<br />
|<br />
|}<br />
Recommendation to add NK1 is largely based on 2 phase III studies<ref name=":2">Yahata H, Kobayashi H, Sonoda K, et al: Effi- cacy of aprepitant for the prevention of chemotherapy- induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: A multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving pac- litaxel and carboplatin. Int J Clin Oncol 21:491-497, 2016 <br />
<br />
https://www.ncbi.nlm.nih.gov/pubmed/26662632<br />
</ref><ref>Hesketh PJ, Schnadig ID, Schwartzberg LS, et al: Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in pa- tients receiving carboplatin-based chemotherapy. Cancer 122:2418-2425, 2016<nowiki/>https://www.ncbi.nlm.nih.gov/pubmed/27176138</ref>. One of them for done in female patients with GYN malignancy only. <ref name=":2" /> 5-HT3 used in those trials was either granisetron or ondansetron. <br />
<br />
=Bone marrow transplant (BMT) conditioning regimens=<br />
<br />
==Allogeneic BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|FMT (fludarabine, melphalan, thiotepa)<br />
|<nowiki>- Fosaprepitant on day -7</nowiki><br />
<br />
- Ondansetron on days -7 to -1<br />
|-<br />
|Flu/Mel (fludarabine, melphalan)<br />
| - Fosaprepitant on day -2<br />
- Ondansetron on days -6 to -1<br />
<br />
- Dexamethasone on days -6 to -1<br />
|-<br />
|Flu/Cy/TBI (fludarabine, cyclophosphamide, total body irradiation)<br />
|<br />
|-<br />
|Cy/TBI (cyclophosphamide, total body irradiation)<br />
|<nowiki>- Fosaprepitant on day -6</nowiki><br />
<br />
- Ondansetron on days -6 to -1<br />
<br />
- Dexamethasone on days -6 to -4<br />
|-<br />
|Bu/Flu (bufulfan, fludarabine)<br />
|<br />
|-<br />
|Bu/Cy (busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
==Autologous BMT conditioning regimens==<br />
{| class="wikitable"<br />
!Conditioning regimen<br />
!CINV prophylaxis<br />
|-<br />
|High dose melphalan<br />
|<br />
|-<br />
|BEAM (busulfan, etoposide, cytarabine, melphalan)<br />
|<br />
|-<br />
|TBC (thiotepa, busulfan, cyclophosphamide)<br />
|<br />
|}<br />
<br />
=Highly to moderately emetogenic PO chemotherapy=<br />
'''These are NCCN recommendations only. ASCO did not provide separate antiemetic recommendations for PO vs. IV chemotherapy.'''<br><br />
Start before chemotherapy and continue once per day:<br />
==Serotonin (5-HT3) antagonist==<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea on days 1 to 4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
=Low emetic risk IV chemotherapy=<br />
{| class="wikitable"<br />
|<br />
|Day 1<br />
|Day 2-4<br />
|-<br />
|ASCO 2017<br />
|Single dose 5-HT3 or DEX 8mg<br />
|No routine prophylaxis<br />
|-<br />
|MASCC 2016<br />
|5-HT3 or DEX or Dopamine RA<br />
|No routine prophylaxis<br />
|-<br />
|NCCN 2019<br />
|5-HT3 or DEX or Dopamine RA<br />
<br />
5-HT3 other than palonosetrone<br />
|No routine prophylaxis<br />
|}<br />
'''Repeat once per day for chemotherapy regimens that last more than one day.''' <br />
<br />
*[[Dexamethasone (Decadron)]] <br />
**NCCN: 12 mg IV or PO on the days of chemotherapy<br />
**ASCO: 8 mg IV or PO on the days of chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10mg IV or PO x1, then Q4-6H prn nausea<br />
<br />
=Minimal emetic risk chemotherapy=<br />
<br />
*No routine prophylaxis recommended by all 3 guideline groups. Assess patient prior to cycle 2 and add single agent prophylactic antiemetic if patient had emesis with cycle 1.<br />
<br />
=Low to minimal emetic risk PO chemotherapy=<br />
<br />
*use antiemetics prn first<br />
<br />
==If nausea/vomiting==<br />
Choose one of the medications below to start before chemotherapy and continue once per day:<br />
<br />
*[[Metoclopramide (Reglan)]] 10-40 mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Prochlorperazine (Compazine)]] 10mg IV or PO x1, then Q4-6H prn nausea<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
<br />
==Optional==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO/IV/sublingual Q4-6H prn nausea days 1-4<br />
*[[:Category:H2-receptor antagonists|H2 blocker]] or [[:Category:Proton pump inhibitors|proton pump inhibitor]]<br />
<br />
==If continued nausea/vomiting==<br />
Use serotonin (5-HT3) antagonist:<br />
<br />
*[[Granisetron]] (choose one of the options below):<br />
**2 mg PO once per day<br />
**1 mg PO twice per day<br />
*[[Ondansetron (Zofran)]] 16 to 24 mg PO once per day<br />
<br />
=Breakthrough CINV treatment=<br />
General Principles<br />
<br />
-Use antiemetic from another class than the prophylactic regimen<br />
<br />
-Agents which are successful in treating a patient’s breakthrough CINV should be given routinely for a period of time rather than on an as needed basis. <br />
<br />
-5-HT3 and NK1 RA are generally not effective or approved for treatment of breakthrough nausea/vomiting (assuming they were used as part of prophylaxis)<br />
==Olanzapine==<br />
<br />
*[[Olanzapine (Zyprexa)]] 10 mg PO daily on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0">R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Cancer, vol. 21, no. 6, pp. 1655–1663, 2013</ref>. Use 5 mg if 10mg is not well tolerated.<ref>S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effectiveness of olanzapine for the treatment of breakthrough chemotherapy induced nausea and vomiting,” Journal of the Medical Association of Thailand, vol. 97, pp. 349–355, 2014</ref><br />
<br />
==Metoclopromide==<br />
<br />
*[[Metoclopramide (Reglan)]] 10 mg PO (IV) every 8 hours on days 1-3 if CINV develop in the first 24 hours after HEC <ref name=":0" />.<br />
<br />
==Benzodiazepine==<br />
<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO (IV) Q4-6H prn nausea<br />
<br />
==Cannabinoid==<br />
<br />
*[[Dronabinol (Marinol)]] 5-10 mg PO Q3-6H prn nausea<br />
*[[Nabilone (Cesamet)]] 1-2 mg PO twice per day prn nausea<br />
<br />
==Other agents==<br />
<br />
*[[Haloperidol (Haldol)]] 0.5 to 2 mg IV or PO Q4-6H prn nausea (monitor for dystonic reactions)<br />
*[[Scopolamine (Scopoderm)]] 1 patch Q72H prn nausea<br />
<br />
*[[Prochlorperazine (Compazine)]] (choose one of the options below):<br />
**25 mg suppository PR every 12 hours prn nausea<br />
**10mg IV or PO Q4-6H prn nausea<br />
*[[Promethazine (Phenergan)]] 12.5-25 mg IV or PO every 6 hours for 1-3 days<br />
*[[Dexamethasone (Decadron)]] 8 mg PO (IV) every 6-8 hours<br />
<br />
==Serotonin 5-HT3 antagonists==<br />
Are generally ineffective for breakthrough CINV (assuming they were used as part of prophylactic regimen). <br />
<br />
*[[Ondansetron (Zofran)]] 8 to 16 mg PO once per day prn nausea<br />
<br />
=Anticipatory nausea/vomiting=<br />
<br />
*Prevent anticipation by optimizing antiemetic therapy for every cycle of chemotherapy<br />
*Behavioral therapy<br />
**Relaxation/systemic desensitization<br />
**Hypnosis/guided imagery<br />
**Music therapy<br />
*Acupuncture/acupressure<br />
*[[Alprazolam (Xanax)]] 0.5 to 2 mg PO three times per day starting the night before treatment<br />
*[[Lorazepam (Ativan)]] 0.5 to 2 mg PO the night before and the morning of treatment<br />
<br />
=Reference=<br />
<references /><br />
<br />
[[Category:General reference pages]]<br />
[[Category:Supportive medications]]</div>Karine