https://hemonc.org/w/api.php?action=feedcontributions&user=Dweeraratne&feedformat=atomHemOnc.org - A Hematology Oncology Wiki - User contributions [en]2024-03-28T17:44:39ZUser contributionsMediaWiki 1.35.14https://hemonc.org/w/index.php?title=Urothelial_carcinoma&diff=41936Urothelial carcinoma2020-01-09T00:23:53Z<p>Dweeraratne: /* Pembrolizumab monotherapy #subobject:b0cd2a */</p>
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<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:Alikhaki.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Alikhaki|Ali Raza Khaki, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/arkhaki arkhaki]<br />
| style="background-color:#F0F0F0" |[[File:ChenEddy Sept2016.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Eddychen|Eddy J. Chen, MD]]<br>Massachusetts General Hospital<br>Boston, MA</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 />
<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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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==<br />
{{:Bacillus Calmette-Guérin (BCG) intravesicular chemotherapy in bladder cancer}}<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" 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 />
| rowspan="2" |[https://www.sciencedirect.com/science/article/pii/S0022534717400024 Martínez-Piñeiro et al. 1990]<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 />
| 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://www.sciencedirect.com/science/article/pii/S0022534717400024 link to SD article] '''contains partial protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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 />
===Variant #1, 1 treatment {{#subobject:170d3b|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/2680547 Messing et al. 2018 (SWOG S0337)]<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 />
===Variant #2, 6 treatments {{#subobject:fa5bb2|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2008.20.8199 Addeo et al. 2009]<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://ascopubs.org/doi/full/10.1200/JCO.2008.20.8199 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/29801011 PubMed]<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 />
===Variant #1, 30 mg x 12 {{#subobject:347e3e|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.europeanurology.com/article/S0302-2838(07)00653-7/fulltext Ojea et al. 2007 (CUETO study 95011)]<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 />
===Variant #2, 40 mg x 11 {{#subobject:531377|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2011.39.2936 Lammers et al. 2012]<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 Group (Club Urológico Español De Tratamiento Oncológico). 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://www.europeanurology.com/article/S0302-2838(07)00653-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/10.1200/JCO.2011.39.2936 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22585689 PubMed]<br />
<br />
==Observation==<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/31/11/1422.long Ito et al. 2013 (THP Monotherapy Study Group Trial)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pirarubicin_monotherapy|Pirarubicin]]<br />
| style="background-color:#fc8d59" |Seems to have inferior RFS<br />
|-<br />
|}<br />
''No active antineoplastic treatment after surgery.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Nephroureterectomy|Nephroureterectomy]]<br />
<br />
===References===<br />
<br />
#'''THP Monotherapy Study Group Trial:''' Ito A, Shintaku I, Satoh M, Ioritani N, Aizawa M, Tochigi T, Kawamura S, Aoki H, Numata I, Takeda A, Namiki S, Namima T, Ikeda Y, Kambe K, Kyan A, Ueno S, Orikasa K, Katoh S, Adachi H, Tokuyama S, Ishidoya S, Yamaguchi T, Arai Y. Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J Clin Oncol. 2013 Apr 10;31(11):1422-7. Epub 2013 Mar 4. [http://jco.ascopubs.org/content/31/11/1422.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23460707 PubMed]<br />
<br />
<br /><br />
==Pembrolizumab {{#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://ascopubs.org/doi/abs/10.1200/JCO.2019.37.7_suppl.350 Balar et al. (Keynote-057)]<br />
| style="background-color:#91cf61" |Phase II (single-arm)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*Pembrolizumab 200 mg IV once on day 1<br />
<br />
'''21-day cycle for 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://ascopubs.org/doi/abs/10.1200/JCO.2019.37.7_suppl.350 link to abstract]<br />
<br />
==Pirarubicin monotherapy {{#subobject:d9be78|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:dfdcd9|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/31/11/1422.long Ito et al. 2013 (THP Monotherapy Study Group Trial)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior RFS<br />
|-<br />
|}<br />
''Pirarubicin was given within 48 hours after nephroureterectomy.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Nephroureterectomy|Nephroureterectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Pirarubicin (THP)]] 30 mg in 30 mL normal saline intravesicularly, delivered through a catheter into the bladder, and retained for 30 minutes<br />
<br />
'''1 dose'''<br />
<br />
===References===<br />
<br />
#'''THP Monotherapy Study Group Trial:''' Ito A, Shintaku I, Satoh M, Ioritani N, Aizawa M, Tochigi T, Kawamura S, Aoki H, Numata I, Takeda A, Namiki S, Namima T, Ikeda Y, Kambe K, Kyan A, Ueno S, Orikasa K, Katoh S, Adachi H, Tokuyama S, Ishidoya S, Yamaguchi T, Arai Y. Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J Clin Oncol. 2013 Apr 10;31(11):1422-7. Epub 2013 Mar 4. [http://jco.ascopubs.org/content/31/11/1422.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23460707 PubMed]<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" 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 />
| rowspan="2" |[https://www.sciencedirect.com/science/article/pii/S0022534717400024 Martínez-Piñeiro et al. 1990]<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://www.sciencedirect.com/science/article/pii/S0022534717400024 link to SD article] '''contains partial protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[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 />
| 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 />
===References===<br />
<br />
#Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M; The 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://www.ncbi.nlm.nih.gov/pubmed/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.ncbi.nlm.nih.gov/pubmed/31686036 Powles et al. 2019] (ABACUS)<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<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://www.ncbi.nlm.nih.gov/pubmed/31686036 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:d08e11|Regimen=1}}==<br />
{{#subobject:be43aa|Variant=1}}<br />
{{#subobject:dc99d5|Variant=1}}<br />
{{:Cisplatin & Gemcitabine for bladder cancer, neoadjuvant}}<br />
<br />
==MCV {{#subobject:553fe2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CMV: '''<u>C</u>'''isplatin, '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine<br />
<br>MCV: '''<u>M</u>'''ethotrexate, '''<u>C</u>'''isplatin, '''<u>V</u>'''inblastine<br />
===Variant #1, 2 cycles {{#subobject:450c9f|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJM199311043291903 Kaufman et al. 1993]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://jco.ascopubs.org/content/14/1/119.long Tester et al. 1996 (RTOG 88-02)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://jco.ascopubs.org/content/16/11/3576.long Shipley et al. 1998 (RTOG 89-03)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#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 />
===Variant #2, 3 cycles {{#subobject:3d008f|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#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 />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_neoadjuvant_therapy|No neoadjuvant therapy]]<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<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 />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Patients in '''Zapatero et al. 2000''' had T2 to T4 Nx M0 disease. Reported efficacy for BA06 30894 is based on the 2011 update.''<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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/14/1/119.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/16/11/3576.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]<br />
#'''BA06 30894:''' Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; 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://www.ncbi.nlm.nih.gov/pubmed/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); European Organisation for Research and Treatment of Cancer 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. [http://jco.ascopubs.org/content/29/16/2171.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107740/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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 />
===Variant #1, 2 cycles {{#subobject:0f1661|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annonc.oxfordjournals.org/content/25/6/1192.long Kitamura et al. 2014 (JCOG0209)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#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 />
===Variant #2, 3 cycles {{#subobject:dc2c80|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa022148 Grossman et al. 2003 (SWOG S8710)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#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://www.ncbi.nlm.nih.gov/pubmed/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. [http://annonc.oxfordjournals.org/content/25/6/1192.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24669010 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 />
===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]<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 />
===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://jco.ascopubs.org/content/32/18/1889.long Choueiri et al. 2014]<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 />
#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. [http://jco.ascopubs.org/content/32/18/1889.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24821883 PubMed]<br />
#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. [http://jco.ascopubs.org/content/32/18/1895.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050203/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24821881 PubMed]<br />
<br />
==No neoadjuvant therapy==<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.auajournals.org/doi/full/10.1016/S0022-5347%2801%2967614-6 Martinez-Piñeiro et al. 1995]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02292-8/abstract Griffiths et al. 1999 (BA06 30894)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MCV|CMV]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa022148 Grossman et al. 2003 (SWOG S8710)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MVAC|MVAC]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[http://annonc.oxfordjournals.org/content/25/6/1192.long Kitamura et al. 2014 (JCOG0209)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MVAC|MVAC]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
''No preoperative treatment; used as a comparator arm and here for reference purposes only. Reported efficacy for BA06 30894 is based on the 2011 update.''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Bladder_cancer_surgery|Surgery]]<br />
<br />
===References===<br />
<br />
#Martinez-Piñeiro JA, Gonzalez Martin M, Arocena F, Flores N, Roncero CR, Portillo JA, Escudero A, Jimenez Cruz F, Isorna S. Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: a prospective randomized phase III study. J Urol. 1995 Mar;153(3 Pt 2):964-73. [https://www.auajournals.org/doi/full/10.1016/S0022-5347%2801%2967614-6 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7853584 PubMed]<br />
#'''BA06 30894:''' Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; 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://www.ncbi.nlm.nih.gov/pubmed/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); European Organisation for Research and Treatment of Cancer 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. [http://jco.ascopubs.org/content/29/16/2171.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107740/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21502557 PubMed]<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://www.ncbi.nlm.nih.gov/pubmed/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. [http://annonc.oxfordjournals.org/content/25/6/1192.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24669010 PubMed]<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://www.ncbi.nlm.nih.gov/pubmed/30343614 Necchi et al. 2018 (PURE-01)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<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://ascopubs.org/doi/suppl/10.1200/JCO.18.01148 Link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30343614 PubMed]<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://www.sciencedirect.com/science/article/pii/S0302283819308255 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/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 />
===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 />
===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 />
|[http://jco.ascopubs.org/content/14/1/119.long 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 />
<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 />
**Patients with CR: [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]<br />
**Patients without CR proceeded immediately to: [[Surgery#Cystectomy|cystectomy]]<br />
<br />
===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 />
|[http://jco.ascopubs.org/content/16/11/3576.long 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 [[#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 />
<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 />
**Patients not in CR usually proceeded to: [[Surgery#Cystectomy|cystectomy]]<br />
**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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/14/1/119.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/16/11/3576.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/22999456 PubMed]<br />
<br />
==Cisplatin, Fluorouracil, RT {{#subobject:b5e26|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===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.2C_Fluorouracil.2C_RT_2|CF & RT consolidation]] in week 9<br />
**Incomplete responders were recommended to undergo [[Surgery#Radical_cystectomy|radical cystectomy]]<br />
<br />
===Variant #2, 135/2400/40.3 {{#subobject:6be392|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 33%" |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.2C_Fluorouracil.2C_RT_2|CF & RT consolidation]]<br />
**Incomplete responders: [[Surgery#Radical_cystectomy|Radical cystectomy]]<br />
<br />
===Variant #3, 135/3600/40.3 {{#subobject:6be39|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 33%" |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.2C_Fluorouracil.2C_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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23823157 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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/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://www.ncbi.nlm.nih.gov/pubmed/30433852 PubMed]<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 />
===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_2|adjuvant cisplatin & gemcitabine]]<br />
<br />
===Variant #2, 45/50 x 3 + 40.3 Gy {{#subobject:6ecd8b|Variant=1}}===<br />
{| class="wikitable" 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_Fluorouracil.2C_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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23823157 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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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" 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/NEJMoa1106106 James et al. 2012 (BC2001)]<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://www.ncbi.nlm.nih.gov/pubmed/22512481 PubMed]<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" style="width: 100%; text-align:center;" <br />
! style="width: 33%" |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.2C_Fluorouracil.2C_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://ascopubs.org/doi/full/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://www.ncbi.nlm.nih.gov/pubmed/30433852 PubMed]<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://www.ncbi.nlm.nih.gov/pubmed/22999456 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" 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://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 />
| 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 />
| 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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/22512481 PubMed]<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 />
===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 />
===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 />
|[http://jco.ascopubs.org/content/14/1/119.long 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 />
===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 />
|[http://jco.ascopubs.org/content/16/11/3576.long 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. [http://jco.ascopubs.org/content/14/1/119.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/16/11/3576.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]<br />
<br />
==Cisplatin, Fluorouracil, RT {{#subobject:fe2538|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 30/1200 x 2 + 64.3 Gy {{#subobject:a18497|Variant=1}}===<br />
{| class="wikitable" 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.2C_Fluorouracil.2C_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 />
===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.2C_Fluorouracil.2C_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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23823157 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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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 />
===Variant #1, 30/50 x 2 + 64.3 Gy {{#subobject:9fefbd|Variant=1}}===<br />
{| class="wikitable" 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_Fluorouracil.2C_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 />
===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_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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23823157 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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/22999456 PubMed]<br />
<br />
=Adjuvant chemotherapy=<br />
==Cisplatin & Gemcitabine {{#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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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" 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://ascopubs.org/doi/full/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-AB 05/95 Study Group. 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://ascopubs.org/doi/full/10.1200/JCO.2005.11.094 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://meetinglibrary.asco.org/content/51401-74 Paz-Ares et al 2010 (SOGUG 99/01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#PGC|PGC]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164246/ Stadler et al. 2011 (SWOG-4B951)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MVAC<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS<br />
|-<br />
|[https://academic.oup.com/annonc/article/23/3/695/227146 Cognetti et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Gemcitabine<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71160-X/fulltext Sternberg et al. 2014 (EORTC 30994)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MVAC<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of 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>). This arm underwent cystectomy and no further treatment. The study prematurely closed due to poor recruitment and lacks adequate power to make firm conclusions. In SWOG-4B951, only patients with positive p53 staining were randomized.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Cystectomy|Cystectomy]]<br />
<br />
====Subsequent treatment====<br />
<br />
*EORTC 30994, upon relapse: [[#MVAC_2|MVAC]] x 6<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. [http://meetinglibrary.asco.org/content/51401-74 link to abstract] '''contains verified protocol'''<br />
#'''SWOG-4B951:''' Stadler WM, Lerner SP, Groshen S, Stein JP, Shi SR, Raghavan D, Esrig D, Steinberg G, Wood D, Klotz L, Hall C, Skinner DG, Cote RJ. Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status. J Clin Oncol. 2011 Sep 1;29(25):3443-9. Epub 2011 Aug 1. [https://ascopubs.org/doi/full/10.1200/JCO.2010.34.4028 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164246/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21810677 PubMed]<br />
#Cognetti F, Ruggeri EM, Felici A, Gallucci M, Muto G, Pollera CF, Massidda B, Rubagotti A, Giannarelli D, Boccardo F; Study Group. Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial. Ann Oncol. 2012 Mar;23(3):695-700. Epub 2011 Aug 22. [https://academic.oup.com/annonc/article/23/3/695/227146 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21859900 PubMed]<br />
#'''EORTC 30994:''' Sternberg CN, Skoneczna I, Kerst JM, Albers P, Fossa SD, Agerbaek M, Dumez H, de Santis M, Théodore C, Leahy MG, Chester JD, Verbaeys A, Daugaard G, Wood L, Witjes JA, de Wit R, Geoffrois L, Sengelov L, Thalmann G, Charpentier D, Rolland F, Mignot L, Sundar S, Symonds P, Graham J, Joly F, Marreaud S, Collette L, Sylvester R; European Organisation for Research and Treatment of Cancer Genito-Urinary Cancers Group; Groupe d'Etude des Tumeurs Urogénitales; National Cancer Research Institute Bladder Cancer Study Group; National Cancer Institute of Canada Clinical Trials Group; German Association of Urologic Oncology. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol. 2015 Jan;16(1):76-86. Epub 2014 Dec 11. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71160-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25498218 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 />
===Variant #1 {{#subobject:ad1bc8|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://meetinglibrary.asco.org/content/51401-74 Paz-Ares et al 2010 (SOGUG 99/01)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#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.''<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 />
===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.2C_Fluorouracil.2C_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. [http://meetinglibrary.asco.org/content/51401-74 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. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23823157 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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]<br />
<br />
=Locally advanced or metastatic disease, first-line=<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" 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://thelancet.com/journals/lancet/article/PIIS0140-6736(16)32455-2/fulltext Balar et al. 2016 (IMvigor210 Cohort 2)]<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 5/18/2018 the FDA released a warning that patients in the monotherapy arms of the ongoing IMVIGOR-130 trial with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy.'''</big><br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''IMvigor210 Cohort 2:''' 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/pubmed/27939400 PubMed] [https://clinicaltrials.gov/ct2/show/NCT02951767 IMvigor210 at ClinicalTrials.gov]<br />
<br />
==Carboplatin & Gemcitabine {{#subobject:8855e5|Regimen=1}}==<br />
{{#subobject:5f00b7|Variant=1}}<br />
{{#subobject:4f0596|Variant=1}}<br />
{{:Carboplatin & gemcitabine for unresectable or metastatic bladder cancer}}<br />
<br />
==Carboplatin & Paclitaxel {{#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" 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.10782/full Vaughn et al. 2002 (ECOG E2896)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#3d3d3d; color:white" |ORR: 24% (95% CI 12-42)<br />
|-<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 over 3 hours once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#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://www.ncbi.nlm.nih.gov/pubmed/12209686 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" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|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 />
| style="background-color:#ffffbe" |Non-randomized, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|<br />
|<br />
|-<br />
|[http://jco.ascopubs.org/content/8/6/1050.long Logothetis et al. 1990]<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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/8/6/1050.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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" 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://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 />
| style="background-color:#1a9851" |Randomized (C)<br />
|Cisplatin & Cyclophosphamide<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1985.3.4.539 Khandekar et al. 1985]<br />
| style="background-color:#1a9851" |Randomized (C)<br />
|CAD<br />
| style="background-color:#fee08b" |Might have inferior ORR<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S002253471744167X Troner et al. 1987]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CAD<br />
| style="background-color:#ffffbf" |Did not meet endpoint of ORR<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.6.706 Hillcoat et al. 1989]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Methotrexate<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1992.10.7.1066 Loehrer et al. 1992]<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. 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://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/abs/10.1200/JCO.1985.3.4.539 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3884746 PubMed]<br />
#Troner M, Birch R, Omura GA, Williams S. 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://www.sciencedirect.com/science/article/pii/S002253471744167X link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/abs/10.1200/JCO.1989.7.6.706 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/abs/10.1200/JCO.1992.10.7.1066 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1607913 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#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 />
===Variant #1, 70/1000, q3wk {{#subobject:69fea8|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annonc.oxfordjournals.org/content/13/7/1080.long Soto Parra et al. 2002]<br />
| style="background-color:#ffffbe" |Randomized Phase II, <20 pts in this subgroup (E-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_3|Cisplatin & Gemcitabine]]; q4wk<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<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 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 cycle for up to 6 cycles'''<br />
<br />
===Variant #2, 70/1000, q4wk {{#subobject:53ad73|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/18/17/3068.long von der Maase et al. 2000]<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 />
|[http://annonc.oxfordjournals.org/content/13/7/1080.long Soto Parra et al. 2002]<br />
| style="background-color:#ffffbe" |Randomized Phase II, <20 pts in this subgroup (E-de-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_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 />
| 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 />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Larotaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<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 />
===Variant #3, 70/1250, q3wk {{#subobject:44c03b|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#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext Dogliotti et al. 2006]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Carboplatin_.26_Gemcitabine|Carboplatin & Gemcitabine]]<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of reduced toxicity<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV 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 />
#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. [http://jco.ascopubs.org/content/18/17/3068.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/10.1200/JCO.2005.07.757 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://annonc.oxfordjournals.org/content/13/7/1080.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/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://www.ncbi.nlm.nih.gov/pubmed/22370319 PubMed]<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://www.ncbi.nlm.nih.gov/pubmed/24080920 PubMed]<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 />
===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 />
===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 />
|[http://jco.ascopubs.org/content/19/12/3018.long 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. [http://jco.ascopubs.org/content/19/12/3018.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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 />
===Variant #1, standard {{#subobject:33db41|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/8/6/1050.long Logothetis et al. 1990]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#CISCA|CISCA]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1992.10.7.1066 Loehrer et al. 1992]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_monotherapy|Cisplatin]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/18/17/3068.long von der Maase et al. 2000]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[http://jco.ascopubs.org/content/19/10/2638.long Sternberg et al. 2001 (EORTC 30924)]<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 (*)<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2002.20.5.1361 Siefker-Radtke et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FAP<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%<br />
|-<br />
|}<br />
''Note: 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 on either day 1 or 2<br />
<br />
'''28-day cycles''' (number of cycles and criteria to continue therapy varies depending on reference)<br />
<br />
===Variant #2, with G-CSF support {{#subobject:72266e|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2004.02.152 Bamias et al. 2003]<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. [http://jco.ascopubs.org/content/8/6/1050.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/abs/10.1200/JCO.1992.10.7.1066 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1607913 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. [http://jco.ascopubs.org/content/18/17/3068.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/10.1200/JCO.2005.07.757 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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; European Organization for Research and Treatment of Cancer 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 Organization for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [http://jco.ascopubs.org/content/19/10/2638.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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; 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://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/10.1200/JCO.2002.20.5.1361 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/10.1200/JCO.2004.02.152 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14665607 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" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[http://jco.ascopubs.org/content/19/10/2638.long Sternberg et al. 2001 (EORTC 30924)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|62% (95% CI 54-70)<br />
|50% (95% CI 42-59)<br />
|-<br />
|[https://academic.oup.com/annonc/article/24/4/1011/259546 Bamias et al. 2012 (HE 16/03)]<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 />
''Note: In contrast to Sternberg et al. 2001, Sternberg et al. 2006 specified 15-day cycles. 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 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]] 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; European Organization for Research and Treatment of Cancer 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 Organization for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [http://jco.ascopubs.org/content/19/10/2638.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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; 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://www.ncbi.nlm.nih.gov/pubmed/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. 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://academic.oup.com/annonc/article/24/4/1011/259546 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23136231 PubMed]<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" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|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 />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_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://ascopubs.org/doi/full/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://www.ncbi.nlm.nih.gov/pubmed/22370319 PubMed]<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" 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(17)30616-2/fulltext Balar et al. 2017 (KEYNOTE-052)]<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 />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<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 />
# '''Abstract:''' Dean F. Bajorin, Elizabeth R. Plimack, Arlene O. Siefker-Radtke, Toni K. Choueiri, Ronald De Wit, Guru Sonpavde, Adrianna Gipson, Holly Brown, Yabing Mai, Lei Pang, Rodolfo F. Perini, Joaquim Bellmunt. KEYNOTE-052: Phase 2 study of pembrolizumab (MK-3475) as first-line therapy for patients (pts) with unresectable or metastatic urothelial cancer ineligible for cisplatin-based therapy. 2015 ASCO Annual Meeting abstract TPS4572. [http://meetinglibrary.asco.org/content/146071-156 link to abstract]<br />
# '''Abstract:''' A. Balar, J. Bellmunt, P.H. O'Donnell, D. Castellano, P. Grivas, J. Vuky, T. Powles, E.R. Plimack, N.M. Hahn, R. de Wit, L. Pang, M.J. Savage, R. Perini, S. Keefe, D. Bajorin. Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: Preliminary results from the phase 2 KEYNOTE-052 study. Ann Oncol (2016) 27 (suppl_6): LBA32_PR. [https://academic.oup.com/annonc/article-abstract/27/suppl_6/LBA32_PR/2800534/Pembrolizumab-pembro-as-first-line-therapy-for?redirectedFrom=fulltext link to abstract] --><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://www.ncbi.nlm.nih.gov/pubmed/28967485 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Placebo==<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2015.66.3468 Powles et al. 2016 (LaMB)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Lapatinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''No active antineoplastic treatment.''<br />
===References===<br />
<br />
#'''LaMB:''' Powles T, Huddart RA, Elliott T, Sarker SJ, Ackerman C, Jones R, Hussain S, Crabb S, Jagdev S, Chester J, Hilman S, Beresford M, Macdonald G, Santhanam S, Frew JA, Stockdale A, Hughes S, Berney D, Chowdhury S. Phase III, double-blind, randomized trial that compared maintenance lapatinib versus placebo after first-line chemotherapy in patients with human epidermal growth factor receptor 1/2-positive metastatic bladder cancer. J Clin Oncol. 2017 Jan;35(1):48-55. Epub 2016 Oct 28. [https://ascopubs.org/doi/full/10.1200/JCO.2015.66.3468 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28034079 PubMed]<br />
<br />
=Locally advanced or metastatic disease, subsequent lines=<br />
==Atezolizumab monotherapy {{#subobject:451e68|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:feb2e2|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/nature13904 Powles et al. 2014]<br />
| style="background-color:#ffffbe" |Phase 1<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00561-4/fulltext Rosenberg et al. 2016 (IMvigor210)]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#88419d; color:white" |ORR: 15% (95% CI 11-20)<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ood)<br />
|1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. [[#Paclitaxel_monotherapy|Paclitaxel]]<br> 3. [[#Vinflunine_monotherapy|Vinflunine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|2015-2016<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Patients are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 5% of the tumor area), as determined by an FDA-approved test<br />
<br />
Patients are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status<br />
<br />
''Note: this regimen did not meet its primary endpoint in phase III; here for historical reference only.''<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Phase 1:''' Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, Teng SL, Shen X, Boyd Z, Hegde PS, Chen DS, Vogelzang NJ. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014 Nov 27;515(7528):558-62. [https://www.nature.com/articles/nature13904 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25428503 PubMed]<br />
#'''IMvigor210:''' Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016 May 7;387(10031):1909-20. Epub 2016 Mar 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00561-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480242/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26952546 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://www.ncbi.nlm.nih.gov/pubmed/29268948 PubMed]<br />
<br />
==Avelumab monotherapy {{#subobject:6C1497|Regimen=1}}==<br />
{{#subobject:D9FB6C|Variant=1}}<br />
{{:Avelumab (Bavencio) for metastatic bladder cancer}}<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: 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%" |Years of study<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2008.20.5534 Bellmunt et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Vinflunine_monotherapy|Vinflunine]]<br />
| style="background-color:#d73027" |Inferior OS (*)<br />
|2003-2006<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Reported efficacy is based on the 2013 update.''<br />
===References===<br />
<br />
#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://ascopubs.org/doi/full/10.1200/JCO.2008.20.5534 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19687335 PubMed]<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://academic.oup.com/annonc/article/24/6/1466/178781 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23419284 PubMed]<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" 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%" |Years of study<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.5.1853 McCaffrey et al. 1997]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ Choueiri et al. 2012 (DFCI 06-116)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel & Vandetanib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|2007-2010<br />
|-<br />
| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/JCO.2015.65.0218 Petrylak et al. 2016 (JCDC)]<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 />
| rowspan="2" |2011-2014<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 />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy_2|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|2014-2015<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext Petrylak et al. 2017 (RANGE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]<br />
| style="background-color:#d73027" |Inferior PFS (*)<br />
|2015-2017<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<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 />
|2015-2016<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. 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 />
'''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://ascopubs.org/doi/abs/10.1200/JCO.1997.15.5.1853 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/30/5/507.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22184381 PubMed]<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://ascopubs.org/doi/full/10.1200/JCO.2015.65.0218 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26926681 PubMed]<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://www.ncbi.nlm.nih.gov/pubmed/28212060 PubMed]<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 May 3. [Epub ahead of print] [https://academic.oup.com/annonc/article/30/6/970/5485243 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/28916371 PubMed]<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. 2019 Nov 18. [Epub ahead of print] [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30668-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/29268948 PubMed]<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" 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%" |Years of study<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2015.65.0218 Petrylak et al. 2016 (JCDC)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|2011-2014<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext Petrylak et al. 2017 (RANGE)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior PFS (*)<br />
|2015-2017<br />
|-<br />
|}<br />
''Note: 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 />
*[[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://ascopubs.org/doi/full/10.1200/JCO.2015.65.0218 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26926681 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://www.ncbi.nlm.nih.gov/pubmed/28916371 PubMed]<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. 2019 Nov 18. [Epub ahead of print] [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30668-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31753727 PubMed]<br />
<br />
==Durvalumab monotherapy {{#subobject:7ae7fb|Regimen=1}}==<br />
{{#subobject:b2af36|Variant=1}}<br />
{{:Durvalumab (Imfinzi) for metastatic bladder cancer}}<br />
<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: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.TPS4590 Rosenberg et al. 2018 (EV-201)]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
====Chemotherapy====<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 />
===References===<br />
<br />
#'''Abstract:''' EV-201 Study: A single-arm, open-label, multicenter study of enfortumab vedotin for treatment of patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor therapy. Jonathan E. Rosenberg, Elisabeth I. Heath, Peter H. O'Donnell, Noah M. Hahn, Arjun Vasant Balar, Elaina M. Gartner, Amal Melhem-Bertrandt, and Daniel Peter Petrylak. Journal of Clinical Oncology 2018 36:15_suppl, TPS4590-TPS4590 [https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.TPS4590 link to abstract]<br />
<br />
==Erdafitinib monotherapy {{#subobject:dbc30d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<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: 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/NEJMoa1817323 Loriot et al. 2019 (BLC2001)]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
====Biomarker eligibility criteria====<br />
<br />
*Alterations: FGFR3 mutation, FGFR2 fusion, or FGFR3 fusion<br />
<br />
====Chemotherapy====<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://www.ncbi.nlm.nih.gov/pubmed/31340094 PubMed]<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 />
===Variant #1, gemcitabine 2 out of 3 weeks {{#subobject:384057|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/22/2/288/171507 Albers et al. 2010 (AUO AB 20/99)]<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 />
===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 />
|[http://jco.ascopubs.org/content/19/12/3018.long 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. [http://jco.ascopubs.org/content/19/12/3018.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://academic.oup.com/annonc/article/22/2/288/171507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.nature.com/bjc/journal/v98/n1/full/6604113a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359702/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18087289 PubMed]<br />
<br />
==Nivolumab monotherapy {{#subobject:86b89c|Regimen=1}}==<br />
{{#subobject:beb7fa|Variant=1}}<br />
{{:Nivolumab (Opdivo) for unresectable or metastatic bladder cancer}}<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, q3wks {{#subobject:9fddc0|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#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |Years of study<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy_2|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|2014-2015<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<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 />
|2015-2016<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.''<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===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 />
|[http://jco.ascopubs.org/content/20/4/937.long 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. [http://jco.ascopubs.org/content/20/4/937.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887921/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27284445 PubMed]<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://www.ncbi.nlm.nih.gov/pubmed/28212060 PubMed]<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 May 3. [Epub ahead of print] [https://academic.oup.com/annonc/article/30/6/970/5485243 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/29268948 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://www.ncbi.nlm.nih.gov/pubmed/23706985 PubMed]<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" 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%" |Years of study<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|Investigator's choice of:<br> [[#Docetaxel_monotherapy|Docetaxel]]<br> [[#Paclitaxel_monotherapy|Paclitaxel]]<br> [[#Vinflunine_monotherapy|Vinflunine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|2014-2015<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://www.ncbi.nlm.nih.gov/pubmed/28212060 PubMed]<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 May 3. [Epub ahead of print] [https://academic.oup.com/annonc/article/30/6/970/5485243 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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 />
|[http://jco.ascopubs.org/content/24/21/3451.long 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. [http://jco.ascopubs.org/content/24/21/3451.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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" 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%" |Years of study<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2008.20.5534 Bellmunt et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|2003-2006<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy_2|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|2014-2015<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<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 />
|2015-2016<br />
|-<br />
|}<br />
''Note: reported efficacy for Bellmunt et al. 2009 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 />
#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://ascopubs.org/doi/full/10.1200/JCO.2008.20.5534 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19687335 PubMed]<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://academic.oup.com/annonc/article/24/6/1466/178781 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/28212060 PubMed]<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 May 3. [Epub ahead of print] [https://academic.oup.com/annonc/article/30/6/970/5485243 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/29268948 PubMed]<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://www.ncbi.nlm.nih.gov/pubmed/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>Dweeraratnehttps://hemonc.org/w/index.php?title=Urothelial_carcinoma&diff=41931Urothelial carcinoma2020-01-09T00:20:20Z<p>Dweeraratne: /* Regimen #subobject:feb2e2 */</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:Alikhaki.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Alikhaki|Ali Raza Khaki, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/arkhaki arkhaki]<br />
| style="background-color:#F0F0F0" |[[File:ChenEddy Sept2016.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Eddychen|Eddy J. Chen, MD]]<br>Massachusetts General Hospital<br>Boston, MA</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 />
<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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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==<br />
{{:Bacillus Calmette-Guérin (BCG) intravesicular chemotherapy in bladder cancer}}<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" 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 />
| rowspan="2" |[https://www.sciencedirect.com/science/article/pii/S0022534717400024 Martínez-Piñeiro et al. 1990]<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 />
| 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://www.sciencedirect.com/science/article/pii/S0022534717400024 link to SD article] '''contains partial protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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 />
===Variant #1, 1 treatment {{#subobject:170d3b|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/2680547 Messing et al. 2018 (SWOG S0337)]<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 />
===Variant #2, 6 treatments {{#subobject:fa5bb2|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2008.20.8199 Addeo et al. 2009]<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://ascopubs.org/doi/full/10.1200/JCO.2008.20.8199 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/29801011 PubMed]<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 />
===Variant #1, 30 mg x 12 {{#subobject:347e3e|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.europeanurology.com/article/S0302-2838(07)00653-7/fulltext Ojea et al. 2007 (CUETO study 95011)]<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 />
===Variant #2, 40 mg x 11 {{#subobject:531377|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2011.39.2936 Lammers et al. 2012]<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 Group (Club Urológico Español De Tratamiento Oncológico). 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://www.europeanurology.com/article/S0302-2838(07)00653-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/10.1200/JCO.2011.39.2936 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22585689 PubMed]<br />
<br />
==Observation==<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/31/11/1422.long Ito et al. 2013 (THP Monotherapy Study Group Trial)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pirarubicin_monotherapy|Pirarubicin]]<br />
| style="background-color:#fc8d59" |Seems to have inferior RFS<br />
|-<br />
|}<br />
''No active antineoplastic treatment after surgery.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Nephroureterectomy|Nephroureterectomy]]<br />
<br />
===References===<br />
<br />
#'''THP Monotherapy Study Group Trial:''' Ito A, Shintaku I, Satoh M, Ioritani N, Aizawa M, Tochigi T, Kawamura S, Aoki H, Numata I, Takeda A, Namiki S, Namima T, Ikeda Y, Kambe K, Kyan A, Ueno S, Orikasa K, Katoh S, Adachi H, Tokuyama S, Ishidoya S, Yamaguchi T, Arai Y. Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J Clin Oncol. 2013 Apr 10;31(11):1422-7. Epub 2013 Mar 4. [http://jco.ascopubs.org/content/31/11/1422.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23460707 PubMed]<br />
<br />
<br /><br />
==Pembrolizumab {{#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://ascopubs.org/doi/abs/10.1200/JCO.2019.37.7_suppl.350 Balar et al. (Keynote-057)]<br />
| style="background-color:#91cf61" |Phase II (single-arm)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*Pembrolizumab 200 mg IV once on day 1<br />
<br />
'''21-day cycle for 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://ascopubs.org/doi/abs/10.1200/JCO.2019.37.7_suppl.350 link to abstract]<br />
<br />
==Pirarubicin monotherapy {{#subobject:d9be78|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:dfdcd9|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/31/11/1422.long Ito et al. 2013 (THP Monotherapy Study Group Trial)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior RFS<br />
|-<br />
|}<br />
''Pirarubicin was given within 48 hours after nephroureterectomy.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Nephroureterectomy|Nephroureterectomy]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Pirarubicin (THP)]] 30 mg in 30 mL normal saline intravesicularly, delivered through a catheter into the bladder, and retained for 30 minutes<br />
<br />
'''1 dose'''<br />
<br />
===References===<br />
<br />
#'''THP Monotherapy Study Group Trial:''' Ito A, Shintaku I, Satoh M, Ioritani N, Aizawa M, Tochigi T, Kawamura S, Aoki H, Numata I, Takeda A, Namiki S, Namima T, Ikeda Y, Kambe K, Kyan A, Ueno S, Orikasa K, Katoh S, Adachi H, Tokuyama S, Ishidoya S, Yamaguchi T, Arai Y. Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J Clin Oncol. 2013 Apr 10;31(11):1422-7. Epub 2013 Mar 4. [http://jco.ascopubs.org/content/31/11/1422.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23460707 PubMed]<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" 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 />
| rowspan="2" |[https://www.sciencedirect.com/science/article/pii/S0022534717400024 Martínez-Piñeiro et al. 1990]<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://www.sciencedirect.com/science/article/pii/S0022534717400024 link to SD article] '''contains partial protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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: 50%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[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 />
| 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 />
===References===<br />
<br />
#Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M; The 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://www.ncbi.nlm.nih.gov/pubmed/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.ncbi.nlm.nih.gov/pubmed/31686036 Powles et al. 2019] (ABACUS)<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<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://www.ncbi.nlm.nih.gov/pubmed/31686036 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:d08e11|Regimen=1}}==<br />
{{#subobject:be43aa|Variant=1}}<br />
{{#subobject:dc99d5|Variant=1}}<br />
{{:Cisplatin & Gemcitabine for bladder cancer, neoadjuvant}}<br />
<br />
==MCV {{#subobject:553fe2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CMV: '''<u>C</u>'''isplatin, '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine<br />
<br>MCV: '''<u>M</u>'''ethotrexate, '''<u>C</u>'''isplatin, '''<u>V</u>'''inblastine<br />
===Variant #1, 2 cycles {{#subobject:450c9f|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/10.1056/NEJM199311043291903 Kaufman et al. 1993]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://jco.ascopubs.org/content/14/1/119.long Tester et al. 1996 (RTOG 88-02)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://jco.ascopubs.org/content/16/11/3576.long Shipley et al. 1998 (RTOG 89-03)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#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 />
===Variant #2, 3 cycles {{#subobject:3d008f|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#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 />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_neoadjuvant_therapy|No neoadjuvant therapy]]<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<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 />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Patients in '''Zapatero et al. 2000''' had T2 to T4 Nx M0 disease. Reported efficacy for BA06 30894 is based on the 2011 update.''<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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/14/1/119.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/16/11/3576.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]<br />
#'''BA06 30894:''' Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; 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://www.ncbi.nlm.nih.gov/pubmed/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); European Organisation for Research and Treatment of Cancer 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. [http://jco.ascopubs.org/content/29/16/2171.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107740/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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 />
===Variant #1, 2 cycles {{#subobject:0f1661|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annonc.oxfordjournals.org/content/25/6/1192.long Kitamura et al. 2014 (JCOG0209)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#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 />
===Variant #2, 3 cycles {{#subobject:dc2c80|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa022148 Grossman et al. 2003 (SWOG S8710)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#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://www.ncbi.nlm.nih.gov/pubmed/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. [http://annonc.oxfordjournals.org/content/25/6/1192.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24669010 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 />
===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]<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 />
===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://jco.ascopubs.org/content/32/18/1889.long Choueiri et al. 2014]<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 />
#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. [http://jco.ascopubs.org/content/32/18/1889.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24821883 PubMed]<br />
#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. [http://jco.ascopubs.org/content/32/18/1895.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050203/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24821881 PubMed]<br />
<br />
==No neoadjuvant therapy==<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.auajournals.org/doi/full/10.1016/S0022-5347%2801%2967614-6 Martinez-Piñeiro et al. 1995]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02292-8/abstract Griffiths et al. 1999 (BA06 30894)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MCV|CMV]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa022148 Grossman et al. 2003 (SWOG S8710)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MVAC|MVAC]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[http://annonc.oxfordjournals.org/content/25/6/1192.long Kitamura et al. 2014 (JCOG0209)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MVAC|MVAC]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
''No preoperative treatment; used as a comparator arm and here for reference purposes only. Reported efficacy for BA06 30894 is based on the 2011 update.''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Bladder_cancer_surgery|Surgery]]<br />
<br />
===References===<br />
<br />
#Martinez-Piñeiro JA, Gonzalez Martin M, Arocena F, Flores N, Roncero CR, Portillo JA, Escudero A, Jimenez Cruz F, Isorna S. Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: a prospective randomized phase III study. J Urol. 1995 Mar;153(3 Pt 2):964-73. [https://www.auajournals.org/doi/full/10.1016/S0022-5347%2801%2967614-6 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7853584 PubMed]<br />
#'''BA06 30894:''' Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; 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://www.ncbi.nlm.nih.gov/pubmed/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); European Organisation for Research and Treatment of Cancer 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. [http://jco.ascopubs.org/content/29/16/2171.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107740/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21502557 PubMed]<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://www.ncbi.nlm.nih.gov/pubmed/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. [http://annonc.oxfordjournals.org/content/25/6/1192.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24669010 PubMed]<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://www.ncbi.nlm.nih.gov/pubmed/30343614 Necchi et al. 2018 (PURE-01)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<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://ascopubs.org/doi/suppl/10.1200/JCO.18.01148 Link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30343614 PubMed]<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://www.sciencedirect.com/science/article/pii/S0302283819308255 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/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 />
===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 />
===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 />
|[http://jco.ascopubs.org/content/14/1/119.long 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 />
<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 />
**Patients with CR: [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]<br />
**Patients without CR proceeded immediately to: [[Surgery#Cystectomy|cystectomy]]<br />
<br />
===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 />
|[http://jco.ascopubs.org/content/16/11/3576.long 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 [[#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 />
<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 />
**Patients not in CR usually proceeded to: [[Surgery#Cystectomy|cystectomy]]<br />
**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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/14/1/119.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/16/11/3576.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/22999456 PubMed]<br />
<br />
==Cisplatin, Fluorouracil, RT {{#subobject:b5e26|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===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.2C_Fluorouracil.2C_RT_2|CF & RT consolidation]] in week 9<br />
**Incomplete responders were recommended to undergo [[Surgery#Radical_cystectomy|radical cystectomy]]<br />
<br />
===Variant #2, 135/2400/40.3 {{#subobject:6be392|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 33%" |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.2C_Fluorouracil.2C_RT_2|CF & RT consolidation]]<br />
**Incomplete responders: [[Surgery#Radical_cystectomy|Radical cystectomy]]<br />
<br />
===Variant #3, 135/3600/40.3 {{#subobject:6be39|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 33%" |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.2C_Fluorouracil.2C_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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23823157 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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/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://www.ncbi.nlm.nih.gov/pubmed/30433852 PubMed]<br />
<br />
==Cisplatin, Paclitaxel, RT {{#subobject:803f28|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===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_2|adjuvant cisplatin & gemcitabine]]<br />
<br />
===Variant #2, 45/50 x 3 + 40.3 Gy {{#subobject:6ecd8b|Variant=1}}===<br />
{| class="wikitable" 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_Fluorouracil.2C_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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23823157 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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]<br />
<br />
==Fluorouracil, Mitomycin, RT {{#subobject:5e89d1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
Fluorouracil, Mitomycin, RT: Fluorouracil, Mitomycin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:6a18dc|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 James et al. 2012 (BC2001)]<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://www.ncbi.nlm.nih.gov/pubmed/22512481 PubMed]<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" style="width: 100%; text-align:center;" <br />
! style="width: 33%" |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.2C_Fluorouracil.2C_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://ascopubs.org/doi/full/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://www.ncbi.nlm.nih.gov/pubmed/30433852 PubMed]<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://www.ncbi.nlm.nih.gov/pubmed/22999456 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" 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://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 />
| 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 />
| 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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/22512481 PubMed]<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 />
===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 />
===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 />
|[http://jco.ascopubs.org/content/14/1/119.long 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 />
===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 />
|[http://jco.ascopubs.org/content/16/11/3576.long 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. [http://jco.ascopubs.org/content/14/1/119.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/16/11/3576.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]<br />
<br />
==Cisplatin, Fluorouracil, RT {{#subobject:fe2538|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 30/1200 x 2 + 64.3 Gy {{#subobject:a18497|Variant=1}}===<br />
{| class="wikitable" 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.2C_Fluorouracil.2C_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 />
===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.2C_Fluorouracil.2C_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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23823157 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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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 />
===Variant #1, 30/50 x 2 + 64.3 Gy {{#subobject:9fefbd|Variant=1}}===<br />
{| class="wikitable" 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_Fluorouracil.2C_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 />
===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_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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23823157 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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/22999456 PubMed]<br />
<br />
=Adjuvant chemotherapy=<br />
==Cisplatin & Gemcitabine {{#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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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" 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://ascopubs.org/doi/full/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-AB 05/95 Study Group. 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://ascopubs.org/doi/full/10.1200/JCO.2005.11.094 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://meetinglibrary.asco.org/content/51401-74 Paz-Ares et al 2010 (SOGUG 99/01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#PGC|PGC]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164246/ Stadler et al. 2011 (SWOG-4B951)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MVAC<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS<br />
|-<br />
|[https://academic.oup.com/annonc/article/23/3/695/227146 Cognetti et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Gemcitabine<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71160-X/fulltext Sternberg et al. 2014 (EORTC 30994)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MVAC<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of 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>). This arm underwent cystectomy and no further treatment. The study prematurely closed due to poor recruitment and lacks adequate power to make firm conclusions. In SWOG-4B951, only patients with positive p53 staining were randomized.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Cystectomy|Cystectomy]]<br />
<br />
====Subsequent treatment====<br />
<br />
*EORTC 30994, upon relapse: [[#MVAC_2|MVAC]] x 6<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. [http://meetinglibrary.asco.org/content/51401-74 link to abstract] '''contains verified protocol'''<br />
#'''SWOG-4B951:''' Stadler WM, Lerner SP, Groshen S, Stein JP, Shi SR, Raghavan D, Esrig D, Steinberg G, Wood D, Klotz L, Hall C, Skinner DG, Cote RJ. Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status. J Clin Oncol. 2011 Sep 1;29(25):3443-9. Epub 2011 Aug 1. [https://ascopubs.org/doi/full/10.1200/JCO.2010.34.4028 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164246/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21810677 PubMed]<br />
#Cognetti F, Ruggeri EM, Felici A, Gallucci M, Muto G, Pollera CF, Massidda B, Rubagotti A, Giannarelli D, Boccardo F; Study Group. Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial. Ann Oncol. 2012 Mar;23(3):695-700. Epub 2011 Aug 22. [https://academic.oup.com/annonc/article/23/3/695/227146 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21859900 PubMed]<br />
#'''EORTC 30994:''' Sternberg CN, Skoneczna I, Kerst JM, Albers P, Fossa SD, Agerbaek M, Dumez H, de Santis M, Théodore C, Leahy MG, Chester JD, Verbaeys A, Daugaard G, Wood L, Witjes JA, de Wit R, Geoffrois L, Sengelov L, Thalmann G, Charpentier D, Rolland F, Mignot L, Sundar S, Symonds P, Graham J, Joly F, Marreaud S, Collette L, Sylvester R; European Organisation for Research and Treatment of Cancer Genito-Urinary Cancers Group; Groupe d'Etude des Tumeurs Urogénitales; National Cancer Research Institute Bladder Cancer Study Group; National Cancer Institute of Canada Clinical Trials Group; German Association of Urologic Oncology. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol. 2015 Jan;16(1):76-86. Epub 2014 Dec 11. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71160-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25498218 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 />
===Variant #1 {{#subobject:ad1bc8|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://meetinglibrary.asco.org/content/51401-74 Paz-Ares et al 2010 (SOGUG 99/01)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#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.''<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 />
===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.2C_Fluorouracil.2C_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. [http://meetinglibrary.asco.org/content/51401-74 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. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23823157 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. [http://jco.ascopubs.org/content/27/25/4055.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/32/34/3801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25366678 PubMed]<br />
<br />
=Locally advanced or metastatic disease, first-line=<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" 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://thelancet.com/journals/lancet/article/PIIS0140-6736(16)32455-2/fulltext Balar et al. 2016 (IMvigor210 Cohort 2)]<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 5/18/2018 the FDA released a warning that patients in the monotherapy arms of the ongoing IMVIGOR-130 trial with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy.'''</big><br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''IMvigor210 Cohort 2:''' 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/pubmed/27939400 PubMed] [https://clinicaltrials.gov/ct2/show/NCT02951767 IMvigor210 at ClinicalTrials.gov]<br />
<br />
==Carboplatin & Gemcitabine {{#subobject:8855e5|Regimen=1}}==<br />
{{#subobject:5f00b7|Variant=1}}<br />
{{#subobject:4f0596|Variant=1}}<br />
{{:Carboplatin & gemcitabine for unresectable or metastatic bladder cancer}}<br />
<br />
==Carboplatin & Paclitaxel {{#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" 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.10782/full Vaughn et al. 2002 (ECOG E2896)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#3d3d3d; color:white" |ORR: 24% (95% CI 12-42)<br />
|-<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 over 3 hours once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#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://www.ncbi.nlm.nih.gov/pubmed/12209686 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" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|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 />
| style="background-color:#ffffbe" |Non-randomized, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|<br />
|<br />
|-<br />
|[http://jco.ascopubs.org/content/8/6/1050.long Logothetis et al. 1990]<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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/8/6/1050.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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" 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://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 />
| style="background-color:#1a9851" |Randomized (C)<br />
|Cisplatin & Cyclophosphamide<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1985.3.4.539 Khandekar et al. 1985]<br />
| style="background-color:#1a9851" |Randomized (C)<br />
|CAD<br />
| style="background-color:#fee08b" |Might have inferior ORR<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S002253471744167X Troner et al. 1987]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CAD<br />
| style="background-color:#ffffbf" |Did not meet endpoint of ORR<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.6.706 Hillcoat et al. 1989]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Methotrexate<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1992.10.7.1066 Loehrer et al. 1992]<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. 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://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/abs/10.1200/JCO.1985.3.4.539 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3884746 PubMed]<br />
#Troner M, Birch R, Omura GA, Williams S. 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://www.sciencedirect.com/science/article/pii/S002253471744167X link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/abs/10.1200/JCO.1989.7.6.706 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/abs/10.1200/JCO.1992.10.7.1066 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1607913 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#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 />
===Variant #1, 70/1000, q3wk {{#subobject:69fea8|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annonc.oxfordjournals.org/content/13/7/1080.long Soto Parra et al. 2002]<br />
| style="background-color:#ffffbe" |Randomized Phase II, <20 pts in this subgroup (E-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_3|Cisplatin & Gemcitabine]]; q4wk<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<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 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 cycle for up to 6 cycles'''<br />
<br />
===Variant #2, 70/1000, q4wk {{#subobject:53ad73|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/18/17/3068.long von der Maase et al. 2000]<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 />
|[http://annonc.oxfordjournals.org/content/13/7/1080.long Soto Parra et al. 2002]<br />
| style="background-color:#ffffbe" |Randomized Phase II, <20 pts in this subgroup (E-de-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_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 />
| 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 />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Larotaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<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 />
===Variant #3, 70/1250, q3wk {{#subobject:44c03b|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#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext Dogliotti et al. 2006]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Carboplatin_.26_Gemcitabine|Carboplatin & Gemcitabine]]<br />
|<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of reduced toxicity<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV 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 />
#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. [http://jco.ascopubs.org/content/18/17/3068.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/10.1200/JCO.2005.07.757 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://annonc.oxfordjournals.org/content/13/7/1080.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/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://www.ncbi.nlm.nih.gov/pubmed/22370319 PubMed]<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://www.ncbi.nlm.nih.gov/pubmed/24080920 PubMed]<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 />
===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 />
===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 />
|[http://jco.ascopubs.org/content/19/12/3018.long 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. [http://jco.ascopubs.org/content/19/12/3018.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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 />
===Variant #1, standard {{#subobject:33db41|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/8/6/1050.long Logothetis et al. 1990]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#CISCA|CISCA]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1992.10.7.1066 Loehrer et al. 1992]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_monotherapy|Cisplatin]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/18/17/3068.long von der Maase et al. 2000]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine_3|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[http://jco.ascopubs.org/content/19/10/2638.long Sternberg et al. 2001 (EORTC 30924)]<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 (*)<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2002.20.5.1361 Siefker-Radtke et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FAP<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%<br />
|-<br />
|}<br />
''Note: 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 on either day 1 or 2<br />
<br />
'''28-day cycles''' (number of cycles and criteria to continue therapy varies depending on reference)<br />
<br />
===Variant #2, with G-CSF support {{#subobject:72266e|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2004.02.152 Bamias et al. 2003]<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. [http://jco.ascopubs.org/content/8/6/1050.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/abs/10.1200/JCO.1992.10.7.1066 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1607913 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. [http://jco.ascopubs.org/content/18/17/3068.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/10.1200/JCO.2005.07.757 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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; European Organization for Research and Treatment of Cancer 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 Organization for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [http://jco.ascopubs.org/content/19/10/2638.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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; 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://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/10.1200/JCO.2002.20.5.1361 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/10.1200/JCO.2004.02.152 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14665607 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" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[http://jco.ascopubs.org/content/19/10/2638.long Sternberg et al. 2001 (EORTC 30924)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#MVAC_2|MVAC]]<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|62% (95% CI 54-70)<br />
|50% (95% CI 42-59)<br />
|-<br />
|[https://academic.oup.com/annonc/article/24/4/1011/259546 Bamias et al. 2012 (HE 16/03)]<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 />
''Note: In contrast to Sternberg et al. 2001, Sternberg et al. 2006 specified 15-day cycles. 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 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]] 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; European Organization for Research and Treatment of Cancer 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 Organization for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [http://jco.ascopubs.org/content/19/10/2638.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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; 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://www.ncbi.nlm.nih.gov/pubmed/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. 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://academic.oup.com/annonc/article/24/4/1011/259546 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23136231 PubMed]<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" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|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 />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_.26_Gemcitabine_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://ascopubs.org/doi/full/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://www.ncbi.nlm.nih.gov/pubmed/22370319 PubMed]<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" 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(17)30616-2/fulltext Balar et al. 2017 (KEYNOTE-052)]<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 />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<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 />
# '''Abstract:''' Dean F. Bajorin, Elizabeth R. Plimack, Arlene O. Siefker-Radtke, Toni K. Choueiri, Ronald De Wit, Guru Sonpavde, Adrianna Gipson, Holly Brown, Yabing Mai, Lei Pang, Rodolfo F. Perini, Joaquim Bellmunt. KEYNOTE-052: Phase 2 study of pembrolizumab (MK-3475) as first-line therapy for patients (pts) with unresectable or metastatic urothelial cancer ineligible for cisplatin-based therapy. 2015 ASCO Annual Meeting abstract TPS4572. [http://meetinglibrary.asco.org/content/146071-156 link to abstract]<br />
# '''Abstract:''' A. Balar, J. Bellmunt, P.H. O'Donnell, D. Castellano, P. Grivas, J. Vuky, T. Powles, E.R. Plimack, N.M. Hahn, R. de Wit, L. Pang, M.J. Savage, R. Perini, S. Keefe, D. Bajorin. Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: Preliminary results from the phase 2 KEYNOTE-052 study. Ann Oncol (2016) 27 (suppl_6): LBA32_PR. [https://academic.oup.com/annonc/article-abstract/27/suppl_6/LBA32_PR/2800534/Pembrolizumab-pembro-as-first-line-therapy-for?redirectedFrom=fulltext link to abstract] --><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://www.ncbi.nlm.nih.gov/pubmed/28967485 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Placebo==<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2015.66.3468 Powles et al. 2016 (LaMB)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Lapatinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''No active antineoplastic treatment.''<br />
===References===<br />
<br />
#'''LaMB:''' Powles T, Huddart RA, Elliott T, Sarker SJ, Ackerman C, Jones R, Hussain S, Crabb S, Jagdev S, Chester J, Hilman S, Beresford M, Macdonald G, Santhanam S, Frew JA, Stockdale A, Hughes S, Berney D, Chowdhury S. Phase III, double-blind, randomized trial that compared maintenance lapatinib versus placebo after first-line chemotherapy in patients with human epidermal growth factor receptor 1/2-positive metastatic bladder cancer. J Clin Oncol. 2017 Jan;35(1):48-55. Epub 2016 Oct 28. [https://ascopubs.org/doi/full/10.1200/JCO.2015.66.3468 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28034079 PubMed]<br />
<br />
=Locally advanced or metastatic disease, subsequent lines=<br />
==Atezolizumab monotherapy {{#subobject:451e68|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:feb2e2|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/nature13904 Powles et al. 2014]<br />
| style="background-color:#ffffbe" |Phase 1<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00561-4/fulltext Rosenberg et al. 2016 (IMvigor210)]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#88419d; color:white" |ORR: 15% (95% CI 11-20)<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ood)<br />
|1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. [[#Paclitaxel_monotherapy|Paclitaxel]]<br> 3. [[#Vinflunine_monotherapy|Vinflunine]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|2015-2016<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Patients are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 5% of the tumor area), as determined by an FDA-approved test<br />
<br />
Patients are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status<br />
<br />
''Note: this regimen did not meet its primary endpoint in phase III; here for historical reference only.''<br />
====Immunotherapy====<br />
<br />
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Phase 1:''' Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, Teng SL, Shen X, Boyd Z, Hegde PS, Chen DS, Vogelzang NJ. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014 Nov 27;515(7528):558-62. [https://www.nature.com/articles/nature13904 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25428503 PubMed]<br />
#'''IMvigor210:''' Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016 May 7;387(10031):1909-20. Epub 2016 Mar 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00561-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480242/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26952546 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://www.ncbi.nlm.nih.gov/pubmed/29268948 PubMed]<br />
<br />
==Avelumab monotherapy {{#subobject:6C1497|Regimen=1}}==<br />
{{#subobject:D9FB6C|Variant=1}}<br />
{{:Avelumab (Bavencio) for metastatic bladder cancer}}<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: 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%" |Years of study<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2008.20.5534 Bellmunt et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Vinflunine_monotherapy|Vinflunine]]<br />
| style="background-color:#d73027" |Inferior OS (*)<br />
|2003-2006<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Reported efficacy is based on the 2013 update.''<br />
===References===<br />
<br />
#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://ascopubs.org/doi/full/10.1200/JCO.2008.20.5534 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19687335 PubMed]<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://academic.oup.com/annonc/article/24/6/1466/178781 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23419284 PubMed]<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" 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%" |Years of study<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.5.1853 McCaffrey et al. 1997]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ Choueiri et al. 2012 (DFCI 06-116)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Docetaxel & Vandetanib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|2007-2010<br />
|-<br />
| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/JCO.2015.65.0218 Petrylak et al. 2016 (JCDC)]<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 />
| rowspan="2" |2011-2014<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 />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy_2|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|2014-2015<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext Petrylak et al. 2017 (RANGE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]<br />
| style="background-color:#d73027" |Inferior PFS (*)<br />
|2015-2017<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<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 />
|2015-2016<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. 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 />
'''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://ascopubs.org/doi/abs/10.1200/JCO.1997.15.5.1853 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/30/5/507.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22184381 PubMed]<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://ascopubs.org/doi/full/10.1200/JCO.2015.65.0218 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26926681 PubMed]<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://www.ncbi.nlm.nih.gov/pubmed/28212060 PubMed]<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 May 3. [Epub ahead of print] [https://academic.oup.com/annonc/article/30/6/970/5485243 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/28916371 PubMed]<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. 2019 Nov 18. [Epub ahead of print] [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30668-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/29268948 PubMed]<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" 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%" |Years of study<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2015.65.0218 Petrylak et al. 2016 (JCDC)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|2011-2014<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext Petrylak et al. 2017 (RANGE)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#1a9850" |Superior PFS (*)<br />
|2015-2017<br />
|-<br />
|}<br />
''Note: 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 />
*[[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://ascopubs.org/doi/full/10.1200/JCO.2015.65.0218 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26926681 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://www.ncbi.nlm.nih.gov/pubmed/28916371 PubMed]<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. 2019 Nov 18. [Epub ahead of print] [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30668-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31753727 PubMed]<br />
<br />
==Durvalumab monotherapy {{#subobject:7ae7fb|Regimen=1}}==<br />
{{#subobject:b2af36|Variant=1}}<br />
{{:Durvalumab (Imfinzi) for metastatic bladder cancer}}<br />
<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: 50%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.TPS4590 Rosenberg et al. 2018 (EV-201)]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
====Chemotherapy====<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 />
===References===<br />
<br />
#'''Abstract:''' EV-201 Study: A single-arm, open-label, multicenter study of enfortumab vedotin for treatment of patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor therapy. Jonathan E. Rosenberg, Elisabeth I. Heath, Peter H. O'Donnell, Noah M. Hahn, Arjun Vasant Balar, Elaina M. Gartner, Amal Melhem-Bertrandt, and Daniel Peter Petrylak. Journal of Clinical Oncology 2018 36:15_suppl, TPS4590-TPS4590 [https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.TPS4590 link to abstract]<br />
<br />
==Erdafitinib monotherapy {{#subobject:dbc30d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<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: 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/NEJMoa1817323 Loriot et al. 2019 (BLC2001)]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
====Biomarker eligibility criteria====<br />
<br />
*Alterations: FGFR3 mutation, FGFR2 fusion, or FGFR3 fusion<br />
<br />
====Chemotherapy====<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://www.ncbi.nlm.nih.gov/pubmed/31340094 PubMed]<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 />
===Variant #1, gemcitabine 2 out of 3 weeks {{#subobject:384057|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/22/2/288/171507 Albers et al. 2010 (AUO AB 20/99)]<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 />
===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 />
|[http://jco.ascopubs.org/content/19/12/3018.long 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. [http://jco.ascopubs.org/content/19/12/3018.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://academic.oup.com/annonc/article/22/2/288/171507 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.nature.com/bjc/journal/v98/n1/full/6604113a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359702/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18087289 PubMed]<br />
<br />
==Nivolumab monotherapy {{#subobject:86b89c|Regimen=1}}==<br />
{{#subobject:beb7fa|Variant=1}}<br />
{{:Nivolumab (Opdivo) for unresectable or metastatic bladder cancer}}<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, q3wks {{#subobject:9fddc0|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#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |Years of study<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy_2|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|2014-2015<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<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 />
|2015-2016<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.''<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===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 />
|[http://jco.ascopubs.org/content/20/4/937.long 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. [http://jco.ascopubs.org/content/20/4/937.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887921/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27284445 PubMed]<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://www.ncbi.nlm.nih.gov/pubmed/28212060 PubMed]<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 May 3. [Epub ahead of print] [https://academic.oup.com/annonc/article/30/6/970/5485243 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/29268948 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://www.ncbi.nlm.nih.gov/pubmed/23706985 PubMed]<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" 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%" |Years of study<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|Investigator's choice of:<br> [[#Docetaxel_monotherapy|Docetaxel]]<br> [[#Paclitaxel_monotherapy|Paclitaxel]]<br> [[#Vinflunine_monotherapy|Vinflunine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|2014-2015<br />
|-<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://www.ncbi.nlm.nih.gov/pubmed/28212060 PubMed]<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 May 3. [Epub ahead of print] [https://academic.oup.com/annonc/article/30/6/970/5485243 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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 />
|[http://jco.ascopubs.org/content/24/21/3451.long 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. [http://jco.ascopubs.org/content/24/21/3451.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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" 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%" |Years of study<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2008.20.5534 Bellmunt et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|2003-2006<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy_2|Pembrolizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|2014-2015<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]<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 />
|2015-2016<br />
|-<br />
|}<br />
''Note: reported efficacy for Bellmunt et al. 2009 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 />
#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://ascopubs.org/doi/full/10.1200/JCO.2008.20.5534 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19687335 PubMed]<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://academic.oup.com/annonc/article/24/6/1466/178781 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/28212060 PubMed]<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 May 3. [Epub ahead of print] [https://academic.oup.com/annonc/article/30/6/970/5485243 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/29268948 PubMed]<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://www.ncbi.nlm.nih.gov/pubmed/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>Dweeraratnehttps://hemonc.org/w/index.php?title=Pancreatic_cancer,_BRCA-mutated&diff=41886Pancreatic cancer, BRCA-mutated2020-01-09T00:01:07Z<p>Dweeraratne: /* Regimen #subobject:3ab86a */</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:C Schwartz.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Candiceschwartz|Candice Schwartz, MD]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br />
| style="background-color:#F0F0F0; width:15%" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>University of Illinois at Chicago<br>Chicago, IL</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 />
<big>'''Note: this page has regimens which are specific to pancreatic cancer that is BRCA-mutated. Please see the [[Pancreatic cancer|main pancreatic cancer]] page for other chemotherapy regimens.'''</big><br />
{{TOC limit|limit=3}}<br />
<br />
=Maintenance after first-line therapy=<br />
<br />
==Olaparib monotherapy {{#subobject:388hc7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:3ab86a|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%" |[[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/PMC6810605/ Golan et al. 2019 (POLO)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Germline BRCA1, BRCA2 mutation<br />
<br />
''Selected inclusion criteria: germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy.''<br />
====Preceding treatment====<br />
<br />
*Platinum-based chemotherapy for at least 16 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Olaparib (Lynparza)]] 300 mg PO twice per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''POLO:''' Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, Park JO, Hochhauser D, Arnold D, Oh DY, Reinacher-Schick A, Tortora G, Algül H, O'Reilly EM, McGuinness D, Cui KY, Schlienger K, Locker GY, Kindler HL. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019 Jul 25;381(4):317-327. Epub 2019 Jun 2. [https://www.nejm.org/doi/full/10.1056/NEJMoa1903387 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810605/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/31157963 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" 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/PMC6810605/ Golan et al. 2019 (POLO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Olaparib_monotherapy|Olaparib]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Platinum-based chemotherapy for at least 16 weeks<br />
<br />
===References===<br />
<br />
#'''POLO:''' Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, Park JO, Hochhauser D, Arnold D, Oh DY, Reinacher-Schick A, Tortora G, Algül H, O'Reilly EM, McGuinness D, Cui KY, Schlienger K, Locker GY, Kindler HL. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019 Jul 25;381(4):317-327. Epub 2019 Jun 2. [https://www.nejm.org/doi/full/10.1056/NEJMoa1903387 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810605/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/31157963 PubMed]<br />
<br />
=Metastatic disease, refractory=<br />
==Olaparib monotherapy {{#subobject:0c2eb3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:21eb78|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/33/3/244.long Kaufman et al. 2014 (Study 42)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients had germline BRCA1/2 mutations.''<br />
====Preceding treatment====<br />
<br />
*Gemcitabine, with progression<br />
<br />
====Chemotherapy====<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. [http://jco.ascopubs.org/content/33/3/244.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed]<br />
<br />
=Additional resources=<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
*[https://oncomx.org/searchview/?gene=BRCA1 OncoMX -- BRCA1]<br />
*[https://oncomx.org/searchview/?gene=BRCA2 OncoMX -- BRCA2]<br />
<br />
[[Category:Pancreatic cancer regimens]]<br />
[[Category:Biomarker-specific pages]]<br />
[[Category:Solid tumors]]</div>Dweeraratnehttps://hemonc.org/w/index.php?title=Gastrointestinal_stromal_tumor&diff=41870Gastrointestinal stromal tumor2020-01-08T23:52:58Z<p>Dweeraratne: /* Variant #2, 2 years of treatment #subobject:3c163c */</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:Eric Marks Headshot.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Emarks|Eric Marks, MD]]<br>Brown University<br>Providence, RI</big><br><br />
| style="background-color:#F0F0F0" |[[File:Elizabethdavis2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Elizabethdavis|Elizabeth J. Davis, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/ejdavis25 ejdavis25]<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 />
<br />
=Guidelines=<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2014:''' [http://annonc.oxfordjournals.org/content/25/suppl_3/iii21.full.pdf+html Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/25210085 PubMed]<br />
<br />
==ESMO/EURACAN==<br />
<br />
*'''2018:''' Casali et al. [https://www.esmo.org/Guidelines/Sarcoma-and-GIST/Gastrointestinal-Stromal-Tumours Gastrointestinal stromal tumours: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf NCCN Guidelines - Soft Tissue Sarcoma]<br />
<br />
=Neoadjuvant therapy=<br />
==Imatinib monotherapy {{#subobject:abb5dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3b663c|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/PMC2606912/ Eisenberg et al. 2009 (RTOG 0132)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Kit (CD117) positive <br />
<br />
====Chemotherapy====<br />
<br />
*[[Imatinib (Gleevec)]] 600 mg PO once per day<br />
<br />
'''28-day cycle for 2 to 3 cycles; stopped on the day prior to surgery'''<br />
<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Surgical_resection|Surgery]], then [[#Imatinib_monotherapy_2|imatinib]] x 2 y, resumed as soon as possible postoperatively<br />
<br />
===References===<br />
<br />
#'''RTOG 0132:''' Eisenberg BL, Harris J, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol. 2009 Jan 1;99(1):42-7. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2606912/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18942073 PubMed]<br />
##'''Update:''' Wang D, Zhang Q, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M, Eisenberg BL. Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: long-term follow-up results of Radiation Therapy Oncology Group 0132. Ann Surg Oncol. 2012 Apr;19(4):1074-80. Epub 2011 Dec 28. Erratum in: Ann Surg Oncol. 2012 Jul;19(7):2420. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800166/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22203182 PubMed]<br />
<br />
=Adjuvant therapy=<br />
==Imatinib monotherapy {{#subobject:32bd51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 12 months of treatment {{#subobject:90c752|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%" |[[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/PMC2915459/ Dematteo et al. 2009 (ACOSOG Z9001)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior RFS<br />
|-<br />
|[http://jama.jamanetwork.com/article.aspx?articleid=1105116 Joensuu et al. 2012 (SSG XVIII/AIO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Imatinib_monotherapy_2|Imatinib]] x 36 mos<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Kit (CD117) positive <br />
<br />
''Treatment is started within 12 weeks after surgery. While this is the FDA-recommended dose, it is noted that the optimal treatment duration is unknown.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Surgical_resection|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Imatinib (Gleevec)]] 400 mg PO once per day<br />
<br />
'''12-month course'''<br />
<br />
===Variant #2, 2 years of treatment {{#subobject:3c163c|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/PMC2606912/ Eisenberg et al. 2009 (RTOG 0132)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Kit (CD117) positive <br />
====Preceding treatment====<br />
<br />
*[[#Imatinib_monotherapy|Neoadjuvant imatinib]], then [[Surgery#Surgical_resection|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Imatinib (Gleevec)]] 600 mg PO once per day<br />
<br />
'''2-year course'''<br />
<br />
===Variant #3, 3 years of treatment {{#subobject:238c82|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%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jama.jamanetwork.com/article.aspx?articleid=1105116 Joensuu et al. 2012 (SSG XVIII/AIO)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Imatinib_monotherapy_2|Imatinib]] x 12 mos<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Kit (CD117) positive <br />
<br />
''Treatment is to be started within 12 weeks after surgery. While this is the FDA-recommended dose, it is noted that the optimal treatment duration is unknown.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Surgical_resection|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Imatinib (Gleevec)]] 400 mg PO once per day<br />
<br />
'''36-month course'''<br />
<br />
===References===<br />
<br />
#'''RTOG 0132:''' Eisenberg BL, Harris J, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol. 2009 Jan 1;99(1):42-7. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2606912/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18942073 PubMed]<br />
##'''Update:''' Wang D, Zhang Q, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M, Eisenberg BL. Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: long-term follow-up results of Radiation Therapy Oncology Group 0132. Ann Surg Oncol. 2012 Apr;19(4):1074-80. Epub 2011 Dec 28. Erratum in: Ann Surg Oncol. 2012 Jul;19(7):2420. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800166/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22203182 PubMed]<br />
#'''ACOSOG Z9001:''' Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF, Patel S, McCarter MD, Polikoff JA, Tan BR, Owzar K; American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Mar 28;373(9669):1097-104. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2915459/ link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2915459/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19303137 PubMed]<br />
#'''SSG XVIII/AIO:''' Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, Ramadori G, Hohenberger P, Duyster J, Al-Batran SE, Schlemmer M, Bauer S, Wardelmann E, Sarlomo-Rikala M, Nilsson B, Sihto H, Monge OR, Bono P, Kallio R, Vehtari A, Leinonen M, Alvegård T, Reichardt P. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012 Mar 28;307(12):1265-72. [http://jama.jamanetwork.com/article.aspx?articleid=1105116 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22453568 PubMed]<br />
##'''Update:''' Joensuu H, Eriksson M, Sundby Hall K, Reichardt A, Hartmann JT, Pink D, Ramadori G, Hohenberger P, Al-Batran SE, Schlemmer M, Bauer S, Wardelmann E, Nilsson B, Sihto H, Bono P, Kallio R, Junnila J, Alvegård T, Reichardt P. Adjuvant imatinib for high-risk GI stromal tumor: analysis of a randomized trial. J Clin Oncol. 2016 Jan 20;34(3):244-50. Epub 2015 Nov 2. [https://ascopubs.org/doi/full/10.1200/JCO.2015.62.9170 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26527782 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" 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/PMC2915459/ Dematteo et al. 2009 (ACOSOG Z9001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Imatinib_monotherapy_2|Imatinib]] x 12 mos<br />
| style="background-color:#d73027" |Inferior RFS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Surgical_resection|Surgery]]<br />
<br />
===References===<br />
<br />
#'''ACOSOG Z9001:''' Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF, Patel S, McCarter MD, Polikoff JA, Tan BR, Owzar K; American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Mar 28;373(9669):1097-104. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2915459/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19303137 PubMed]<br />
<br />
=Metastatic or unresectable disease=<br />
==Best supportive care==<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/23/7/1680/202540 Reichardt et al. 2012 (ENEST g3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Nilotinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00075-9/fulltext Mir et al. 2016 (PAZOGIST)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Pazopanib_monotherapy|Pazopanib]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|}<br />
''No active treatment. Used as a comparator arm and here for reference purposes only.''<br />
<br />
===References===<br />
<br />
#'''ENEST g3:''' Reichardt P, Blay JY, Gelderblom H, Schlemmer M, Demetri GD, Bui-Nguyen B, McArthur GA, Yazji S, Hsu Y, Galetic I, Rutkowski P. Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol. 2012 Jul;23(7):1680-7. Epub 2012 Feb 21. [https://academic.oup.com/annonc/article/23/7/1680/202540 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22357255 PubMed]<br />
#'''PAZOGIST:''' Mir O, Cropet C, Toulmonde M, Cesne AL, Molimard M, Bompas E, Cassier P, Ray-Coquard I, Rios M, Adenis A, Italiano A, Bouché O, Chauzit E, Duffaud F, Bertucci F, Isambert N, Gautier J, Blay JY, Pérol D; PAZOGIST study group of the French Sarcoma Groupe-Groupe d'Etude des Tumeurs Osseuses (GSF-GETO). Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial. Lancet Oncol. 2016 May;17(5):632-41. Epub 2016 Apr 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00075-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27068858 PubMed]<br />
<br />
==Imatinib monotherapy {{#subobject:16a4ba|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, standard-dose (400 mg/day) {{#subobject:58de4b|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%" |[[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/NEJMoa020461 Demetri et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Imatinib_monotherapy_3|Imatinib]]; higher-dose (600 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(04)17098-0/fulltext Verweij et al. 2004 (EORTC 62005)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Imatinib_monotherapy_3|Imatinib]]; high-dose<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS (*)<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2006.09.0183 Blay et al. 2007 (BFR14)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Imatinib_monotherapy_3|Imatinib]]; 1 year<br> 2. [[#Imatinib_monotherapy_3|Imatinib]]; 3 years<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347867/ Kang et al. 2013 (RIGHT)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Placebo_2|Placebo]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521211/ Blay et al. 2015 (ENESTg1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Nilotinib<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679092/ Blanke et al. 2015 (SWOG S0502)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Bevacizumab & Imatinib<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: Efficacy reported for EORTC 62005 is based on the 2017 update. BFR14 had two separate comparisons, to one year and to three years of imatinib versus continuous (this arm); the efficacy outcome was the same in both reports.''<br />
====Chemotherapy====<br />
<br />
*[[Imatinib (Gleevec)]] 400 mg PO once per day, taken with food<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, higher-dose (600 mg/day) {{#subobject:304d2f|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa020461 Demetri et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Imatinib_monotherapy_3|Imatinib]]; standard-dose (400 mg/day)<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Imatinib (Gleevec)]] 600 mg PO once per day, taken with food<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, high-dose (800 mg/day) {{#subobject:4e83a6|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0140673601065357 Van Oosterom et al. 2001]<br />
| style="background-color:#ffffbe" |Phase 1, <20 pts in this cohort<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049%2802%2900836-5/abstract Verweij et al. 2003]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(04)17098-0/fulltext Verweij et al. 2004 (EORTC 62005)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Imatinib_monotherapy_3|Imatinib]]; standard-dose<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS (*)<br />
|-<br />
|[http://jco.ascopubs.org/content/26/4/626.long Blanke et al. 2008 (SWOG S0033)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Imatinib_monotherapy_3|Imatinib]]; standard-dose with pre-planned dose-escalation at progression<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521211/ Blay et al. 2015 (ENESTg1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Nilotinib<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679092/ Blanke et al. 2015 (SWOG S0502)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Bevacizumab & Imatinib<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: this was the MTD in Van Oosterom et al. 2001. In some studies, high-dose imatinib was offered to patients with KIT exon 9 mutations in ENESTg1 and SWOG S0502; all other patients received standard-dose imatinib. Efficacy reported for EORTC 62005 is based on the 2017 update.''<br />
====Chemotherapy====<br />
<br />
*[[Imatinib (Gleevec)]] 400 mg PO twice a day, taken after a meal<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #4, standard-dose with pre-planned dose-escalation at progression {{#subobject:854522|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/26/4/626.long Blanke et al. 2008 (SWOG S0033)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Imatinib_monotherapy_3|Imatinib]]; high-dose (800 mg/day)<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS<br />
|-<br />
|}<br />
====Chemotherapy, standard-dose====<br />
<br />
*[[Imatinib (Gleevec)]] 400 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
''Patients who progressed could receive high-dose therapy, as follows:''<br />
<br />
====Chemotherapy, high-dose====<br />
<br />
*[[Imatinib (Gleevec)]] 400 mg PO twice per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''Phase 1:''' van Oosterom AT, Judson I, Verweij J, Stroobants S, Donato di Paola E, Dimitrijevic S, Martens M, Webb A, Sciot R, Van Glabbeke M, Silberman S, Nielsen OS; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet. 2001 Oct 27;358(9291):1421-3. [https://www.sciencedirect.com/science/article/pii/S0140673601065357 link to SD article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11705489 PubMed]<br />
#Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002 Aug 15;347(7):472-80. [https://www.nejm.org/doi/full/10.1056/NEJMoa020461 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12181401 PubMed]<br />
#Verweij J, van Oosterom A, Blay JY, Judson I, Rodenhuis S, van der Graaf W, Radford J, Le Cesne A, Hogendoorn PC, di Paola ED, Brown M, Nielsen OS. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target: results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer. 2003 Sep;39(14):2006-11. [https://www.ejcancer.com/article/S0959-8049%2802%2900836-5/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12957454 PubMed]<br />
#'''EORTC 62005:''' Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, Issels R, van Oosterom A, Hogendoorn PC, Van Glabbeke M, Bertulli R, Judson I. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004 Sep 25-Oct 1;364(9440):1127-34. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(04)17098-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15451219 PubMed]<br />
##'''Update:''' Zalcberg JR, Verweij J, Casali PG, Le Cesne A, Reichardt P, Blay JY, Schlemmer M, Van Glabbeke M, Brown M, Judson IR; EORTC Soft Tissue and Bone Sarcoma Group; Italian Sarcoma Group; Australasian Gastrointestinal Trials Group. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer. 2005 Aug;41(12):1751-7. [https://www.ejcancer.com/article/S0959-8049(05)00440-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16098458 PubMed]<br />
##'''Update:''' Casali PG, Zalcberg J, Le Cesne A, Reichardt P, Blay JY, Lindner LH, Judson IR, Schöffski P, Leyvraz S, Italiano A, Grünwald V, Pousa AL, Kotasek D, Sleijfer S, Kerst JM, Rutkowski P, Fumagalli E, Hogendoorn P, Litière S, Marreaud S, van der Graaf W, Gronchi A, Verweij J; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group and Italian Sarcoma Group and Australasian Gastrointestinal Trials Group. Ten-year progression-free and overall survival in patients with unresectable or metastatic GI stromal tumors: long-term analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group intergroup phase III randomized trial on imatinib at two dose levels. J Clin Oncol. 2017 May 20;35(15):1713-1720. Epub 2017 Mar 31. [https://ascopubs.org/doi/full/10.1200/JCO.2016.71.0228 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28362562 PubMed]<br />
#'''BFR14:''' Blay JY, Le Cesne A, Ray-Coquard I, Bui B, Duffaud F, Delbaldo C, Adenis A, Viens P, Rios M, Bompas E, Cupissol D, Guillemet C, Kerbrat P, Fayette J, Chabaud S, Berthaud P, Perol D. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol. 2007 Mar 20;25(9):1107-13. [https://ascopubs.org/doi/full/10.1200/JCO.2006.09.0183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17369574 PubMed]<br />
##'''Update:''' Le Cesne A, Ray-Coquard I, Bui BN, Adenis A, Rios M, Bertucci F, Duffaud F, Chevreau C, Cupissol D, Cioffi A, Emile JF, Chabaud S, Pérol D, Blay JY; French Sarcoma Group. Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial. Lancet Oncol. 2010 Oct;11(10):942-9. Epub 2010 Sep 21. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70222-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20864406 PubMed]<br />
#'''SWOG S0033:''' Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, Raymond AK, Bramwell VH, Baker LH, Maki RG, Tanaka M, Hecht JR, Heinrich MC, Fletcher CD, Crowley JJ, Borden EC. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008 Feb 1;26(4):626-32. [http://jco.ascopubs.org/content/26/4/626.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18235122 PubMed]<br />
#'''Meta-analysis:''' Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol. 2010 Mar 1;28(7):1247-53. Epub 2010 Feb 1. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834472/ link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834472/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20124181 PubMed]<br />
#'''RIGHT:''' Kang YK, Ryu MH, Yoo C, Ryoo BY, Kim HJ, Lee JJ, Nam BH, Ramaiya N, Jagannathan J, Demetri GD. Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1175-82. Epub 2013 Oct 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70453-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347867/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24140183 PubMed]<br />
#'''ENESTg1:''' Blay JY, Shen L, Kang YK, Rutkowski P, Qin S, Nosov D, Wan D, Trent J, Srimuninnimit V, Pápai Z, Le Cesne A, Novick S, Taningco L, Mo S, Green S, Reichardt P, Demetri GD. Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial. Lancet Oncol. 2015 May;16(5):550-60. Epub 2015 Apr 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70105-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521211/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25882987 PubMed]<br />
#'''SWOG S0502:''' Blanke CD, Rankin C, Corless C, Eary JF, Mulder K, Okuno SH, George S, Heinrich M. S0502: A SWOG phase III randomized study of imatinib, with or without bevacizumab, in patients with untreated metastatic or unresectable gastrointestinal stromal tumors. Oncologist. 2015 Dec;20(12):1353-4. Epub 2015 Nov 17. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679092/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26576593 PubMed]<br />
<br />
==Pazopanib monotherapy {{#subobject:cfbaff|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:1debcd|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00075-9/fulltext Mir et al. 2016 (PAZOGIST)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Pazopanib (Votrient)]] 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#Mir O, Cropet C, Toulmonde M, Cesne AL, Molimard M, Bompas E, Cassier P, Ray-Coquard I, Rios M, Adenis A, Italiano A, Bouché O, Chauzit E, Duffaud F, Bertucci F, Isambert N, Gautier J, Blay JY, Pérol D; PAZOGIST study group of the French Sarcoma Groupe-Groupe d'Etude des Tumeurs Osseuses (GSF-GETO). Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial. Lancet Oncol. 2016 May;17(5):632-41. Epub 2016 Apr 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00075-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27068858 PubMed]<br />
<br />
==Placebo==<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(06)69446-4/abstract Demetri et al. 2006 (A6181004)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Sunitinib_monotherapy|Sunitinib]]<br />
| style="background-color:#d73027" |Inferior TTP<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819942/ Demetri et al. 2012 (GRID)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Regorafenib_monotherapy|Regorafenib]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347867/ Kang et al. 2013 (RIGHT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Imatinib_monotherapy_3|Imatinib]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.''<br />
<br />
===References===<br />
<br />
#'''A6181004:''' Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006 Oct 14;368(9544):1329-38. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(06)69446-4/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17046465 PubMed]<br />
##'''Update:''' Demetri GD, Garrett CR, Schöffski P, Shah MH, Verweij J, Leyvraz S, Hurwitz HI, Pousa AL, Le Cesne A, Goldstein D, Paz-Ares L, Blay JY, McArthur GA, Xu QC, Huang X, Harmon CS, Tassell V, Cohen DP, Casali PG. Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure. Clin Cancer Res. 2012 Jun 1;18(11):3170-9. [https://clincancerres.aacrjournals.org/content/18/11/3170.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030710/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22661587 PubMed]<br />
#'''GRID:''' Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, Leahy M, von Mehren M, Joensuu H, Badalamenti G, Blackstein M, Le Cesne A, Schöffski P, Maki RG, Bauer S, Nguyen BB, Xu J, Nishida T, Chung J, Kappeler C, Kuss I, Laurent D, Casali PG; GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):295-302. Epub 2012 Nov 22. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819942/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23177515 PubMed]<br />
#'''RIGHT:''' Kang YK, Ryu MH, Yoo C, Ryoo BY, Kim HJ, Lee JJ, Nam BH, Ramaiya N, Jagannathan J, Demetri GD. Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1175-82. Epub 2013 Oct 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70453-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347867/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24140183 PubMed]<br />
<br />
==Regorafenib monotherapy {{#subobject:bd09ce|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:6dcadc|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819942/ Demetri et al. 2012 (GRID)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Placebo_2|Placebo]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
''Patients in this study already had treatment failure with imatinib and sunitinib.''<br />
====Chemotherapy====<br />
<br />
*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''GRID:''' Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, Leahy M, von Mehren M, Joensuu H, Badalamenti G, Blackstein M, Le Cesne A, Schöffski P, Maki RG, Bauer S, Nguyen BB, Xu J, Nishida T, Chung J, Kappeler C, Kuss I, Laurent D, Casali PG; GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):295-302. Epub 2012 Nov 22. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819942/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23177515 PubMed]<br />
<br />
==Sorafenib monotherapy {{#subobject:ec8ga1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:381ibg3|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/abs/10.1200/jco.2011.29.15_suppl.10009 Kindler et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://doi.org/10.1007/s10637-012-9795-9 Park et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
<br />
*[[Sorafenib (Nexavar)]] 400mg PO BID<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''Abstract:''' Kindler HL, Campbell NP, Wroblewski K, Maki RG, D’Adamo DR, Chow WA, Gandara DR, Antonescu C, Stadler WM, Vokes EE. Sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST): Final results of a University of Chicago Phase II Consortium trial. 2011. 29 (15_suppl) 10009-10009. [https://ascopubs.org/doi/abs/10.1200/jco.2011.29.15_suppl.10009 link to original article (abstract only)]<br />
#Park SH, Ryu MH, Ryoo BY, Im SA, Kwon HC, Lee SS, Park SR, Kang BY, Kang YK. Sorafenib in patients with metastatic gastrointestinal stromal tumors who failed two or more prior tyrosine kinase inhibitors: a phase II study of Korean gastrointestinal stromal tumors study group. Invest New Drugs. 2012 Dec; 30(6) 2377-83. Epub 2012 Jan 25.[https://doi.org/10.1007/s10637-012-9795-9 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22270258 PubMed]<br />
<br />
==Sunitinib monotherapy {{#subobject:ec3261|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:38e8e3|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(06)69446-4/abstract Demetri et al. 2006 (A6181004)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Placebo_2|Placebo]]<br />
| style="background-color:#1a9850" |Superior TTP<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143095/ Adenis et al. 2014]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Masitinib<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Patients had treatment failure with imatinib.''<br />
====Chemotherapy====<br />
<br />
*[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 28<br />
**Dose may be decreased to 37.5 mg or 25 mg depending on tolerability<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<br />
#'''A6181004:''' Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006 Oct 14;368(9544):1329-38. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(06)69446-4/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17046465 PubMed]<br />
##'''Update:''' Demetri GD, Garrett CR, Schöffski P, Shah MH, Verweij J, Leyvraz S, Hurwitz HI, Pousa AL, Le Cesne A, Goldstein D, Paz-Ares L, Blay JY, McArthur GA, Xu QC, Huang X, Harmon CS, Tassell V, Cohen DP, Casali PG. Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure. Clin Cancer Res. 2012 Jun 1;18(11):3170-9. [https://clincancerres.aacrjournals.org/content/18/11/3170.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030710/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22661587 PubMed]<br />
#Adenis A, Blay JY, Bui-Nguyen B, Bouché O, Bertucci F, Isambert N, Bompas E, Chaigneau L, Domont J, Ray-Coquard I, Blésius A, Van Tine BA, Bulusu VR, Dubreuil P, Mansfield CD, Acin Y, Moussy A, Hermine O, Le Cesne A. Masitinib in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib: a randomized controlled open-label trial. Ann Oncol. 2014 Sep;25(9):1762-9. Epub 2014 Jul 25. [https://academic.oup.com/annonc/article/25/9/1762/2801236 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143095/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25122671 PubMed]<br />
<br />
[[Category:Gastrointestinal stromal tumor regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Soft tissue sarcomas]]<br />
[[Category:Gastrointestinal cancers]]</div>Dweeraratnehttps://hemonc.org/w/index.php?title=Gastrointestinal_stromal_tumor&diff=41862Gastrointestinal stromal tumor2020-01-08T23:51:01Z<p>Dweeraratne: /* Regimen #subobject:3b663c */</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:Eric Marks Headshot.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Emarks|Eric Marks, MD]]<br>Brown University<br>Providence, RI</big><br><br />
| style="background-color:#F0F0F0" |[[File:Elizabethdavis2.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Elizabethdavis|Elizabeth J. Davis, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/ejdavis25 ejdavis25]<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 />
<br />
=Guidelines=<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2014:''' [http://annonc.oxfordjournals.org/content/25/suppl_3/iii21.full.pdf+html Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/25210085 PubMed]<br />
<br />
==ESMO/EURACAN==<br />
<br />
*'''2018:''' Casali et al. [https://www.esmo.org/Guidelines/Sarcoma-and-GIST/Gastrointestinal-Stromal-Tumours Gastrointestinal stromal tumours: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf NCCN Guidelines - Soft Tissue Sarcoma]<br />
<br />
=Neoadjuvant therapy=<br />
==Imatinib monotherapy {{#subobject:abb5dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3b663c|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/PMC2606912/ Eisenberg et al. 2009 (RTOG 0132)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Kit (CD117) positive <br />
<br />
====Chemotherapy====<br />
<br />
*[[Imatinib (Gleevec)]] 600 mg PO once per day<br />
<br />
'''28-day cycle for 2 to 3 cycles; stopped on the day prior to surgery'''<br />
<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Surgical_resection|Surgery]], then [[#Imatinib_monotherapy_2|imatinib]] x 2 y, resumed as soon as possible postoperatively<br />
<br />
===References===<br />
<br />
#'''RTOG 0132:''' Eisenberg BL, Harris J, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol. 2009 Jan 1;99(1):42-7. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2606912/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18942073 PubMed]<br />
##'''Update:''' Wang D, Zhang Q, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M, Eisenberg BL. Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: long-term follow-up results of Radiation Therapy Oncology Group 0132. Ann Surg Oncol. 2012 Apr;19(4):1074-80. Epub 2011 Dec 28. Erratum in: Ann Surg Oncol. 2012 Jul;19(7):2420. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800166/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22203182 PubMed]<br />
<br />
=Adjuvant therapy=<br />
==Imatinib monotherapy {{#subobject:32bd51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 12 months of treatment {{#subobject:90c752|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%" |[[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/PMC2915459/ Dematteo et al. 2009 (ACOSOG Z9001)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior RFS<br />
|-<br />
|[http://jama.jamanetwork.com/article.aspx?articleid=1105116 Joensuu et al. 2012 (SSG XVIII/AIO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Imatinib_monotherapy_2|Imatinib]] x 36 mos<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Kit (CD117) positive <br />
<br />
''Treatment is started within 12 weeks after surgery. While this is the FDA-recommended dose, it is noted that the optimal treatment duration is unknown.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Surgical_resection|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Imatinib (Gleevec)]] 400 mg PO once per day<br />
<br />
'''12-month course'''<br />
<br />
===Variant #2, 2 years of treatment {{#subobject:3c163c|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/PMC2606912/ Eisenberg et al. 2009 (RTOG 0132)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Imatinib_monotherapy|Neoadjuvant imatinib]], then [[Surgery#Surgical_resection|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Imatinib (Gleevec)]] 600 mg PO once per day<br />
<br />
'''2-year course'''<br />
<br />
===Variant #3, 3 years of treatment {{#subobject:238c82|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%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jama.jamanetwork.com/article.aspx?articleid=1105116 Joensuu et al. 2012 (SSG XVIII/AIO)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Imatinib_monotherapy_2|Imatinib]] x 12 mos<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Treatment is to be started within 12 weeks after surgery. While this is the FDA-recommended dose, it is noted that the optimal treatment duration is unknown.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Surgical_resection|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Imatinib (Gleevec)]] 400 mg PO once per day<br />
<br />
'''36-month course'''<br />
<br />
===References===<br />
<br />
#'''RTOG 0132:''' Eisenberg BL, Harris J, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol. 2009 Jan 1;99(1):42-7. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2606912/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18942073 PubMed]<br />
##'''Update:''' Wang D, Zhang Q, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M, Eisenberg BL. Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: long-term follow-up results of Radiation Therapy Oncology Group 0132. Ann Surg Oncol. 2012 Apr;19(4):1074-80. Epub 2011 Dec 28. Erratum in: Ann Surg Oncol. 2012 Jul;19(7):2420. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800166/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22203182 PubMed]<br />
#'''ACOSOG Z9001:''' Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF, Patel S, McCarter MD, Polikoff JA, Tan BR, Owzar K; American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Mar 28;373(9669):1097-104. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2915459/ link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2915459/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19303137 PubMed]<br />
#'''SSG XVIII/AIO:''' Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, Ramadori G, Hohenberger P, Duyster J, Al-Batran SE, Schlemmer M, Bauer S, Wardelmann E, Sarlomo-Rikala M, Nilsson B, Sihto H, Monge OR, Bono P, Kallio R, Vehtari A, Leinonen M, Alvegård T, Reichardt P. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012 Mar 28;307(12):1265-72. [http://jama.jamanetwork.com/article.aspx?articleid=1105116 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22453568 PubMed]<br />
##'''Update:''' Joensuu H, Eriksson M, Sundby Hall K, Reichardt A, Hartmann JT, Pink D, Ramadori G, Hohenberger P, Al-Batran SE, Schlemmer M, Bauer S, Wardelmann E, Nilsson B, Sihto H, Bono P, Kallio R, Junnila J, Alvegård T, Reichardt P. Adjuvant imatinib for high-risk GI stromal tumor: analysis of a randomized trial. J Clin Oncol. 2016 Jan 20;34(3):244-50. Epub 2015 Nov 2. [https://ascopubs.org/doi/full/10.1200/JCO.2015.62.9170 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26527782 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" 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/PMC2915459/ Dematteo et al. 2009 (ACOSOG Z9001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Imatinib_monotherapy_2|Imatinib]] x 12 mos<br />
| style="background-color:#d73027" |Inferior RFS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Surgical_resection|Surgery]]<br />
<br />
===References===<br />
<br />
#'''ACOSOG Z9001:''' Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF, Patel S, McCarter MD, Polikoff JA, Tan BR, Owzar K; American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Mar 28;373(9669):1097-104. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2915459/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19303137 PubMed]<br />
<br />
=Metastatic or unresectable disease=<br />
==Best supportive care==<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/23/7/1680/202540 Reichardt et al. 2012 (ENEST g3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Nilotinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00075-9/fulltext Mir et al. 2016 (PAZOGIST)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Pazopanib_monotherapy|Pazopanib]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|}<br />
''No active treatment. Used as a comparator arm and here for reference purposes only.''<br />
<br />
===References===<br />
<br />
#'''ENEST g3:''' Reichardt P, Blay JY, Gelderblom H, Schlemmer M, Demetri GD, Bui-Nguyen B, McArthur GA, Yazji S, Hsu Y, Galetic I, Rutkowski P. Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol. 2012 Jul;23(7):1680-7. Epub 2012 Feb 21. [https://academic.oup.com/annonc/article/23/7/1680/202540 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22357255 PubMed]<br />
#'''PAZOGIST:''' Mir O, Cropet C, Toulmonde M, Cesne AL, Molimard M, Bompas E, Cassier P, Ray-Coquard I, Rios M, Adenis A, Italiano A, Bouché O, Chauzit E, Duffaud F, Bertucci F, Isambert N, Gautier J, Blay JY, Pérol D; PAZOGIST study group of the French Sarcoma Groupe-Groupe d'Etude des Tumeurs Osseuses (GSF-GETO). Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial. Lancet Oncol. 2016 May;17(5):632-41. Epub 2016 Apr 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00075-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27068858 PubMed]<br />
<br />
==Imatinib monotherapy {{#subobject:16a4ba|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, standard-dose (400 mg/day) {{#subobject:58de4b|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%" |[[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/NEJMoa020461 Demetri et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Imatinib_monotherapy_3|Imatinib]]; higher-dose (600 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(04)17098-0/fulltext Verweij et al. 2004 (EORTC 62005)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Imatinib_monotherapy_3|Imatinib]]; high-dose<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS (*)<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2006.09.0183 Blay et al. 2007 (BFR14)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Imatinib_monotherapy_3|Imatinib]]; 1 year<br> 2. [[#Imatinib_monotherapy_3|Imatinib]]; 3 years<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347867/ Kang et al. 2013 (RIGHT)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Placebo_2|Placebo]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521211/ Blay et al. 2015 (ENESTg1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Nilotinib<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679092/ Blanke et al. 2015 (SWOG S0502)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Bevacizumab & Imatinib<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: Efficacy reported for EORTC 62005 is based on the 2017 update. BFR14 had two separate comparisons, to one year and to three years of imatinib versus continuous (this arm); the efficacy outcome was the same in both reports.''<br />
====Chemotherapy====<br />
<br />
*[[Imatinib (Gleevec)]] 400 mg PO once per day, taken with food<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, higher-dose (600 mg/day) {{#subobject:304d2f|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa020461 Demetri et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Imatinib_monotherapy_3|Imatinib]]; standard-dose (400 mg/day)<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Imatinib (Gleevec)]] 600 mg PO once per day, taken with food<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, high-dose (800 mg/day) {{#subobject:4e83a6|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0140673601065357 Van Oosterom et al. 2001]<br />
| style="background-color:#ffffbe" |Phase 1, <20 pts in this cohort<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049%2802%2900836-5/abstract Verweij et al. 2003]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(04)17098-0/fulltext Verweij et al. 2004 (EORTC 62005)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Imatinib_monotherapy_3|Imatinib]]; standard-dose<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS (*)<br />
|-<br />
|[http://jco.ascopubs.org/content/26/4/626.long Blanke et al. 2008 (SWOG S0033)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Imatinib_monotherapy_3|Imatinib]]; standard-dose with pre-planned dose-escalation at progression<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521211/ Blay et al. 2015 (ENESTg1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Nilotinib<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679092/ Blanke et al. 2015 (SWOG S0502)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Bevacizumab & Imatinib<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: this was the MTD in Van Oosterom et al. 2001. In some studies, high-dose imatinib was offered to patients with KIT exon 9 mutations in ENESTg1 and SWOG S0502; all other patients received standard-dose imatinib. Efficacy reported for EORTC 62005 is based on the 2017 update.''<br />
====Chemotherapy====<br />
<br />
*[[Imatinib (Gleevec)]] 400 mg PO twice a day, taken after a meal<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #4, standard-dose with pre-planned dose-escalation at progression {{#subobject:854522|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/26/4/626.long Blanke et al. 2008 (SWOG S0033)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Imatinib_monotherapy_3|Imatinib]]; high-dose (800 mg/day)<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS<br />
|-<br />
|}<br />
====Chemotherapy, standard-dose====<br />
<br />
*[[Imatinib (Gleevec)]] 400 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
''Patients who progressed could receive high-dose therapy, as follows:''<br />
<br />
====Chemotherapy, high-dose====<br />
<br />
*[[Imatinib (Gleevec)]] 400 mg PO twice per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''Phase 1:''' van Oosterom AT, Judson I, Verweij J, Stroobants S, Donato di Paola E, Dimitrijevic S, Martens M, Webb A, Sciot R, Van Glabbeke M, Silberman S, Nielsen OS; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet. 2001 Oct 27;358(9291):1421-3. [https://www.sciencedirect.com/science/article/pii/S0140673601065357 link to SD article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11705489 PubMed]<br />
#Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002 Aug 15;347(7):472-80. [https://www.nejm.org/doi/full/10.1056/NEJMoa020461 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12181401 PubMed]<br />
#Verweij J, van Oosterom A, Blay JY, Judson I, Rodenhuis S, van der Graaf W, Radford J, Le Cesne A, Hogendoorn PC, di Paola ED, Brown M, Nielsen OS. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target: results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer. 2003 Sep;39(14):2006-11. [https://www.ejcancer.com/article/S0959-8049%2802%2900836-5/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12957454 PubMed]<br />
#'''EORTC 62005:''' Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, Issels R, van Oosterom A, Hogendoorn PC, Van Glabbeke M, Bertulli R, Judson I. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004 Sep 25-Oct 1;364(9440):1127-34. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(04)17098-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15451219 PubMed]<br />
##'''Update:''' Zalcberg JR, Verweij J, Casali PG, Le Cesne A, Reichardt P, Blay JY, Schlemmer M, Van Glabbeke M, Brown M, Judson IR; EORTC Soft Tissue and Bone Sarcoma Group; Italian Sarcoma Group; Australasian Gastrointestinal Trials Group. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer. 2005 Aug;41(12):1751-7. [https://www.ejcancer.com/article/S0959-8049(05)00440-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16098458 PubMed]<br />
##'''Update:''' Casali PG, Zalcberg J, Le Cesne A, Reichardt P, Blay JY, Lindner LH, Judson IR, Schöffski P, Leyvraz S, Italiano A, Grünwald V, Pousa AL, Kotasek D, Sleijfer S, Kerst JM, Rutkowski P, Fumagalli E, Hogendoorn P, Litière S, Marreaud S, van der Graaf W, Gronchi A, Verweij J; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group and Italian Sarcoma Group and Australasian Gastrointestinal Trials Group. Ten-year progression-free and overall survival in patients with unresectable or metastatic GI stromal tumors: long-term analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group intergroup phase III randomized trial on imatinib at two dose levels. J Clin Oncol. 2017 May 20;35(15):1713-1720. Epub 2017 Mar 31. [https://ascopubs.org/doi/full/10.1200/JCO.2016.71.0228 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28362562 PubMed]<br />
#'''BFR14:''' Blay JY, Le Cesne A, Ray-Coquard I, Bui B, Duffaud F, Delbaldo C, Adenis A, Viens P, Rios M, Bompas E, Cupissol D, Guillemet C, Kerbrat P, Fayette J, Chabaud S, Berthaud P, Perol D. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol. 2007 Mar 20;25(9):1107-13. [https://ascopubs.org/doi/full/10.1200/JCO.2006.09.0183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17369574 PubMed]<br />
##'''Update:''' Le Cesne A, Ray-Coquard I, Bui BN, Adenis A, Rios M, Bertucci F, Duffaud F, Chevreau C, Cupissol D, Cioffi A, Emile JF, Chabaud S, Pérol D, Blay JY; French Sarcoma Group. Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial. Lancet Oncol. 2010 Oct;11(10):942-9. Epub 2010 Sep 21. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70222-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20864406 PubMed]<br />
#'''SWOG S0033:''' Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, Raymond AK, Bramwell VH, Baker LH, Maki RG, Tanaka M, Hecht JR, Heinrich MC, Fletcher CD, Crowley JJ, Borden EC. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008 Feb 1;26(4):626-32. [http://jco.ascopubs.org/content/26/4/626.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18235122 PubMed]<br />
#'''Meta-analysis:''' Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol. 2010 Mar 1;28(7):1247-53. Epub 2010 Feb 1. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834472/ link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834472/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20124181 PubMed]<br />
#'''RIGHT:''' Kang YK, Ryu MH, Yoo C, Ryoo BY, Kim HJ, Lee JJ, Nam BH, Ramaiya N, Jagannathan J, Demetri GD. Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1175-82. Epub 2013 Oct 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70453-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347867/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24140183 PubMed]<br />
#'''ENESTg1:''' Blay JY, Shen L, Kang YK, Rutkowski P, Qin S, Nosov D, Wan D, Trent J, Srimuninnimit V, Pápai Z, Le Cesne A, Novick S, Taningco L, Mo S, Green S, Reichardt P, Demetri GD. Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial. Lancet Oncol. 2015 May;16(5):550-60. Epub 2015 Apr 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70105-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521211/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25882987 PubMed]<br />
#'''SWOG S0502:''' Blanke CD, Rankin C, Corless C, Eary JF, Mulder K, Okuno SH, George S, Heinrich M. S0502: A SWOG phase III randomized study of imatinib, with or without bevacizumab, in patients with untreated metastatic or unresectable gastrointestinal stromal tumors. Oncologist. 2015 Dec;20(12):1353-4. Epub 2015 Nov 17. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679092/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26576593 PubMed]<br />
<br />
==Pazopanib monotherapy {{#subobject:cfbaff|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:1debcd|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00075-9/fulltext Mir et al. 2016 (PAZOGIST)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Pazopanib (Votrient)]] 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#Mir O, Cropet C, Toulmonde M, Cesne AL, Molimard M, Bompas E, Cassier P, Ray-Coquard I, Rios M, Adenis A, Italiano A, Bouché O, Chauzit E, Duffaud F, Bertucci F, Isambert N, Gautier J, Blay JY, Pérol D; PAZOGIST study group of the French Sarcoma Groupe-Groupe d'Etude des Tumeurs Osseuses (GSF-GETO). Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial. Lancet Oncol. 2016 May;17(5):632-41. Epub 2016 Apr 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00075-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27068858 PubMed]<br />
<br />
==Placebo==<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(06)69446-4/abstract Demetri et al. 2006 (A6181004)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Sunitinib_monotherapy|Sunitinib]]<br />
| style="background-color:#d73027" |Inferior TTP<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819942/ Demetri et al. 2012 (GRID)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Regorafenib_monotherapy|Regorafenib]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347867/ Kang et al. 2013 (RIGHT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Imatinib_monotherapy_3|Imatinib]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.''<br />
<br />
===References===<br />
<br />
#'''A6181004:''' Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006 Oct 14;368(9544):1329-38. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(06)69446-4/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17046465 PubMed]<br />
##'''Update:''' Demetri GD, Garrett CR, Schöffski P, Shah MH, Verweij J, Leyvraz S, Hurwitz HI, Pousa AL, Le Cesne A, Goldstein D, Paz-Ares L, Blay JY, McArthur GA, Xu QC, Huang X, Harmon CS, Tassell V, Cohen DP, Casali PG. Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure. Clin Cancer Res. 2012 Jun 1;18(11):3170-9. [https://clincancerres.aacrjournals.org/content/18/11/3170.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030710/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22661587 PubMed]<br />
#'''GRID:''' Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, Leahy M, von Mehren M, Joensuu H, Badalamenti G, Blackstein M, Le Cesne A, Schöffski P, Maki RG, Bauer S, Nguyen BB, Xu J, Nishida T, Chung J, Kappeler C, Kuss I, Laurent D, Casali PG; GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):295-302. Epub 2012 Nov 22. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819942/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23177515 PubMed]<br />
#'''RIGHT:''' Kang YK, Ryu MH, Yoo C, Ryoo BY, Kim HJ, Lee JJ, Nam BH, Ramaiya N, Jagannathan J, Demetri GD. Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1175-82. Epub 2013 Oct 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70453-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347867/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24140183 PubMed]<br />
<br />
==Regorafenib monotherapy {{#subobject:bd09ce|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:6dcadc|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819942/ Demetri et al. 2012 (GRID)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Placebo_2|Placebo]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
''Patients in this study already had treatment failure with imatinib and sunitinib.''<br />
====Chemotherapy====<br />
<br />
*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''GRID:''' Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, Leahy M, von Mehren M, Joensuu H, Badalamenti G, Blackstein M, Le Cesne A, Schöffski P, Maki RG, Bauer S, Nguyen BB, Xu J, Nishida T, Chung J, Kappeler C, Kuss I, Laurent D, Casali PG; GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):295-302. Epub 2012 Nov 22. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819942/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23177515 PubMed]<br />
<br />
==Sorafenib monotherapy {{#subobject:ec8ga1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:381ibg3|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/abs/10.1200/jco.2011.29.15_suppl.10009 Kindler et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://doi.org/10.1007/s10637-012-9795-9 Park et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
<br />
*[[Sorafenib (Nexavar)]] 400mg PO BID<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''Abstract:''' Kindler HL, Campbell NP, Wroblewski K, Maki RG, D’Adamo DR, Chow WA, Gandara DR, Antonescu C, Stadler WM, Vokes EE. Sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST): Final results of a University of Chicago Phase II Consortium trial. 2011. 29 (15_suppl) 10009-10009. [https://ascopubs.org/doi/abs/10.1200/jco.2011.29.15_suppl.10009 link to original article (abstract only)]<br />
#Park SH, Ryu MH, Ryoo BY, Im SA, Kwon HC, Lee SS, Park SR, Kang BY, Kang YK. Sorafenib in patients with metastatic gastrointestinal stromal tumors who failed two or more prior tyrosine kinase inhibitors: a phase II study of Korean gastrointestinal stromal tumors study group. Invest New Drugs. 2012 Dec; 30(6) 2377-83. Epub 2012 Jan 25.[https://doi.org/10.1007/s10637-012-9795-9 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22270258 PubMed]<br />
<br />
==Sunitinib monotherapy {{#subobject:ec3261|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:38e8e3|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(06)69446-4/abstract Demetri et al. 2006 (A6181004)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Placebo_2|Placebo]]<br />
| style="background-color:#1a9850" |Superior TTP<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143095/ Adenis et al. 2014]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Masitinib<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Patients had treatment failure with imatinib.''<br />
====Chemotherapy====<br />
<br />
*[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 28<br />
**Dose may be decreased to 37.5 mg or 25 mg depending on tolerability<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<br />
#'''A6181004:''' Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006 Oct 14;368(9544):1329-38. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(06)69446-4/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17046465 PubMed]<br />
##'''Update:''' Demetri GD, Garrett CR, Schöffski P, Shah MH, Verweij J, Leyvraz S, Hurwitz HI, Pousa AL, Le Cesne A, Goldstein D, Paz-Ares L, Blay JY, McArthur GA, Xu QC, Huang X, Harmon CS, Tassell V, Cohen DP, Casali PG. Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure. Clin Cancer Res. 2012 Jun 1;18(11):3170-9. [https://clincancerres.aacrjournals.org/content/18/11/3170.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030710/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22661587 PubMed]<br />
#Adenis A, Blay JY, Bui-Nguyen B, Bouché O, Bertucci F, Isambert N, Bompas E, Chaigneau L, Domont J, Ray-Coquard I, Blésius A, Van Tine BA, Bulusu VR, Dubreuil P, Mansfield CD, Acin Y, Moussy A, Hermine O, Le Cesne A. Masitinib in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib: a randomized controlled open-label trial. Ann Oncol. 2014 Sep;25(9):1762-9. Epub 2014 Jul 25. [https://academic.oup.com/annonc/article/25/9/1762/2801236 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143095/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25122671 PubMed]<br />
<br />
[[Category:Gastrointestinal stromal tumor regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Soft tissue sarcomas]]<br />
[[Category:Gastrointestinal cancers]]</div>Dweeraratnehttps://hemonc.org/w/index.php?title=Gastric_cancer&diff=41855Gastric cancer2020-01-08T23:45:46Z<p>Dweeraratne: /* Regimen #subobject:ac7d94 */</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; width:15%" |[[File:Ivy_Abraham.JPG|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Ivyabraham|Ivy Abraham, MD]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br />
| style="background-color:#F0F0F0; width:15%" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br />
|-<br />
|}<br />
<big>Note: there is significant overlap between regimens for gastric cancer and '''[[esophageal cancer]]''', if you can't find the regimen you're looking for here, please try the esophageal cancer page. If you still can't find it, it is possible that we've moved it to the [[Gastric_cancer_-_historical|historical regimens page]].</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 />
==CAP/ASCP/ASCO==<br />
<br />
*'''2017:''' Bartley et al. [https://ascopubs.org/doi/full/10.1200/JCO.2016.69.4836 HER2 testing and clinical decision making in gastroesophageal adenocarcinoma] [https://www.ncbi.nlm.nih.gov/pubmed/28129524 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2019:''' Stjepanovic et al. [https://academic.oup.com/annonc/article/30/10/1558/5543095 Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
*'''2016:''' Smyth et al. [https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Gastric-Cancer Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/27664260 PubMed]<br />
<br />
==ESMO/ESSO/ESTRO==<br />
<br />
*'''2013:''' Waddell et al. [https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mdt344 Gastric cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/24078663 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf NCCN Guidelines - Gastric Cancer]<br />
<br />
=Neoadjuvant chemotherapy=<br />
==Cisplatin & Fluorouracil {{#subobject:7b88be|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FP: '''<u>F</u>'''luorouracil & '''<u>P</u>'''latinol (Cisplatin)<br />
===Regimen {{#subobject:c2dc1e|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/29/13/1715.long Ychou et al. 2011 (ACCORD 07)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Surgery alone<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''This is the neoadjuvant portion of pre-planned "perioperative" therapy.''<br />
<br />
''Study included patients with lower esophageal malignancy as well (25% gastric, 11% lower esophagus, and 64% GE junction).''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycle for 2 to 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Gastrectomy|Surgical resection]], then [[#Cisplatin_.26_Fluorouracil_2|adjuvant cisplatin & 5-FU]]<br />
<br />
===References===<br />
<br />
#'''ACCORD 07:''' Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. [http://jco.ascopubs.org/content/29/13/1715.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21444866 PubMed]<br />
<br />
==ECF {{#subobject:f0281c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:66f602|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/NEJMoa055531 Cunningham et al. 2006 (MAGIC)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation|Surgery alone]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext Cats et al. 2018 (CRITICS)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''This is the neoadjuvant portion of pre-planned perioperative therapy. In CRITICS, only patients with difficulties swallowing tablets were assigned to this treatment.''<br />
<br />
''CRITICS trial included few patients with GE junction malignancy: 83% gastric, 17% GE junction'' <br />
<br />
''MAGIC included patients with lower esophageal malignancy as well (74% gastric, 14.8% lower esophagus, and 11.2% GE junction).''<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*MAGIC, suggested as thrombosis prophylaxis:<br />
**[[Warfarin (Coumadin)]] 1 mg PO once per day<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*MAGIC: [[Surgery#Gastrectomy|Surgical resection]] is performed 3 to 6 weeks after the completion of cycle 3, followed in 6 to 12 weeks by [[#ECF_2|adjuvant ECF]]<br />
*CRITICS: [[Surgery#Gastrectomy|Surgery]] with a D1+ lymph node resection, then adjuvant [[#ECF_2|ECF]] versus capecitabine, cisplatin, RT<br />
<br />
===References===<br />
<br />
#'''MAGIC:''' Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa055531 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16822992 PubMed]<br />
#'''CRITICS:''' Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29650363 PubMed]<br />
<br />
==ECX {{#subobject:c8ab0e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECX: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:27f848|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)30132-3/fulltext Cats et al. 2018 (CRITICS)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''CRITICS trial included few patients with GE junction malignancy: 83% gastric, 17% GE junction''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Gastrectomy|Surgery]] with a D1+ lymph node resection, then adjuvant [[#ECX_2|ECX]] versus capecitabine, cisplatin, RT<br />
<br />
===References===<br />
<br />
#'''CRITICS:''' Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29650363 PubMed]<br />
<br />
==EOF {{#subobject:139705|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
EOF: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luourouracil<br />
===Regimen {{#subobject:bf7464|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)30132-3/fulltext Cats et al. 2018 (CRITICS)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''CRITICS trial included few patients with GE junction malignancy: 83% gastric, 17% GE junction''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Gastrectomy|Surgery]] with a D1+ lymph node resection, then adjuvant [[#EOF_2|EOF]] versus capecitabine, cisplatin, RT<br />
<br />
===References===<br />
<br />
#'''CRITICS:''' Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29650363 PubMed]<br />
<br />
==EOX {{#subobject:86ee8e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
EOX: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:edae45|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)30132-3/fulltext Cats et al. 2018 (CRITICS)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''CRITICS trial included few patients with GE junction malignancy: 83% gastric, 17% GE junction''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Gastrectomy|Surgery]] with a D1+ lymph node resection, then adjuvant [[#EOX_2|EOX]] versus capecitabine, cisplatin, RT<br />
<br />
===References===<br />
<br />
#'''CRITICS:''' Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29650363 PubMed]<br />
<br />
==FLOT {{#subobject:aa7f4f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FLOT: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>O</u>'''xaliplatin, '''<u>T</u>'''axotere (Docetaxel)<br />
===Regimen {{#subobject:16408e|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(16)30531-9/fulltext Al-Batran et al. 2016 (FLOT4-AIO)]<br />
| style="background-color:#1a9851" |Phase II/III (E-switch-ic)<br />
|ECF/ECX [[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
| style="background-color:#91cf60" |Seems to have superior OS [[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
|-<br />
|}<br />
''This is the neoadjuvant portion of pre-planned perioperative chemotherapy.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV continuous infusion over 24 hours on day 1<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
*[[Docetaxel (Taxotere)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Gastrectomy|Surgery]], then [[#FLOT_2|adjuvant FLOT]]<br />
<br />
===References===<br />
<br />
#'''FLOT4-AIO:''' Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, Meiler J, Homann N, Lorenzen S, Schmalenberg H, Probst S, Koenigsmann M, Egger M, Prasnikar N, Caca K, Trojan J, Martens UM, Block A, Fischbach W, Mahlberg R, Clemens M, Illerhaus G, Zirlik K, Behringer DM, Schmiegel W, Pohl M, Heike M, Ronellenfitsch U, Schuler M, Bechstein WO, Königsrainer A, Gaiser T, Schirmacher P, Hozaeel W, Reichart A, Goetze TO, Sievert M, Jäger E, Mönig S, Tannapfel A. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016 Dec;17(12):1697-1708. Epub 2016 Oct 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30531-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27776843 PubMed]<br />
##'''Update:''' Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, Kopp HG, Mayer F, Haag GM, Luley K, Lindig U, Schmiegel W, Pohl M, Stoehlmacher J, Folprecht G, Probst S, Prasnikar N, Fischbach W, Mahlberg R, Trojan J, Koenigsmann M, Martens UM, Thuss-Patience P, Egger M, Block A, Heinemann V, Illerhaus G, Moehler M, Schenk M, Kullmann F, Behringer DM, Heike M, Pink D, Teschendorf C, Löhr C, Bernhard H, Schuch G, Rethwisch V, from Weikersthal LF, Hartmann JT, Kneba M, Daum S, Schulmann K, Less J, Belle S, Gaiser T, Oduncu FS, Güntner M, Hozaeel W, Reichart A, Hunter E, Kraus T, Mönig S, Bechstein WO, Schuler M, Schmalenberg H, Hofheinz RD; FLOT4-AIO Investigators. perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomized, phase 2/3 trial. Lancet. 2019 Apr 10. [Epub ahead of print] [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32557-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30982686 PubMed]<br />
<br />
==No neoadjuvant therapy==<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.ncbi.nlm.nih.gov/pmc/articles/PMC3020693/ Schuhmacher et al. 2010 (EORTC 40954)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin, 5-FU, Folinic acid<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''No antineoplastic treatment prior to surgery.''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Gastrectomy|Surgery]]<br />
<br />
===References===<br />
<br />
#'''EORTC 40954:''' Schuhmacher C, Gretschel S, Lordick F, Reichardt P, Hohenberger W, Eisenberger CF, Haag C, Mauer ME, Hasan B, Welch J, Ott K, Hoelscher A, Schneider PM, Bechstein W, Wilke H, Lutz MP, Nordlinger B, Van Cutsem E, Siewert JR, Schlag PM. Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and Treatment of Cancer randomized trial 40954. J Clin Oncol. 2010 Dec 10;28(35):5210-8. Epub 2010 Nov 8. [https://ascopubs.org/doi/10.1200/JCO.2009.26.6114 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3020693/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21060024 PubMed]<br />
<br />
=Adjuvant therapy=<br />
<br />
==CapeOx {{#subobject:cf9acc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine & '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:1ef938|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(11)61873-4/fulltext Bang et al. 2012 (CLASSIC)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Surgery alone<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|}<br />
''Note: Reported efficacy is based on the 2014 update.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Gastrectomy|Gastrectomy]] with D2 dissection<br />
<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 8 cycles'''<br />
<br />
===References===<br />
<br />
#'''CLASSIC:''' Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, Lee KW, Kim YH, Noh SI, Cho JY, Mok YJ, Kim YH, Ji J, Yeh TS, Button P, Sirzén F, Noh SH; CLASSIC trial investigators. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012 Jan 28;379(9813):315-21. Epub 2012 Jan 7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61873-4/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22226517 PubMed]<br />
##'''Update:''' Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW, Kim HH, Choi JH, Kim HK, Yu W, Lee JI, Shin DB, Ji J, Chen JS, Lim Y, Ha S, Bang YJ; CLASSIC trial investigators. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1389-96. Epub 2014 Oct 15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70473-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25439693 PubMed]<br />
<br />
==Carboplatin & Docetaxel {{#subobject:7263b8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cd8hbq|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://link.springer.com/article/10.1007%2Fs00280-010-1256-6 Bamias et al. 2010]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Carboplatin, Docetaxel, RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: the original protocol was for cisplatin & docetaxel but was changed due to excess CINV. 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 />
*[[Surgery#Gastrectomy|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 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 6 cycles'''<br />
<br />
===References===<br />
<br />
#Bamias A, Karina M, Papakostas P, Kostopoulos I, Bobos M, Vourli G, Samantas E, Christodoulou Ch, Pentheroudakis G, Pectasides D, Dimopoulos MA, Fountzilas G. A randomized phase III study of adjuvant platinum/docetaxel chemotherapy with or without radiation therapy in patients with gastric cancer. Cancer Chemother Pharmacol. 2010 May;65(6):1009-21. Epub 2010 Feb 4. [https://link.springer.com/article/10.1007%2Fs00280-010-1256-6 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20130877 PubMed]<br />
<br />
==Cisplatin & Fluorouracil {{#subobject:7b88be|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c2dc1e|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/29/13/1715.long Ychou et al. 2011 (ACCORD 07)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Surgery alone<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''This is the adjuvant portion of pre-planned "perioperative" therapy. ''<br />
<br />
''Study included patients with lower esophageal malignancy as well (25% gastric, 11% lower esophagus, and 64% GE junction).''<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin_.26_Fluorouracil|Neoadjuvant cisplatin & 5-FU]], then [[Surgery#Gastrectomy|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 28<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycle for 3 to 4 cycles, for a total of 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''ACCORD 07:''' Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. [http://jco.ascopubs.org/content/29/13/1715.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21444866 PubMed]<br />
<br />
==CX {{#subobject:4896bc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CX: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
<br>XP: '''<u>X</u>'''eloda (Capecitabine), '''<u>P</u>'''latinol (Cisplatin)<br />
===Regimen {{#subobject:877085|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/30/3/268.full Lee et al. 2011 (ARTIST<sub>gastric</sub>)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|XP, then RT, then XP<br />
| style="background-color:#fee08b" |Might have inferior DFS<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. This trial should not be confused for the one by the same name in colorectal cancer.''<br />
====Preceding treatment====<br />
<br />
*R0 [[Surgery#Gastrectomy|gastrectomy]] and at least D2 dissection<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''ARTIST:''' Lee J, Lim DH, Kim S, Park SH, Park JO, Park YS, Lim HY, Choi MG, Sohn TS, Noh JH, Bae JM, Ahn YC, Sohn I, Jung SH, Park CK, Kim KM, Kang WK. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol. 2012 Jan 20;30(3):268-73. Epub 2011 Dec 19. [http://jco.ascopubs.org/content/30/3/268.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22184384 PubMed]<br />
##'''Update:''' Park SH, Sohn TS, Lee J, Lim DH, Hong ME, Kim KM, Sohn I, Jung SH, Choi MG, Lee JH, Bae JM, Kim S, Kim ST, Park JO, Park YS, Lim HY, Kang WK. Phase III trial to compare adjuvant chemotherapy with capecitabine and cisplatin versus concurrent chemoradiotherapy in gastric cancer: Final report of the adjuvant chemoradiotherapy in stomach tumors trial, including survival and subset analyses. J Clin Oncol. 2015 Oct 1;33(28):3130-6. Epub 2015 Jan 5. [http://jco.ascopubs.org/content/33/28/3130.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25559811 PubMed]<br />
<br />
==Docetaxel & S-1 {{#subobject:a22c2a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[Gastric cancer#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:82ca03|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 />
|Kodera et al. (JACCRO GC-07)<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Gastric cancer#S-1 monotherapy 2|S-1]]<br />
| style="background-color:#91cf60" |Seems to have superior RFS<br />
|}<br />
====Chemotherapy (given sequentially, as below)====<br />
'''1 Cycle of:''' <br />
<br />
*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV once on day 1<br />
*S-1 at 80-120 mg/body PO on day 1-14 followed by 7 days of rest<br />
<br />
'''Followed by 6 Cycles of:''' <br />
<br />
*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV once on day 1<br />
*S-1 at 80-120 mg/body PO on day 1-14<br />
<br />
'''Followed by 4 Cycles of:''' <br />
<br />
*S-1 at 80-120 mg/body PO on days 1-28<br />
<br />
'''42-day cycles'''<br />
===References===<br />
<br />
#'''Abstract:''' Kodera Y, Yoshida K, Kochi M, Ichikawa W, Kakeji Y, Sano T, Nagao N, Takahashi M, Takagane A, Nakamura M, Kaji M, Okitsu H, Nomura T, Matsui T, Yoshikawa T, Matssuyama J, Yamada M, Ito Y, Takeuchi M, Fujii M. A randomized phase III study comparing S-1 plus docetaxel with S-1 alone as a postoperative adjuvant chemotherapy for curatively resected stage III gastric cancer (JACCRO GC-07 trial). 2019 American Society of Clinical Oncology annual meeting. DOI: 10.1200/JCO.2018.36.15_suppl.4007 36, no. 15_suppl (May 20, 2018) 4007-4007.<br />
<br />
==ECF {{#subobject:f0281c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:66f602|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/NEJMoa055531 Cunningham et al. 2006 (MAGIC)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation|Surgery alone]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext Cats et al. 2018 (CRITICS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''This is the adjuvant portion of pre-planned "perioperative" therapy. In CRITICS, only patients with trouble swallowing pills were assigned to this treatment arm.''<br />
<br />
''MAGIC included patients with lower esophageal malignancy (74% gastric, 14.8% lower esophagus, and 11.2% GE junction).''<br />
<br />
====Preceding treatment====<br />
<br />
*[[#ECF|Neoadjuvant ECF]] x 3, then [[Surgery#Gastrectomy|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*MAGIC, suggested as thrombosis prophylaxis:<br />
**[[Warfarin (Coumadin)]] 1 mg PO once per day<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''MAGIC:''' Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa055531 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16822992 PubMed]<br />
#'''CRITICS:''' Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29650363 PubMed]<br />
<br />
==ECX {{#subobject:4be711|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECX: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:af32a3|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(18)30132-3/fulltext Cats et al. 2018 (CRITICS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#ECX|ECX]] x 3, then [[Surgery#Gastrectomy|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''CRITICS:''' Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29650363 PubMed]<br />
<br />
==EOF {{#subobject:46c9e7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
EOF: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:415ab0|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(18)30132-3/fulltext Cats et al. 2018 (CRITICS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Only patients with trouble swallowing pills were assigned to this treatment arm.''<br />
====Preceding treatment====<br />
<br />
*[[#EOF|EOF]] x 3, then [[Surgery#Gastrectomy|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''CRITICS:''' Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29650363 PubMed]<br />
<br />
==EOX {{#subobject:64769a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
EOX: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:996244|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(18)30132-3/fulltext Cats et al. 2018 (CRITICS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#EOX|EOX]] x 3, then [[Surgery#Gastrectomy|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''CRITICS:''' Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29650363 PubMed]<br />
<br />
==FLOT {{#subobject:3ad093|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FLOT: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>O</u>'''xaliplatin, '''<u>T</u>'''axotere (Docetaxel)<br />
===Regimen {{#subobject:e6d646|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(16)30531-9/fulltext Al-Batran et al. 2016 (FLOT4-AIO)]<br />
| style="background-color:#1a9851" |Phase II/III (E-switch-ic)<br />
|ECF/ECX [[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
| style="background-color:#91cf60" |Seems to have superior OS [[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
|-<br />
|}<br />
''This is the adjuvant portion of pre-planned perioperative chemotherapy.''<br />
====Preceding treatment====<br />
<br />
*[[#FLOT|Neoadjuvant FLOT]] x 4, then [[Surgery#Gastrectomy|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV continuous infusion over 24 hours on day 1<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
*[[Docetaxel (Taxotere)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#'''FLOT4-AIO:''' Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, Meiler J, Homann N, Lorenzen S, Schmalenberg H, Probst S, Koenigsmann M, Egger M, Prasnikar N, Caca K, Trojan J, Martens UM, Block A, Fischbach W, Mahlberg R, Clemens M, Illerhaus G, Zirlik K, Behringer DM, Schmiegel W, Pohl M, Heike M, Ronellenfitsch U, Schuler M, Bechstein WO, Königsrainer A, Gaiser T, Schirmacher P, Hozaeel W, Reichart A, Goetze TO, Sievert M, Jäger E, Mönig S, Tannapfel A. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016 Dec;17(12):1697-1708. Epub 2016 Oct 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30531-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27776843 PubMed]<br />
##'''Update:''' Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, Kopp HG, Mayer F, Haag GM, Luley K, Lindig U, Schmiegel W, Pohl M, Stoehlmacher J, Folprecht G, Probst S, Prasnikar N, Fischbach W, Mahlberg R, Trojan J, Koenigsmann M, Martens UM, Thuss-Patience P, Egger M, Block A, Heinemann V, Illerhaus G, Moehler M, Schenk M, Kullmann F, Behringer DM, Heike M, Pink D, Teschendorf C, Löhr C, Bernhard H, Schuch G, Rethwisch V, from Weikersthal LF, Hartmann JT, Kneba M, Daum S, Schulmann K, Less J, Belle S, Gaiser T, Oduncu FS, Güntner M, Hozaeel W, Reichart A, Hunter E, Kraus T, Mönig S, Bechstein WO, Schuler M, Schmalenberg H, Hofheinz RD; FLOT4-AIO Investigators. perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomized, phase 2/3 trial. Lancet. 2019 Apr 10. [Epub ahead of print] [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32557-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30982686 PubMed]<br />
<br />
==FP/Capecitabine & RT {{#subobject:778727|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FP/Capecitabine & RT: '''<u>F</u>'''luorouracil & '''<u>P</u>'''latinol (Cisplatin) alternating with Capecitabine & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:20ea7f|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/PMC4066094/ Lee et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: In contrast to the primary reference, some guidelines list this regimen without FP cycles 1, 3, 4, 5. Dosage of [[Capecitabine (Xeloda)]] was listed as 625 to 825 mg/m<sup>2</sup> PO twice per day on days 1 to 5 or 1 to 7 while radiation is being given.'' <br />
====Preceding treatment====<br />
<br />
*[[Surgery#Gastrectomy|Surgery]], 3 weeks prior<br />
<br />
====Chemotherapy, part 1====<br />
<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose: 5000 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle, followed immediately by:'''<br />
<br />
====Chemotherapy, part 2====<br />
<br />
*[[Capecitabine (Xeloda)]] 825 mg/m<sup>2</sup> PO twice per day<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions (total dose of 45 Gy)<br />
<br />
'''5-week course, followed 4 weeks later by:'''<br />
<br />
====Chemotherapy, part 3====<br />
<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#Lee HS, Choi Y, Hur WJ, Kim HJ, Kwon HC, Kim SH, Kim JS, Lee JH, Jung GJ, Kim MC. Pilot study of postoperative adjuvant chemoradiation for advanced gastric cancer: adjuvant 5-FU/cisplatin and chemoradiation with capecitabine. World J Gastroenterol. 2006 Jan 28;12(4):603-7. [http://www.wjgnet.com/1007-9327/full/v12/i4/603.htm link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066094/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/16489675 PubMed]<br />
<br />
==FULV/FULV & RT {{#subobject:2cd29|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FULV/FULV & RT: '''<u>F</u>'''luoro'''<u>U</u>'''racil & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid) alternating with '''<u>F</u>'''luoro'''<u>U</u>'''racil, '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid) & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:dfd3ec|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/NEJMoa010187 Macdonald et al. 2001 (INT-0116)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation|Surgery alone]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678342/ Fuchs et al. 2017 (CALGB 80101)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ECF, then FULV & RT, then ECF<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Treatment is to start 20 to 40 days after surgery.''<br />
<br />
''Study included patients with GE junction malignancy as well (20% GE junction) and included patients with a performance status of 2.'' <br />
====Preceding treatment====<br />
<br />
*INT-0116: [[Surgery#Gastrectomy|Surgery]] with R0 resection (10% underwent D2 dissection, 36% underwent D1 dissection and 54% underwent D0 dissection)<br />
*CALGB 80101: [[Surgery#Gastrectomy|Surgery]]<br />
<br />
====Chemotherapy, part 1====<br />
<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
<br />
'''28-day cycle for 1 cycle, followed by:'''<br />
<br />
====Chemotherapy, part 2====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 180 cGy x 25 fractions (total of 45 Gy)<br />
<br />
'''35-day course, followed in 1 month by:'''<br />
<br />
====Chemotherapy, part 3====<br />
<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
<br />
'''28-day cycle for 2 cycles'''<br />
===References===<br />
<br />
#'''INT-0116:''' Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6;345(10):725-30. [https://www.nejm.org/doi/full/10.1056/NEJMoa010187 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11547741 PubMed]<br />
##'''Update:''' Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA, Gunderson LL, Goldman B, Martenson JA, Jessup JM, Stemmermann GN, Blanke CD, Macdonald JS. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol. 2012 Jul 1;30(19):2327-33. Epub 2012 May 14. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.7136 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517071/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22585691 PubMed]<br />
#'''CALGB 80101:''' Fuchs CS, Niedzwiecki D, Mamon HJ, Tepper JE, Ye X, Swanson RS, Enzinger PC, Haller DG, Dragovich T, Alberts SR, Bjarnason GA, Willett CG, Gunderson LL, Goldberg RM, Venook AP, Ilson D, O'Reilly E, Ciombor K, Berg DJ, Meyerhardt J, Mayer RJ. Adjuvant chemoradiotherapy with epirubicin, cisplatin, and fluorouracil compared with adjuvant chemoradiotherapy with fluorouracil and leucovorin after curative resection of gastric cancer: results from CALGB 80101 (Alliance). J Clin Oncol. 2017 Nov 10;35(32):3671-3677. Epub 2017 Oct 4. [https://ascopubs.org/doi/full/10.1200/JCO.2017.74.2130 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678342/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28976791 PubMed]<br />
<br />
==Observation==<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 />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(89)91607-3/fulltext Allum et al. 1989]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Gastric_cancer_-_historical#Fluorouracil_.26_Mitomycin|5-FU & Mitomycin]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1990.8.8.1362 Coombes et al. 1990]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FAM<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints of DFS/OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(94)92464-3/fulltext Hallissey et al. 1994]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. FAM<br> 2. Radiation therapy<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1995.13.11.2757 Lise et al. 1995 (EORTC 40813)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FAM2<br />
| style="background-color:#fee08b" |Might have inferior DFS<br />
|-<br />
|[https://link.springer.com/article/10.1007/BF02307081 Macdonald et al. 1995 (SWOG-7804)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FAM<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)01048-X/fulltext Nakajima et al. 1999 (JCOG8801)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & Mitomycin, then UFT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.1999.17.12.3810 Cirera et al. 1999]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Mitomycin & Tegafur<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa010187 Macdonald et al. 2001 (INT-0116)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FULV.2FFULV_.26_RT|FULV/FULV & RT]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2003.06.103 Nashimoto et al. 2003 (JCOG 9206-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU, Ara-C, Mitomycin, then 5-FU<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS<br />
|-<br />
|[https://academic.oup.com/annonc/article/16/9/1488/180180 Bouché et al. 2005 (FFCD 8801)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Fluorouracil_2|Cisplatin & 5-FU]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/17/2/262/165316 Nitti et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. FAMTX<br> 2. FEMTX<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa055531 Cunningham et al. 2006 (MAGIC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ECF_2|ECF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/18/8/1354/178453 De Vita et al. 2007 (GOIM 9602)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ELFE<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa072252 Sakuramoto et al. 2007 (ACTS-GC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://academic.oup.com/jnci/article/100/6/388/997958 Di Costanzo et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PELF<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.karger.com/Article/Abstract/292360 Kulig et al. 2010]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|EAP<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs10120-011-0027-3 Miyashiro et al. 2011 (JCOG 9206-2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|IV/IP Cisplatin, then UFT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''No further treatment after surgery.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Gastrectomy|Surgery]], with varying requirements for level of dissection (see papers for details)<br />
<br />
===References===<br />
<br />
#Allum WH, Hallissey MT, Kelly KA; British Stomach Cancer Group. Adjuvant chemotherapy in operable gastric cancer: 5 year follow-up of first British Stomach Cancer Group trial. Lancet. 1989 Mar 18;1(8638):571-4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(89)91607-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2564109 PubMed]<br />
#Coombes RC, Schein PS, Chilvers CE, Wils J, Beretta G, Bliss JM, Rutten A, Amadori D, Cortes-Funes H, Villar-Grimalt A, McArdle C, Rauschecker HF, Boven E, Vassilopoulos P, Welvaart K, Pinto Ferreira E, Wiig J, Gisselbrecht C, Rougier P, Woods EMA; International Collaborative Cancer Group. A randomized trial comparing adjuvant fluorouracil, doxorubicin, and mitomycin with no treatment in operable gastric cancer. J Clin Oncol. 1990 Aug;8(8):1362-9. [https://ascopubs.org/doi/abs/10.1200/JCO.1990.8.8.1362 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2199622 PubMed]<br />
#Hallissey MT, Dunn JA, Ward LC, Allum WH; British Stomach Cancer Group. The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: five-year follow-up. Lancet. 1994 May 28;343(8909):1309-12. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(94)92464-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7910321 PubMed]<br />
#'''EORTC 40813:''' Lise M, Nitti D, Marchet A, Sahmoud T, Buyse M, Duez N, Fiorentino M, Dos Santos JG, Labianca R, Rougier P, Gignoux M. Final results of a phase III clinical trial of adjuvant chemotherapy with the modified fluorouracil, doxorubicin, and mitomycin regimen in resectable gastric cancer. J Clin Oncol. 1995 Nov;13(11):2757-63. [https://ascopubs.org/doi/abs/10.1200/JCO.1995.13.11.2757 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7595735 PubMed]<br />
#'''SWOG-7804:''' Macdonald JS, Fleming TR, Peterson RF, Berenberg JL, McClure S, Chapman RA, Eyre HJ, Solanki D, Cruz AB Jr, Gagliano R, Estes NC, Tangen CM, Rivkin S. Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: A Southwest Oncology Group study. Ann Surg Oncol. 1995 Nov;2(6):488-94. [https://link.springer.com/article/10.1007/BF02307081 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8591078 PubMed]<br />
#'''JCOG8801:''' Nakajima T, Nashimoto A, Kitamura M, Kito T, Iwanaga T, Okabayashi K, Goto M; Gastric Cancer Surgical Study Group. Adjuvant mitomycin and fluorouracil followed by oral uracil plus tegafur in serosa-negative gastric cancer: a randomised trial. Lancet. 1999 Jul 24;354(9175):273-7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)01048-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10440302 PubMed]<br />
#Cirera L, Balil A, Batiste-Alentorn E, Tusquets I, Cardona T, Arcusa A, Jolis L, Saigí E, Guasch I, Badia A, Boleda M. Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer. J Clin Oncol. 1999 Dec;17(12):3810-5. [https://ascopubs.org/doi/full/10.1200/JCO.1999.17.12.3810 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10577853 PubMed]<br />
#'''INT-0116:''' Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6;345(10):725-30. [https://www.nejm.org/doi/full/10.1056/NEJMoa010187 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11547741 PubMed]<br />
##'''Update:''' Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA, Gunderson LL, Goldman B, Martenson JA, Jessup JM, Stemmermann GN, Blanke CD, Macdonald JS. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol. 2012 Jul 1;30(19):2327-33. Epub 2012 May 14. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.7136 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517071/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22585691 PubMed]<br />
#'''JCOG 9206-1:''' Nashimoto A, Nakajima T, Furukawa H, Kitamura M, Kinoshita T, Yamamura Y, Sasako M, Kunii Y, Motohashi H, Yamamoto S; Gastric Cancer Surgical Study Group, Japan Clinical Oncology Group. Randomized trial of adjuvant chemotherapy with mitomycin, Fluorouracil, and Cytosine arabinoside followed by oral Fluorouracil in serosa-negative gastric cancer: Japan Clinical Oncology Group 9206-1. J Clin Oncol. 2003 Jun 15;21(12):2282-7. [https://ascopubs.org/doi/full/10.1200/JCO.2003.06.103 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12805327 PubMed]<br />
#'''FFCD 8801:''' Bouché O, Ychou M, Burtin P, Bedenne L, Ducreux M, Lebreton G, Baulieux J, Nordlinger B, Martin C, Seitz JF, Tigaud JM, Echinard E, Stremsdoerfer N, Milan C, Rougier P; Fédération Francophone de Cancérologie Digestive Group. Adjuvant chemotherapy with 5-fluorouracil and cisplatin compared with surgery alone for gastric cancer: 7-year results of the FFCD randomized phase III trial (8801). Ann Oncol. 2005 Sep;16(9):1488-97. Epub 2005 Jun 6. [https://academic.oup.com/annonc/article/16/9/1488/180180 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15939717 PubMed]<br />
#Nitti D, Wils J, Dos Santos JG, Fountzilas G, Conte PF, Sava C, Tres A, Coombes RC, Crivellari D, Marchet A, Sanchez E, Bliss JM, Homewood J, Couvreur ML, Hall E, Baron B, Woods E, Emson M, Van Cutsem E, Lise M; EORTC GI Group; ICCG. Randomized phase III trials of adjuvant FAMTX or FEMTX compared with surgery alone in resected gastric cancer: a combined analysis of the EORTC GI Group and the ICCG. Ann Oncol. 2006 Feb;17(2):262-9. Epub 2005 Nov 17. [https://academic.oup.com/annonc/article/17/2/262/165316 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16293676 PubMed]<br />
#'''MAGIC:''' Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa055531 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16822992 PubMed]<br />
#'''GOIM 9602:''' De Vita F, Giuliani F, Orditura M, Maiello E, Galizia G, Di Martino N, Montemurro F, Cartenì G, Manzione L, Romito S, Gebbia V, Ciardiello F, Catalano G, Colucci G; Gruppo Oncologico Italia Meridionale. Adjuvant chemotherapy with epirubicin, leucovorin, 5-fluorouracil and etoposide regimen in resected gastric cancer patients: a randomized phase III trial by the Gruppo Oncologico Italia Meridionale (GOIM 9602 Study). Ann Oncol. 2007 Aug;18(8):1354-8. Epub 2007 May 24. [https://academic.oup.com/annonc/article/18/8/1354/178453 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17525087 PubMed]<br />
#'''ACTS-GC:''' Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K; ACTS-GC Group. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007 Nov 1;357(18):1810-20. Erratum in: N Engl J Med. 2008 May 1;358(18):1977. [https://www.nejm.org/doi/full/10.1056/NEJMoa072252 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17978289 PubMed]<br />
##'''Update:''' Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T, Ohashi Y. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011 Nov 20;29(33):4387-93. Epub 2011 Oct 17. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.5908 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22010012 PubMed]<br />
#Di Costanzo F, Gasperoni S, Manzione L, Bisagni G, Labianca R, Bravi S, Cortesi E, Carlini P, Bracci R, Tomao S, Messerini L, Arcangeli A, Torri V, Bilancia D, Floriani I, Tonato M; Italian Oncology Group for Cancer Research. Adjuvant chemotherapy in completely resected gastric cancer: a randomized phase III trial conducted by GOIRC. J Natl Cancer Inst. 2008 Mar 19;100(6):388-98. Epub 2008 Mar 11. [https://academic.oup.com/jnci/article/100/6/388/997958 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18334706 PubMed]<br />
#Kulig J, Kolodziejczyk P, Sierzega M, Bobrzynski L, Jedrys J, Popiela T, Dadan J, Drews M, Jeziorski A, Krawczyk M, Starzynska T, Wallner G. Adjuvant chemotherapy with etoposide, adriamycin and cisplatin compared with surgery alone in the treatment of gastric cancer: a phase III randomized, multicenter, clinical trial. Oncology. 2010;78(1):54-61. Epub 2010 Mar 6. [https://www.karger.com/Article/Abstract/292360 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20215786 PubMed]<br />
#'''JCOG 9206-2:''' Miyashiro I, Furukawa H, Sasako M, Yamamoto S, Nashimoto A, Nakajima T, Kinoshita T, Kobayashi O, Arai K; Gastric Cancer Surgical Study Group in the Japan Clinical Oncology Group. Randomized clinical trial of adjuvant chemotherapy with intraperitoneal and intravenous cisplatin followed by oral fluorouracil (UFT) in serosa-positive gastric cancer versus curative resection alone: final results of the Japan Clinical Oncology Group trial JCOG9206-2. Gastric Cancer. 2011 Aug;14(3):212-8. Epub 2011 Feb 19. [https://link.springer.com/article/10.1007%2Fs10120-011-0027-3 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21336855 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:ec10ef|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 21-day cycles {{#subobject:5dbc53|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(14)70025-7/fulltext Tsuburaya et al. 2014 (SAMIT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Paclitaxel, then S-1<br> 2. Paclitaxel, then UFT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|3. UFT<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*R0 or R1 [[Surgery#Gastrectomy|gastrectomy]] with at least D2 dissection, within 2 to 8 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] 80 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for 16 cycles'''<br />
<br />
===Variant #2, 42-day cycles {{#subobject:0ee98c|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/NEJMoa072252 Sakuramoto et al. 2007 (ACTS-GC)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/langas/article/PIIS2468-1253(18)30383-2/fulltext Yoshikawa et al. 2019 (OPAS-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|S-1 x 6 mo<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*R0 [[Surgery#Gastrectomy|gastrectomy]] with at least D2 dissection, within 6 weeks<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 between 1.25 and 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 cycle for 8 cycles'''<br />
===References===<br />
<br />
#'''ACTS-GC:''' Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K; ACTS-GC Group. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007 Nov 1;357(18):1810-20. Erratum in: N Engl J Med. 2008 May 1;358(18):1977. [https://www.nejm.org/doi/full/10.1056/NEJMoa072252 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17978289 PubMed]<br />
##'''Update:''' Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T, Ohashi Y. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011 Nov 20;29(33):4387-93. Epub 2011 Oct 17. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.5908 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22010012 PubMed]<br />
#'''SAMIT:''' Tsuburaya A, Yoshida K, Kobayashi M, Yoshino S, Takahashi M, Takiguchi N, Tanabe K, Takahashi N, Imamura H, Tatsumoto N, Hara A, Nishikawa K, Fukushima R, Nozaki I, Kojima H, Miyashita Y, Oba K, Buyse M, Morita S, Sakamoto J. Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. Lancet Oncol. 2014 Jul;15(8):886-93. Epub 2014 Jun 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70025-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24954805 PubMed]<br />
#'''OPAS-1:''' Yoshikawa T, Terashima M, Mizusawa J, Nunobe S, Nishida Y, Yamada T, Kaji M, Fukushima N, Hato S, Choda Y, Yabusaki H, Yoshida K, Ito S, Takeno A, Yasuda T, Kawachi Y, Katayama H, Fukuda H, Boku N, Sano T, Sasako M. Four courses versus eight courses of adjuvant S-1 for patients with stage II gastric cancer (JCOG1104[OPAS-1]): an open-label, phase 3, non-inferiority, randomised trial. Lancet Gastroenterol Hepatol. 2019 Mar;4(3):208-216. Epub 2019 Jan 22. Erratum in: Lancet Gastroenterol Hepatol. 2019 Apr;4(4):e3. [https://www.thelancet.com/journals/langas/article/PIIS2468-1253(18)30383-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30679107 PubMed]<br />
<br />
=Metastatic or locally advanced disease, first-line=<br />
==Capecitabine monotherapy {{#subobject:a9eb0b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
X: '''<u>X</u>'''eloda (Capecitabine)<br />
===Variant #1, 2000 mg/m<sup>2</sup>/day {{#subobject:b6ba4c|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.geriatriconcology.net/article/S1879-4068(17)30022-X/fulltext Hwang et al. 2017]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CapeOx_2|XELOX]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2, 2500 mg/m<sup>2</sup>/day {{#subobject:b6ba4c|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://annonc.oxfordjournals.org/content/15/9/1344.long Hong et al. 2004]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Study only included patients with Karnofsky status of at least 70%''<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Hong YS, Song SY, Lee SI, Chung HC, Choi SH, Noh SH, Park JN, Han JY, Kang JH, Lee KS, Cho JY. A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Ann Oncol. 2004 Sep;15(9):1344-7. [http://annonc.oxfordjournals.org/content/15/9/1344.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15319239 PubMed]<br />
#Hwang IG, Ji JH, Kang JH, Lee HR, Lee HY, Chi KC, Park SW, Lee SJ, Kim ST, Lee J, Park SH, Park JO, Park YS, Lim HY, Kang WK. A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer. J Geriatr Oncol. 2017 May;8(3):170-175. Epub 2017 Jan 21. [https://www.geriatriconcology.net/article/S1879-4068(17)30022-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28119041 PubMed]<br />
<br />
==CapeOx {{#subobject:4e3bb4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine & '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:4faee3|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://academic.oup.com/annonc/article/17/1/29/161212 Jatoi et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 850 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Jatoi A, Murphy BR, Foster NR, Nikcevich DA, Alberts SR, Knost JA, Fitch TR, Rowland KM Jr; North Central Cancer Treatment Group. Oxaliplatin and capecitabine in patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction and gastric cardia: a phase II study from the North Central Cancer Treatment Group. Ann Oncol. 2006 Jan;17(1):29-34. Epub 2005 Nov 22. [https://academic.oup.com/annonc/article/17/1/29/161212 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16303863 PubMed]<br />
<br />
==Carboplatin & Paclitaxel {{#subobject:4df570|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9725d8|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/9427274 Philip et al. 1997]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2003&issue=02000&article=00008&type=abstract Gadgeel et al. 2003]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: In contrast to the original reference, some guidelines list the dosage of carboplatin as AUC 6.''<br />
<br />
''Philip et al. included patients with locally advanced metastatic or recurrent esophageal or gastric cancer''<br />
<br />
''Gadgeel et al. study showed an ORR of 35%'' <br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV 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 cycles'''<br />
<br />
===References===<br />
<br />
#Philip PA, Zalupski MM, Gadgeel S, Hussain M, Shields A. A phase II study of carboplatin and paclitaxel in the treatment of patients with advanced esophageal and gastric cancer. Semin Oncol. 1997 Dec;24(6 Suppl 19):S19-86-S19-88. '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9427274 PubMed]<br />
#Gadgeel SM, Shields AF, Heilbrun LK, Labadidi S, Zalupski M, Chaplen R, Philip PA. Phase II study of paclitaxel and carboplatin in patients with advanced gastric cancer. Am J Clin Oncol. 2003 Feb;26(1):37-41. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2003&issue=02000&article=00008&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12576922 PubMed]<br />
<br />
==Cisplatin & Docetaxel {{#subobject:724868|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>TC: '''<u>T</u>'''axotere (Docetaxel), '''<u>C</u>'''isplatin<br />
<br />
===Variant #1, 75/75 {{#subobject:cd0910|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" |[http://jco.ascopubs.org/content/25/22/3217.long Roth et al. 2007]<br />
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-de-esc)<br />
|1. [[#ECF_3|ECF]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#DCF|TCF]]<br />
| style="background-color:#fee08b" |Might have inferior ORR<br />
|-<br />
|}<br />
''Note: the protocol was amended to change the original dose of docetaxel from 85 mg/m<sup>2</sup> to 75 mg/m<sup>2</sup> based on high incidence of febrile neutropenia.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 4 hours 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 />
<br />
*3 liters per day "hyperhydration"<br />
*[[Dexamethasone (Decadron)]] 8 mg PO given 12 hours & 6 hours before [[Docetaxel (Taxotere)]], then 8 mg PO twice per day for 4 days after [[Docetaxel (Taxotere)]]<br />
*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] for emesis prophylaxis<br />
*Growth factor support allowed, such as with [[Filgrastim (Neupogen)]]<br />
<br />
'''21-day cycle for up to 8 cycles'''<br />
<br />
===Variant #2, 75/85 {{#subobject:f1913d|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/23/24/5660.long Ajani et al. 2005 (V-325)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#DCF|DCF]]<br />
| style="background-color:#fc8d59" |Seems to have inferior ORR<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma histology (32% esophagogastric junction/fundus and 68% gastric antrum/body). 95% were metastatic. 1% with Karnofsky PS score of 70.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1<br />
*[[Docetaxel (Taxotere)]] 85 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 8 mg PO the night before chemotherapy, the morning of day 1, 1 hour before chemotherapy, the night of day 1, the morning of day 2, and the evening of day 2 (total dose per cycle: 48 mg)<br />
*[[Dexamethasone (Decadron)]] 20 mg IV before [[Cisplatin (Platinol)]] and 8 hours after [[Cisplatin (Platinol)]]<br />
*[[Ondansetron (Zofran)]] 8 mg IV before [[Cisplatin (Platinol)]], 4 hours after [[Cisplatin (Platinol)]], and 8 hours after [[Cisplatin (Platinol)]]<br />
*"Hydration was administered in a standard manner"<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''V-325:''' Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Cabral Filho S, Majlis A, Assadourian S, Van Cutsem E. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005 Aug 20;23(24):5660-7. [http://jco.ascopubs.org/content/23/24/5660.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16110025 PubMed]<br />
#Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. [http://jco.ascopubs.org/content/25/22/3217.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17664469 PubMed]<br />
<br />
==Cisplatin & Fluorouracil {{#subobject:4d9936|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CF: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
<br>FP: '''<u>F</u>'''luorouracil, '''<u>P</u>'''latinol (Cisplatin)<br />
===Variant #1, 80/4000 x 6 {{#subobject:782e95|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%2810%2961121-X/fulltext Bang et al. 2010 (ToGA)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CF_.26_Trastuzumab|CF & Trastuzumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Patients in '''ToGA''' had overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation.''<br />
<br />
''ToGA Patients: 100% adenocarcinoma (19% gastroesophageal junction, 81% gastric). 10% with ECOG of 2.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1, '''given second''' (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*Some protocols: "Hyperhydration" for [[Cisplatin (Platinol)]]<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Variant #2, 80/4000 x 8 {{#subobject:9abe95|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://academic.oup.com/annonc/article/28/9/2142/4061259 Ajani et al. 2017 (DIGEST)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_S-1|CS]]<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 over 1 to 3 hours once on day 1, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1, '''given second''' (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*Some protocols: "Hyperhydration" for [[Cisplatin (Platinol)]]<br />
<br />
'''21-day cycle for 8 cycles'''<br />
<br />
===Variant #3, 80/4000, indefinite {{#subobject:69c795|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://annonc.oxfordjournals.org/content/20/4/666.long Kang et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CX_2|CX]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.18_suppl.LBA4007 Tabernero et al. 2019 (KEYNOTE-062)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin.2C_Fluorouracil.2C_Pembrolizumab|CF & Pembrolizumab]]<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 over 1 to 3 hours once on day 1, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1, '''given second''' (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*Some protocols: "Hyperhydration" for [[Cisplatin (Platinol)]]<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, 100/4000 {{#subobject:16f88f|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/26/5B/3877.long Duffour et al. 2006 (FFCD 9404)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CLF|FLP]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on either day 1 or 2<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #5, 100/4000, split-dose cisplatin {{#subobject:16f18e|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" |[http://jco.ascopubs.org/content/21/1/54.long Ohtsu et al. 2003 (JCOG 9205)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Fluorouracil_monotherapy|Fluorouracil]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#UFTM|UFTM]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Study included patients with PFS of 2 (9.6%)'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===Variant #6, 100/5000 {{#subobject:10f0c6|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/24/31/4991.long Van Cutsem et al. 2006 (TAX 325)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#DCF|DCF]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://annonc.oxfordjournals.org/content/19/8/1450.long Dank et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRI|IF]]<br />
| style="background-color:#fee08b" |Might have inferior TTP<br />
|-<br />
|[https://ascopubs.org/doi/10.1200/JCO.2009.25.4706 Ajani et al. 2010 (FLAGS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_S-1|CS]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Van Cutsem et al Patients: 100% adenocarcinoma histology (22% Esophagogastric junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS of 70.'' <br />
<br />
''Dank et al Patients: 100% adenocarcinoma histology (20% Esophagogastric junction, 80% gastric origin). 96% with metastatic disease. 1% with Karnofsky PS of 70.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1, '''given second''' (total dose per cycle: 5000 mg/m<sup>2</sup> )<br />
<br />
====Supportive medications====<br />
<br />
*As described in Dank et al. 2008:<br />
*"Hyperhydration" for 2 to 3 days with each infusion<br />
*[[Ondansetron (Zofran)]] IV for antiemetic prophylaxis<br />
*[[Dexamethasone (Decadron)]] IV for antiemetic prophylaxis, then PO for 2 to 3 days<br />
*[[Metoclopramide (Reglan)]] for antiemetic prophylaxis<br />
*[[Filgrastim (Neupogen)]] (dose not specified) SC once per day, starting on day 4, to be continued until ANC greater than 1000/uL for grade 3 to 4 neutropenia, febrile neutropenia, or neutropenic infection<br />
*[[Atropine (Atropen)]] prn cholinergic symptoms<br />
*[[Loperamide (Imodium)]] prn delayed diarrhea<br />
<br />
'''28-day cycles'''<br />
===References===<br />
<br />
#'''JCOG 9205:''' Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; Japan Clinical Oncology Group Study (JCOG9205). Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. [http://jco.ascopubs.org/content/21/1/54.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506170 PubMed]<br />
#'''FFCD 9404:''' Duffour J, Bouché O, Rougier P, Milan C, Bedenne L, Seitz JF, Buecher B, Legoux JL, Ducreux M, Vetter D, Raoul JL, François E, Ychou M. Safety of cisplatin combined with continuous 5-FU versus bolus 5-FU and leucovorin, in metastatic gastrointestinal cancer (FFCD 9404 randomised trial). Anticancer Res. 2006 Sep-Oct;26(5B):3877-83. [http://ar.iiarjournals.org/content/26/5B/3877.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17094417 PubMed]<br />
#'''TAX 325:''' Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006 Nov 1;24(31):4991-7. [http://jco.ascopubs.org/content/24/31/4991.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17075117 PubMed]<br />
#Dank M, Zaluski J, Barone C, Valvere V, Yalcin S, Peschel C, Wenczl M, Goker E, Cisar L, Wang K, Bugat R. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2008 Aug;19(8):1450-7. Epub 2008 Jun 16. [http://annonc.oxfordjournals.org/content/19/8/1450.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18558665 PubMed]<br />
#Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009 Apr;20(4):666-73. Epub 2009 Jan 19. [http://annonc.oxfordjournals.org/content/20/4/666.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19153121 PubMed]<br />
#'''FLAGS:''' Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010 Mar 20;28(9):1547-53. Epub 2010 Feb 16. [https://ascopubs.org/doi/10.1200/JCO.2009.25.4706 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20159816 PubMed]<br />
#'''ToGA:''' Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961121-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20728210 PubMed]<br />
#'''AVAGAST:''' Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. Epub 2011 Aug 15. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.2236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21844504 PubMed]<br />
#'''DIGEST:''' Ajani JA, Abramov M, Bondarenko I, Shparyk Y, Gorbunova V, Hontsa A, Otchenash N, Alsina M, Lazarev S, Feliu J, Elme A, Esko V, Abdalla K, Verma U, Benedetti F, Aoyama T, Mizuguchi H, Makris L, Rosati G; DIGEST Study Group. A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol. 2017 Sep 1;28(9):2142-2148. [https://academic.oup.com/annonc/article/28/9/2142/4061259 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28911091 PubMed]<br />
#'''Abstract:''' Tabernero J, Van Cutsem E, Yung-Jue B, Fuchs CS, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Salguero HR, Mansoor W, Freitas MI, Brachiroli M, Goekkurt E, Chao J, Wainberg ZA, Kher U, Shah S, Kang SP, Shitara K. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophgeal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. 2019 American Society of Clinical Oncology annual meeting. [[https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.18_suppl.LBA4007 link to abstract]<br />
<br />
<br />
==Cisplatin, Fluorouracil, Pembrolizumab==<br />
{| class="wikitable"<br />
|[[Gastric cancer#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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.18_suppl.LBA4007 Tabernero et al. 2019 (KEYNOTE-062)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_.26_Fluorouracil_3|CF]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test<br />
<br />
''KEYNOTE-062 included patients with GEJ malignancy''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup> IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
**Alternative: capecitabine 1000 mg/m<sup>2</sup> PO BID on days 1-14<br />
<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Abstract:''' Tabernero J, Van Cutsem E, Yung-Jue B, Fuchs CS, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Salguero HR, Mansoor W, Freitas MI, Brachiroli M, Goekkurt E, Chao J, Wainberg ZA, Kher U, Shah S, Kang SP, Shitara K. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophgeal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. 2019 American Society of Clinical Oncology annual meeting. [[https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.18_suppl.LBA4007 link to abstract]<br />
<br />
==Cisplatin & S-1 {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CS: '''<u>C</u>'''isplatin & '''<u>S</u>'''-1<br />
<br>SP: '''<u>S</u>'''-1 & '''<u>P</u>'''latinol (Cisplatin)<br />
===Variant #1, q3wk ("SP3") {{#subobject:4ff7cf|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://academic.oup.com/annonc/article/26/10/2097/144476 Ryu et al. 2015 (SOS)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|SP5<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2, q4wk {{#subobject:03b3c4|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://ascopubs.org/doi/10.1200/JCO.2009.25.4706 Ajani et al. 2010 (FLAGS)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Fluorouracil_3|CF]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/28/9/2142/4061259 Ajani et al. 2017 (DIGEST)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Fluorouracil_3|CF]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: this is an experimental arm of a study where the primary endpoint was not met. Included because CS has been shown to be superior in comparison to other regimens (see above).''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] 25 mg/m<sup>2</sup> PO twice per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, q5wk ("SP5") {{#subobject:cdcc15|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(08)70035-4/fulltext Koizumi et al. 2008 (SPIRITS)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/26/1/141/2802628 Yamada et al. 2014 (G-SOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|SOX<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|[https://academic.oup.com/annonc/article/26/10/2097/144476 Ryu et al. 2015 (SOS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|SP3<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00553-7/fulltext Fujitani et al. 2016 (REGATTA)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2018.77.8613 Ishigami et al. 2018 (PHOENIX-GC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Paclitaxel_.26_S-1|IV/IP Paclitaxel & S-1]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/langas/article/PIIS2468-1253(19)30083-4/fulltext Yamada et al. 2019 (JCOG1013)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin, Docetaxel, S-1<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: in REGATTA, there was no difference in outcome amongst patients who did or did not undergo surgery.'' <br />
<br />
''Inclusion criteria for REGATTA included the presence of a single non-curable factor (ex: hepatic, peritoneal, and para-aortic mets), see link for further details''<br />
<br />
''SPIRITS trial included patients with ECOG of 2 (3% of patients)''<br />
<br />
''Inclusion criteria for PHOENIX-GC included patients with peritoneal metastasis who had received less than or equal to 2 months of prior chemotherapy without disease progression, see link for further details''<br />
====Preceding treatment====<br />
<br />
*REGATTA: Non-laparoscopic [[Surgery#Gastrectomy|gastrectomy]] with D1 [[Surgery#Lymphadenectomy|lymphadenectomy]] versus no surgery; chemotherapy began within 8 weeks of surgery<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 8<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 21<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 21<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 21<br />
<br />
'''35-day cycles'''<br />
<br />
===References===<br />
<br />
#'''SPIRITS:''' Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008 Mar;9(3):215-21. Epub 2008 Feb 20. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(08)70035-4/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18282805 PubMed]<br />
#'''FLAGS:''' Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010 Mar 20;28(9):1547-53. Epub 2010 Feb 16. [https://ascopubs.org/doi/10.1200/JCO.2009.25.4706 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20159816 PubMed]<br />
#'''G-SOX:''' Yamada Y, Higuchi K, Nishikawa K, Gotoh M, Fuse N, Sugimoto N, Nishina T, Amagai K, Chin K, Niwa Y, Tsuji A, Imamura H, Tsuda M, Yasui H, Fujii H, Yamaguchi K, Yasui H, Hironaka S, Shimada K, Miwa H, Hamada C, Hyodo I. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer. Ann Oncol. 2015 Jan;26(1):141-8. Epub 2014 Oct 14. [https://academic.oup.com/annonc/article/26/1/141/2802628 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25316259 PubMed]<br />
#'''SOS:''' Ryu MH, Baba E, Lee KH, Park YI, Boku N, Hyodo I, Nam BH, Esaki T, Yoo C, Ryoo BY, Song EK, Cho SH, Kang WK, Yang SH, Zang DY, Shin DB, Park SR, Shinozaki K, Takano T, Kang YK; SOS study investigators. Comparison of two different S-1 plus cisplatin dosing schedules as first-line chemotherapy for metastatic and/or recurrent gastric cancer: a multicenter, randomized phase III trial (SOS). Ann Oncol. 2015 Oct;26(10):2097-101. Epub 2015 Jul 27. [https://academic.oup.com/annonc/article/26/10/2097/144476 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26216386 PubMed]<br />
#'''REGATTA:''' Fujitani K, Yang HK, Mizusawa J, Kim YW, Terashima M, Han SU, Iwasaki Y, Hyung WJ, Takagane A, Park DJ, Yoshikawa T, Hahn S, Nakamura K, Park CH, Kurokawa Y, Bang YJ, Park BJ, Sasako M, Tsujinaka T; REGATTA study investigators. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial. Lancet Oncol. 2016 Mar;17(3):309-18. Epub 2016 Jan 26. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00553-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26822397 PubMed]<br />
#'''DIGEST:''' Ajani JA, Abramov M, Bondarenko I, Shparyk Y, Gorbunova V, Hontsa A, Otchenash N, Alsina M, Lazarev S, Feliu J, Elme A, Esko V, Abdalla K, Verma U, Benedetti F, Aoyama T, Mizuguchi H, Makris L, Rosati G; DIGEST Study Group. A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol. 2017 Sep 1;28(9):2142-2148. [https://academic.oup.com/annonc/article/28/9/2142/4061259 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28911091 PubMed]<br />
#'''PHOENIX-GC:''' Ishigami H, Fujiwara Y, Fukushima R, Nashimoto A, Yabusaki H, Imano M, Imamoto H, Kodera Y, Uenosono Y, Amagai K, Kadowaki S, Miwa H, Yamaguchi H, Yamaguchi T, Miyaji T, Kitayama J. Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial. J Clin Oncol. 2018 Jul 1;36(19):1922-1929. Epub 2018 May 10. [https://ascopubs.org/doi/full/10.1200/JCO.2018.77.8613 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746229 PubMed]<br />
#'''JCOG1013:''' Yamada Y, Boku N, Mizusawa J, Iwasa S, Kadowaki S, Nakayama N, Azuma M, Sakamoto T, Shitara K, Tamura T, Chin K, Hata H, Nakamori M, Hara H, Yasui H, Katayama H, Fukuda H, Yoshikawa T, Sasako M, Terashima M. Docetaxel plus cisplatin and S-1 versus cisplatin and S-1 in patients with advanced gastric cancer (JCOG1013): an open-label, phase 3, randomised controlled trial. Lancet Gastroenterol Hepatol. 2019 May 14. [Epub ahead of print] [https://www.thelancet.com/journals/langas/article/PIIS2468-1253(19)30083-4/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31101534 PubMed]<br />
<br />
==CLF {{#subobject:b913d6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CLF: '''<u>C</u>'''isplatin, '''<u>L</u>'''eucovorin, '''<u>F</u>'''luorouracil<br />
<br>FLP: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>P</u>'''latinol (Cisplatin)<br />
===Variant #1 {{#subobject:beef19|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/26/9/1435.long Al-Batran et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#OLF|FLO]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|}<br />
''Note: In contrast to the original reference, some guidelines list 5-FU as being given every 2 weeks rather than the schedule below.''<br />
<br />
''Patients: 100% adenocarcinoma histology (20% gastroesophageal junction, 80% gastric'').<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29, 43<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29, 43<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 12,000 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*Up to 3 liters normal saline as hydration with [[Cisplatin (Platinol)]]<br />
*Antiemetic medications per "local protocols"<br />
<br />
'''8-week cycles'''<br />
<br />
===Variant #2 {{#subobject:34890|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/22/21/4319.long Bouché et al. 2004 (FFCD 9803)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|1. [[Esophageal_cancer#Fluorouracil_.26_Folinic_acid|LV5FU2]]<br> 2. [[Esophageal_cancer#FOLFIRI|LV5FU2 & Irinotecan]]<br />
| style="background-color:#d3d3d3" |Not powered to draw conclusions<br />
|-<br />
|}<br />
''Note: the primary reference said every cycle was 15 days, but also said that medications were given every 14 days, so the assumption was made that this more regular schedule was used.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once on either day 1 or 2<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup> IV continuous infusion over 22 hours (total dose per cycle: 1600 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*1 liter hydration over 3 hours before and after [[Cisplatin (Platinol)]]<br />
*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] IV before [[Cisplatin (Platinol)]]<br />
*[[Methylprednisolone (Solumedrol)]] 120 mg IV 10 minutes before [[Cisplatin (Platinol)]]<br />
*Oral antiemetics and corticosteroids from days 2 to 5<br />
<br />
'''14-day cycle for at least 4 cycles'''<br />
<br />
===References===<br />
<br />
#'''FFCD 9803:''' Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, Arsène D, Paitel JF, Guérin-Meyer V, Mitry E, Buecher B, Kaminsky MC, Seitz JF, Rougier P, Bedenne L, Milan C; Fédération Francophone de Cancérologie Digestive Group. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1;22(21):4319-28. [http://jco.ascopubs.org/content/22/21/4319.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15514373 PubMed]<br />
#Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jäger E; Arbeitsgemeinschaft Internistische Onkologie. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008 Mar 20;26(9):1435-42. [http://jco.ascopubs.org/content/26/9/1435.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18349393 PubMed]<br />
<br />
==CX {{#subobject:2bd34d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CX: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
<br>XP: '''<u>X</u>'''eloda (Capecitabine), '''<u>P</u>'''latinol (Cisplatin)<br />
===Regimen {{#subobject:82b184|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://annonc.oxfordjournals.org/content/20/4/666.long Kang et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Fluorouracil_3|CF]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2011.36.2236 Ohtsu et al. 2011 (AVAGAST)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & 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)70102-5/abstract Lordick et al. 2013 (EXPAND)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & Cetuximab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544634/ Shen et al. 2014 (AVATAR)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(14)00884-3/fulltext Kim et al. 2014 (SMC 2008-12-019)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & Simvastatin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097104/ Lu et al. 2018 (PAC-C)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Capecitabine & Paclitaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30791-5/fulltext Fuchs et al. 2019 (RAINFALL)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & Ramucirumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS (*)<br />
|-<br />
|}<br />
The following studies included patients with GE junction malignancy as well: <br />
<br />
*''AVAGAST patients: 86% gastric and 14% GE junction. 5.4% of patients had an ECOG of 2.''<br />
*''EXPAND patients: 83% gastric, 5% GE junction and 16% unknown''<br />
*''Kim et al patients: 79% gastric, 16% GE junction and 5% unknown''<br />
<br />
''Note: while the primary analysis of RAINFALL showed that this arm seemed to have inferior PFS, independent central review did not confirm this finding.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
**EXPAND: 1000 mg/m<sup>2</sup> PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)<br />
<br />
====Supportive medications====<br />
<br />
*Some protocols: "Hyperhydration" for [[Cisplatin (Platinol)]]<br />
<br />
'''21-day cycles, varied duration (see below)'''<br />
====Subsequent treatment====<br />
<br />
*AVAGAST & AVATAR: after 6 cycles, [[#Capecitabine_monotherapy_2|capecitabine maintenance]]<br />
*Kim et al. 2014: after 8 cycles, [[#Capecitabine_monotherapy_2|capecitabine maintenance]]<br />
<br />
===References===<br />
<br />
#Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009 Apr;20(4):666-73. Epub 2009 Jan 19. [http://annonc.oxfordjournals.org/content/20/4/666.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19153121 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
#'''AVAGAST:''' Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. Epub 2011 Aug 15. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.2236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21844504 PubMed]<br />
#'''EXPAND:''' Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V, Park JO, Sawaki A, Celik I, Götte H, Melezínková H, Moehler M; Arbeitsgemeinschaft Internistische Onkologie (AIO) and EXPAND Investigators. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013 May;14(6):490-9. Epub 2013 Apr 15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70102-5/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23594786 PubMed]<br />
#'''AVATAR:''' Shen L, Li J, Xu J, Pan H, Dai G, Qin S, Wang L, Wang J, Yang Z, Shu Y, Xu R, Chen L, Liu Y, Yu S, Bu L, Piao Y. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer. 2015 Jan;18(1):168-76. Epub 2014 Feb 21. [https://link.springer.com/article/10.1007%2Fs10120-014-0351-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544634/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24557418 PubMed]<br />
#'''SMC 2008-12-019:''' Kim ST, Kang JH, Lee J, Park SH, Park JO, Park YS, Lim HY, Hwang IG, Lee SC, Park KW, Lee HR, Kang WK. Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study. Eur J Cancer. 2014 Nov;50(16):2822-30. Epub 2014 Sep 15. [https://www.ejcancer.com/article/S0959-8049(14)00884-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25218337 PubMed]<br />
#'''PAC-C:''' Lu Z, Zhang X, Liu W, Liu T, Hu B, Li W, Fan Q, Xu J, Xu N, Bai Y, Pan Y, Xu Q, Bai W, Xia L, Gao Y, Wang W, Shu Y, Shen L. A multicenter, randomized trial comparing efficacy and safety of paclitaxel/capecitabine and cisplatin/capecitabine in advanced gastric cancer. Gastric Cancer. 2018 Sep;21(5):782-791. Epub 2018 Feb 27. [https://link.springer.com/article/10.1007%2Fs10120-018-0809-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097104/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29488121 PubMed]<br />
#'''RAINFALL:''' Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, Ilson DH, Alsina M, Chau I, Lacy J, Ducreux M, Mendez GA, Alavez AM, Takahari D, Mansoor W, Enzinger PC, Gorbounova V, Wainberg ZA, Hegewisch-Becker S, Ferry D, Lin J, Carlesi R, Das M, Shah MA; RAINFALL Study Group. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):420-435. Epub 2019 Feb 1. Erratum in: Lancet Oncol. 2019 May;20(5):e242. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30791-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30718072 PubMed]<br />
<br />
==CX & Trastuzumab {{#subobject:7cbb79|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CX & Trastuzumab: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine), Trastuzumab<br />
===Variant #1, 80/1600 {{#subobject:cdee6d|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://ascopubs.org/doi/full/10.1200/JCO.2016.71.6852 Shah et al. 2017 (HELOISE)]<br />
| style="background-color:#1a9851" |Phase IIIb (C)<br />
|[[#CX_.26_Trastuzumab|CX & Trastuzumab]]; high-dose<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Patients had overexpression of HER2 protein by immunohistochemistry AND gene amplification by in-situ hybridization.<br />
<br />
''Patients: 79% gastric, 21% GE junction, and all patients had an ECOG of 2''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1 (compared to HD-Trastuzumab at 10 mg/kg IV)<br />
**Subsequent cycles: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*Trastuzumab maintenance<br />
<br />
===Variant #2, 80/2000 {{#subobject:27adc6|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%2810%2961121-X/fulltext Bang et al. 2010 (ToGA)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#CX|CX]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30481-9/fulltext Tabernero et al. 2018 (JACOB)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX, Pertuzumab, Trastuzumab<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
ToGA patients had overexpression of HER2 protein by immunohistochemistry OR gene amplification by fluorescence in-situ hybridization.<br />
<br />
''ToGA patients: 81% gastric, 19% GE junction. 10% of patients with ECOG of 2.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Subsequent cycles: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ToGA:''' Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961121-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20728210 PubMed]<br />
#'''HELOISE:''' Shah MA, Xu RH, Bang YJ, Hoff PM, Liu T, Herráez-Baranda LA, Xia F, Garg A, Shing M, Tabernero J. HELOISE: Phase IIIb randomized multicenter study comparing standard-of-care and higher-dose trastuzumab regimens combined with chemotherapy as first-line therapy in patients with human epidermal growth factor receptor 2-positive metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol. 2017 Aug 1;35(22):2558-2567. Epub 2017 Jun 2.[https://ascopubs.org/doi/full/10.1200/JCO.2016.71.6852 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28574779 PubMed]<br />
#'''JACOB:''' Tabernero J, Hoff PM, Shen L, Ohtsu A, Shah MA, Cheng K, Song C, Wu H, Eng-Wong J, Kim K, Kang YK. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018 Oct;19(10):1372-1384. Epub 2018 Sep 11. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30481-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30217672 PubMed]<br />
<br />
==DCF {{#subobject:efbdc5|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 />
<br>TCF: '''<u>T</u>'''axotere (Docetaxel), '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
<br />
===Variant #1 {{#subobject:5aba07|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/23/24/5660.long Ajani et al. 2005 (V-325)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Cisplatin_.26_Docetaxel|DC]]<br />
| style="background-color:#91cf60" |Seems to have superior ORR<br />
|-<br />
|[http://jco.ascopubs.org/content/24/31/4991.long Van Cutsem et al. 2006 (TAX 325)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Cisplatin_.26_Fluorouracil_3|CF]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
<br />
''Note: In contrast to the original references, some guidelines list each cycle as lasting 28 days.''<br />
<br />
''Anjani et al. Patients: 100% adenocarcinoma histology (32% gastroesophageal junction/fundus and 68% gastric antrum/body). 95% were metastatic. 1% with Karnofsky PS score of 70.'' <br />
<br />
''Van Cutsem et al Patients: 100% adenocarcinoma histology (22% gastroesophageal junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS score of 70.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 1 to 3 hours 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 />
<br />
*(varied depending on reference):<br />
*[[Dexamethasone (Decadron)]] 8 mg PO once the night before chemotherapy, then 8 mg PO once on day 1; 1 hour prior to chemotherapy, then 8 mg PO twice per day until day 2 (total dose per cycle: 48 mg)<br />
*[[Dexamethasone (Decadron)]] 20 mg IV before [[Cisplatin (Platinol)]] and 8 hours after [[Cisplatin (Platinol)]]<br />
*[[Ondansetron (Zofran)]] 8 mg IV before [[Cisplatin (Platinol)]], 4 hours after [[Cisplatin (Platinol)]], and 8 hours after [[Cisplatin (Platinol)]]<br />
*"Hydration [was] administered in a standard manner"<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2 {{#subobject:baa015|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" |[http://jco.ascopubs.org/content/25/22/3217.long Roth et al. 2007]<br />
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|1. [[#ECF_3|ECF]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Cisplatin_.26_Docetaxel|TC]]<br />
| style="background-color:#d9ef8b" |Might have superior ORR<br />
|-<br />
|}<br />
''Note: the protocol was amended to change the original dose of ''docetaxel from'' 85 mg/m<sup>2</sup> to 75 mg/m<sup>2</sup> based on high incidence of febrile neutropenia.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 4 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion over 14 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*3 liters per day "hyperhydration"<br />
*[[Dexamethasone (Decadron)]] 8 mg PO given 12 hours & 6 hours before [[Docetaxel (Taxotere)]], then 8 mg PO twice per day for 4 days after [[Docetaxel (Taxotere)]]<br />
*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] for emesis prophylaxis<br />
*Growth factor support allowed, such as with [[Filgrastim (Neupogen)]]<br />
<br />
'''21-day cycle for up to 8 cycles'''<br />
<br />
===References===<br />
<br />
#'''V-325:''' Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Cabral Filho S, Majlis A, Assadourian S, Van Cutsem E. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005 Aug 20;23(24):5660-7. [http://jco.ascopubs.org/content/23/24/5660.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16110025 PubMed]<br />
#'''TAX 325:''' Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006 Nov 1;24(31):4991-7. [http://jco.ascopubs.org/content/24/31/4991.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17075117 PubMed]<br />
#Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. [http://jco.ascopubs.org/content/25/22/3217.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17664469 PubMed]<br />
<br />
==mDCF {{#subobject:70e20f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mDCF: '''<u>m</u>'''odified '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
===Variant #1, 40/40/2800 {{#subobject:372f9c|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/PMC3646322/ Shah et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: In contrast to the primary reference, some guidelines list this regimen without bevacizumab. Please see below for the original mDCF regimen that included bevacizumab.''<br />
<br />
''Patients: 100% adenocarcinoma (50% gastric, 45% gastroesophageal junction, 5% esophagus). 93% received no prior therapy.'' <br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Cisplatin (Platinol)]] 40 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 3<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*"Standard premedication and delayed emesis regimens"<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, 60/60/3000 {{#subobject:323b13|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://meetinglibrary.asco.org/content/1882-72 Ozal et al. 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/PMC4688303/ Wang et al. 2015 (DOCET_L_02195)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_.26_Fluorouracil_3|CF]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] by one of the following:<br />
**600 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3000 mg/m<sup>2</sup>)<br />
**750 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3000 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#'''Abstract:''' G. Ozal, M. Dogan, H. Akbulut, B. Yalcin, G. Utkan, Y. Urun, F. Icli. The safety and efficacy of modified-dose docetaxel, cisplatin, and 5-fluorouracil (mDCF) combination in the front-line treatment of advanced gastric cancer. 2010 Gastrointestinal Cancers Symposium abstract 113. [http://meetinglibrary.asco.org/content/1882-72 link to abstract]<br />
#Shah MA, Jhawer M, Ilson DH, Lefkowitz RA, Robinson E, Capanu M, Kelsen DP. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011 Mar 1;29(7):868-74. Epub 2010 Dec 28. [http://jco.ascopubs.org/content/29/7/868.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646322/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21189380 PubMed]<br />
#'''DOCET_L_02195:''' Wang J, Xu R, Li J, Bai Y, Liu T, Jiao S, Dai G, Xu J, Liu Y, Fan N, Shu Y, Ba Y, Ma D, Qin S, Zheng L, Chen W, Shen L. Randomized multicenter phase III study of a modified docetaxel and cisplatin plus fluorouracil regimen compared with cisplatin and fluorouracil as first-line therapy for advanced or locally recurrent gastric cancer. Gastric Cancer. 2016 Jan;19(1):234-44. Epub 2015 Jan 21. [https://link.springer.com/article/10.1007%2Fs10120-015-0457-4 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688303/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25604851 PubMed]<br />
<br />
==mDCF & Bevacizumab {{#subobject:30ea9e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mDCF & Bevacizumab: '''<u>m</u>'''odified '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil & Bevacizumab<br />
===Regimen {{#subobject:5485f9|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/PMC3646322/ Shah et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma (50% gastric, 45% gastroesophageal junction, 5% esophagus). 93% received no prior therapy.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Cisplatin (Platinol)]] 40 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 3<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*"Standard premedication and delayed emesis regimens"<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#Shah MA, Jhawer M, Ilson DH, Lefkowitz RA, Robinson E, Capanu M, Kelsen DP. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011 Mar 1;29(7):868-74. Epub 2010 Dec 28. [http://jco.ascopubs.org/content/29/7/868.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646322/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21189380 PubMed]<br />
<br />
==Docetaxel & S-1 {{#subobject:a22c2a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:82ca03|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/PMC3895196/ Koizumi et al. 2013 (START<sub>gastric</sub>)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV once on day 1<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 14<br />
**BSA between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''START:''' Koizumi W, Kim YH, Fujii M, Kim HK, Imamura H, Lee KH, Hara T, Chung HC, Satoh T, Cho JY, Hosaka H, Tsuji A, Takagane A, Inokuchi M, Tanabe K, Okuno T, Ogura M, Yoshida K, Takeuchi M, Nakajima T; JACCRO and KCSG Study Group. Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START). J Cancer Res Clin Oncol. 2014 Feb;140(2):319-28. Epub 2013 Dec 24. [https://link.springer.com/article/10.1007%2Fs00432-013-1563-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895196/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24366758 PubMed]<br />
<br />
==ECF {{#subobject:6325cb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:e5ede0|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://annonc.oxfordjournals.org/content/5/7/609.long Findlay et al. 1994]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://ascopubs.org/doi/10.1200/JCO.1997.15.1.261 Webb et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Gastric_cancer_-_historical#FAMTX|FAMTX]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/20/8/1996.long Ross et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MCF|MCF]]<br />
| style="background-color:#eeee01" |Seems to have non-inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/22/3217.long Roth et al. 2007]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|1. [[#Cisplatin_.26_Docetaxel|TC]]<br> 2. [[#DCF|TCF]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
| rowspan="3" |[https://www.nejm.org/doi/full/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#ECX_2|ECX]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|2. [[#EOF_2|EOF]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|3. [[#EOX_2|EOX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Findlay et al. Patients: all metastatic gastric cancer''<br />
<br />
''Ross et al. Patients: adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma histology, all advanced esophagogastric cancer.''<br />
<br />
''Roth et al. Patients: all metastatic gastric cancer'' <br />
<br />
''REAL-2 Patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 4 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*(varied depending on reference):<br />
*3 liters per day "hyperhydration"<br />
*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] for emesis prophylaxis<br />
*Growth factor support allowed, such as with [[Filgrastim (Neupogen)]]<br />
*Ross et al. 2002 & Cunningham et al. 2008 used [[Warfarin (Coumadin)]] 1 mg PO once per day for catheter thrombosis prophylaxis<br />
<br />
'''21-day cycle for up to 8 cycles'''<br />
<br />
===References===<br />
<br />
#Findlay M, Cunningham D, Norman A, Mansi J, Nicolson M, Hickish T, Nicolson V, Nash A, Sacks N, Ford H, Carter R, Hill A. A phase II study in advanced gastro-esophageal cancer using epirubicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF). Ann Oncol. 1994 Sep;5(7):609-16. [http://annonc.oxfordjournals.org/content/5/7/609.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7993836 PubMed]<br />
#Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, Hughes M, Mansi J, Findlay M, Hill A, Oates J, Nicolson M, Hickish T, O'Brien M, Iveson T, Watson M, Underhill C, Wardley A, Meehan M. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol. 1997 Jan;15(1):261-7. [https://ascopubs.org/doi/10.1200/JCO.1997.15.1.261 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8996151 PubMed]<br />
##'''Update:''' Waters JS, Norman A, Cunningham D, Scarffe JH, Webb A, Harper P, Joffe JK, Mackean M, Mansi J, Leahy M, Hill A, Oates J, Rao S, Nicolson M, Hickish T. Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer. 1999 Apr;80(1-2):269-72. [https://www.nature.com/articles/6690350 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363002/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/10390007 PubMed]<br />
#Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, Price T, Anderson H, Iveson T, Hickish T, Lofts F, Norman A. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol. 2002 Apr 15;20(8):1996-2004. [http://jco.ascopubs.org/content/20/8/1996.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11956258 PubMed]<br />
#Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. [http://jco.ascopubs.org/content/25/22/3217.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17664469 PubMed]<br />
#'''REAL-2:''' Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. [https://www.nejm.org/doi/full/10.1056/NEJMoa073149 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18172173 PubMed]<br />
<br />
==ECX {{#subobject:36cac7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECX: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
<br>ECC: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>C</u>'''apecitabine<br />
===Variant #1, continuous capecitabine {{#subobject:f0efc0|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(17)30566-1/fulltext Catenacci et al. 2017 (RILOMET-1)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|ECX & Rilotumumab<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Patients had unresectable or metastatic MET-positive gastric or gastro-esophageal junction cancer.''<br />
<br />
''Patients: ~80% gastric, 20% GE junction and 10% distal esophageal''<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day<br />
<br />
'''21-day cycle for up to 10 cycles'''<br />
<br />
===Variant #2, intermittent capecitabine {{#subobject:f0efc0|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.ejcancer.com/article/S0959-8049(10)00731-8/fulltext Konings et al. 2010]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|ECC & Pravastatin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS6<br />
|-<br />
|}<br />
''Patients: 6.6% of patients had an ECOG of 2''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1, '''given first'''<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given second'''<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Konings IR, van der Gaast A, van der Wijk LJ, de Jongh FE, Eskens FA, Sleijfer S. The addition of pravastatin to chemotherapy in advanced gastric carcinoma: a randomised phase II trial. Eur J Cancer. 2010 Dec;46(18):3200-4. Epub 2010 Aug 18. [https://www.ejcancer.com/article/S0959-8049(10)00731-8/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20727735 PubMed]<br />
#'''RILOMET-1:''' Catenacci DVT, Tebbutt NC, Davidenko I, Murad AM, Al-Batran SE, Ilson DH, Tjulandin S, Gotovkin E, Karaszewska B, Bondarenko I, Tejani MA, Udrea AA, Tehfe M, De Vita F, Turkington C, Tang R, Ang A, Zhang Y, Hoang T, Sidhu R, Cunningham D. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1467-1482. Epub 2017 Sep 25. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30566-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28958504 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:588907|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, CI {{#subobject:3289d8|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" |[http://jco.ascopubs.org/content/21/1/54.long Ohtsu et al. 2003 (JCOG 9205)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Cisplatin_.26_Fluorouracil_3|FP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#UFTM|UFTM]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70259-1/fulltext Boku et al. 2009 (JCOG 9912)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Cisplatin & Irinotecan<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|2. [[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|[https://academic.oup.com/jjco/article/43/10/972/851849 Shirao et al. 2013 (JCOG 0106)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MF<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%<br />
|-<br />
|}<br />
''JCOG 9205 included patients with PFS of 2 (9.6%)''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, intermittent, BSA-based {{#subobject:27a992|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://jamanetwork.com/journals/jama/fullarticle/397816 Cullinan et al. 1985]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|1. FA<br> 2. [[Gastric_cancer_-_historical#FAM|FAM]]<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 represents a de-escalation strategy.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycles'''<br />
<br />
===Variant #3, intermittent, weight-based {{#subobject:27jb82|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.karger.com/Article/Abstract/226337 Kolarić et al. 1986]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Epirubicin & Fluorouracil<br />
| style="background-color:#fc8d59" |Seems to have inferior DOR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 12 mg/kg IV once per day on days 1 to 5<br />
<br />
'''21- to 28-day cycles'''<br />
<br />
===Variant #4, PVI {{#subobject:d98c9f|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://academic.oup.com/annonc/article/13/10/1568/167797 Tebbutt et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & Mitomycin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion<br />
<br />
'''Up to 24-week course'''<br />
<br />
===References===<br />
<br />
#Cullinan SA, Moertel CG, Fleming TR, Rubin JR, Krook JE, Everson LK, Windschitl HE, Twito DI, Marschke RF, Foley JF, Pfeifle DM, Barlow JF. A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma: fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA. 1985 Apr 12;253(14):2061-7. [https://jamanetwork.com/journals/jama/fullarticle/397816 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2579257 PubMed]<br />
#Kolarić K, Potrebica V, Stanovnik M. Controlled phase III clinical study of 4-epi-doxorubicin + 5-fluorouracil versus 5-fluorouracil alone in metastatic gastric and rectosigmoid cancer. Oncology. 1986;43(2):73-7. [https://www.karger.com/Article/Abstract/226337 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/3513075 PubMed]<br />
#Tebbutt NC, Norman A, Cunningham D, Iveson T, Seymour M, Hickish T, Harper P, Maisey N, Mochlinski K, Prior Y, Hill M. A multicentre, randomised phase III trial comparing protracted venous infusion (PVI) 5-fluorouracil (5-FU) with PVI 5-FU plus mitomycin C in patients with inoperable oesophago-gastric cancer. Ann Oncol. 2002 Oct;13(10):1568-75. [https://academic.oup.com/annonc/article/13/10/1568/167797 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12377644 PubMed]<br />
#'''JCOG 9205:''' Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; Japan Clinical Oncology Group Study (JCOG9205). Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. [http://jco.ascopubs.org/content/21/1/54.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506170 PubMed]<br />
#'''JCOG 9912:''' Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, Koizumi W, Saito H, Yamaguchi K, Takiuchi H, Nasu J, Ohtsu A; Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group. Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study. Lancet Oncol. 2009 Nov;10(11):1063-9. Epub 2009 Oct 7. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70259-1/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19818685 PubMed]<br />
#'''JCOG 0106:''' Shirao K, Boku N, Yamada Y, Yamaguchi K, Doi T, Goto M, Nasu J, Denda T, Hamamoto Y, Takashima A, Fukuda H, Ohtsu A; Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group. Randomized Phase III study of 5-fluorouracil continuous infusion vs sequential methotrexate and 5-fluorouracil therapy in far advanced gastric cancer with peritoneal metastasis (JCOG0106). Jpn J Clin Oncol. 2013 Oct;43(10):972-80. Epub 2013 Sep 7. [https://academic.oup.com/jjco/article/43/10/972/851849 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24014884 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, Mitomycin {{#subobject:a4ca9d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:672a28|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.karger.com/Article/Abstract/64319 Hofheinz et al. 2002]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts in this subgroup<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV continuous infusion over 24 hours once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Mitomycin (Mutamycin)]] 10 mg/m<sup>2</sup> IV once per day on days 1 & 22<br />
<br />
'''56-day cycle for 2 cycles'''<br />
<br />
===References===<br />
<br />
#Hofheinz RD, Hartung G, Samel S, Hochhaus A, Pichlmeier U, Post S, Hehlmann R, Queisser W. High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer: a phase II study. Onkologie. 2002 Jun;25(3):255-60. [http://www.karger.com/Article/Abstract/64319 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12119460 PubMed]<br />
<br />
==Irinotecan monotherapy {{#subobject:41e063|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9fb427|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://link.springer.com/article/10.1007%2Fs10620-005-3038-2 Enzinger et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: In contrast to the primary references, some guidelines list a dosing schedule of 125 mg/m<sup>2</sup> IV once per day on days 1 & 8, with 21-day cycles. Enzinger et al. 2005 comment that "when irinotecan is used as a single-agent, a tri-weekly schedule may be preferable."''<br />
<br />
''Study included patients with GE junction and distal esophageal malignancy as well (~59% gastric, 9% GEJ and 33% distal esophagus)''<br />
<br />
''Regimen showed a 14% response rate and 53% disease control rate.''<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<br />
#Enzinger PC, Kulke MH, Clark JW, Ryan DP, Kim H, Earle CC, Vincitore MM, Michelini AL, Mayer RJ, Fuchs CS. A phase II trial of irinotecan in patients with previously untreated advanced esophageal and gastric adenocarcinoma. Dig Dis Sci. 2005 Dec;50(12):2218-23. [http://link.springer.com/article/10.1007%2Fs10620-005-3038-2 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16416165 PubMed]<br />
<br />
==OLF {{#subobject:98b4fa|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OLF: '''<u>O</u>'''xaliplatin, '''<u>L</u>'''eucovorin, '''<u>F</u>'''luorouracil<br />
<br>FLO: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>O</u>'''xaliplatin<br />
===Regimen {{#subobject:3d7273|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/26/9/1435.long Al-Batran et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#CLF|FLP]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma histology (20% esophagogastric junction, 80% gastric'').<br />
<br />
====Chemotherapy====<br />
<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29, 43<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29, 43<br />
*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on days 1, 15, 29, 43 (total dose per cycle: 10,400 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*Antiemetic medications per "local protocols"<br />
<br />
'''8-week cycles'''<br />
<br />
===References===<br />
<br />
#Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jäger E; Arbeitsgemeinschaft Internistische Onkologie. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008 Mar 20;26(9):1435-42. [http://jco.ascopubs.org/content/26/9/1435.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18349393 PubMed]<br />
<br />
==Paclitaxel & S-1 {{#subobject:a88c2a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:82ca09|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://ascopubs.org/doi/full/10.1200/JCO.2018.77.8613 Ishigami et al. 2018 (PHOENIX-GC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_S-1|Cisplatin & S-1]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|}<br />
''Note: Inclusion criteria for PHOENIX-GC included patients with peritoneal metastasis who had received less than or equal to 2 months of prior chemotherapy without disease progression, see link for further details''<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 and 8<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**40 to 60 mg twice per day, depending on body surface area, as follows:<br />
***if less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14<br />
***if 1.25 to less than 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14<br />
***if more than 1.5 m<sup>2</sup>: 60 mg PO twice per day on days 1 to 14<br />
*[[Paclitaxel (Taxol)]] 20 mg/m<sup>2</sup> IP once per day over 1 hour on days 1 and 8<br />
<br />
====Supportive medications====<br />
<br />
*500 mL of normal saline was given prior to intraperitoneal [[Paclitaxel (Taxol)]]<br />
<br />
'''35-day cycles'''<br />
<br />
===References===<br />
<br />
#'''PHOENIX-GC:''' Ishigami H, Fujiwara Y, Fukushima R, Nashimoto A, Yabusaki H, Imano M, Imamoto H, Kodera Y, Uenosono Y, Amagai K, Kadowaki S, Miwa H, Yamaguchi H, Yamaguchi T, Miyaji T, Kitayama J. Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial. J Clin Oncol. 2018 Jul 1;36(19):1922-1929. Epub 2018 May 10. [https://ascopubs.org/doi/full/10.1200/JCO.2018.77.8613 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746229 PubMed]<br />
<br />
==Pembrolizumab monotherapy==<br />
{| class="wikitable"<br />
|[[Gastric cancer#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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.18_suppl.LBA4007 Tabernero et al. 2019 (KEYNOTE-062)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|Chemotherapy<br />
| style="background-color:#ffffbf" |Mixed endpoints<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Improved OS was seen in patients with PD-L1 CPS score of 10 or more (HR: 0.62) but was not tested per analysis plan<br />
<br />
''KEYNOTE-062 included patients with GEJ malignancy''<br />
<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Abstract:''' Tabernero J, Van Cutsem E, Yung-Jue B, Fuchs CS, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Salguero HR, Mansoor W, Freitas MI, Brachiroli M, Goekkurt E, Chao J, Wainberg ZA, Kher U, Shah S, Kang SP, Shitara K. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophgeal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. 2019 American Society of Clinical Oncology annual meeting. [https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.18_suppl.LBA4007 link to abstract]<br />
<br />
==S-1 monotherapy {{#subobject:a12a2a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, BSA-based {{#subobject:86c009|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(09)70259-1/fulltext Boku et al. 2009 (JCOG 9912)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. Cisplatin & Irinotecan<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===Variant #2, weight-based {{#subobject:f90b1b|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(08)70035-4/fulltext Koizumi et al. 2008 (SPIRITS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_S-1|Cisplatin & S-1]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056989/ Narahara et al. 2011 (TOP-002)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|IRIS<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895196/ Koizumi et al. 2013 (START<sub>gastric</sub>)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_S-1|Docetaxel & S-1]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(16)32267-5/fulltext Yoshino et al. 2016 (JFMC36-0701)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Lentinan & S-1<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: there is another trial named START in NSCLC.''<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 between 1.25 and 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 />
===References===<br />
<br />
#'''SPIRITS:''' Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008 Mar;9(3):215-21. Epub 2008 Feb 20. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(08)70035-4/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18282805 PubMed]<br />
#'''JCOG 9912:''' Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, Koizumi W, Saito H, Yamaguchi K, Takiuchi H, Nasu J, Ohtsu A; Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group. Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study. Lancet Oncol. 2009 Nov;10(11):1063-9. Epub 2009 Oct 7. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70259-1/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19818685 PubMed]<br />
#'''TOP-002:''' Narahara H, Iishi H, Imamura H, Tsuburaya A, Chin K, Imamoto H, Esaki T, Furukawa H, Hamada C, Sakata Y. Randomized phase III study comparing the efficacy and safety of irinotecan plus S-1 with S-1 alone as first-line treatment for advanced gastric cancer (study GC0301/TOP-002). Gastric Cancer. 2011 Mar;14(1):72-80. Epub 2011 Feb 23. [https://link.springer.com/article/10.1007%2Fs10120-011-0009-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056989/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21340666 PubMed]<br />
#'''START:''' Koizumi W, Kim YH, Fujii M, Kim HK, Imamura H, Lee KH, Hara T, Chung HC, Satoh T, Cho JY, Hosaka H, Tsuji A, Takagane A, Inokuchi M, Tanabe K, Okuno T, Ogura M, Yoshida K, Takeuchi M, Nakajima T; JACCRO and KCSG Study Group. Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START). J Cancer Res Clin Oncol. 2014 Feb;140(2):319-28. Epub 2013 Dec 24. [https://link.springer.com/article/10.1007%2Fs00432-013-1563-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895196/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24366758 PubMed]<br />
#'''JFMC36-0701:''' Yoshino S, Nishikawa K, Morita S, Takahashi T, Sakata K, Nagao J, Nemoto H, Murakami N, Matsuda T, Hasegawa H, Shimizu R, Yoshikawa T, Osanai H, Imano M, Naitoh H, Tanaka A, Tajiri T, Gochi A, Suzuki M, Sakamoto J, Saji S, Oka M. Randomised phase III study of S-1 alone versus S-1 plus lentinan for unresectable or recurrent gastric cancer (JFMC36-0701). Eur J Cancer. 2016 Sep;65:164-71. Epub 2016 Aug 5. [https://www.ejcancer.com/article/S0959-8049(16)32267-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27501505 PubMed]<br />
<br />
==UFTM {{#subobject:96e8bf|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
UFTM: '''<u>UFT</u>''' (Tegafur and uracil) & '''<u>M</u>'''itomycin <br />
<br />
===Regimen {{#subobject:3a603b|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" |[http://jco.ascopubs.org/content/21/1/54.long Ohtsu et al. 2003 (JCOG 9205)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Fluorouracil_monotherapy|Fluorouracil]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Cisplatin_.26_Fluorouracil_3|FP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Study included patients with PFS of 2 (9.6%)''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Tegafur and uracil (UFT)]] 187.5 mg/m<sup>2</sup> PO twice per day<br />
*[[Mitomycin (Mutamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**"Mitomycin was interrupted for 1 month after patients received a total dose of 60 mg."<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''JCOG 9205:''' Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; Japan Clinical Oncology Group Study (JCOG9205). Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. [http://jco.ascopubs.org/content/21/1/54.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506170 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Capecitabine monotherapy {{#subobject:c6df5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:878a56|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.2011.36.2236 Ohtsu et al. 2011 (AVAGAST)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(14)00884-3/fulltext Kim et al. 2014]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Ohtsu et al patients: 86% gastric and 14% GEJ. 5.4% of patients had an ECOG of 2.''<br />
<br />
''Kim et al patients: 79% gastric, 5% GEJ, and 16% unknown. 2% of patients had an ECOG of 2.''<br />
====Preceding treatment====<br />
<br />
*AVAGAST: [[#CX_2|CX]] x 6<br />
*Kim et al. 2014: [[#CX_2|CX]] x 8<br />
<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. Epub 2011 Aug 15. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.2236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21844504 PubMed]<br />
#Kim ST, Kang JH, Lee J, Park SH, Park JO, Park YS, Lim HY, Hwang IG, Lee SC, Park KW, Lee HR, Kang WK. Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study. Eur J Cancer. 2014 Nov;50(16):2822-30. Epub 2014 Sep 15. [https://www.ejcancer.com/article/S0959-8049(14)00884-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25218337 PubMed]<br />
<br />
=Metastatic or locally advanced disease, subsequent lines of therapy=<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 />
|[https://www.ejcancer.com/article/S0959-8049(11)00396-0/fulltext Thuss-Patience et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Irinotecan_monotherapy_2|Irinotecan]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/30/13/1513.full Kang et al. 2012]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. [[#Irinotecan_monotherapy_2|Irinotecan]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70549-7/fulltext Ford et al. 2014 (COUGAR-02)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2012.48.3552 Ohtsu et al. 2013 (GRANITE-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Everolimus<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.''<br />
<br />
''Thuss-Patience et al. patients: ~58% gastric, 43% GEJ. 21% of patients had an ECOG of 2.''<br />
<br />
''GRANITE-1 study patients: 29% had GEJ involvement. 7.9% of patients had an ECOG of 2.''<br />
<br />
===References===<br />
<br />
#Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, Dogan Y, Gebauer B, Schumacher G, Reichardt P. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011 Oct;47(15):2306-14. [https://www.ejcancer.com/article/S0959-8049(11)00396-0/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21742485 PubMed]<br />
#Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. [http://jco.ascopubs.org/content/30/13/1513.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22412140 PubMed]<br />
#'''COUGAR-02:''' Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA; COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):78-86. Epub 2013 Dec 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70549-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24332238 PubMed]<br />
#'''GRANITE-1:''' Ohtsu A, Ajani JA, Bai YX, Bang YJ, Chung HC, Pan HM, Sahmoud T, Shen L, Yeh KH, Chin K, Muro K, Kim YH, Ferry D, Tebbutt NC, Al-Batran SE, Smith H, Costantini C, Rizvi S, Lebwohl D, Van Cutsem E. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol. 2013 Nov 1;31(31):3935-43. Epub 2013 Sep 16. [https://ascopubs.org/doi/full/10.1200/JCO.2012.48.3552 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24043745 PubMed]<br />
<br />
==Apatinib monotherapy==<br />
{| class="wikitable"<br />
|[[Gastric cancer#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable"<br />
!Study<br />
![[Levels of Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels of Evidence#Efficacy|Efficacy]]<br />
|-<br />
|Kang et al. 2019 (ANGEL)<br />
|Randomized Phase III<br />
|[[Gastric cancer#Placebo|Placebo]]<br />
|Superior PFS<br />
|}<br />
''ANGEL included patients with GEJ malignancy''<br />
<br />
====Chemotherapy====<br />
<br />
*Apatinib (Rivoceranib) 700 mg daily on days 1-28<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Abstract:''' Kang Y, Kang WK, Di Bartolomeo M, Chau I, Yoon HH, Cascinu S, Ryu M, Kim JG, Lee K, Oh SC, Takashima A, Kryzhanivska A, Chao Y, Vladimirov V, Evesque L, Schenker M, McGinn A, Sankar N, Wyrwicz L, Boku N. Randomized Phase 3 ANGEL study of rivoceranib (apatinib) + best supportive care (BSC) vs placebo + BSC in patients with advanced/metastatic gastric cancer. 2019 European Society of Medical Oncology annual meeting. Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394<br />
<br />
==Docetaxel monotherapy {{#subobject:4f3230|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 60 mg/m<sup>2</sup> {{#subobject:577cd6|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/30/13/1513.full Kang et al. 2012]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2, 75 mg/m<sup>2</sup> x 6 {{#subobject:3b4816|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(13)70549-7/fulltext Ford et al. 2014 (COUGAR-02)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<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 />
===Variant #3, 75 mg/m<sup>2</sup>, indefinite {{#subobject:3b47ab|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(17)30111-0/fulltext Thuss-Patience et al. 2017 (GATSBY)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|T-DM1<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Patients in GATSBY had HER2-positive disease. Study patients could only have been treated by one other regimen and could not have been exposed to anthracyclines''<br />
<br />
''Patients: 68% gastric, 32% GEJ''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. [http://jco.ascopubs.org/content/30/13/1513.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22412140 PubMed]<br />
#'''COUGAR-02:''' Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA; COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):78-86. Epub 2013 Dec 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70549-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24332238 PubMed]<br />
#'''GATSBY:''' Thuss-Patience PC, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, Castro H, Mansoor W, Chung HC, Bodoky G, Shitara K, Phillips GDL, van der Horst T, Harle-Yge ML, Althaus BL, Kang YK. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017 May;18(5):640-653. Epub 2017 Mar 23. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30111-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28343975 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, Mitomycin {{#subobject:b4ca9d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:672b28|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.karger.com/Article/Abstract/64319 Hofheinz et al. 2002]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts in this subgroup<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV continuous infusion over 24 hours once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Mitomycin (Mutamycin)]] 10 mg/m<sup>2</sup> IV once per day on days 1 & 22<br />
<br />
'''56-day cycle for 2 cycles'''<br />
<br />
===References===<br />
<br />
#Hofheinz RD, Hartung G, Samel S, Hochhaus A, Pichlmeier U, Post S, Hehlmann R, Queisser W. High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer: a phase II study. Onkologie. 2002 Jun;25(3):255-60. [http://www.karger.com/Article/Abstract/64319 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12119460 PubMed]<br />
<br />
==Irinotecan monotherapy {{#subobject:6df2c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 125 mg/m<sup>2</sup>, 4 weeks out of 6 {{#subobject:9fb427|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://link.springer.com/article/10.1007%2Fs10620-005-3038-2 Enzinger et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: In contrast to the primary references, some guidelines list a dosing schedule of 125 mg/m<sup>2</sup> IV once per day on days 1 & 8, with 21-day cycles. Enzinger et al. 2005 comment that "when irinotecan is used as a single-agent, a tri-weekly schedule may be preferable."''<br />
<br />
''Study included patients with GE junction and distal esophageal malignancy as well (~59% gastric, 9% GE junction and 33% distal esophagus)''<br />
<br />
''Regimen showed a 14% response rate and 53% disease control rate.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22<br />
<br />
'''42-day cycles'''<br />
<br />
===Variant #2, 150 mg/m<sup>2</sup> q2wk {{#subobject:fa1ef9|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/30/13/1513.full Kang et al. 2012]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2012.48.5805 Hironaka et al. 2013 (WJOG 4007)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Paclitaxel_monotherapy|Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(14)00093-8/fulltext Higuchi et al. 2014 (BIRIP)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Irinotecan|Cisplatin & Irinotecan]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(15)00209-9/fulltext Nishikawa et al. 2015 (TRICS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Irinotecan|Cisplatin & Irinotecan]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/26/9/1916/189421 Tanabe et al. 2015 (JACCRO GC-05)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Irinotecan & S-1<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225815/ Bang et al. 2018 (JAVELIN Gastric 300)]<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 />
''Hironaka et al patients: 3.7% patients with an ECOG PS of 2''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #3, 300 mg/m<sup>2</sup> q3wk {{#subobject:c410d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
|-<br />
|[http://annonc.oxfordjournals.org/content/24/6/1567.long Roy et al. 2013 (PEP0206)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. Irinotecan liposome<br />
|-<br />
|}<br />
''Study included patients with GE junction malignancy (77% gastric, 23% GE junction) and included patients with ECOG of 2''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 300 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, 350 mg/m<sup>2</sup> q3wk {{#subobject:160f2f|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.ejcancer.com/article/S0959-8049(11)00396-0/fulltext Thuss-Patience et al. 2011]<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 />
|}<br />
''Thuss-Patience et al. included patients with GE junction malignancy (~58% gastric, 43% GE junction) and included patients with ECOG of 2''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] as follows:<br />
**Cycle 1: 250 mg/m<sup>2</sup> (maximum dose of 500 mg) IV over 30 minutes once on day 1<br />
**Cycles 2 to 10 (depending on toxicity): 350 mg/m<sup>2</sup> IV over 30 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[Atropine (Atropen)]] 0.25 mg SC once on day 1, given prior to [[Irinotecan (Camptosar)]]<br />
*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]]<br />
*[[Dexamethasone (Decadron)]]<br />
<br />
'''21-day cycle for up to 10 cycles'''<br />
<br />
===References===<br />
<br />
#Enzinger PC, Kulke MH, Clark JW, Ryan DP, Kim H, Earle CC, Vincitore MM, Michelini AL, Mayer RJ, Fuchs CS. A phase II trial of irinotecan in patients with previously untreated advanced esophageal and gastric adenocarcinoma. Dig Dis Sci. 2005 Dec;50(12):2218-23. [http://link.springer.com/article/10.1007%2Fs10620-005-3038-2 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16416165 PubMed]<br />
#Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, Dogan Y, Gebauer B, Schumacher G, Reichardt P. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011 Oct;47(15):2306-14. [https://www.ejcancer.com/article/S0959-8049(11)00396-0/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21742485 PubMed]<br />
#Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. [http://jco.ascopubs.org/content/30/13/1513.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22412140 PubMed]<br />
#'''PEP0206:''' Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. [http://annonc.oxfordjournals.org/content/24/6/1567.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23406728 PubMed]<br />
#'''WJOG 4007:''' Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y, Morita S, Okamoto I, Boku N, Hyodo I. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013 Dec 10;31(35):4438-44. Epub 2013 Nov 4. [https://ascopubs.org/doi/full/10.1200/JCO.2012.48.5805 link to original artile] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24190112 PubMed]<br />
#'''BIRIP:''' Higuchi K, Tanabe S, Shimada K, Hosaka H, Sasaki E, Nakayama N, Takeda Y, Moriwaki T, Amagai K, Sekikawa T, Sakuyama T, Kanda T, Sasaki T, Azuma M, Takahashi F, Takeuchi M, Koizumi W; Tokyo Cooperative Oncology Group, Tokyo, Japan. Biweekly irinotecan plus cisplatin versus irinotecan alone as second-line treatment for advanced gastric cancer: a randomised phase III trial (TCOG GI-0801/BIRIP trial). Eur J Cancer. 2014 May;50(8):1437-45. Epub 2014 Feb 20. [https://www.ejcancer.com/article/S0959-8049(14)00093-8/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24560487 PubMed]<br />
#'''TRICS:''' Nishikawa K, Fujitani K, Inagaki H, Akamaru Y, Tokunaga S, Takagi M, Tamura S, Sugimoto N, Shigematsu T, Yoshikawa T, Ishiguro T, Nakamura M, Morita S, Miyashita Y, Tsuburaya A, Sakamoto J, Tsujinaka T. Randomised phase III trial of second-line irinotecan plus cisplatin versus irinotecan alone in patients with advanced gastric cancer refractory to S-1 monotherapy: TRICS trial. Eur J Cancer. 2015 May;51(7):808-16. Epub 2015 Mar 18. [https://www.ejcancer.com/article/S0959-8049(15)00209-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25797356 PubMed]<br />
#'''JACCRO GC-05:''' Tanabe K, Fujii M, Nishikawa K, Kunisaki C, Tsuji A, Matsuhashi N, Takagane A, Ohno T, Kawase T, Kochi M, Yoshida K, Kakeji Y, Ichikawa W, Chin K, Terashima M, Takeuchi M, Nakajima T; JACCRO GC-05 study group. Phase II/III study of second-line chemotherapy comparing irinotecan-alone with S-1 plus irinotecan in advanced gastric cancer refractory to first-line treatment with S-1 (JACCRO GC-05). Ann Oncol. 2015 Sep;26(9):1916-22. Epub 2015 Jun 24. [https://academic.oup.com/annonc/article/26/9/1916/189421 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26109630 PubMed]<br />
#'''JAVELIN Gastric 300:''' Bang YJ, Ruiz EY, Van Cutsem E, Lee KW, Wyrwicz L, Schenker M, Alsina M, Ryu MH, Chung HC, Evesque L, Al-Batran SE, Park SH, Lichinitser M, Boku N, Moehler MH, Hong J, Xiong H, Hallwachs R, Conti I, Taieb J. Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol. 2018 Oct 1;29(10):2052-2060. [https://academic.oup.com/annonc/article/29/10/2052/5058079 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225815/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30052729 PubMed]<br />
<br />
==Irinotecan liposomal monotherapy {{#subobject:9a99c8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c50e15|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://annonc.oxfordjournals.org/content/24/6/1567.long Roy et al. 2013 (PEP0206)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. [[#Irinotecan_monotherapy|Irinotecan]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan liposome (Onivyde)]] 120 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''PEP0206:''' Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. [https://annonc.oxfordjournals.org/content/24/6/1567.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23406728 PubMed]<br />
<br />
==Nivolumab monotherapy {{#subobject:7011e1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:#f2fd8e|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(17)31827-5/fulltext Kang et al. 2017 (ATTRACTION-2)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161834/ Janjigian et al. 2018 (fpembrCheckMate-032)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''ATTRACTION-2 included patients with GE junction malignancy (82.6% gastric, 8.5% GE junction) and 12.3% of patients had a PD-L1 CPS score of at least 1''<br />
<br />
====Immunotherapy====<br />
<br />
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ATTRACTION-2:''' Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Dec 2;390(10111):2461-2471. Epub 2017 Oct 6. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31827-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28993052 PubMed]<br />
##'''Subgroup analysis:''' Kato K, Satoh T, Muro K, Yoshikawa T, Tamura T, Hamamoto Y, Chin K, Minashi K, Tsuda M, Yamaguchi K, Machida N, Esaki T, Goto M, Komatsu Y, Nakajima TE, Sugimoto N, Yoshida K, Oki E, Nishina T, Tsuji A, Fujii H, Kunieda K, Saitoh S, Omuro Y, Azuma M, Iwamoto Y, Taku K, Fushida S, Chen LT, Kang YK, Boku N. A subanalysis of Japanese patients in a randomized, double-blind, placebo-controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2). Gastric Cancer. 2019 Mar;22(2):344-354. Epub 2018 Dec 1. [https://link.springer.com/article/10.1007%2Fs10120-018-0899-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394726/ link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30506519 PubMed]<br />
#'''CheckMate-032:''' Janjigian YY, Bendell J, Calvo E, Kim JW, Ascierto PA, Sharma P, Ott PA, Peltola K, Jaeger D, Evans J, de Braud F, Chau I, Harbison CT, Dorange C, Tschaika M, Le DT. CheckMate-032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer. J Clin Oncol. 2018 Oct 1;36(28):2836-2844. Epub 2018 Aug 15. [https://ascopubs.org/doi/full/10.1200/JCO.2017.76.6212 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161834/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30110194 PubMed]<br />
<br />
==Paclitaxel monotherapy {{#subobject:2dcad9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 70 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:gg21e8|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/PMC6324622/ Lee et al. 2018 (KCSG ST10-01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Irinotecan_monotherapy_2|Irinotecan]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 70 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 80 mg/m<sup>2</sup> weekly {{#subobject:0e8f41|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/27/4C/2667.long Kodera et al. 2007 (CCOG0302)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30111-0/fulltext Thuss-Patience et al. 2017 (GATSBY)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|T-DM1<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Patients in GATSBY had overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation''<br />
<br />
''GATSBY included patients with GE junction malignancy (68% gastric, 32% GE junction)''<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #3, 80 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:dd21e8|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://link.springer.com/article/10.1007%2Fs10120-005-0351-6 Hironaka et al. 2006]<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2012.48.5805 Hironaka et al. 2013 (WJOG 4007)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Irinotecan_monotherapy_2|Irinotecan]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2013.53.6136 Satoh et al. 2014 (TyTAN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Lapatinib & Paclitaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2970420-6/fulltext Wilke et al. 2014 (RAINBOW)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Paclitaxel_.26_Ramucirumab|Paclitaxel & Ramucirumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/langas/article/PIIS2468-1253(16)30219-9/fulltext Shitara et al. 2017 (ABSOLUTE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]] weekly<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|2. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]] q3wk<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30682-4/fulltext Bang et al. 2017 (GOLD)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Olaparib & Paclitaxel<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31257-1/fulltext Shitara et al. 2018 (KEYNOTE-061)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225815/ Bang et al. 2018 (JAVELIN Gastric 300)]<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 />
''Eligibility criteria for patients in RAINBOW included: "documented objective radiological or clinical disease progression during or within 4 months of the last dose of first-line platinum and fluoropyrimidine doublet with or without anthracycline." Patients in TyTAN had HER2-positive disease.''<br />
<br />
''RAINBOW included patients with GE junction malignancy (79% gastric, 21% GE junction)''<br />
<br />
''Satoh et al. patients: 98.5% gastric. 1.5 other''<br />
<br />
''Hironaka et al patients: 3.7% patients with a PFS of 2''<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 />
===Variant #4, 175 mg/m<sup>2</sup> q3wk {{#subobject:a4bdf6|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://academic.oup.com/annonc/article-abstract/29/5/1220/4846849 Kang et al. 2018 (DREAM)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|DHP107<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Hironaka S, Zenda S, Boku N, Fukutomi A, Yoshino T, Onozawa Y. Weekly paclitaxel as second-line chemotherapy for advanced or recurrent gastric cancer. Gastric Cancer. 2006;9(1):14-8. [https://link.springer.com/article/10.1007%2Fs10120-005-0351-6 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16557431 PubMed]<br />
#'''CCOG0302:''' Kodera Y, Ito S, Mochizuki Y, Fujitake S, Koshikawa K, Kanyama Y, Matsui T, Kojima H, Takase T, Ohashi N, Fujiwara M, Sakamoto J, Akimasa N; Chubu Clinical Cancer Group. A phase II study of weekly paclitaxel as second-line chemotherapy for advanced gastric cancer (CCOG0302 study). Anticancer Res. 2007 Jul-Aug;27(4C):2667-71. [http://ar.iiarjournals.org/content/27/4C/2667.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17695430 PubMed]<br />
#'''WJOG 4007:''' Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y, Morita S, Okamoto I, Boku N, Hyodo I. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013 Dec 10;31(35):4438-44. Epub 2013 Nov 4. [https://ascopubs.org/doi/full/10.1200/JCO.2012.48.5805 link to original artile] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24190112 PubMed]<br />
#'''TyTAN:''' Satoh T, Xu RH, Chung HC, Sun GP, Doi T, Xu JM, Tsuji A, Omuro Y, Li J, Wang JW, Miwa H, Qin SK, Chung IJ, Yeh KH, Feng JF, Mukaiyama A, Kobayashi M, Ohtsu A, Bang YJ. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN--a randomized, phase III study. J Clin Oncol. 2014 Jul 1;32(19):2039-49. Epub 2014 May 27. [https://ascopubs.org/doi/full/10.1200/JCO.2013.53.6136 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24868024 PubMed]<br />
#'''RAINBOW:''' Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2970420-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25240821 PubMed]<br />
#'''ABSOLUTE:''' Shitara K, Takashima A, Fujitani K, Koeda K, Hara H, Nakayama N, Hironaka S, Nishikawa K, Makari Y, Amagai K, Ueda S, Yoshida K, Shimodaira H, Nishina T, Tsuda M, Kurokawa Y, Tamura T, Sasaki Y, Morita S, Koizumi W. Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, randomised, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2017 Apr;2(4):277-287. Epub 2017 Jan 19. [https://www.thelancet.com/journals/langas/article/PIIS2468-1253(16)30219-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28404157 PubMed]<br />
#'''GATSBY:''' Thuss-Patience PC, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, Castro H, Mansoor W, Chung HC, Bodoky G, Shitara K, Phillips GDL, van der Horst T, Harle-Yge ML, Althaus BL, Kang YK. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017 May;18(5):640-653. Epub 2017 Mar 23. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30111-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28343975 PubMed]<br />
#'''GOLD:''' Bang YJ, Xu RH, Chin K, Lee KW, Park SH, Rha SY, Shen L, Qin S, Xu N, Im SA, Locker G, Rowe P, Shi X, Hodgson D, Liu YZ, Boku N. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1637-1651. Epub 2017 Nov 2. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30682-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29103871 PubMed]<br />
#'''DREAM:''' Kang YK, Ryu MH, Park SH, Kim JG, Kim JW, Cho SH, Park YI, Park SR, Rha SY, Kang MJ, Cho JY, Kang SY, Roh SY, Ryoo BY, Nam BH, Jo YW, Yoon KE, Oh SC. Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus IV paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy. Ann Oncol. 2018 May 1;29(5):1220-1226. [https://academic.oup.com/annonc/article-abstract/29/5/1220/4846849 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29438463 PubMed]<br />
#'''KEYNOTE-061:''' Shitara K, Özgüroğlu M, Bang YJ, Di Bartolomeo MD, Mandalà M, Ryu MH, Fornaro L, Olesiński T, Caglevic C, Chung HC, Muro K, Goekkurt E, Mansoor W, McDermott RS, Shacham-Shmueli E, Chen X, Mayo C, Kang SP, Ohtsu A, Fuchs CS; KEYNOTE-061 investigators. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018 Jul 14;392(10142):123-133. Epub 2018 Jun 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31257-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29880231 PubMed]<br />
#'''KCSG ST10-01:''' Lee KW, Maeng CH, Kim TY, Zang DY, Kim YH, Hwang IG, Oh SC, Chung JS, Song HS, Kim JW, Jeong SJ, Cho JY. A phase III study to compare the efficacy and safety of paclitaxel versus irinotecan in patients with metastatic or recurrent gastric cancer who failed in first-line therapy (KCSG ST10-01). Oncologist. 2019 Jan;24(1):18-e24. Epub 2018 Aug 20. [http://theoncologist.alphamedpress.org/content/24/1/18.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324622/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30126861 PubMed]<br />
#'''JAVELIN Gastric 300:''' Bang YJ, Ruiz EY, Van Cutsem E, Lee KW, Wyrwicz L, Schenker M, Alsina M, Ryu MH, Chung HC, Evesque L, Al-Batran SE, Park SH, Lichinitser M, Boku N, Moehler MH, Hong J, Xiong H, Hallwachs R, Conti I, Taieb J. Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol. 2018 Oct 1;29(10):2052-2060. [https://academic.oup.com/annonc/article/29/10/2052/5058079 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225815/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30052729 PubMed]<br />
<br />
==nab-Paclitaxel monotherapy {{#subobject:8f6227|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:fe2978|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/langas/article/PIIS2468-1253(16)30219-9/fulltext Shitara et al. 2017 (ABSOLUTE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Paclitaxel_monotherapy|Weekly Paclitaxel]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|2. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]] q3wk<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ABSOLUTE:''' Shitara K, Takashima A, Fujitani K, Koeda K, Hara H, Nakayama N, Hironaka S, Nishikawa K, Makari Y, Amagai K, Ueda S, Yoshida K, Shimodaira H, Nishina T, Tsuda M, Kurokawa Y, Tamura T, Sasaki Y, Morita S, Koizumi W. Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, randomised, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2017 Apr;2(4):277-287. Epub 2017 Jan 19. [https://www.thelancet.com/journals/langas/article/PIIS2468-1253(16)30219-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28404157 PubMed]<br />
<br />
==Paclitaxel & Ramucirumab {{#subobject:fdd93f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f66446|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 />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2970420-6/fulltext Wilke et al. 2014 (RAINBOW)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
| style="background-color:#8c6bb1" |28% (95% CI 23-33%)<br />
|[[#Paclitaxel_monotherapy|Paclitaxel]]<br />
| style="background-color:#88419d; color:white " |16% (95% CI 13-20%)<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Eligibility criteria for patients in RAINBOW included: "documented objective radiological or clinical disease progression during or within 4 months of the last dose of first-line platinum and fluoropyrimidine doublet with or without anthracycline."''<br />
<br />
''RAINBOW included patients with GE junction malignancy (79% gastric, 21% GE junction).''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Ramucirumab (Cyramza)]] 8 mg/kg IV over 60 minutes once per day on days 1 & 15, '''given first'''<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, '''given second'''<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''RAINBOW:''' Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2970420-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25240821 PubMed]<br />
<br />
==Pembrolizumab monotherapy {{#subobject:88c665|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:ac7d94|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/PMC5885175/ Fuchs et al. 2018 (KEYNOTE-059)]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|<br />
|ORR: 12% (95% CI 8-16)<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31257-1/fulltext Shitara et al. 2018 (KEYNOTE-061)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[#Paclitaxel_monotherapy|Paclitaxel]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
PD-L1 (combined positive score > 1%) as determined by an FDA-approved test.<br />
<br />
''Both studies included patients with GE junction malignancy:''<br />
<br />
*''KEYNOTE-059: 48.3% gastric, 51.4% GE junction and 57.1% of patients had a PD-L1 CPS score of at least 1''<br />
<br />
*''KEYNOTE-061: 68.8% gastric, 31.2% GE junction and 66% of all patients receiving pembrolizumab had a PD-L1 CPS score of at least 1''<br />
<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycle for up to 35 cycles (2 years)'''<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Charles S. Fuchs, Toshihiko Doi, Raymond Woo-Jun Jang, Kei Muro, Taroh Satoh, Manuela Machado, ...Weijing Sun, Shadia Ibrahim Jalal, Manish A. Shah, Jean-Philippe Metges, Marcelo Garrido, Talia Golan, Mario Mandala, Zev A. Wainberg, Daniel V.T. Catenacci, Yung-Jue Bang, Jiangdian Wang, Minori Koshiji, Rita P. Dalal, Harry H. Yoon (2017). KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. Journal of Clinical Oncology 35, no. 15_suppl (May 2017) 4003-4003. [https://ascopubs.org/doi/full/10.1200/JCO.2017.35.15_suppl.4003 link to abstract] --><br />
<br />
#'''KEYNOTE-059:''' Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges JP, Garrido M, Golan T, Mandala M, Wainberg ZA, Catenacci DV, Ohtsu A, Shitara K, Geva R, Bleeker J, Ko AH, Ku G, Philip P, Enzinger PC, Bang YJ, Levitan D, Wang J, Rosales M, Dalal RP, Yoon HH. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018 May 10;4(5):e180013. Epub 2018 May 10. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2675013 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885175/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29543932 PubMed]<br />
#'''KEYNOTE-061:''' Shitara K, Özgüroğlu M, Bang YJ, Di Bartolomeo MD, Mandalà M, Ryu MH, Fornaro L, Olesiński T, Caglevic C, Chung HC, Muro K, Goekkurt E, Mansoor W, McDermott RS, Shacham-Shmueli E, Chen X, Mayo C, Kang SP, Ohtsu A, Fuchs CS; KEYNOTE-061 investigators. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018 Jul 14;392(10142):123-133. Epub 2018 Jun 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31257-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29880231 PubMed]<br />
<br />
==Placebo==<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 />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961719-5/fulltext Fuchs et al. 2013 (REGARD)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ramucirumab_monotherapy|Ramucirumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019744/ Pavlakis et al. 2016 (INTEGRATE)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Regorafenib_monotherapy|Regorafenib]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31827-5/fulltext Kang et al. 2017 (ATTRACTION-2)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Nivolumab_monotherapy|Nivolumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30739-3/fulltext Shitara et al. 2018 (TAGS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Trifluridine_and_tipiracil_monotherapy|Trifluridine/tipiracil]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''All studies included patients with GE junction malignancy:''<br />
<br />
*''REGARD: 75% gastric, 25% GE junction''<br />
*''INTEGRATE: 62% stomach or other, 38% GE junction''<br />
*''ATTRACTION-2: 82.6% gastric, 8.5% GE junction''<br />
<br />
''Patients in '''REGARD''' previously had "disease progression within 4 months of the last dose of first-line platinum-containing or fluoropyrimidine-containing chemotherapy for metastatic disease, or within 6 months of the last dose of platinum-containing or fluoropyrimidine-containing adjuvant treatment."''<br />
<br />
''No active antineoplastic treatment.''<br />
<br />
===References===<br />
<br />
#'''REGARD:''' Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9. Epub 2013 Oct 3.[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961719-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24094768 PubMed]<br />
#'''INTEGRATE:''' Pavlakis N, Sjoquist KM, Martin AJ, Tsobanis E, Yip S, Kang YK, Bang YJ, Alcindor T, O'Callaghan CJ, Burnell MJ, Tebbutt NC, Rha SY, Lee J, Cho JY, Lipton LR, Wong M, Strickland A, Kim JW, Zalcberg JR, Simes J, Goldstein D. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): A multinational placebo-controlled phase II trial. J Clin Oncol. 2016 Aug 10;34(23):2728-35. Epub 2016 Jun 20. [https://ascopubs.org/doi/full/10.1200/JCO.2015.65.1901 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019744/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27325864 PubMed]<br />
#'''ATTRACTION-2:''' Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Dec 2;390(10111):2461-2471. Epub 2017 Oct 6. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31827-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28993052 PubMed]<br />
#'''TAGS:''' Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Alsina M, Ghidini M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Hosokawa A, Yalçın Ş, Fujitani K, Beretta GD, Van Cutsem E, Winkler RE, Makris L, Ilson DH, Tabernero J. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Nov 1;19(11):1437-48. Epub 2018 Oct 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30739-3/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30355453 PubMed]<br />
<br />
==Ramucirumab monotherapy {{#subobject:425b15|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:813cff|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 />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961719-5/fulltext Fuchs et al. 2013 (REGARD)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
| style="background-color:#6e016b; color:white " |3%<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#6e016b; color:white " |3%<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Patients in REGARD previously had "disease progression within 4 months of the last dose of first-line platinum-containing or fluoropyrimidine-containing chemotherapy for metastatic disease, or within 6 months of the last dose of platinum-containing or fluoropyrimidine-containing adjuvant treatment."''<br />
<br />
''Study includes patients with GE junction malignancy (75% gastric, 25% GE junction).''<br />
====Chemotherapy====<br />
<br />
*[[Ramucirumab (Cyramza)]] 8 mg/kg IV over 60 minutes once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''REGARD:''' Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9. Epub 2013 Oct 3. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961719-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24094768 PubMed]<br />
<br />
==Regorafenib monotherapy {{#subobject:022ef0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5f203f|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/PMC5019744/ Pavlakis et al. 2016 (INTEGRATE)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
''INTEGRATE included patients with GEJ malignancy: 62% stomach or other, 38% GEJ''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''INTEGRATE:''' Pavlakis N, Sjoquist KM, Martin AJ, Tsobanis E, Yip S, Kang YK, Bang YJ, Alcindor T, O'Callaghan CJ, Burnell MJ, Tebbutt NC, Rha SY, Lee J, Cho JY, Lipton LR, Wong M, Strickland A, Kim JW, Zalcberg JR, Simes J, Goldstein D. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): A multinational placebo-controlled phase II trial. J Clin Oncol. 2016 Aug 10;34(23):2728-35. Epub 2016 Jun 20. [https://ascopubs.org/doi/full/10.1200/JCO.2015.65.1901 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019744/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27325864 PubMed]<br />
<br />
==Trifluridine and tipiracil monotherapy {{#subobject:938bf3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cfc20c|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(18)30739-3/fulltext Shitara et al. 2018 (TAGS)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Trifluridine and tipiracil (Lonsurf)]] 35 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 8 to 12<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''TAGS:''' Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Alsina M, Ghidini M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Hosokawa A, Yalçın Ş, Fujitani K, Beretta GD, Van Cutsem E, Winkler RE, Makris L, Ilson DH, Tabernero J. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Nov 1;19(11):1437-48. Epub 2018 Oct 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30739-3/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30355453 PubMed]<br />
<br />
[[Category:Gastric cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Dweeraratnehttps://hemonc.org/w/index.php?title=Gastric_cancer&diff=41835Gastric cancer2020-01-08T23:29:16Z<p>Dweeraratne: /* Variant #1, 80/1600 #subobject:cdee6d */</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; width:15%" |[[File:Ivy_Abraham.JPG|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Ivyabraham|Ivy Abraham, MD]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br />
| style="background-color:#F0F0F0; width:15%" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br />
|-<br />
|}<br />
<big>Note: there is significant overlap between regimens for gastric cancer and '''[[esophageal cancer]]''', if you can't find the regimen you're looking for here, please try the esophageal cancer page. If you still can't find it, it is possible that we've moved it to the [[Gastric_cancer_-_historical|historical regimens page]].</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 />
==CAP/ASCP/ASCO==<br />
<br />
*'''2017:''' Bartley et al. [https://ascopubs.org/doi/full/10.1200/JCO.2016.69.4836 HER2 testing and clinical decision making in gastroesophageal adenocarcinoma] [https://www.ncbi.nlm.nih.gov/pubmed/28129524 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2019:''' Stjepanovic et al. [https://academic.oup.com/annonc/article/30/10/1558/5543095 Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
*'''2016:''' Smyth et al. [https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Gastric-Cancer Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/27664260 PubMed]<br />
<br />
==ESMO/ESSO/ESTRO==<br />
<br />
*'''2013:''' Waddell et al. [https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mdt344 Gastric cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/24078663 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf NCCN Guidelines - Gastric Cancer]<br />
<br />
=Neoadjuvant chemotherapy=<br />
==Cisplatin & Fluorouracil {{#subobject:7b88be|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FP: '''<u>F</u>'''luorouracil & '''<u>P</u>'''latinol (Cisplatin)<br />
===Regimen {{#subobject:c2dc1e|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/29/13/1715.long Ychou et al. 2011 (ACCORD 07)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Surgery alone<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''This is the neoadjuvant portion of pre-planned "perioperative" therapy.''<br />
<br />
''Study included patients with lower esophageal malignancy as well (25% gastric, 11% lower esophagus, and 64% GE junction).''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycle for 2 to 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Gastrectomy|Surgical resection]], then [[#Cisplatin_.26_Fluorouracil_2|adjuvant cisplatin & 5-FU]]<br />
<br />
===References===<br />
<br />
#'''ACCORD 07:''' Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. [http://jco.ascopubs.org/content/29/13/1715.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21444866 PubMed]<br />
<br />
==ECF {{#subobject:f0281c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:66f602|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/NEJMoa055531 Cunningham et al. 2006 (MAGIC)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation|Surgery alone]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext Cats et al. 2018 (CRITICS)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''This is the neoadjuvant portion of pre-planned perioperative therapy. In CRITICS, only patients with difficulties swallowing tablets were assigned to this treatment.''<br />
<br />
''CRITICS trial included few patients with GE junction malignancy: 83% gastric, 17% GE junction'' <br />
<br />
''MAGIC included patients with lower esophageal malignancy as well (74% gastric, 14.8% lower esophagus, and 11.2% GE junction).''<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*MAGIC, suggested as thrombosis prophylaxis:<br />
**[[Warfarin (Coumadin)]] 1 mg PO once per day<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*MAGIC: [[Surgery#Gastrectomy|Surgical resection]] is performed 3 to 6 weeks after the completion of cycle 3, followed in 6 to 12 weeks by [[#ECF_2|adjuvant ECF]]<br />
*CRITICS: [[Surgery#Gastrectomy|Surgery]] with a D1+ lymph node resection, then adjuvant [[#ECF_2|ECF]] versus capecitabine, cisplatin, RT<br />
<br />
===References===<br />
<br />
#'''MAGIC:''' Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa055531 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16822992 PubMed]<br />
#'''CRITICS:''' Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29650363 PubMed]<br />
<br />
==ECX {{#subobject:c8ab0e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECX: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:27f848|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)30132-3/fulltext Cats et al. 2018 (CRITICS)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''CRITICS trial included few patients with GE junction malignancy: 83% gastric, 17% GE junction''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Gastrectomy|Surgery]] with a D1+ lymph node resection, then adjuvant [[#ECX_2|ECX]] versus capecitabine, cisplatin, RT<br />
<br />
===References===<br />
<br />
#'''CRITICS:''' Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29650363 PubMed]<br />
<br />
==EOF {{#subobject:139705|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
EOF: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luourouracil<br />
===Regimen {{#subobject:bf7464|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)30132-3/fulltext Cats et al. 2018 (CRITICS)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''CRITICS trial included few patients with GE junction malignancy: 83% gastric, 17% GE junction''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Gastrectomy|Surgery]] with a D1+ lymph node resection, then adjuvant [[#EOF_2|EOF]] versus capecitabine, cisplatin, RT<br />
<br />
===References===<br />
<br />
#'''CRITICS:''' Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29650363 PubMed]<br />
<br />
==EOX {{#subobject:86ee8e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
EOX: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:edae45|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)30132-3/fulltext Cats et al. 2018 (CRITICS)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''CRITICS trial included few patients with GE junction malignancy: 83% gastric, 17% GE junction''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Gastrectomy|Surgery]] with a D1+ lymph node resection, then adjuvant [[#EOX_2|EOX]] versus capecitabine, cisplatin, RT<br />
<br />
===References===<br />
<br />
#'''CRITICS:''' Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29650363 PubMed]<br />
<br />
==FLOT {{#subobject:aa7f4f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FLOT: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>O</u>'''xaliplatin, '''<u>T</u>'''axotere (Docetaxel)<br />
===Regimen {{#subobject:16408e|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(16)30531-9/fulltext Al-Batran et al. 2016 (FLOT4-AIO)]<br />
| style="background-color:#1a9851" |Phase II/III (E-switch-ic)<br />
|ECF/ECX [[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
| style="background-color:#91cf60" |Seems to have superior OS [[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
|-<br />
|}<br />
''This is the neoadjuvant portion of pre-planned perioperative chemotherapy.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV continuous infusion over 24 hours on day 1<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
*[[Docetaxel (Taxotere)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Gastrectomy|Surgery]], then [[#FLOT_2|adjuvant FLOT]]<br />
<br />
===References===<br />
<br />
#'''FLOT4-AIO:''' Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, Meiler J, Homann N, Lorenzen S, Schmalenberg H, Probst S, Koenigsmann M, Egger M, Prasnikar N, Caca K, Trojan J, Martens UM, Block A, Fischbach W, Mahlberg R, Clemens M, Illerhaus G, Zirlik K, Behringer DM, Schmiegel W, Pohl M, Heike M, Ronellenfitsch U, Schuler M, Bechstein WO, Königsrainer A, Gaiser T, Schirmacher P, Hozaeel W, Reichart A, Goetze TO, Sievert M, Jäger E, Mönig S, Tannapfel A. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016 Dec;17(12):1697-1708. Epub 2016 Oct 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30531-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27776843 PubMed]<br />
##'''Update:''' Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, Kopp HG, Mayer F, Haag GM, Luley K, Lindig U, Schmiegel W, Pohl M, Stoehlmacher J, Folprecht G, Probst S, Prasnikar N, Fischbach W, Mahlberg R, Trojan J, Koenigsmann M, Martens UM, Thuss-Patience P, Egger M, Block A, Heinemann V, Illerhaus G, Moehler M, Schenk M, Kullmann F, Behringer DM, Heike M, Pink D, Teschendorf C, Löhr C, Bernhard H, Schuch G, Rethwisch V, from Weikersthal LF, Hartmann JT, Kneba M, Daum S, Schulmann K, Less J, Belle S, Gaiser T, Oduncu FS, Güntner M, Hozaeel W, Reichart A, Hunter E, Kraus T, Mönig S, Bechstein WO, Schuler M, Schmalenberg H, Hofheinz RD; FLOT4-AIO Investigators. perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomized, phase 2/3 trial. Lancet. 2019 Apr 10. [Epub ahead of print] [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32557-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30982686 PubMed]<br />
<br />
==No neoadjuvant therapy==<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.ncbi.nlm.nih.gov/pmc/articles/PMC3020693/ Schuhmacher et al. 2010 (EORTC 40954)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin, 5-FU, Folinic acid<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''No antineoplastic treatment prior to surgery.''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Gastrectomy|Surgery]]<br />
<br />
===References===<br />
<br />
#'''EORTC 40954:''' Schuhmacher C, Gretschel S, Lordick F, Reichardt P, Hohenberger W, Eisenberger CF, Haag C, Mauer ME, Hasan B, Welch J, Ott K, Hoelscher A, Schneider PM, Bechstein W, Wilke H, Lutz MP, Nordlinger B, Van Cutsem E, Siewert JR, Schlag PM. Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and Treatment of Cancer randomized trial 40954. J Clin Oncol. 2010 Dec 10;28(35):5210-8. Epub 2010 Nov 8. [https://ascopubs.org/doi/10.1200/JCO.2009.26.6114 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3020693/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21060024 PubMed]<br />
<br />
=Adjuvant therapy=<br />
<br />
==CapeOx {{#subobject:cf9acc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine & '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:1ef938|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(11)61873-4/fulltext Bang et al. 2012 (CLASSIC)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Surgery alone<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|}<br />
''Note: Reported efficacy is based on the 2014 update.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Gastrectomy|Gastrectomy]] with D2 dissection<br />
<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 8 cycles'''<br />
<br />
===References===<br />
<br />
#'''CLASSIC:''' Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, Lee KW, Kim YH, Noh SI, Cho JY, Mok YJ, Kim YH, Ji J, Yeh TS, Button P, Sirzén F, Noh SH; CLASSIC trial investigators. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012 Jan 28;379(9813):315-21. Epub 2012 Jan 7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61873-4/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22226517 PubMed]<br />
##'''Update:''' Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW, Kim HH, Choi JH, Kim HK, Yu W, Lee JI, Shin DB, Ji J, Chen JS, Lim Y, Ha S, Bang YJ; CLASSIC trial investigators. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1389-96. Epub 2014 Oct 15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70473-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25439693 PubMed]<br />
<br />
==Carboplatin & Docetaxel {{#subobject:7263b8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cd8hbq|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://link.springer.com/article/10.1007%2Fs00280-010-1256-6 Bamias et al. 2010]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Carboplatin, Docetaxel, RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: the original protocol was for cisplatin & docetaxel but was changed due to excess CINV. 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 />
*[[Surgery#Gastrectomy|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 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 6 cycles'''<br />
<br />
===References===<br />
<br />
#Bamias A, Karina M, Papakostas P, Kostopoulos I, Bobos M, Vourli G, Samantas E, Christodoulou Ch, Pentheroudakis G, Pectasides D, Dimopoulos MA, Fountzilas G. A randomized phase III study of adjuvant platinum/docetaxel chemotherapy with or without radiation therapy in patients with gastric cancer. Cancer Chemother Pharmacol. 2010 May;65(6):1009-21. Epub 2010 Feb 4. [https://link.springer.com/article/10.1007%2Fs00280-010-1256-6 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20130877 PubMed]<br />
<br />
==Cisplatin & Fluorouracil {{#subobject:7b88be|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c2dc1e|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/29/13/1715.long Ychou et al. 2011 (ACCORD 07)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Surgery alone<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''This is the adjuvant portion of pre-planned "perioperative" therapy. ''<br />
<br />
''Study included patients with lower esophageal malignancy as well (25% gastric, 11% lower esophagus, and 64% GE junction).''<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin_.26_Fluorouracil|Neoadjuvant cisplatin & 5-FU]], then [[Surgery#Gastrectomy|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 28<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycle for 3 to 4 cycles, for a total of 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''ACCORD 07:''' Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. [http://jco.ascopubs.org/content/29/13/1715.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21444866 PubMed]<br />
<br />
==CX {{#subobject:4896bc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CX: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
<br>XP: '''<u>X</u>'''eloda (Capecitabine), '''<u>P</u>'''latinol (Cisplatin)<br />
===Regimen {{#subobject:877085|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/30/3/268.full Lee et al. 2011 (ARTIST<sub>gastric</sub>)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|XP, then RT, then XP<br />
| style="background-color:#fee08b" |Might have inferior DFS<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. This trial should not be confused for the one by the same name in colorectal cancer.''<br />
====Preceding treatment====<br />
<br />
*R0 [[Surgery#Gastrectomy|gastrectomy]] and at least D2 dissection<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''ARTIST:''' Lee J, Lim DH, Kim S, Park SH, Park JO, Park YS, Lim HY, Choi MG, Sohn TS, Noh JH, Bae JM, Ahn YC, Sohn I, Jung SH, Park CK, Kim KM, Kang WK. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol. 2012 Jan 20;30(3):268-73. Epub 2011 Dec 19. [http://jco.ascopubs.org/content/30/3/268.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22184384 PubMed]<br />
##'''Update:''' Park SH, Sohn TS, Lee J, Lim DH, Hong ME, Kim KM, Sohn I, Jung SH, Choi MG, Lee JH, Bae JM, Kim S, Kim ST, Park JO, Park YS, Lim HY, Kang WK. Phase III trial to compare adjuvant chemotherapy with capecitabine and cisplatin versus concurrent chemoradiotherapy in gastric cancer: Final report of the adjuvant chemoradiotherapy in stomach tumors trial, including survival and subset analyses. J Clin Oncol. 2015 Oct 1;33(28):3130-6. Epub 2015 Jan 5. [http://jco.ascopubs.org/content/33/28/3130.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25559811 PubMed]<br />
<br />
==Docetaxel & S-1 {{#subobject:a22c2a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[Gastric cancer#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:82ca03|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 />
|Kodera et al. (JACCRO GC-07)<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Gastric cancer#S-1 monotherapy 2|S-1]]<br />
| style="background-color:#91cf60" |Seems to have superior RFS<br />
|}<br />
====Chemotherapy (given sequentially, as below)====<br />
'''1 Cycle of:''' <br />
<br />
*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV once on day 1<br />
*S-1 at 80-120 mg/body PO on day 1-14 followed by 7 days of rest<br />
<br />
'''Followed by 6 Cycles of:''' <br />
<br />
*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV once on day 1<br />
*S-1 at 80-120 mg/body PO on day 1-14<br />
<br />
'''Followed by 4 Cycles of:''' <br />
<br />
*S-1 at 80-120 mg/body PO on days 1-28<br />
<br />
'''42-day cycles'''<br />
===References===<br />
<br />
#'''Abstract:''' Kodera Y, Yoshida K, Kochi M, Ichikawa W, Kakeji Y, Sano T, Nagao N, Takahashi M, Takagane A, Nakamura M, Kaji M, Okitsu H, Nomura T, Matsui T, Yoshikawa T, Matssuyama J, Yamada M, Ito Y, Takeuchi M, Fujii M. A randomized phase III study comparing S-1 plus docetaxel with S-1 alone as a postoperative adjuvant chemotherapy for curatively resected stage III gastric cancer (JACCRO GC-07 trial). 2019 American Society of Clinical Oncology annual meeting. DOI: 10.1200/JCO.2018.36.15_suppl.4007 36, no. 15_suppl (May 20, 2018) 4007-4007.<br />
<br />
==ECF {{#subobject:f0281c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:66f602|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/NEJMoa055531 Cunningham et al. 2006 (MAGIC)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation|Surgery alone]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext Cats et al. 2018 (CRITICS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''This is the adjuvant portion of pre-planned "perioperative" therapy. In CRITICS, only patients with trouble swallowing pills were assigned to this treatment arm.''<br />
<br />
''MAGIC included patients with lower esophageal malignancy (74% gastric, 14.8% lower esophagus, and 11.2% GE junction).''<br />
<br />
====Preceding treatment====<br />
<br />
*[[#ECF|Neoadjuvant ECF]] x 3, then [[Surgery#Gastrectomy|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*MAGIC, suggested as thrombosis prophylaxis:<br />
**[[Warfarin (Coumadin)]] 1 mg PO once per day<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''MAGIC:''' Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa055531 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16822992 PubMed]<br />
#'''CRITICS:''' Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29650363 PubMed]<br />
<br />
==ECX {{#subobject:4be711|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECX: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:af32a3|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(18)30132-3/fulltext Cats et al. 2018 (CRITICS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#ECX|ECX]] x 3, then [[Surgery#Gastrectomy|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''CRITICS:''' Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29650363 PubMed]<br />
<br />
==EOF {{#subobject:46c9e7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
EOF: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:415ab0|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(18)30132-3/fulltext Cats et al. 2018 (CRITICS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Only patients with trouble swallowing pills were assigned to this treatment arm.''<br />
====Preceding treatment====<br />
<br />
*[[#EOF|EOF]] x 3, then [[Surgery#Gastrectomy|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''CRITICS:''' Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29650363 PubMed]<br />
<br />
==EOX {{#subobject:64769a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
EOX: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:996244|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(18)30132-3/fulltext Cats et al. 2018 (CRITICS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#EOX|EOX]] x 3, then [[Surgery#Gastrectomy|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''CRITICS:''' Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. Epub 2018 Apr 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30132-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29650363 PubMed]<br />
<br />
==FLOT {{#subobject:3ad093|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FLOT: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>O</u>'''xaliplatin, '''<u>T</u>'''axotere (Docetaxel)<br />
===Regimen {{#subobject:e6d646|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(16)30531-9/fulltext Al-Batran et al. 2016 (FLOT4-AIO)]<br />
| style="background-color:#1a9851" |Phase II/III (E-switch-ic)<br />
|ECF/ECX [[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
| style="background-color:#91cf60" |Seems to have superior OS [[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
|-<br />
|}<br />
''This is the adjuvant portion of pre-planned perioperative chemotherapy.''<br />
====Preceding treatment====<br />
<br />
*[[#FLOT|Neoadjuvant FLOT]] x 4, then [[Surgery#Gastrectomy|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV continuous infusion over 24 hours on day 1<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
*[[Docetaxel (Taxotere)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#'''FLOT4-AIO:''' Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, Meiler J, Homann N, Lorenzen S, Schmalenberg H, Probst S, Koenigsmann M, Egger M, Prasnikar N, Caca K, Trojan J, Martens UM, Block A, Fischbach W, Mahlberg R, Clemens M, Illerhaus G, Zirlik K, Behringer DM, Schmiegel W, Pohl M, Heike M, Ronellenfitsch U, Schuler M, Bechstein WO, Königsrainer A, Gaiser T, Schirmacher P, Hozaeel W, Reichart A, Goetze TO, Sievert M, Jäger E, Mönig S, Tannapfel A. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016 Dec;17(12):1697-1708. Epub 2016 Oct 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30531-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27776843 PubMed]<br />
##'''Update:''' Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, Kopp HG, Mayer F, Haag GM, Luley K, Lindig U, Schmiegel W, Pohl M, Stoehlmacher J, Folprecht G, Probst S, Prasnikar N, Fischbach W, Mahlberg R, Trojan J, Koenigsmann M, Martens UM, Thuss-Patience P, Egger M, Block A, Heinemann V, Illerhaus G, Moehler M, Schenk M, Kullmann F, Behringer DM, Heike M, Pink D, Teschendorf C, Löhr C, Bernhard H, Schuch G, Rethwisch V, from Weikersthal LF, Hartmann JT, Kneba M, Daum S, Schulmann K, Less J, Belle S, Gaiser T, Oduncu FS, Güntner M, Hozaeel W, Reichart A, Hunter E, Kraus T, Mönig S, Bechstein WO, Schuler M, Schmalenberg H, Hofheinz RD; FLOT4-AIO Investigators. perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomized, phase 2/3 trial. Lancet. 2019 Apr 10. [Epub ahead of print] [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32557-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30982686 PubMed]<br />
<br />
==FP/Capecitabine & RT {{#subobject:778727|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FP/Capecitabine & RT: '''<u>F</u>'''luorouracil & '''<u>P</u>'''latinol (Cisplatin) alternating with Capecitabine & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:20ea7f|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/PMC4066094/ Lee et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: In contrast to the primary reference, some guidelines list this regimen without FP cycles 1, 3, 4, 5. Dosage of [[Capecitabine (Xeloda)]] was listed as 625 to 825 mg/m<sup>2</sup> PO twice per day on days 1 to 5 or 1 to 7 while radiation is being given.'' <br />
====Preceding treatment====<br />
<br />
*[[Surgery#Gastrectomy|Surgery]], 3 weeks prior<br />
<br />
====Chemotherapy, part 1====<br />
<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose: 5000 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle, followed immediately by:'''<br />
<br />
====Chemotherapy, part 2====<br />
<br />
*[[Capecitabine (Xeloda)]] 825 mg/m<sup>2</sup> PO twice per day<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions (total dose of 45 Gy)<br />
<br />
'''5-week course, followed 4 weeks later by:'''<br />
<br />
====Chemotherapy, part 3====<br />
<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#Lee HS, Choi Y, Hur WJ, Kim HJ, Kwon HC, Kim SH, Kim JS, Lee JH, Jung GJ, Kim MC. Pilot study of postoperative adjuvant chemoradiation for advanced gastric cancer: adjuvant 5-FU/cisplatin and chemoradiation with capecitabine. World J Gastroenterol. 2006 Jan 28;12(4):603-7. [http://www.wjgnet.com/1007-9327/full/v12/i4/603.htm link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066094/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/16489675 PubMed]<br />
<br />
==FULV/FULV & RT {{#subobject:2cd29|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FULV/FULV & RT: '''<u>F</u>'''luoro'''<u>U</u>'''racil & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid) alternating with '''<u>F</u>'''luoro'''<u>U</u>'''racil, '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid) & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:dfd3ec|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/NEJMoa010187 Macdonald et al. 2001 (INT-0116)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation|Surgery alone]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678342/ Fuchs et al. 2017 (CALGB 80101)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ECF, then FULV & RT, then ECF<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Treatment is to start 20 to 40 days after surgery.''<br />
<br />
''Study included patients with GE junction malignancy as well (20% GE junction) and included patients with a performance status of 2.'' <br />
====Preceding treatment====<br />
<br />
*INT-0116: [[Surgery#Gastrectomy|Surgery]] with R0 resection (10% underwent D2 dissection, 36% underwent D1 dissection and 54% underwent D0 dissection)<br />
*CALGB 80101: [[Surgery#Gastrectomy|Surgery]]<br />
<br />
====Chemotherapy, part 1====<br />
<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
<br />
'''28-day cycle for 1 cycle, followed by:'''<br />
<br />
====Chemotherapy, part 2====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 180 cGy x 25 fractions (total of 45 Gy)<br />
<br />
'''35-day course, followed in 1 month by:'''<br />
<br />
====Chemotherapy, part 3====<br />
<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
<br />
'''28-day cycle for 2 cycles'''<br />
===References===<br />
<br />
#'''INT-0116:''' Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6;345(10):725-30. [https://www.nejm.org/doi/full/10.1056/NEJMoa010187 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11547741 PubMed]<br />
##'''Update:''' Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA, Gunderson LL, Goldman B, Martenson JA, Jessup JM, Stemmermann GN, Blanke CD, Macdonald JS. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol. 2012 Jul 1;30(19):2327-33. Epub 2012 May 14. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.7136 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517071/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22585691 PubMed]<br />
#'''CALGB 80101:''' Fuchs CS, Niedzwiecki D, Mamon HJ, Tepper JE, Ye X, Swanson RS, Enzinger PC, Haller DG, Dragovich T, Alberts SR, Bjarnason GA, Willett CG, Gunderson LL, Goldberg RM, Venook AP, Ilson D, O'Reilly E, Ciombor K, Berg DJ, Meyerhardt J, Mayer RJ. Adjuvant chemoradiotherapy with epirubicin, cisplatin, and fluorouracil compared with adjuvant chemoradiotherapy with fluorouracil and leucovorin after curative resection of gastric cancer: results from CALGB 80101 (Alliance). J Clin Oncol. 2017 Nov 10;35(32):3671-3677. Epub 2017 Oct 4. [https://ascopubs.org/doi/full/10.1200/JCO.2017.74.2130 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678342/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28976791 PubMed]<br />
<br />
==Observation==<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 />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(89)91607-3/fulltext Allum et al. 1989]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Gastric_cancer_-_historical#Fluorouracil_.26_Mitomycin|5-FU & Mitomycin]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1990.8.8.1362 Coombes et al. 1990]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FAM<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints of DFS/OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(94)92464-3/fulltext Hallissey et al. 1994]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. FAM<br> 2. Radiation therapy<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1995.13.11.2757 Lise et al. 1995 (EORTC 40813)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FAM2<br />
| style="background-color:#fee08b" |Might have inferior DFS<br />
|-<br />
|[https://link.springer.com/article/10.1007/BF02307081 Macdonald et al. 1995 (SWOG-7804)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FAM<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)01048-X/fulltext Nakajima et al. 1999 (JCOG8801)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & Mitomycin, then UFT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.1999.17.12.3810 Cirera et al. 1999]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Mitomycin & Tegafur<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa010187 Macdonald et al. 2001 (INT-0116)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FULV.2FFULV_.26_RT|FULV/FULV & RT]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2003.06.103 Nashimoto et al. 2003 (JCOG 9206-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU, Ara-C, Mitomycin, then 5-FU<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS<br />
|-<br />
|[https://academic.oup.com/annonc/article/16/9/1488/180180 Bouché et al. 2005 (FFCD 8801)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Fluorouracil_2|Cisplatin & 5-FU]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/17/2/262/165316 Nitti et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. FAMTX<br> 2. FEMTX<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa055531 Cunningham et al. 2006 (MAGIC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ECF_2|ECF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/18/8/1354/178453 De Vita et al. 2007 (GOIM 9602)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ELFE<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa072252 Sakuramoto et al. 2007 (ACTS-GC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://academic.oup.com/jnci/article/100/6/388/997958 Di Costanzo et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PELF<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.karger.com/Article/Abstract/292360 Kulig et al. 2010]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|EAP<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs10120-011-0027-3 Miyashiro et al. 2011 (JCOG 9206-2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|IV/IP Cisplatin, then UFT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''No further treatment after surgery.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Gastrectomy|Surgery]], with varying requirements for level of dissection (see papers for details)<br />
<br />
===References===<br />
<br />
#Allum WH, Hallissey MT, Kelly KA; British Stomach Cancer Group. Adjuvant chemotherapy in operable gastric cancer: 5 year follow-up of first British Stomach Cancer Group trial. Lancet. 1989 Mar 18;1(8638):571-4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(89)91607-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2564109 PubMed]<br />
#Coombes RC, Schein PS, Chilvers CE, Wils J, Beretta G, Bliss JM, Rutten A, Amadori D, Cortes-Funes H, Villar-Grimalt A, McArdle C, Rauschecker HF, Boven E, Vassilopoulos P, Welvaart K, Pinto Ferreira E, Wiig J, Gisselbrecht C, Rougier P, Woods EMA; International Collaborative Cancer Group. A randomized trial comparing adjuvant fluorouracil, doxorubicin, and mitomycin with no treatment in operable gastric cancer. J Clin Oncol. 1990 Aug;8(8):1362-9. [https://ascopubs.org/doi/abs/10.1200/JCO.1990.8.8.1362 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2199622 PubMed]<br />
#Hallissey MT, Dunn JA, Ward LC, Allum WH; British Stomach Cancer Group. The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: five-year follow-up. Lancet. 1994 May 28;343(8909):1309-12. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(94)92464-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7910321 PubMed]<br />
#'''EORTC 40813:''' Lise M, Nitti D, Marchet A, Sahmoud T, Buyse M, Duez N, Fiorentino M, Dos Santos JG, Labianca R, Rougier P, Gignoux M. Final results of a phase III clinical trial of adjuvant chemotherapy with the modified fluorouracil, doxorubicin, and mitomycin regimen in resectable gastric cancer. J Clin Oncol. 1995 Nov;13(11):2757-63. [https://ascopubs.org/doi/abs/10.1200/JCO.1995.13.11.2757 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7595735 PubMed]<br />
#'''SWOG-7804:''' Macdonald JS, Fleming TR, Peterson RF, Berenberg JL, McClure S, Chapman RA, Eyre HJ, Solanki D, Cruz AB Jr, Gagliano R, Estes NC, Tangen CM, Rivkin S. Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: A Southwest Oncology Group study. Ann Surg Oncol. 1995 Nov;2(6):488-94. [https://link.springer.com/article/10.1007/BF02307081 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8591078 PubMed]<br />
#'''JCOG8801:''' Nakajima T, Nashimoto A, Kitamura M, Kito T, Iwanaga T, Okabayashi K, Goto M; Gastric Cancer Surgical Study Group. Adjuvant mitomycin and fluorouracil followed by oral uracil plus tegafur in serosa-negative gastric cancer: a randomised trial. Lancet. 1999 Jul 24;354(9175):273-7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)01048-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10440302 PubMed]<br />
#Cirera L, Balil A, Batiste-Alentorn E, Tusquets I, Cardona T, Arcusa A, Jolis L, Saigí E, Guasch I, Badia A, Boleda M. Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer. J Clin Oncol. 1999 Dec;17(12):3810-5. [https://ascopubs.org/doi/full/10.1200/JCO.1999.17.12.3810 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10577853 PubMed]<br />
#'''INT-0116:''' Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6;345(10):725-30. [https://www.nejm.org/doi/full/10.1056/NEJMoa010187 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11547741 PubMed]<br />
##'''Update:''' Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA, Gunderson LL, Goldman B, Martenson JA, Jessup JM, Stemmermann GN, Blanke CD, Macdonald JS. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol. 2012 Jul 1;30(19):2327-33. Epub 2012 May 14. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.7136 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517071/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22585691 PubMed]<br />
#'''JCOG 9206-1:''' Nashimoto A, Nakajima T, Furukawa H, Kitamura M, Kinoshita T, Yamamura Y, Sasako M, Kunii Y, Motohashi H, Yamamoto S; Gastric Cancer Surgical Study Group, Japan Clinical Oncology Group. Randomized trial of adjuvant chemotherapy with mitomycin, Fluorouracil, and Cytosine arabinoside followed by oral Fluorouracil in serosa-negative gastric cancer: Japan Clinical Oncology Group 9206-1. J Clin Oncol. 2003 Jun 15;21(12):2282-7. [https://ascopubs.org/doi/full/10.1200/JCO.2003.06.103 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12805327 PubMed]<br />
#'''FFCD 8801:''' Bouché O, Ychou M, Burtin P, Bedenne L, Ducreux M, Lebreton G, Baulieux J, Nordlinger B, Martin C, Seitz JF, Tigaud JM, Echinard E, Stremsdoerfer N, Milan C, Rougier P; Fédération Francophone de Cancérologie Digestive Group. Adjuvant chemotherapy with 5-fluorouracil and cisplatin compared with surgery alone for gastric cancer: 7-year results of the FFCD randomized phase III trial (8801). Ann Oncol. 2005 Sep;16(9):1488-97. Epub 2005 Jun 6. [https://academic.oup.com/annonc/article/16/9/1488/180180 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15939717 PubMed]<br />
#Nitti D, Wils J, Dos Santos JG, Fountzilas G, Conte PF, Sava C, Tres A, Coombes RC, Crivellari D, Marchet A, Sanchez E, Bliss JM, Homewood J, Couvreur ML, Hall E, Baron B, Woods E, Emson M, Van Cutsem E, Lise M; EORTC GI Group; ICCG. Randomized phase III trials of adjuvant FAMTX or FEMTX compared with surgery alone in resected gastric cancer: a combined analysis of the EORTC GI Group and the ICCG. Ann Oncol. 2006 Feb;17(2):262-9. Epub 2005 Nov 17. [https://academic.oup.com/annonc/article/17/2/262/165316 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16293676 PubMed]<br />
#'''MAGIC:''' Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa055531 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16822992 PubMed]<br />
#'''GOIM 9602:''' De Vita F, Giuliani F, Orditura M, Maiello E, Galizia G, Di Martino N, Montemurro F, Cartenì G, Manzione L, Romito S, Gebbia V, Ciardiello F, Catalano G, Colucci G; Gruppo Oncologico Italia Meridionale. Adjuvant chemotherapy with epirubicin, leucovorin, 5-fluorouracil and etoposide regimen in resected gastric cancer patients: a randomized phase III trial by the Gruppo Oncologico Italia Meridionale (GOIM 9602 Study). Ann Oncol. 2007 Aug;18(8):1354-8. Epub 2007 May 24. [https://academic.oup.com/annonc/article/18/8/1354/178453 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17525087 PubMed]<br />
#'''ACTS-GC:''' Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K; ACTS-GC Group. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007 Nov 1;357(18):1810-20. Erratum in: N Engl J Med. 2008 May 1;358(18):1977. [https://www.nejm.org/doi/full/10.1056/NEJMoa072252 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17978289 PubMed]<br />
##'''Update:''' Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T, Ohashi Y. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011 Nov 20;29(33):4387-93. Epub 2011 Oct 17. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.5908 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22010012 PubMed]<br />
#Di Costanzo F, Gasperoni S, Manzione L, Bisagni G, Labianca R, Bravi S, Cortesi E, Carlini P, Bracci R, Tomao S, Messerini L, Arcangeli A, Torri V, Bilancia D, Floriani I, Tonato M; Italian Oncology Group for Cancer Research. Adjuvant chemotherapy in completely resected gastric cancer: a randomized phase III trial conducted by GOIRC. J Natl Cancer Inst. 2008 Mar 19;100(6):388-98. Epub 2008 Mar 11. [https://academic.oup.com/jnci/article/100/6/388/997958 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18334706 PubMed]<br />
#Kulig J, Kolodziejczyk P, Sierzega M, Bobrzynski L, Jedrys J, Popiela T, Dadan J, Drews M, Jeziorski A, Krawczyk M, Starzynska T, Wallner G. Adjuvant chemotherapy with etoposide, adriamycin and cisplatin compared with surgery alone in the treatment of gastric cancer: a phase III randomized, multicenter, clinical trial. Oncology. 2010;78(1):54-61. Epub 2010 Mar 6. [https://www.karger.com/Article/Abstract/292360 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20215786 PubMed]<br />
#'''JCOG 9206-2:''' Miyashiro I, Furukawa H, Sasako M, Yamamoto S, Nashimoto A, Nakajima T, Kinoshita T, Kobayashi O, Arai K; Gastric Cancer Surgical Study Group in the Japan Clinical Oncology Group. Randomized clinical trial of adjuvant chemotherapy with intraperitoneal and intravenous cisplatin followed by oral fluorouracil (UFT) in serosa-positive gastric cancer versus curative resection alone: final results of the Japan Clinical Oncology Group trial JCOG9206-2. Gastric Cancer. 2011 Aug;14(3):212-8. Epub 2011 Feb 19. [https://link.springer.com/article/10.1007%2Fs10120-011-0027-3 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21336855 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:ec10ef|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 21-day cycles {{#subobject:5dbc53|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(14)70025-7/fulltext Tsuburaya et al. 2014 (SAMIT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Paclitaxel, then S-1<br> 2. Paclitaxel, then UFT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|3. UFT<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*R0 or R1 [[Surgery#Gastrectomy|gastrectomy]] with at least D2 dissection, within 2 to 8 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] 80 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for 16 cycles'''<br />
<br />
===Variant #2, 42-day cycles {{#subobject:0ee98c|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/NEJMoa072252 Sakuramoto et al. 2007 (ACTS-GC)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/langas/article/PIIS2468-1253(18)30383-2/fulltext Yoshikawa et al. 2019 (OPAS-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|S-1 x 6 mo<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*R0 [[Surgery#Gastrectomy|gastrectomy]] with at least D2 dissection, within 6 weeks<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 between 1.25 and 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 cycle for 8 cycles'''<br />
===References===<br />
<br />
#'''ACTS-GC:''' Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K; ACTS-GC Group. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007 Nov 1;357(18):1810-20. Erratum in: N Engl J Med. 2008 May 1;358(18):1977. [https://www.nejm.org/doi/full/10.1056/NEJMoa072252 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17978289 PubMed]<br />
##'''Update:''' Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T, Ohashi Y. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011 Nov 20;29(33):4387-93. Epub 2011 Oct 17. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.5908 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22010012 PubMed]<br />
#'''SAMIT:''' Tsuburaya A, Yoshida K, Kobayashi M, Yoshino S, Takahashi M, Takiguchi N, Tanabe K, Takahashi N, Imamura H, Tatsumoto N, Hara A, Nishikawa K, Fukushima R, Nozaki I, Kojima H, Miyashita Y, Oba K, Buyse M, Morita S, Sakamoto J. Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. Lancet Oncol. 2014 Jul;15(8):886-93. Epub 2014 Jun 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70025-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24954805 PubMed]<br />
#'''OPAS-1:''' Yoshikawa T, Terashima M, Mizusawa J, Nunobe S, Nishida Y, Yamada T, Kaji M, Fukushima N, Hato S, Choda Y, Yabusaki H, Yoshida K, Ito S, Takeno A, Yasuda T, Kawachi Y, Katayama H, Fukuda H, Boku N, Sano T, Sasako M. Four courses versus eight courses of adjuvant S-1 for patients with stage II gastric cancer (JCOG1104[OPAS-1]): an open-label, phase 3, non-inferiority, randomised trial. Lancet Gastroenterol Hepatol. 2019 Mar;4(3):208-216. Epub 2019 Jan 22. Erratum in: Lancet Gastroenterol Hepatol. 2019 Apr;4(4):e3. [https://www.thelancet.com/journals/langas/article/PIIS2468-1253(18)30383-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30679107 PubMed]<br />
<br />
=Metastatic or locally advanced disease, first-line=<br />
==Capecitabine monotherapy {{#subobject:a9eb0b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
X: '''<u>X</u>'''eloda (Capecitabine)<br />
===Variant #1, 2000 mg/m<sup>2</sup>/day {{#subobject:b6ba4c|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.geriatriconcology.net/article/S1879-4068(17)30022-X/fulltext Hwang et al. 2017]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CapeOx_2|XELOX]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2, 2500 mg/m<sup>2</sup>/day {{#subobject:b6ba4c|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://annonc.oxfordjournals.org/content/15/9/1344.long Hong et al. 2004]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Study only included patients with Karnofsky status of at least 70%''<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Hong YS, Song SY, Lee SI, Chung HC, Choi SH, Noh SH, Park JN, Han JY, Kang JH, Lee KS, Cho JY. A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Ann Oncol. 2004 Sep;15(9):1344-7. [http://annonc.oxfordjournals.org/content/15/9/1344.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15319239 PubMed]<br />
#Hwang IG, Ji JH, Kang JH, Lee HR, Lee HY, Chi KC, Park SW, Lee SJ, Kim ST, Lee J, Park SH, Park JO, Park YS, Lim HY, Kang WK. A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer. J Geriatr Oncol. 2017 May;8(3):170-175. Epub 2017 Jan 21. [https://www.geriatriconcology.net/article/S1879-4068(17)30022-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28119041 PubMed]<br />
<br />
==CapeOx {{#subobject:4e3bb4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine & '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:4faee3|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://academic.oup.com/annonc/article/17/1/29/161212 Jatoi et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 850 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Jatoi A, Murphy BR, Foster NR, Nikcevich DA, Alberts SR, Knost JA, Fitch TR, Rowland KM Jr; North Central Cancer Treatment Group. Oxaliplatin and capecitabine in patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction and gastric cardia: a phase II study from the North Central Cancer Treatment Group. Ann Oncol. 2006 Jan;17(1):29-34. Epub 2005 Nov 22. [https://academic.oup.com/annonc/article/17/1/29/161212 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16303863 PubMed]<br />
<br />
==Carboplatin & Paclitaxel {{#subobject:4df570|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9725d8|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/9427274 Philip et al. 1997]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2003&issue=02000&article=00008&type=abstract Gadgeel et al. 2003]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: In contrast to the original reference, some guidelines list the dosage of carboplatin as AUC 6.''<br />
<br />
''Philip et al. included patients with locally advanced metastatic or recurrent esophageal or gastric cancer''<br />
<br />
''Gadgeel et al. study showed an ORR of 35%'' <br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV 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 cycles'''<br />
<br />
===References===<br />
<br />
#Philip PA, Zalupski MM, Gadgeel S, Hussain M, Shields A. A phase II study of carboplatin and paclitaxel in the treatment of patients with advanced esophageal and gastric cancer. Semin Oncol. 1997 Dec;24(6 Suppl 19):S19-86-S19-88. '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9427274 PubMed]<br />
#Gadgeel SM, Shields AF, Heilbrun LK, Labadidi S, Zalupski M, Chaplen R, Philip PA. Phase II study of paclitaxel and carboplatin in patients with advanced gastric cancer. Am J Clin Oncol. 2003 Feb;26(1):37-41. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2003&issue=02000&article=00008&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12576922 PubMed]<br />
<br />
==Cisplatin & Docetaxel {{#subobject:724868|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>TC: '''<u>T</u>'''axotere (Docetaxel), '''<u>C</u>'''isplatin<br />
<br />
===Variant #1, 75/75 {{#subobject:cd0910|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" |[http://jco.ascopubs.org/content/25/22/3217.long Roth et al. 2007]<br />
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-de-esc)<br />
|1. [[#ECF_3|ECF]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#DCF|TCF]]<br />
| style="background-color:#fee08b" |Might have inferior ORR<br />
|-<br />
|}<br />
''Note: the protocol was amended to change the original dose of docetaxel from 85 mg/m<sup>2</sup> to 75 mg/m<sup>2</sup> based on high incidence of febrile neutropenia.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 4 hours 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 />
<br />
*3 liters per day "hyperhydration"<br />
*[[Dexamethasone (Decadron)]] 8 mg PO given 12 hours & 6 hours before [[Docetaxel (Taxotere)]], then 8 mg PO twice per day for 4 days after [[Docetaxel (Taxotere)]]<br />
*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] for emesis prophylaxis<br />
*Growth factor support allowed, such as with [[Filgrastim (Neupogen)]]<br />
<br />
'''21-day cycle for up to 8 cycles'''<br />
<br />
===Variant #2, 75/85 {{#subobject:f1913d|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/23/24/5660.long Ajani et al. 2005 (V-325)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#DCF|DCF]]<br />
| style="background-color:#fc8d59" |Seems to have inferior ORR<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma histology (32% esophagogastric junction/fundus and 68% gastric antrum/body). 95% were metastatic. 1% with Karnofsky PS score of 70.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1<br />
*[[Docetaxel (Taxotere)]] 85 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 8 mg PO the night before chemotherapy, the morning of day 1, 1 hour before chemotherapy, the night of day 1, the morning of day 2, and the evening of day 2 (total dose per cycle: 48 mg)<br />
*[[Dexamethasone (Decadron)]] 20 mg IV before [[Cisplatin (Platinol)]] and 8 hours after [[Cisplatin (Platinol)]]<br />
*[[Ondansetron (Zofran)]] 8 mg IV before [[Cisplatin (Platinol)]], 4 hours after [[Cisplatin (Platinol)]], and 8 hours after [[Cisplatin (Platinol)]]<br />
*"Hydration was administered in a standard manner"<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''V-325:''' Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Cabral Filho S, Majlis A, Assadourian S, Van Cutsem E. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005 Aug 20;23(24):5660-7. [http://jco.ascopubs.org/content/23/24/5660.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16110025 PubMed]<br />
#Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. [http://jco.ascopubs.org/content/25/22/3217.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17664469 PubMed]<br />
<br />
==Cisplatin & Fluorouracil {{#subobject:4d9936|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CF: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
<br>FP: '''<u>F</u>'''luorouracil, '''<u>P</u>'''latinol (Cisplatin)<br />
===Variant #1, 80/4000 x 6 {{#subobject:782e95|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%2810%2961121-X/fulltext Bang et al. 2010 (ToGA)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CF_.26_Trastuzumab|CF & Trastuzumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Patients in '''ToGA''' had overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation.''<br />
<br />
''ToGA Patients: 100% adenocarcinoma (19% gastroesophageal junction, 81% gastric). 10% with ECOG of 2.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1, '''given second''' (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*Some protocols: "Hyperhydration" for [[Cisplatin (Platinol)]]<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Variant #2, 80/4000 x 8 {{#subobject:9abe95|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://academic.oup.com/annonc/article/28/9/2142/4061259 Ajani et al. 2017 (DIGEST)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_S-1|CS]]<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 over 1 to 3 hours once on day 1, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1, '''given second''' (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*Some protocols: "Hyperhydration" for [[Cisplatin (Platinol)]]<br />
<br />
'''21-day cycle for 8 cycles'''<br />
<br />
===Variant #3, 80/4000, indefinite {{#subobject:69c795|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://annonc.oxfordjournals.org/content/20/4/666.long Kang et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CX_2|CX]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.18_suppl.LBA4007 Tabernero et al. 2019 (KEYNOTE-062)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin.2C_Fluorouracil.2C_Pembrolizumab|CF & Pembrolizumab]]<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 over 1 to 3 hours once on day 1, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1, '''given second''' (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*Some protocols: "Hyperhydration" for [[Cisplatin (Platinol)]]<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, 100/4000 {{#subobject:16f88f|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/26/5B/3877.long Duffour et al. 2006 (FFCD 9404)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CLF|FLP]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on either day 1 or 2<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #5, 100/4000, split-dose cisplatin {{#subobject:16f18e|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" |[http://jco.ascopubs.org/content/21/1/54.long Ohtsu et al. 2003 (JCOG 9205)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Fluorouracil_monotherapy|Fluorouracil]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#UFTM|UFTM]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Study included patients with PFS of 2 (9.6%)'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===Variant #6, 100/5000 {{#subobject:10f0c6|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/24/31/4991.long Van Cutsem et al. 2006 (TAX 325)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#DCF|DCF]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://annonc.oxfordjournals.org/content/19/8/1450.long Dank et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRI|IF]]<br />
| style="background-color:#fee08b" |Might have inferior TTP<br />
|-<br />
|[https://ascopubs.org/doi/10.1200/JCO.2009.25.4706 Ajani et al. 2010 (FLAGS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_S-1|CS]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Van Cutsem et al Patients: 100% adenocarcinoma histology (22% Esophagogastric junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS of 70.'' <br />
<br />
''Dank et al Patients: 100% adenocarcinoma histology (20% Esophagogastric junction, 80% gastric origin). 96% with metastatic disease. 1% with Karnofsky PS of 70.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1, '''given second''' (total dose per cycle: 5000 mg/m<sup>2</sup> )<br />
<br />
====Supportive medications====<br />
<br />
*As described in Dank et al. 2008:<br />
*"Hyperhydration" for 2 to 3 days with each infusion<br />
*[[Ondansetron (Zofran)]] IV for antiemetic prophylaxis<br />
*[[Dexamethasone (Decadron)]] IV for antiemetic prophylaxis, then PO for 2 to 3 days<br />
*[[Metoclopramide (Reglan)]] for antiemetic prophylaxis<br />
*[[Filgrastim (Neupogen)]] (dose not specified) SC once per day, starting on day 4, to be continued until ANC greater than 1000/uL for grade 3 to 4 neutropenia, febrile neutropenia, or neutropenic infection<br />
*[[Atropine (Atropen)]] prn cholinergic symptoms<br />
*[[Loperamide (Imodium)]] prn delayed diarrhea<br />
<br />
'''28-day cycles'''<br />
===References===<br />
<br />
#'''JCOG 9205:''' Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; Japan Clinical Oncology Group Study (JCOG9205). Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. [http://jco.ascopubs.org/content/21/1/54.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506170 PubMed]<br />
#'''FFCD 9404:''' Duffour J, Bouché O, Rougier P, Milan C, Bedenne L, Seitz JF, Buecher B, Legoux JL, Ducreux M, Vetter D, Raoul JL, François E, Ychou M. Safety of cisplatin combined with continuous 5-FU versus bolus 5-FU and leucovorin, in metastatic gastrointestinal cancer (FFCD 9404 randomised trial). Anticancer Res. 2006 Sep-Oct;26(5B):3877-83. [http://ar.iiarjournals.org/content/26/5B/3877.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17094417 PubMed]<br />
#'''TAX 325:''' Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006 Nov 1;24(31):4991-7. [http://jco.ascopubs.org/content/24/31/4991.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17075117 PubMed]<br />
#Dank M, Zaluski J, Barone C, Valvere V, Yalcin S, Peschel C, Wenczl M, Goker E, Cisar L, Wang K, Bugat R. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2008 Aug;19(8):1450-7. Epub 2008 Jun 16. [http://annonc.oxfordjournals.org/content/19/8/1450.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18558665 PubMed]<br />
#Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009 Apr;20(4):666-73. Epub 2009 Jan 19. [http://annonc.oxfordjournals.org/content/20/4/666.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19153121 PubMed]<br />
#'''FLAGS:''' Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010 Mar 20;28(9):1547-53. Epub 2010 Feb 16. [https://ascopubs.org/doi/10.1200/JCO.2009.25.4706 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20159816 PubMed]<br />
#'''ToGA:''' Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961121-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20728210 PubMed]<br />
#'''AVAGAST:''' Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. Epub 2011 Aug 15. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.2236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21844504 PubMed]<br />
#'''DIGEST:''' Ajani JA, Abramov M, Bondarenko I, Shparyk Y, Gorbunova V, Hontsa A, Otchenash N, Alsina M, Lazarev S, Feliu J, Elme A, Esko V, Abdalla K, Verma U, Benedetti F, Aoyama T, Mizuguchi H, Makris L, Rosati G; DIGEST Study Group. A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol. 2017 Sep 1;28(9):2142-2148. [https://academic.oup.com/annonc/article/28/9/2142/4061259 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28911091 PubMed]<br />
#'''Abstract:''' Tabernero J, Van Cutsem E, Yung-Jue B, Fuchs CS, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Salguero HR, Mansoor W, Freitas MI, Brachiroli M, Goekkurt E, Chao J, Wainberg ZA, Kher U, Shah S, Kang SP, Shitara K. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophgeal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. 2019 American Society of Clinical Oncology annual meeting. [[https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.18_suppl.LBA4007 link to abstract]<br />
<br />
<br />
==Cisplatin, Fluorouracil, Pembrolizumab==<br />
{| class="wikitable"<br />
|[[Gastric cancer#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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.18_suppl.LBA4007 Tabernero et al. 2019 (KEYNOTE-062)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_.26_Fluorouracil_3|CF]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|}<br />
''KEYNOTE-062 included patients with GEJ malignancy''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup> IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
**Alternative: capecitabine 1000 mg/m<sup>2</sup> PO BID on days 1-14<br />
<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Abstract:''' Tabernero J, Van Cutsem E, Yung-Jue B, Fuchs CS, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Salguero HR, Mansoor W, Freitas MI, Brachiroli M, Goekkurt E, Chao J, Wainberg ZA, Kher U, Shah S, Kang SP, Shitara K. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophgeal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. 2019 American Society of Clinical Oncology annual meeting. [[https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.18_suppl.LBA4007 link to abstract]<br />
<br />
==Cisplatin & S-1 {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CS: '''<u>C</u>'''isplatin & '''<u>S</u>'''-1<br />
<br>SP: '''<u>S</u>'''-1 & '''<u>P</u>'''latinol (Cisplatin)<br />
===Variant #1, q3wk ("SP3") {{#subobject:4ff7cf|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://academic.oup.com/annonc/article/26/10/2097/144476 Ryu et al. 2015 (SOS)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|SP5<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2, q4wk {{#subobject:03b3c4|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://ascopubs.org/doi/10.1200/JCO.2009.25.4706 Ajani et al. 2010 (FLAGS)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Fluorouracil_3|CF]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/28/9/2142/4061259 Ajani et al. 2017 (DIGEST)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Fluorouracil_3|CF]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: this is an experimental arm of a study where the primary endpoint was not met. Included because CS has been shown to be superior in comparison to other regimens (see above).''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] 25 mg/m<sup>2</sup> PO twice per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, q5wk ("SP5") {{#subobject:cdcc15|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(08)70035-4/fulltext Koizumi et al. 2008 (SPIRITS)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/26/1/141/2802628 Yamada et al. 2014 (G-SOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|SOX<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|[https://academic.oup.com/annonc/article/26/10/2097/144476 Ryu et al. 2015 (SOS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|SP3<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00553-7/fulltext Fujitani et al. 2016 (REGATTA)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2018.77.8613 Ishigami et al. 2018 (PHOENIX-GC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Paclitaxel_.26_S-1|IV/IP Paclitaxel & S-1]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/langas/article/PIIS2468-1253(19)30083-4/fulltext Yamada et al. 2019 (JCOG1013)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin, Docetaxel, S-1<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: in REGATTA, there was no difference in outcome amongst patients who did or did not undergo surgery.'' <br />
<br />
''Inclusion criteria for REGATTA included the presence of a single non-curable factor (ex: hepatic, peritoneal, and para-aortic mets), see link for further details''<br />
<br />
''SPIRITS trial included patients with ECOG of 2 (3% of patients)''<br />
<br />
''Inclusion criteria for PHOENIX-GC included patients with peritoneal metastasis who had received less than or equal to 2 months of prior chemotherapy without disease progression, see link for further details''<br />
====Preceding treatment====<br />
<br />
*REGATTA: Non-laparoscopic [[Surgery#Gastrectomy|gastrectomy]] with D1 [[Surgery#Lymphadenectomy|lymphadenectomy]] versus no surgery; chemotherapy began within 8 weeks of surgery<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 8<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 21<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 21<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 21<br />
<br />
'''35-day cycles'''<br />
<br />
===References===<br />
<br />
#'''SPIRITS:''' Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008 Mar;9(3):215-21. Epub 2008 Feb 20. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(08)70035-4/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18282805 PubMed]<br />
#'''FLAGS:''' Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010 Mar 20;28(9):1547-53. Epub 2010 Feb 16. [https://ascopubs.org/doi/10.1200/JCO.2009.25.4706 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20159816 PubMed]<br />
#'''G-SOX:''' Yamada Y, Higuchi K, Nishikawa K, Gotoh M, Fuse N, Sugimoto N, Nishina T, Amagai K, Chin K, Niwa Y, Tsuji A, Imamura H, Tsuda M, Yasui H, Fujii H, Yamaguchi K, Yasui H, Hironaka S, Shimada K, Miwa H, Hamada C, Hyodo I. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer. Ann Oncol. 2015 Jan;26(1):141-8. Epub 2014 Oct 14. [https://academic.oup.com/annonc/article/26/1/141/2802628 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25316259 PubMed]<br />
#'''SOS:''' Ryu MH, Baba E, Lee KH, Park YI, Boku N, Hyodo I, Nam BH, Esaki T, Yoo C, Ryoo BY, Song EK, Cho SH, Kang WK, Yang SH, Zang DY, Shin DB, Park SR, Shinozaki K, Takano T, Kang YK; SOS study investigators. Comparison of two different S-1 plus cisplatin dosing schedules as first-line chemotherapy for metastatic and/or recurrent gastric cancer: a multicenter, randomized phase III trial (SOS). Ann Oncol. 2015 Oct;26(10):2097-101. Epub 2015 Jul 27. [https://academic.oup.com/annonc/article/26/10/2097/144476 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26216386 PubMed]<br />
#'''REGATTA:''' Fujitani K, Yang HK, Mizusawa J, Kim YW, Terashima M, Han SU, Iwasaki Y, Hyung WJ, Takagane A, Park DJ, Yoshikawa T, Hahn S, Nakamura K, Park CH, Kurokawa Y, Bang YJ, Park BJ, Sasako M, Tsujinaka T; REGATTA study investigators. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial. Lancet Oncol. 2016 Mar;17(3):309-18. Epub 2016 Jan 26. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00553-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26822397 PubMed]<br />
#'''DIGEST:''' Ajani JA, Abramov M, Bondarenko I, Shparyk Y, Gorbunova V, Hontsa A, Otchenash N, Alsina M, Lazarev S, Feliu J, Elme A, Esko V, Abdalla K, Verma U, Benedetti F, Aoyama T, Mizuguchi H, Makris L, Rosati G; DIGEST Study Group. A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol. 2017 Sep 1;28(9):2142-2148. [https://academic.oup.com/annonc/article/28/9/2142/4061259 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28911091 PubMed]<br />
#'''PHOENIX-GC:''' Ishigami H, Fujiwara Y, Fukushima R, Nashimoto A, Yabusaki H, Imano M, Imamoto H, Kodera Y, Uenosono Y, Amagai K, Kadowaki S, Miwa H, Yamaguchi H, Yamaguchi T, Miyaji T, Kitayama J. Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial. J Clin Oncol. 2018 Jul 1;36(19):1922-1929. Epub 2018 May 10. [https://ascopubs.org/doi/full/10.1200/JCO.2018.77.8613 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746229 PubMed]<br />
#'''JCOG1013:''' Yamada Y, Boku N, Mizusawa J, Iwasa S, Kadowaki S, Nakayama N, Azuma M, Sakamoto T, Shitara K, Tamura T, Chin K, Hata H, Nakamori M, Hara H, Yasui H, Katayama H, Fukuda H, Yoshikawa T, Sasako M, Terashima M. Docetaxel plus cisplatin and S-1 versus cisplatin and S-1 in patients with advanced gastric cancer (JCOG1013): an open-label, phase 3, randomised controlled trial. Lancet Gastroenterol Hepatol. 2019 May 14. [Epub ahead of print] [https://www.thelancet.com/journals/langas/article/PIIS2468-1253(19)30083-4/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31101534 PubMed]<br />
<br />
==CLF {{#subobject:b913d6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CLF: '''<u>C</u>'''isplatin, '''<u>L</u>'''eucovorin, '''<u>F</u>'''luorouracil<br />
<br>FLP: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>P</u>'''latinol (Cisplatin)<br />
===Variant #1 {{#subobject:beef19|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/26/9/1435.long Al-Batran et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#OLF|FLO]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|}<br />
''Note: In contrast to the original reference, some guidelines list 5-FU as being given every 2 weeks rather than the schedule below.''<br />
<br />
''Patients: 100% adenocarcinoma histology (20% gastroesophageal junction, 80% gastric'').<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29, 43<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29, 43<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 12,000 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*Up to 3 liters normal saline as hydration with [[Cisplatin (Platinol)]]<br />
*Antiemetic medications per "local protocols"<br />
<br />
'''8-week cycles'''<br />
<br />
===Variant #2 {{#subobject:34890|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/22/21/4319.long Bouché et al. 2004 (FFCD 9803)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|1. [[Esophageal_cancer#Fluorouracil_.26_Folinic_acid|LV5FU2]]<br> 2. [[Esophageal_cancer#FOLFIRI|LV5FU2 & Irinotecan]]<br />
| style="background-color:#d3d3d3" |Not powered to draw conclusions<br />
|-<br />
|}<br />
''Note: the primary reference said every cycle was 15 days, but also said that medications were given every 14 days, so the assumption was made that this more regular schedule was used.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once on either day 1 or 2<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup> IV continuous infusion over 22 hours (total dose per cycle: 1600 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*1 liter hydration over 3 hours before and after [[Cisplatin (Platinol)]]<br />
*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] IV before [[Cisplatin (Platinol)]]<br />
*[[Methylprednisolone (Solumedrol)]] 120 mg IV 10 minutes before [[Cisplatin (Platinol)]]<br />
*Oral antiemetics and corticosteroids from days 2 to 5<br />
<br />
'''14-day cycle for at least 4 cycles'''<br />
<br />
===References===<br />
<br />
#'''FFCD 9803:''' Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, Arsène D, Paitel JF, Guérin-Meyer V, Mitry E, Buecher B, Kaminsky MC, Seitz JF, Rougier P, Bedenne L, Milan C; Fédération Francophone de Cancérologie Digestive Group. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1;22(21):4319-28. [http://jco.ascopubs.org/content/22/21/4319.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15514373 PubMed]<br />
#Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jäger E; Arbeitsgemeinschaft Internistische Onkologie. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008 Mar 20;26(9):1435-42. [http://jco.ascopubs.org/content/26/9/1435.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18349393 PubMed]<br />
<br />
==CX {{#subobject:2bd34d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CX: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
<br>XP: '''<u>X</u>'''eloda (Capecitabine), '''<u>P</u>'''latinol (Cisplatin)<br />
===Regimen {{#subobject:82b184|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://annonc.oxfordjournals.org/content/20/4/666.long Kang et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Fluorouracil_3|CF]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2011.36.2236 Ohtsu et al. 2011 (AVAGAST)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & 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)70102-5/abstract Lordick et al. 2013 (EXPAND)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & Cetuximab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544634/ Shen et al. 2014 (AVATAR)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(14)00884-3/fulltext Kim et al. 2014 (SMC 2008-12-019)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & Simvastatin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097104/ Lu et al. 2018 (PAC-C)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Capecitabine & Paclitaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30791-5/fulltext Fuchs et al. 2019 (RAINFALL)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX & Ramucirumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS (*)<br />
|-<br />
|}<br />
The following studies included patients with GE junction malignancy as well: <br />
<br />
*''AVAGAST patients: 86% gastric and 14% GE junction. 5.4% of patients had an ECOG of 2.''<br />
*''EXPAND patients: 83% gastric, 5% GE junction and 16% unknown''<br />
*''Kim et al patients: 79% gastric, 16% GE junction and 5% unknown''<br />
<br />
''Note: while the primary analysis of RAINFALL showed that this arm seemed to have inferior PFS, independent central review did not confirm this finding.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
**EXPAND: 1000 mg/m<sup>2</sup> PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)<br />
<br />
====Supportive medications====<br />
<br />
*Some protocols: "Hyperhydration" for [[Cisplatin (Platinol)]]<br />
<br />
'''21-day cycles, varied duration (see below)'''<br />
====Subsequent treatment====<br />
<br />
*AVAGAST & AVATAR: after 6 cycles, [[#Capecitabine_monotherapy_2|capecitabine maintenance]]<br />
*Kim et al. 2014: after 8 cycles, [[#Capecitabine_monotherapy_2|capecitabine maintenance]]<br />
<br />
===References===<br />
<br />
#Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009 Apr;20(4):666-73. Epub 2009 Jan 19. [http://annonc.oxfordjournals.org/content/20/4/666.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19153121 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
#'''AVAGAST:''' Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. Epub 2011 Aug 15. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.2236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21844504 PubMed]<br />
#'''EXPAND:''' Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V, Park JO, Sawaki A, Celik I, Götte H, Melezínková H, Moehler M; Arbeitsgemeinschaft Internistische Onkologie (AIO) and EXPAND Investigators. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013 May;14(6):490-9. Epub 2013 Apr 15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70102-5/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23594786 PubMed]<br />
#'''AVATAR:''' Shen L, Li J, Xu J, Pan H, Dai G, Qin S, Wang L, Wang J, Yang Z, Shu Y, Xu R, Chen L, Liu Y, Yu S, Bu L, Piao Y. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer. 2015 Jan;18(1):168-76. Epub 2014 Feb 21. [https://link.springer.com/article/10.1007%2Fs10120-014-0351-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544634/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24557418 PubMed]<br />
#'''SMC 2008-12-019:''' Kim ST, Kang JH, Lee J, Park SH, Park JO, Park YS, Lim HY, Hwang IG, Lee SC, Park KW, Lee HR, Kang WK. Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study. Eur J Cancer. 2014 Nov;50(16):2822-30. Epub 2014 Sep 15. [https://www.ejcancer.com/article/S0959-8049(14)00884-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25218337 PubMed]<br />
#'''PAC-C:''' Lu Z, Zhang X, Liu W, Liu T, Hu B, Li W, Fan Q, Xu J, Xu N, Bai Y, Pan Y, Xu Q, Bai W, Xia L, Gao Y, Wang W, Shu Y, Shen L. A multicenter, randomized trial comparing efficacy and safety of paclitaxel/capecitabine and cisplatin/capecitabine in advanced gastric cancer. Gastric Cancer. 2018 Sep;21(5):782-791. Epub 2018 Feb 27. [https://link.springer.com/article/10.1007%2Fs10120-018-0809-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097104/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29488121 PubMed]<br />
#'''RAINFALL:''' Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, Ilson DH, Alsina M, Chau I, Lacy J, Ducreux M, Mendez GA, Alavez AM, Takahari D, Mansoor W, Enzinger PC, Gorbounova V, Wainberg ZA, Hegewisch-Becker S, Ferry D, Lin J, Carlesi R, Das M, Shah MA; RAINFALL Study Group. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):420-435. Epub 2019 Feb 1. Erratum in: Lancet Oncol. 2019 May;20(5):e242. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30791-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30718072 PubMed]<br />
<br />
==CX & Trastuzumab {{#subobject:7cbb79|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CX & Trastuzumab: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine), Trastuzumab<br />
===Variant #1, 80/1600 {{#subobject:cdee6d|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://ascopubs.org/doi/full/10.1200/JCO.2016.71.6852 Shah et al. 2017 (HELOISE)]<br />
| style="background-color:#1a9851" |Phase IIIb (C)<br />
|[[#CX_.26_Trastuzumab|CX & Trastuzumab]]; high-dose<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Patients had overexpression of HER2 protein by immunohistochemistry AND gene amplification by in-situ hybridization.<br />
<br />
''Patients: 79% gastric, 21% GE junction, and all patients had an ECOG of 2''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1 (compared to HD-Trastuzumab at 10 mg/kg IV)<br />
**Subsequent cycles: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*Trastuzumab maintenance<br />
<br />
===Variant #2, 80/2000 {{#subobject:27adc6|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%2810%2961121-X/fulltext Bang et al. 2010 (ToGA)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#CX|CX]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30481-9/fulltext Tabernero et al. 2018 (JACOB)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CX, Pertuzumab, Trastuzumab<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
ToGA patients had overexpression of HER2 protein by immunohistochemistry OR gene amplification by fluorescence in-situ hybridization.<br />
<br />
''ToGA patients: 81% gastric, 19% GE junction. 10% of patients with ECOG of 2.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Subsequent cycles: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ToGA:''' Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961121-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20728210 PubMed]<br />
#'''HELOISE:''' Shah MA, Xu RH, Bang YJ, Hoff PM, Liu T, Herráez-Baranda LA, Xia F, Garg A, Shing M, Tabernero J. HELOISE: Phase IIIb randomized multicenter study comparing standard-of-care and higher-dose trastuzumab regimens combined with chemotherapy as first-line therapy in patients with human epidermal growth factor receptor 2-positive metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol. 2017 Aug 1;35(22):2558-2567. Epub 2017 Jun 2.[https://ascopubs.org/doi/full/10.1200/JCO.2016.71.6852 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28574779 PubMed]<br />
#'''JACOB:''' Tabernero J, Hoff PM, Shen L, Ohtsu A, Shah MA, Cheng K, Song C, Wu H, Eng-Wong J, Kim K, Kang YK. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018 Oct;19(10):1372-1384. Epub 2018 Sep 11. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30481-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30217672 PubMed]<br />
<br />
==DCF {{#subobject:efbdc5|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 />
<br>TCF: '''<u>T</u>'''axotere (Docetaxel), '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
<br />
===Variant #1 {{#subobject:5aba07|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/23/24/5660.long Ajani et al. 2005 (V-325)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Cisplatin_.26_Docetaxel|DC]]<br />
| style="background-color:#91cf60" |Seems to have superior ORR<br />
|-<br />
|[http://jco.ascopubs.org/content/24/31/4991.long Van Cutsem et al. 2006 (TAX 325)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Cisplatin_.26_Fluorouracil_3|CF]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
<br />
''Note: In contrast to the original references, some guidelines list each cycle as lasting 28 days.''<br />
<br />
''Anjani et al. Patients: 100% adenocarcinoma histology (32% gastroesophageal junction/fundus and 68% gastric antrum/body). 95% were metastatic. 1% with Karnofsky PS score of 70.'' <br />
<br />
''Van Cutsem et al Patients: 100% adenocarcinoma histology (22% gastroesophageal junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS score of 70.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 1 to 3 hours 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 />
<br />
*(varied depending on reference):<br />
*[[Dexamethasone (Decadron)]] 8 mg PO once the night before chemotherapy, then 8 mg PO once on day 1; 1 hour prior to chemotherapy, then 8 mg PO twice per day until day 2 (total dose per cycle: 48 mg)<br />
*[[Dexamethasone (Decadron)]] 20 mg IV before [[Cisplatin (Platinol)]] and 8 hours after [[Cisplatin (Platinol)]]<br />
*[[Ondansetron (Zofran)]] 8 mg IV before [[Cisplatin (Platinol)]], 4 hours after [[Cisplatin (Platinol)]], and 8 hours after [[Cisplatin (Platinol)]]<br />
*"Hydration [was] administered in a standard manner"<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2 {{#subobject:baa015|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" |[http://jco.ascopubs.org/content/25/22/3217.long Roth et al. 2007]<br />
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|1. [[#ECF_3|ECF]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Cisplatin_.26_Docetaxel|TC]]<br />
| style="background-color:#d9ef8b" |Might have superior ORR<br />
|-<br />
|}<br />
''Note: the protocol was amended to change the original dose of ''docetaxel from'' 85 mg/m<sup>2</sup> to 75 mg/m<sup>2</sup> based on high incidence of febrile neutropenia.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 4 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion over 14 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*3 liters per day "hyperhydration"<br />
*[[Dexamethasone (Decadron)]] 8 mg PO given 12 hours & 6 hours before [[Docetaxel (Taxotere)]], then 8 mg PO twice per day for 4 days after [[Docetaxel (Taxotere)]]<br />
*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] for emesis prophylaxis<br />
*Growth factor support allowed, such as with [[Filgrastim (Neupogen)]]<br />
<br />
'''21-day cycle for up to 8 cycles'''<br />
<br />
===References===<br />
<br />
#'''V-325:''' Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Cabral Filho S, Majlis A, Assadourian S, Van Cutsem E. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005 Aug 20;23(24):5660-7. [http://jco.ascopubs.org/content/23/24/5660.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16110025 PubMed]<br />
#'''TAX 325:''' Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006 Nov 1;24(31):4991-7. [http://jco.ascopubs.org/content/24/31/4991.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17075117 PubMed]<br />
#Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. [http://jco.ascopubs.org/content/25/22/3217.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17664469 PubMed]<br />
<br />
==mDCF {{#subobject:70e20f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mDCF: '''<u>m</u>'''odified '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
===Variant #1, 40/40/2800 {{#subobject:372f9c|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/PMC3646322/ Shah et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: In contrast to the primary reference, some guidelines list this regimen without bevacizumab. Please see below for the original mDCF regimen that included bevacizumab.''<br />
<br />
''Patients: 100% adenocarcinoma (50% gastric, 45% gastroesophageal junction, 5% esophagus). 93% received no prior therapy.'' <br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Cisplatin (Platinol)]] 40 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 3<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*"Standard premedication and delayed emesis regimens"<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, 60/60/3000 {{#subobject:323b13|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://meetinglibrary.asco.org/content/1882-72 Ozal et al. 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/PMC4688303/ Wang et al. 2015 (DOCET_L_02195)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_.26_Fluorouracil_3|CF]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] by one of the following:<br />
**600 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3000 mg/m<sup>2</sup>)<br />
**750 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3000 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#'''Abstract:''' G. Ozal, M. Dogan, H. Akbulut, B. Yalcin, G. Utkan, Y. Urun, F. Icli. The safety and efficacy of modified-dose docetaxel, cisplatin, and 5-fluorouracil (mDCF) combination in the front-line treatment of advanced gastric cancer. 2010 Gastrointestinal Cancers Symposium abstract 113. [http://meetinglibrary.asco.org/content/1882-72 link to abstract]<br />
#Shah MA, Jhawer M, Ilson DH, Lefkowitz RA, Robinson E, Capanu M, Kelsen DP. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011 Mar 1;29(7):868-74. Epub 2010 Dec 28. [http://jco.ascopubs.org/content/29/7/868.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646322/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21189380 PubMed]<br />
#'''DOCET_L_02195:''' Wang J, Xu R, Li J, Bai Y, Liu T, Jiao S, Dai G, Xu J, Liu Y, Fan N, Shu Y, Ba Y, Ma D, Qin S, Zheng L, Chen W, Shen L. Randomized multicenter phase III study of a modified docetaxel and cisplatin plus fluorouracil regimen compared with cisplatin and fluorouracil as first-line therapy for advanced or locally recurrent gastric cancer. Gastric Cancer. 2016 Jan;19(1):234-44. Epub 2015 Jan 21. [https://link.springer.com/article/10.1007%2Fs10120-015-0457-4 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688303/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25604851 PubMed]<br />
<br />
==mDCF & Bevacizumab {{#subobject:30ea9e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mDCF & Bevacizumab: '''<u>m</u>'''odified '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil & Bevacizumab<br />
===Regimen {{#subobject:5485f9|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/PMC3646322/ Shah et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma (50% gastric, 45% gastroesophageal junction, 5% esophagus). 93% received no prior therapy.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Cisplatin (Platinol)]] 40 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 3<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*"Standard premedication and delayed emesis regimens"<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#Shah MA, Jhawer M, Ilson DH, Lefkowitz RA, Robinson E, Capanu M, Kelsen DP. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011 Mar 1;29(7):868-74. Epub 2010 Dec 28. [http://jco.ascopubs.org/content/29/7/868.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646322/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21189380 PubMed]<br />
<br />
==Docetaxel & S-1 {{#subobject:a22c2a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:82ca03|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/PMC3895196/ Koizumi et al. 2013 (START<sub>gastric</sub>)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV once on day 1<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 14<br />
**BSA between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''START:''' Koizumi W, Kim YH, Fujii M, Kim HK, Imamura H, Lee KH, Hara T, Chung HC, Satoh T, Cho JY, Hosaka H, Tsuji A, Takagane A, Inokuchi M, Tanabe K, Okuno T, Ogura M, Yoshida K, Takeuchi M, Nakajima T; JACCRO and KCSG Study Group. Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START). J Cancer Res Clin Oncol. 2014 Feb;140(2):319-28. Epub 2013 Dec 24. [https://link.springer.com/article/10.1007%2Fs00432-013-1563-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895196/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24366758 PubMed]<br />
<br />
==ECF {{#subobject:6325cb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:e5ede0|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://annonc.oxfordjournals.org/content/5/7/609.long Findlay et al. 1994]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://ascopubs.org/doi/10.1200/JCO.1997.15.1.261 Webb et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Gastric_cancer_-_historical#FAMTX|FAMTX]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/20/8/1996.long Ross et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MCF|MCF]]<br />
| style="background-color:#eeee01" |Seems to have non-inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/22/3217.long Roth et al. 2007]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|1. [[#Cisplatin_.26_Docetaxel|TC]]<br> 2. [[#DCF|TCF]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
| rowspan="3" |[https://www.nejm.org/doi/full/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#ECX_2|ECX]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|2. [[#EOF_2|EOF]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|3. [[#EOX_2|EOX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Findlay et al. Patients: all metastatic gastric cancer''<br />
<br />
''Ross et al. Patients: adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma histology, all advanced esophagogastric cancer.''<br />
<br />
''Roth et al. Patients: all metastatic gastric cancer'' <br />
<br />
''REAL-2 Patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 4 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*(varied depending on reference):<br />
*3 liters per day "hyperhydration"<br />
*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] for emesis prophylaxis<br />
*Growth factor support allowed, such as with [[Filgrastim (Neupogen)]]<br />
*Ross et al. 2002 & Cunningham et al. 2008 used [[Warfarin (Coumadin)]] 1 mg PO once per day for catheter thrombosis prophylaxis<br />
<br />
'''21-day cycle for up to 8 cycles'''<br />
<br />
===References===<br />
<br />
#Findlay M, Cunningham D, Norman A, Mansi J, Nicolson M, Hickish T, Nicolson V, Nash A, Sacks N, Ford H, Carter R, Hill A. A phase II study in advanced gastro-esophageal cancer using epirubicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF). Ann Oncol. 1994 Sep;5(7):609-16. [http://annonc.oxfordjournals.org/content/5/7/609.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7993836 PubMed]<br />
#Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, Hughes M, Mansi J, Findlay M, Hill A, Oates J, Nicolson M, Hickish T, O'Brien M, Iveson T, Watson M, Underhill C, Wardley A, Meehan M. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol. 1997 Jan;15(1):261-7. [https://ascopubs.org/doi/10.1200/JCO.1997.15.1.261 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8996151 PubMed]<br />
##'''Update:''' Waters JS, Norman A, Cunningham D, Scarffe JH, Webb A, Harper P, Joffe JK, Mackean M, Mansi J, Leahy M, Hill A, Oates J, Rao S, Nicolson M, Hickish T. Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer. 1999 Apr;80(1-2):269-72. [https://www.nature.com/articles/6690350 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363002/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/10390007 PubMed]<br />
#Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, Price T, Anderson H, Iveson T, Hickish T, Lofts F, Norman A. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol. 2002 Apr 15;20(8):1996-2004. [http://jco.ascopubs.org/content/20/8/1996.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11956258 PubMed]<br />
#Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Köberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1;25(22):3217-23. [http://jco.ascopubs.org/content/25/22/3217.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17664469 PubMed]<br />
#'''REAL-2:''' Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. [https://www.nejm.org/doi/full/10.1056/NEJMoa073149 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18172173 PubMed]<br />
<br />
==ECX {{#subobject:36cac7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECX: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
<br>ECC: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>C</u>'''apecitabine<br />
===Variant #1, continuous capecitabine {{#subobject:f0efc0|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(17)30566-1/fulltext Catenacci et al. 2017 (RILOMET-1)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|ECX & Rilotumumab<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Patients had unresectable or metastatic MET-positive gastric or gastro-esophageal junction cancer.''<br />
<br />
''Patients: ~80% gastric, 20% GE junction and 10% distal esophageal''<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day<br />
<br />
'''21-day cycle for up to 10 cycles'''<br />
<br />
===Variant #2, intermittent capecitabine {{#subobject:f0efc0|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.ejcancer.com/article/S0959-8049(10)00731-8/fulltext Konings et al. 2010]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|ECC & Pravastatin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS6<br />
|-<br />
|}<br />
''Patients: 6.6% of patients had an ECOG of 2''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1, '''given first'''<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given second'''<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Konings IR, van der Gaast A, van der Wijk LJ, de Jongh FE, Eskens FA, Sleijfer S. The addition of pravastatin to chemotherapy in advanced gastric carcinoma: a randomised phase II trial. Eur J Cancer. 2010 Dec;46(18):3200-4. Epub 2010 Aug 18. [https://www.ejcancer.com/article/S0959-8049(10)00731-8/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20727735 PubMed]<br />
#'''RILOMET-1:''' Catenacci DVT, Tebbutt NC, Davidenko I, Murad AM, Al-Batran SE, Ilson DH, Tjulandin S, Gotovkin E, Karaszewska B, Bondarenko I, Tejani MA, Udrea AA, Tehfe M, De Vita F, Turkington C, Tang R, Ang A, Zhang Y, Hoang T, Sidhu R, Cunningham D. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1467-1482. Epub 2017 Sep 25. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30566-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28958504 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:588907|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, CI {{#subobject:3289d8|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" |[http://jco.ascopubs.org/content/21/1/54.long Ohtsu et al. 2003 (JCOG 9205)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Cisplatin_.26_Fluorouracil_3|FP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#UFTM|UFTM]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70259-1/fulltext Boku et al. 2009 (JCOG 9912)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Cisplatin & Irinotecan<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|2. [[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|[https://academic.oup.com/jjco/article/43/10/972/851849 Shirao et al. 2013 (JCOG 0106)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MF<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%<br />
|-<br />
|}<br />
''JCOG 9205 included patients with PFS of 2 (9.6%)''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, intermittent, BSA-based {{#subobject:27a992|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://jamanetwork.com/journals/jama/fullarticle/397816 Cullinan et al. 1985]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|1. FA<br> 2. [[Gastric_cancer_-_historical#FAM|FAM]]<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 represents a de-escalation strategy.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycles'''<br />
<br />
===Variant #3, intermittent, weight-based {{#subobject:27jb82|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.karger.com/Article/Abstract/226337 Kolarić et al. 1986]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Epirubicin & Fluorouracil<br />
| style="background-color:#fc8d59" |Seems to have inferior DOR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 12 mg/kg IV once per day on days 1 to 5<br />
<br />
'''21- to 28-day cycles'''<br />
<br />
===Variant #4, PVI {{#subobject:d98c9f|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://academic.oup.com/annonc/article/13/10/1568/167797 Tebbutt et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & Mitomycin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion<br />
<br />
'''Up to 24-week course'''<br />
<br />
===References===<br />
<br />
#Cullinan SA, Moertel CG, Fleming TR, Rubin JR, Krook JE, Everson LK, Windschitl HE, Twito DI, Marschke RF, Foley JF, Pfeifle DM, Barlow JF. A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma: fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA. 1985 Apr 12;253(14):2061-7. [https://jamanetwork.com/journals/jama/fullarticle/397816 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2579257 PubMed]<br />
#Kolarić K, Potrebica V, Stanovnik M. Controlled phase III clinical study of 4-epi-doxorubicin + 5-fluorouracil versus 5-fluorouracil alone in metastatic gastric and rectosigmoid cancer. Oncology. 1986;43(2):73-7. [https://www.karger.com/Article/Abstract/226337 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/3513075 PubMed]<br />
#Tebbutt NC, Norman A, Cunningham D, Iveson T, Seymour M, Hickish T, Harper P, Maisey N, Mochlinski K, Prior Y, Hill M. A multicentre, randomised phase III trial comparing protracted venous infusion (PVI) 5-fluorouracil (5-FU) with PVI 5-FU plus mitomycin C in patients with inoperable oesophago-gastric cancer. Ann Oncol. 2002 Oct;13(10):1568-75. [https://academic.oup.com/annonc/article/13/10/1568/167797 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12377644 PubMed]<br />
#'''JCOG 9205:''' Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; Japan Clinical Oncology Group Study (JCOG9205). Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. [http://jco.ascopubs.org/content/21/1/54.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506170 PubMed]<br />
#'''JCOG 9912:''' Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, Koizumi W, Saito H, Yamaguchi K, Takiuchi H, Nasu J, Ohtsu A; Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group. Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study. Lancet Oncol. 2009 Nov;10(11):1063-9. Epub 2009 Oct 7. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70259-1/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19818685 PubMed]<br />
#'''JCOG 0106:''' Shirao K, Boku N, Yamada Y, Yamaguchi K, Doi T, Goto M, Nasu J, Denda T, Hamamoto Y, Takashima A, Fukuda H, Ohtsu A; Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group. Randomized Phase III study of 5-fluorouracil continuous infusion vs sequential methotrexate and 5-fluorouracil therapy in far advanced gastric cancer with peritoneal metastasis (JCOG0106). Jpn J Clin Oncol. 2013 Oct;43(10):972-80. Epub 2013 Sep 7. [https://academic.oup.com/jjco/article/43/10/972/851849 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24014884 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, Mitomycin {{#subobject:a4ca9d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:672a28|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.karger.com/Article/Abstract/64319 Hofheinz et al. 2002]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts in this subgroup<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV continuous infusion over 24 hours once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Mitomycin (Mutamycin)]] 10 mg/m<sup>2</sup> IV once per day on days 1 & 22<br />
<br />
'''56-day cycle for 2 cycles'''<br />
<br />
===References===<br />
<br />
#Hofheinz RD, Hartung G, Samel S, Hochhaus A, Pichlmeier U, Post S, Hehlmann R, Queisser W. High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer: a phase II study. Onkologie. 2002 Jun;25(3):255-60. [http://www.karger.com/Article/Abstract/64319 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12119460 PubMed]<br />
<br />
==Irinotecan monotherapy {{#subobject:41e063|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9fb427|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://link.springer.com/article/10.1007%2Fs10620-005-3038-2 Enzinger et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: In contrast to the primary references, some guidelines list a dosing schedule of 125 mg/m<sup>2</sup> IV once per day on days 1 & 8, with 21-day cycles. Enzinger et al. 2005 comment that "when irinotecan is used as a single-agent, a tri-weekly schedule may be preferable."''<br />
<br />
''Study included patients with GE junction and distal esophageal malignancy as well (~59% gastric, 9% GEJ and 33% distal esophagus)''<br />
<br />
''Regimen showed a 14% response rate and 53% disease control rate.''<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<br />
#Enzinger PC, Kulke MH, Clark JW, Ryan DP, Kim H, Earle CC, Vincitore MM, Michelini AL, Mayer RJ, Fuchs CS. A phase II trial of irinotecan in patients with previously untreated advanced esophageal and gastric adenocarcinoma. Dig Dis Sci. 2005 Dec;50(12):2218-23. [http://link.springer.com/article/10.1007%2Fs10620-005-3038-2 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16416165 PubMed]<br />
<br />
==OLF {{#subobject:98b4fa|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OLF: '''<u>O</u>'''xaliplatin, '''<u>L</u>'''eucovorin, '''<u>F</u>'''luorouracil<br />
<br>FLO: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>O</u>'''xaliplatin<br />
===Regimen {{#subobject:3d7273|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/26/9/1435.long Al-Batran et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#CLF|FLP]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma histology (20% esophagogastric junction, 80% gastric'').<br />
<br />
====Chemotherapy====<br />
<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29, 43<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29, 43<br />
*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on days 1, 15, 29, 43 (total dose per cycle: 10,400 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*Antiemetic medications per "local protocols"<br />
<br />
'''8-week cycles'''<br />
<br />
===References===<br />
<br />
#Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jäger E; Arbeitsgemeinschaft Internistische Onkologie. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008 Mar 20;26(9):1435-42. [http://jco.ascopubs.org/content/26/9/1435.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18349393 PubMed]<br />
<br />
==Paclitaxel & S-1 {{#subobject:a88c2a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:82ca09|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://ascopubs.org/doi/full/10.1200/JCO.2018.77.8613 Ishigami et al. 2018 (PHOENIX-GC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_S-1|Cisplatin & S-1]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|}<br />
''Note: Inclusion criteria for PHOENIX-GC included patients with peritoneal metastasis who had received less than or equal to 2 months of prior chemotherapy without disease progression, see link for further details''<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 and 8<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**40 to 60 mg twice per day, depending on body surface area, as follows:<br />
***if less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14<br />
***if 1.25 to less than 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14<br />
***if more than 1.5 m<sup>2</sup>: 60 mg PO twice per day on days 1 to 14<br />
*[[Paclitaxel (Taxol)]] 20 mg/m<sup>2</sup> IP once per day over 1 hour on days 1 and 8<br />
<br />
====Supportive medications====<br />
<br />
*500 mL of normal saline was given prior to intraperitoneal [[Paclitaxel (Taxol)]]<br />
<br />
'''35-day cycles'''<br />
<br />
===References===<br />
<br />
#'''PHOENIX-GC:''' Ishigami H, Fujiwara Y, Fukushima R, Nashimoto A, Yabusaki H, Imano M, Imamoto H, Kodera Y, Uenosono Y, Amagai K, Kadowaki S, Miwa H, Yamaguchi H, Yamaguchi T, Miyaji T, Kitayama J. Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial. J Clin Oncol. 2018 Jul 1;36(19):1922-1929. Epub 2018 May 10. [https://ascopubs.org/doi/full/10.1200/JCO.2018.77.8613 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29746229 PubMed]<br />
<br />
==Pembrolizumab monotherapy==<br />
{| class="wikitable"<br />
|[[Gastric cancer#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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.18_suppl.LBA4007 Tabernero et al. 2019 (KEYNOTE-062)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|Chemotherapy<br />
| style="background-color:#ffffbf" |Mixed endpoints<br />
|-<br />
|}<br />
''KEYNOTE-062 included patients with GEJ malignancy''<br />
<br />
''*Improved OS was seen in patients with PD-L1 CPS score of 10 or more (HR: 0.62) but was not tested per analysis plan''<br />
<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Abstract:''' Tabernero J, Van Cutsem E, Yung-Jue B, Fuchs CS, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Salguero HR, Mansoor W, Freitas MI, Brachiroli M, Goekkurt E, Chao J, Wainberg ZA, Kher U, Shah S, Kang SP, Shitara K. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophgeal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. 2019 American Society of Clinical Oncology annual meeting. [https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.18_suppl.LBA4007 link to abstract]<br />
<br />
==S-1 monotherapy {{#subobject:a12a2a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, BSA-based {{#subobject:86c009|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(09)70259-1/fulltext Boku et al. 2009 (JCOG 9912)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. Cisplatin & Irinotecan<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===Variant #2, weight-based {{#subobject:f90b1b|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(08)70035-4/fulltext Koizumi et al. 2008 (SPIRITS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_S-1|Cisplatin & S-1]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056989/ Narahara et al. 2011 (TOP-002)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|IRIS<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895196/ Koizumi et al. 2013 (START<sub>gastric</sub>)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_.26_S-1|Docetaxel & S-1]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(16)32267-5/fulltext Yoshino et al. 2016 (JFMC36-0701)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Lentinan & S-1<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: there is another trial named START in NSCLC.''<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 between 1.25 and 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 />
===References===<br />
<br />
#'''SPIRITS:''' Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008 Mar;9(3):215-21. Epub 2008 Feb 20. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(08)70035-4/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18282805 PubMed]<br />
#'''JCOG 9912:''' Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, Koizumi W, Saito H, Yamaguchi K, Takiuchi H, Nasu J, Ohtsu A; Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group. Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study. Lancet Oncol. 2009 Nov;10(11):1063-9. Epub 2009 Oct 7. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70259-1/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19818685 PubMed]<br />
#'''TOP-002:''' Narahara H, Iishi H, Imamura H, Tsuburaya A, Chin K, Imamoto H, Esaki T, Furukawa H, Hamada C, Sakata Y. Randomized phase III study comparing the efficacy and safety of irinotecan plus S-1 with S-1 alone as first-line treatment for advanced gastric cancer (study GC0301/TOP-002). Gastric Cancer. 2011 Mar;14(1):72-80. Epub 2011 Feb 23. [https://link.springer.com/article/10.1007%2Fs10120-011-0009-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056989/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21340666 PubMed]<br />
#'''START:''' Koizumi W, Kim YH, Fujii M, Kim HK, Imamura H, Lee KH, Hara T, Chung HC, Satoh T, Cho JY, Hosaka H, Tsuji A, Takagane A, Inokuchi M, Tanabe K, Okuno T, Ogura M, Yoshida K, Takeuchi M, Nakajima T; JACCRO and KCSG Study Group. Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START). J Cancer Res Clin Oncol. 2014 Feb;140(2):319-28. Epub 2013 Dec 24. [https://link.springer.com/article/10.1007%2Fs00432-013-1563-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895196/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24366758 PubMed]<br />
#'''JFMC36-0701:''' Yoshino S, Nishikawa K, Morita S, Takahashi T, Sakata K, Nagao J, Nemoto H, Murakami N, Matsuda T, Hasegawa H, Shimizu R, Yoshikawa T, Osanai H, Imano M, Naitoh H, Tanaka A, Tajiri T, Gochi A, Suzuki M, Sakamoto J, Saji S, Oka M. Randomised phase III study of S-1 alone versus S-1 plus lentinan for unresectable or recurrent gastric cancer (JFMC36-0701). Eur J Cancer. 2016 Sep;65:164-71. Epub 2016 Aug 5. [https://www.ejcancer.com/article/S0959-8049(16)32267-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27501505 PubMed]<br />
<br />
==UFTM {{#subobject:96e8bf|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
UFTM: '''<u>UFT</u>''' (Tegafur and uracil) & '''<u>M</u>'''itomycin <br />
<br />
===Regimen {{#subobject:3a603b|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" |[http://jco.ascopubs.org/content/21/1/54.long Ohtsu et al. 2003 (JCOG 9205)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Fluorouracil_monotherapy|Fluorouracil]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[#Cisplatin_.26_Fluorouracil_3|FP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Study included patients with PFS of 2 (9.6%)''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Tegafur and uracil (UFT)]] 187.5 mg/m<sup>2</sup> PO twice per day<br />
*[[Mitomycin (Mutamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**"Mitomycin was interrupted for 1 month after patients received a total dose of 60 mg."<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''JCOG 9205:''' Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; Japan Clinical Oncology Group Study (JCOG9205). Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. [http://jco.ascopubs.org/content/21/1/54.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506170 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Capecitabine monotherapy {{#subobject:c6df5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:878a56|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.2011.36.2236 Ohtsu et al. 2011 (AVAGAST)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(14)00884-3/fulltext Kim et al. 2014]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Ohtsu et al patients: 86% gastric and 14% GEJ. 5.4% of patients had an ECOG of 2.''<br />
<br />
''Kim et al patients: 79% gastric, 5% GEJ, and 16% unknown. 2% of patients had an ECOG of 2.''<br />
====Preceding treatment====<br />
<br />
*AVAGAST: [[#CX_2|CX]] x 6<br />
*Kim et al. 2014: [[#CX_2|CX]] x 8<br />
<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. Epub 2011 Aug 15. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.2236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21844504 PubMed]<br />
#Kim ST, Kang JH, Lee J, Park SH, Park JO, Park YS, Lim HY, Hwang IG, Lee SC, Park KW, Lee HR, Kang WK. Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study. Eur J Cancer. 2014 Nov;50(16):2822-30. Epub 2014 Sep 15. [https://www.ejcancer.com/article/S0959-8049(14)00884-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25218337 PubMed]<br />
<br />
=Metastatic or locally advanced disease, subsequent lines of therapy=<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 />
|[https://www.ejcancer.com/article/S0959-8049(11)00396-0/fulltext Thuss-Patience et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Irinotecan_monotherapy_2|Irinotecan]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/30/13/1513.full Kang et al. 2012]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. [[#Irinotecan_monotherapy_2|Irinotecan]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70549-7/fulltext Ford et al. 2014 (COUGAR-02)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2012.48.3552 Ohtsu et al. 2013 (GRANITE-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Everolimus<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.''<br />
<br />
''Thuss-Patience et al. patients: ~58% gastric, 43% GEJ. 21% of patients had an ECOG of 2.''<br />
<br />
''GRANITE-1 study patients: 29% had GEJ involvement. 7.9% of patients had an ECOG of 2.''<br />
<br />
===References===<br />
<br />
#Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, Dogan Y, Gebauer B, Schumacher G, Reichardt P. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011 Oct;47(15):2306-14. [https://www.ejcancer.com/article/S0959-8049(11)00396-0/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21742485 PubMed]<br />
#Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. [http://jco.ascopubs.org/content/30/13/1513.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22412140 PubMed]<br />
#'''COUGAR-02:''' Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA; COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):78-86. Epub 2013 Dec 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70549-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24332238 PubMed]<br />
#'''GRANITE-1:''' Ohtsu A, Ajani JA, Bai YX, Bang YJ, Chung HC, Pan HM, Sahmoud T, Shen L, Yeh KH, Chin K, Muro K, Kim YH, Ferry D, Tebbutt NC, Al-Batran SE, Smith H, Costantini C, Rizvi S, Lebwohl D, Van Cutsem E. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol. 2013 Nov 1;31(31):3935-43. Epub 2013 Sep 16. [https://ascopubs.org/doi/full/10.1200/JCO.2012.48.3552 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24043745 PubMed]<br />
<br />
==Apatinib monotherapy==<br />
{| class="wikitable"<br />
|[[Gastric cancer#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable"<br />
!Study<br />
![[Levels of Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels of Evidence#Efficacy|Efficacy]]<br />
|-<br />
|Kang et al. 2019 (ANGEL)<br />
|Randomized Phase III<br />
|[[Gastric cancer#Placebo|Placebo]]<br />
|Superior PFS<br />
|}<br />
''ANGEL included patients with GEJ malignancy''<br />
<br />
====Chemotherapy====<br />
<br />
*Apatinib (Rivoceranib) 700 mg daily on days 1-28<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Abstract:''' Kang Y, Kang WK, Di Bartolomeo M, Chau I, Yoon HH, Cascinu S, Ryu M, Kim JG, Lee K, Oh SC, Takashima A, Kryzhanivska A, Chao Y, Vladimirov V, Evesque L, Schenker M, McGinn A, Sankar N, Wyrwicz L, Boku N. Randomized Phase 3 ANGEL study of rivoceranib (apatinib) + best supportive care (BSC) vs placebo + BSC in patients with advanced/metastatic gastric cancer. 2019 European Society of Medical Oncology annual meeting. Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394<br />
<br />
==Docetaxel monotherapy {{#subobject:4f3230|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 60 mg/m<sup>2</sup> {{#subobject:577cd6|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/30/13/1513.full Kang et al. 2012]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2, 75 mg/m<sup>2</sup> x 6 {{#subobject:3b4816|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(13)70549-7/fulltext Ford et al. 2014 (COUGAR-02)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<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 />
===Variant #3, 75 mg/m<sup>2</sup>, indefinite {{#subobject:3b47ab|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(17)30111-0/fulltext Thuss-Patience et al. 2017 (GATSBY)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|T-DM1<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Patients in GATSBY had HER2-positive disease. Study patients could only have been treated by one other regimen and could not have been exposed to anthracyclines''<br />
<br />
''Patients: 68% gastric, 32% GEJ''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. [http://jco.ascopubs.org/content/30/13/1513.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22412140 PubMed]<br />
#'''COUGAR-02:''' Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA; COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):78-86. Epub 2013 Dec 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70549-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24332238 PubMed]<br />
#'''GATSBY:''' Thuss-Patience PC, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, Castro H, Mansoor W, Chung HC, Bodoky G, Shitara K, Phillips GDL, van der Horst T, Harle-Yge ML, Althaus BL, Kang YK. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017 May;18(5):640-653. Epub 2017 Mar 23. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30111-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28343975 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, Mitomycin {{#subobject:b4ca9d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:672b28|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.karger.com/Article/Abstract/64319 Hofheinz et al. 2002]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts in this subgroup<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV continuous infusion over 24 hours once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Mitomycin (Mutamycin)]] 10 mg/m<sup>2</sup> IV once per day on days 1 & 22<br />
<br />
'''56-day cycle for 2 cycles'''<br />
<br />
===References===<br />
<br />
#Hofheinz RD, Hartung G, Samel S, Hochhaus A, Pichlmeier U, Post S, Hehlmann R, Queisser W. High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer: a phase II study. Onkologie. 2002 Jun;25(3):255-60. [http://www.karger.com/Article/Abstract/64319 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12119460 PubMed]<br />
<br />
==Irinotecan monotherapy {{#subobject:6df2c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 125 mg/m<sup>2</sup>, 4 weeks out of 6 {{#subobject:9fb427|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://link.springer.com/article/10.1007%2Fs10620-005-3038-2 Enzinger et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: In contrast to the primary references, some guidelines list a dosing schedule of 125 mg/m<sup>2</sup> IV once per day on days 1 & 8, with 21-day cycles. Enzinger et al. 2005 comment that "when irinotecan is used as a single-agent, a tri-weekly schedule may be preferable."''<br />
<br />
''Study included patients with GE junction and distal esophageal malignancy as well (~59% gastric, 9% GE junction and 33% distal esophagus)''<br />
<br />
''Regimen showed a 14% response rate and 53% disease control rate.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22<br />
<br />
'''42-day cycles'''<br />
<br />
===Variant #2, 150 mg/m<sup>2</sup> q2wk {{#subobject:fa1ef9|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/30/13/1513.full Kang et al. 2012]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2012.48.5805 Hironaka et al. 2013 (WJOG 4007)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Paclitaxel_monotherapy|Paclitaxel]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(14)00093-8/fulltext Higuchi et al. 2014 (BIRIP)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Irinotecan|Cisplatin & Irinotecan]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(15)00209-9/fulltext Nishikawa et al. 2015 (TRICS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Irinotecan|Cisplatin & Irinotecan]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/26/9/1916/189421 Tanabe et al. 2015 (JACCRO GC-05)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Irinotecan & S-1<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225815/ Bang et al. 2018 (JAVELIN Gastric 300)]<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 />
''Hironaka et al patients: 3.7% patients with an ECOG PS of 2''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #3, 300 mg/m<sup>2</sup> q3wk {{#subobject:c410d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
|-<br />
|[http://annonc.oxfordjournals.org/content/24/6/1567.long Roy et al. 2013 (PEP0206)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. Irinotecan liposome<br />
|-<br />
|}<br />
''Study included patients with GE junction malignancy (77% gastric, 23% GE junction) and included patients with ECOG of 2''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 300 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, 350 mg/m<sup>2</sup> q3wk {{#subobject:160f2f|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.ejcancer.com/article/S0959-8049(11)00396-0/fulltext Thuss-Patience et al. 2011]<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 />
|}<br />
''Thuss-Patience et al. included patients with GE junction malignancy (~58% gastric, 43% GE junction) and included patients with ECOG of 2''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] as follows:<br />
**Cycle 1: 250 mg/m<sup>2</sup> (maximum dose of 500 mg) IV over 30 minutes once on day 1<br />
**Cycles 2 to 10 (depending on toxicity): 350 mg/m<sup>2</sup> IV over 30 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[Atropine (Atropen)]] 0.25 mg SC once on day 1, given prior to [[Irinotecan (Camptosar)]]<br />
*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]]<br />
*[[Dexamethasone (Decadron)]]<br />
<br />
'''21-day cycle for up to 10 cycles'''<br />
<br />
===References===<br />
<br />
#Enzinger PC, Kulke MH, Clark JW, Ryan DP, Kim H, Earle CC, Vincitore MM, Michelini AL, Mayer RJ, Fuchs CS. A phase II trial of irinotecan in patients with previously untreated advanced esophageal and gastric adenocarcinoma. Dig Dis Sci. 2005 Dec;50(12):2218-23. [http://link.springer.com/article/10.1007%2Fs10620-005-3038-2 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16416165 PubMed]<br />
#Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, Dogan Y, Gebauer B, Schumacher G, Reichardt P. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011 Oct;47(15):2306-14. [https://www.ejcancer.com/article/S0959-8049(11)00396-0/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21742485 PubMed]<br />
#Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8. Epub 2012 Mar 12. Erratum in: J Clin Oncol. 2012 Aug 20;30(24):3035. [http://jco.ascopubs.org/content/30/13/1513.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22412140 PubMed]<br />
#'''PEP0206:''' Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. [http://annonc.oxfordjournals.org/content/24/6/1567.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23406728 PubMed]<br />
#'''WJOG 4007:''' Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y, Morita S, Okamoto I, Boku N, Hyodo I. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013 Dec 10;31(35):4438-44. Epub 2013 Nov 4. [https://ascopubs.org/doi/full/10.1200/JCO.2012.48.5805 link to original artile] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24190112 PubMed]<br />
#'''BIRIP:''' Higuchi K, Tanabe S, Shimada K, Hosaka H, Sasaki E, Nakayama N, Takeda Y, Moriwaki T, Amagai K, Sekikawa T, Sakuyama T, Kanda T, Sasaki T, Azuma M, Takahashi F, Takeuchi M, Koizumi W; Tokyo Cooperative Oncology Group, Tokyo, Japan. Biweekly irinotecan plus cisplatin versus irinotecan alone as second-line treatment for advanced gastric cancer: a randomised phase III trial (TCOG GI-0801/BIRIP trial). Eur J Cancer. 2014 May;50(8):1437-45. Epub 2014 Feb 20. [https://www.ejcancer.com/article/S0959-8049(14)00093-8/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24560487 PubMed]<br />
#'''TRICS:''' Nishikawa K, Fujitani K, Inagaki H, Akamaru Y, Tokunaga S, Takagi M, Tamura S, Sugimoto N, Shigematsu T, Yoshikawa T, Ishiguro T, Nakamura M, Morita S, Miyashita Y, Tsuburaya A, Sakamoto J, Tsujinaka T. Randomised phase III trial of second-line irinotecan plus cisplatin versus irinotecan alone in patients with advanced gastric cancer refractory to S-1 monotherapy: TRICS trial. Eur J Cancer. 2015 May;51(7):808-16. Epub 2015 Mar 18. [https://www.ejcancer.com/article/S0959-8049(15)00209-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25797356 PubMed]<br />
#'''JACCRO GC-05:''' Tanabe K, Fujii M, Nishikawa K, Kunisaki C, Tsuji A, Matsuhashi N, Takagane A, Ohno T, Kawase T, Kochi M, Yoshida K, Kakeji Y, Ichikawa W, Chin K, Terashima M, Takeuchi M, Nakajima T; JACCRO GC-05 study group. Phase II/III study of second-line chemotherapy comparing irinotecan-alone with S-1 plus irinotecan in advanced gastric cancer refractory to first-line treatment with S-1 (JACCRO GC-05). Ann Oncol. 2015 Sep;26(9):1916-22. Epub 2015 Jun 24. [https://academic.oup.com/annonc/article/26/9/1916/189421 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26109630 PubMed]<br />
#'''JAVELIN Gastric 300:''' Bang YJ, Ruiz EY, Van Cutsem E, Lee KW, Wyrwicz L, Schenker M, Alsina M, Ryu MH, Chung HC, Evesque L, Al-Batran SE, Park SH, Lichinitser M, Boku N, Moehler MH, Hong J, Xiong H, Hallwachs R, Conti I, Taieb J. Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol. 2018 Oct 1;29(10):2052-2060. [https://academic.oup.com/annonc/article/29/10/2052/5058079 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225815/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30052729 PubMed]<br />
<br />
==Irinotecan liposomal monotherapy {{#subobject:9a99c8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c50e15|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://annonc.oxfordjournals.org/content/24/6/1567.long Roy et al. 2013 (PEP0206)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. [[#Irinotecan_monotherapy|Irinotecan]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan liposome (Onivyde)]] 120 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''PEP0206:''' Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. [https://annonc.oxfordjournals.org/content/24/6/1567.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23406728 PubMed]<br />
<br />
==Nivolumab monotherapy {{#subobject:7011e1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:#f2fd8e|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(17)31827-5/fulltext Kang et al. 2017 (ATTRACTION-2)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161834/ Janjigian et al. 2018 (CheckMate-032)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''ATTRACTION-2 included patients with GE junction malignancy (82.6% gastric, 8.5% GE junction) and 12.3% of patients had a PD-L1 CPS score of at least 1''<br />
<br />
====Immunotherapy====<br />
<br />
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ATTRACTION-2:''' Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Dec 2;390(10111):2461-2471. Epub 2017 Oct 6. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31827-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28993052 PubMed]<br />
##'''Subgroup analysis:''' Kato K, Satoh T, Muro K, Yoshikawa T, Tamura T, Hamamoto Y, Chin K, Minashi K, Tsuda M, Yamaguchi K, Machida N, Esaki T, Goto M, Komatsu Y, Nakajima TE, Sugimoto N, Yoshida K, Oki E, Nishina T, Tsuji A, Fujii H, Kunieda K, Saitoh S, Omuro Y, Azuma M, Iwamoto Y, Taku K, Fushida S, Chen LT, Kang YK, Boku N. A subanalysis of Japanese patients in a randomized, double-blind, placebo-controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2). Gastric Cancer. 2019 Mar;22(2):344-354. Epub 2018 Dec 1. [https://link.springer.com/article/10.1007%2Fs10120-018-0899-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394726/ link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30506519 PubMed]<br />
#'''CheckMate-032:''' Janjigian YY, Bendell J, Calvo E, Kim JW, Ascierto PA, Sharma P, Ott PA, Peltola K, Jaeger D, Evans J, de Braud F, Chau I, Harbison CT, Dorange C, Tschaika M, Le DT. CheckMate-032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer. J Clin Oncol. 2018 Oct 1;36(28):2836-2844. Epub 2018 Aug 15. [https://ascopubs.org/doi/full/10.1200/JCO.2017.76.6212 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161834/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30110194 PubMed]<br />
<br />
==Paclitaxel monotherapy {{#subobject:2dcad9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 70 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:gg21e8|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/PMC6324622/ Lee et al. 2018 (KCSG ST10-01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Irinotecan_monotherapy_2|Irinotecan]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 70 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 80 mg/m<sup>2</sup> weekly {{#subobject:0e8f41|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/27/4C/2667.long Kodera et al. 2007 (CCOG0302)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30111-0/fulltext Thuss-Patience et al. 2017 (GATSBY)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|T-DM1<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Patients in GATSBY had overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation''<br />
<br />
''GATSBY included patients with GE junction malignancy (68% gastric, 32% GE junction)''<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #3, 80 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:dd21e8|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://link.springer.com/article/10.1007%2Fs10120-005-0351-6 Hironaka et al. 2006]<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2012.48.5805 Hironaka et al. 2013 (WJOG 4007)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Irinotecan_monotherapy_2|Irinotecan]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2013.53.6136 Satoh et al. 2014 (TyTAN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Lapatinib & Paclitaxel<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2970420-6/fulltext Wilke et al. 2014 (RAINBOW)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Paclitaxel_.26_Ramucirumab|Paclitaxel & Ramucirumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/langas/article/PIIS2468-1253(16)30219-9/fulltext Shitara et al. 2017 (ABSOLUTE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]] weekly<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|2. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]] q3wk<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30682-4/fulltext Bang et al. 2017 (GOLD)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Olaparib & Paclitaxel<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31257-1/fulltext Shitara et al. 2018 (KEYNOTE-061)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225815/ Bang et al. 2018 (JAVELIN Gastric 300)]<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 />
''Eligibility criteria for patients in RAINBOW included: "documented objective radiological or clinical disease progression during or within 4 months of the last dose of first-line platinum and fluoropyrimidine doublet with or without anthracycline." Patients in TyTAN had HER2-positive disease.''<br />
<br />
''RAINBOW included patients with GE junction malignancy (79% gastric, 21% GE junction)''<br />
<br />
''Satoh et al. patients: 98.5% gastric. 1.5 other''<br />
<br />
''Hironaka et al patients: 3.7% patients with a PFS of 2''<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 />
===Variant #4, 175 mg/m<sup>2</sup> q3wk {{#subobject:a4bdf6|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://academic.oup.com/annonc/article-abstract/29/5/1220/4846849 Kang et al. 2018 (DREAM)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|DHP107<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Hironaka S, Zenda S, Boku N, Fukutomi A, Yoshino T, Onozawa Y. Weekly paclitaxel as second-line chemotherapy for advanced or recurrent gastric cancer. Gastric Cancer. 2006;9(1):14-8. [https://link.springer.com/article/10.1007%2Fs10120-005-0351-6 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16557431 PubMed]<br />
#'''CCOG0302:''' Kodera Y, Ito S, Mochizuki Y, Fujitake S, Koshikawa K, Kanyama Y, Matsui T, Kojima H, Takase T, Ohashi N, Fujiwara M, Sakamoto J, Akimasa N; Chubu Clinical Cancer Group. A phase II study of weekly paclitaxel as second-line chemotherapy for advanced gastric cancer (CCOG0302 study). Anticancer Res. 2007 Jul-Aug;27(4C):2667-71. [http://ar.iiarjournals.org/content/27/4C/2667.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17695430 PubMed]<br />
#'''WJOG 4007:''' Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y, Morita S, Okamoto I, Boku N, Hyodo I. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013 Dec 10;31(35):4438-44. Epub 2013 Nov 4. [https://ascopubs.org/doi/full/10.1200/JCO.2012.48.5805 link to original artile] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24190112 PubMed]<br />
#'''TyTAN:''' Satoh T, Xu RH, Chung HC, Sun GP, Doi T, Xu JM, Tsuji A, Omuro Y, Li J, Wang JW, Miwa H, Qin SK, Chung IJ, Yeh KH, Feng JF, Mukaiyama A, Kobayashi M, Ohtsu A, Bang YJ. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN--a randomized, phase III study. J Clin Oncol. 2014 Jul 1;32(19):2039-49. Epub 2014 May 27. [https://ascopubs.org/doi/full/10.1200/JCO.2013.53.6136 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24868024 PubMed]<br />
#'''RAINBOW:''' Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2970420-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25240821 PubMed]<br />
#'''ABSOLUTE:''' Shitara K, Takashima A, Fujitani K, Koeda K, Hara H, Nakayama N, Hironaka S, Nishikawa K, Makari Y, Amagai K, Ueda S, Yoshida K, Shimodaira H, Nishina T, Tsuda M, Kurokawa Y, Tamura T, Sasaki Y, Morita S, Koizumi W. Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, randomised, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2017 Apr;2(4):277-287. Epub 2017 Jan 19. [https://www.thelancet.com/journals/langas/article/PIIS2468-1253(16)30219-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28404157 PubMed]<br />
#'''GATSBY:''' Thuss-Patience PC, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, Castro H, Mansoor W, Chung HC, Bodoky G, Shitara K, Phillips GDL, van der Horst T, Harle-Yge ML, Althaus BL, Kang YK. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017 May;18(5):640-653. Epub 2017 Mar 23. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30111-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28343975 PubMed]<br />
#'''GOLD:''' Bang YJ, Xu RH, Chin K, Lee KW, Park SH, Rha SY, Shen L, Qin S, Xu N, Im SA, Locker G, Rowe P, Shi X, Hodgson D, Liu YZ, Boku N. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1637-1651. Epub 2017 Nov 2. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30682-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29103871 PubMed]<br />
#'''DREAM:''' Kang YK, Ryu MH, Park SH, Kim JG, Kim JW, Cho SH, Park YI, Park SR, Rha SY, Kang MJ, Cho JY, Kang SY, Roh SY, Ryoo BY, Nam BH, Jo YW, Yoon KE, Oh SC. Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus IV paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy. Ann Oncol. 2018 May 1;29(5):1220-1226. [https://academic.oup.com/annonc/article-abstract/29/5/1220/4846849 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29438463 PubMed]<br />
#'''KEYNOTE-061:''' Shitara K, Özgüroğlu M, Bang YJ, Di Bartolomeo MD, Mandalà M, Ryu MH, Fornaro L, Olesiński T, Caglevic C, Chung HC, Muro K, Goekkurt E, Mansoor W, McDermott RS, Shacham-Shmueli E, Chen X, Mayo C, Kang SP, Ohtsu A, Fuchs CS; KEYNOTE-061 investigators. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018 Jul 14;392(10142):123-133. Epub 2018 Jun 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31257-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29880231 PubMed]<br />
#'''KCSG ST10-01:''' Lee KW, Maeng CH, Kim TY, Zang DY, Kim YH, Hwang IG, Oh SC, Chung JS, Song HS, Kim JW, Jeong SJ, Cho JY. A phase III study to compare the efficacy and safety of paclitaxel versus irinotecan in patients with metastatic or recurrent gastric cancer who failed in first-line therapy (KCSG ST10-01). Oncologist. 2019 Jan;24(1):18-e24. Epub 2018 Aug 20. [http://theoncologist.alphamedpress.org/content/24/1/18.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324622/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30126861 PubMed]<br />
#'''JAVELIN Gastric 300:''' Bang YJ, Ruiz EY, Van Cutsem E, Lee KW, Wyrwicz L, Schenker M, Alsina M, Ryu MH, Chung HC, Evesque L, Al-Batran SE, Park SH, Lichinitser M, Boku N, Moehler MH, Hong J, Xiong H, Hallwachs R, Conti I, Taieb J. Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol. 2018 Oct 1;29(10):2052-2060. [https://academic.oup.com/annonc/article/29/10/2052/5058079 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225815/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30052729 PubMed]<br />
<br />
==nab-Paclitaxel monotherapy {{#subobject:8f6227|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:fe2978|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/langas/article/PIIS2468-1253(16)30219-9/fulltext Shitara et al. 2017 (ABSOLUTE)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#Paclitaxel_monotherapy|Weekly Paclitaxel]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|2. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]] q3wk<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ABSOLUTE:''' Shitara K, Takashima A, Fujitani K, Koeda K, Hara H, Nakayama N, Hironaka S, Nishikawa K, Makari Y, Amagai K, Ueda S, Yoshida K, Shimodaira H, Nishina T, Tsuda M, Kurokawa Y, Tamura T, Sasaki Y, Morita S, Koizumi W. Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, randomised, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2017 Apr;2(4):277-287. Epub 2017 Jan 19. [https://www.thelancet.com/journals/langas/article/PIIS2468-1253(16)30219-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28404157 PubMed]<br />
<br />
==Paclitaxel & Ramucirumab {{#subobject:fdd93f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f66446|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 />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2970420-6/fulltext Wilke et al. 2014 (RAINBOW)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
| style="background-color:#8c6bb1" |28% (95% CI 23-33%)<br />
|[[#Paclitaxel_monotherapy|Paclitaxel]]<br />
| style="background-color:#88419d; color:white " |16% (95% CI 13-20%)<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Eligibility criteria for patients in RAINBOW included: "documented objective radiological or clinical disease progression during or within 4 months of the last dose of first-line platinum and fluoropyrimidine doublet with or without anthracycline."''<br />
<br />
''RAINBOW included patients with GE junction malignancy (79% gastric, 21% GE junction).''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Ramucirumab (Cyramza)]] 8 mg/kg IV over 60 minutes once per day on days 1 & 15, '''given first'''<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, '''given second'''<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''RAINBOW:''' Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2970420-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25240821 PubMed]<br />
<br />
==Pembrolizumab monotherapy {{#subobject:88c665|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:ac7d94|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/PMC5885175/ Fuchs et al. 2018 (KEYNOTE-059)]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|<br />
|ORR: 12% (95% CI 8-16)<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31257-1/fulltext Shitara et al. 2018 (KEYNOTE-061)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[#Paclitaxel_monotherapy|Paclitaxel]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Both studies included patients with GE junction malignancy:''<br />
<br />
*''KEYNOTE-059: 48.3% gastric, 51.4% GE junction and 57.1% of patients had a PD-L1 CPS score of at least 1''<br />
<br />
*''KEYNOTE-061: 68.8% gastric, 31.2% GE junction and 66% of all patients receiving pembrolizumab had a PD-L1 CPS score of at least 1''<br />
<br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycle for up to 35 cycles (2 years)'''<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Charles S. Fuchs, Toshihiko Doi, Raymond Woo-Jun Jang, Kei Muro, Taroh Satoh, Manuela Machado, ...Weijing Sun, Shadia Ibrahim Jalal, Manish A. Shah, Jean-Philippe Metges, Marcelo Garrido, Talia Golan, Mario Mandala, Zev A. Wainberg, Daniel V.T. Catenacci, Yung-Jue Bang, Jiangdian Wang, Minori Koshiji, Rita P. Dalal, Harry H. Yoon (2017). KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. Journal of Clinical Oncology 35, no. 15_suppl (May 2017) 4003-4003. [https://ascopubs.org/doi/full/10.1200/JCO.2017.35.15_suppl.4003 link to abstract] --><br />
<br />
#'''KEYNOTE-059:''' Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges JP, Garrido M, Golan T, Mandala M, Wainberg ZA, Catenacci DV, Ohtsu A, Shitara K, Geva R, Bleeker J, Ko AH, Ku G, Philip P, Enzinger PC, Bang YJ, Levitan D, Wang J, Rosales M, Dalal RP, Yoon HH. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018 May 10;4(5):e180013. Epub 2018 May 10. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2675013 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885175/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29543932 PubMed]<br />
#'''KEYNOTE-061:''' Shitara K, Özgüroğlu M, Bang YJ, Di Bartolomeo MD, Mandalà M, Ryu MH, Fornaro L, Olesiński T, Caglevic C, Chung HC, Muro K, Goekkurt E, Mansoor W, McDermott RS, Shacham-Shmueli E, Chen X, Mayo C, Kang SP, Ohtsu A, Fuchs CS; KEYNOTE-061 investigators. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018 Jul 14;392(10142):123-133. Epub 2018 Jun 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31257-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29880231 PubMed]<br />
<br />
==Placebo==<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 />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961719-5/fulltext Fuchs et al. 2013 (REGARD)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ramucirumab_monotherapy|Ramucirumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019744/ Pavlakis et al. 2016 (INTEGRATE)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Regorafenib_monotherapy|Regorafenib]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31827-5/fulltext Kang et al. 2017 (ATTRACTION-2)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Nivolumab_monotherapy|Nivolumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30739-3/fulltext Shitara et al. 2018 (TAGS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Trifluridine_and_tipiracil_monotherapy|Trifluridine/tipiracil]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''All studies included patients with GE junction malignancy:''<br />
<br />
*''REGARD: 75% gastric, 25% GE junction''<br />
*''INTEGRATE: 62% stomach or other, 38% GE junction''<br />
*''ATTRACTION-2: 82.6% gastric, 8.5% GE junction''<br />
<br />
''Patients in '''REGARD''' previously had "disease progression within 4 months of the last dose of first-line platinum-containing or fluoropyrimidine-containing chemotherapy for metastatic disease, or within 6 months of the last dose of platinum-containing or fluoropyrimidine-containing adjuvant treatment."''<br />
<br />
''No active antineoplastic treatment.''<br />
<br />
===References===<br />
<br />
#'''REGARD:''' Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9. Epub 2013 Oct 3.[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961719-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24094768 PubMed]<br />
#'''INTEGRATE:''' Pavlakis N, Sjoquist KM, Martin AJ, Tsobanis E, Yip S, Kang YK, Bang YJ, Alcindor T, O'Callaghan CJ, Burnell MJ, Tebbutt NC, Rha SY, Lee J, Cho JY, Lipton LR, Wong M, Strickland A, Kim JW, Zalcberg JR, Simes J, Goldstein D. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): A multinational placebo-controlled phase II trial. J Clin Oncol. 2016 Aug 10;34(23):2728-35. Epub 2016 Jun 20. [https://ascopubs.org/doi/full/10.1200/JCO.2015.65.1901 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019744/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27325864 PubMed]<br />
#'''ATTRACTION-2:''' Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Dec 2;390(10111):2461-2471. Epub 2017 Oct 6. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31827-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28993052 PubMed]<br />
#'''TAGS:''' Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Alsina M, Ghidini M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Hosokawa A, Yalçın Ş, Fujitani K, Beretta GD, Van Cutsem E, Winkler RE, Makris L, Ilson DH, Tabernero J. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Nov 1;19(11):1437-48. Epub 2018 Oct 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30739-3/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30355453 PubMed]<br />
<br />
==Ramucirumab monotherapy {{#subobject:425b15|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:813cff|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 />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961719-5/fulltext Fuchs et al. 2013 (REGARD)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
| style="background-color:#6e016b; color:white " |3%<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#6e016b; color:white " |3%<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Patients in REGARD previously had "disease progression within 4 months of the last dose of first-line platinum-containing or fluoropyrimidine-containing chemotherapy for metastatic disease, or within 6 months of the last dose of platinum-containing or fluoropyrimidine-containing adjuvant treatment."''<br />
<br />
''Study includes patients with GE junction malignancy (75% gastric, 25% GE junction).''<br />
====Chemotherapy====<br />
<br />
*[[Ramucirumab (Cyramza)]] 8 mg/kg IV over 60 minutes once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''REGARD:''' Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9. Epub 2013 Oct 3. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961719-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24094768 PubMed]<br />
<br />
==Regorafenib monotherapy {{#subobject:022ef0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:5f203f|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/PMC5019744/ Pavlakis et al. 2016 (INTEGRATE)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
''INTEGRATE included patients with GEJ malignancy: 62% stomach or other, 38% GEJ''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''INTEGRATE:''' Pavlakis N, Sjoquist KM, Martin AJ, Tsobanis E, Yip S, Kang YK, Bang YJ, Alcindor T, O'Callaghan CJ, Burnell MJ, Tebbutt NC, Rha SY, Lee J, Cho JY, Lipton LR, Wong M, Strickland A, Kim JW, Zalcberg JR, Simes J, Goldstein D. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): A multinational placebo-controlled phase II trial. J Clin Oncol. 2016 Aug 10;34(23):2728-35. Epub 2016 Jun 20. [https://ascopubs.org/doi/full/10.1200/JCO.2015.65.1901 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019744/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27325864 PubMed]<br />
<br />
==Trifluridine and tipiracil monotherapy {{#subobject:938bf3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cfc20c|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(18)30739-3/fulltext Shitara et al. 2018 (TAGS)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Trifluridine and tipiracil (Lonsurf)]] 35 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 8 to 12<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''TAGS:''' Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Alsina M, Ghidini M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Hosokawa A, Yalçın Ş, Fujitani K, Beretta GD, Van Cutsem E, Winkler RE, Makris L, Ilson DH, Tabernero J. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Nov 1;19(11):1437-48. Epub 2018 Oct 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30739-3/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30355453 PubMed]<br />
<br />
[[Category:Gastric cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Dweeraratnehttps://hemonc.org/w/index.php?title=Esophageal_cancer&diff=41828Esophageal cancer2020-01-08T23:25:50Z<p>Dweeraratne: /* Regimen #subobject:d18acj2 */</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:RyanNguyen.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Ryannguyen|Ryan Nguyen, DO]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br>[https://www.linkedin.com/in/ryan-nguyen-0b12a432/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br />
|-<br />
|}<br />
<big>Please be aware that some regimens listed here are studies for '''[[gastric cancer]]''', not esophageal cancer, reflecting the overlap between treatments of esophageal and gastric cancer. In the future we will likely add a dedicated gastroesophageal junction (GEJ) cancer page</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 />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==CAP/ASCP/ASCO==<br />
<br />
*'''2017:''' Bartley et al. [https://ascopubs.org/doi/full/10.1200/JCO.2016.69.4836 HER2 testing and clinical decision making in gastroesophageal adenocarcinoma] [https://www.ncbi.nlm.nih.gov/pubmed/28129524 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2016:''' Lordick et al. [https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Oesophageal-Cancer Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf NCCN Guidelines - Esophageal and Esophagogastric Junction Cancers]<br />
<br />
=Neoadjuvant induction therapy=<br />
==Cisplatin & Docetaxel {{#subobject:eed8f6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:523945|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://annonc.oxfordjournals.org/content/20/9/1522.long Ruhstaller et al. 2009 (SAKK 75/02)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://academic.oup.com/annonc/article/29/6/1386/4959906 Ruhstaller et al. 2018 (SAKK 75/08)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin, Docetaxel, Cetuximab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''SAKK 75/02 patients: 55% adenocarcinoma, 45% squamous cell histology''<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 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[#Cisplatin.2C_Docetaxel.2C_RT|Neoadjuvant cisplatin, docetaxel, RT]], then [[Surgery#Esophageal_cancer_surgery|surgery]]<br />
<br />
===References===<br />
<br />
#'''SAKK 75/02:''' Ruhstaller T, Widmer L, Schuller JC, Roth A, Hess V, Mingrone W, von Moos R, Borner M, Pestalozzi BC, Balmermajno S, Köberle D, Terraciano L, Schnider A, Bodis S, Popescu R; Swiss Group for Clinical Cancer Research (SAKK). Multicenter phase II trial of preoperative induction chemotherapy followed by chemoradiation with docetaxel and cisplatin for locally advanced esophageal carcinoma (SAKK 75/02). Ann Oncol. 2009 Sep;20(9):1522-8. Epub 2009 May 22. [http://annonc.oxfordjournals.org/content/20/9/1522.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19465425 PubMed]<br />
#'''SAKK 75/08:''' Ruhstaller T, Thuss-Patience P, Hayoz S, Schacher S, Knorrenschild JR, Schnider A, Plasswilm L, Budach W, Eisterer W, Hawle H, Mariette C, Hess V, Mingrone W, Montemurro M, Girschikofsky M, Schmidt SC, Bitzer M, Bedenne L, Brauchli P, Stahl M; Swiss Group for Clinical Cancer Research (SAKK), the German Esophageal Cancer Study Group, the Austrian ‘Arbeitsgemeinschaft Medikamentöse Tumortherapie’ (AGMT), and the Fédération Francophone de Cancérologie Digestive (FFCD)/Fédération de Recherche en Ch. Neoadjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08). Ann Oncol. 2018 Jun 1;29(6):1386-1393. [https://academic.oup.com/annonc/article/29/6/1386/4959906 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29635438 PubMed]<br />
<br />
==Cisplatin & Etoposide {{#subobject:5a71ff|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f93c95|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/PMC3123658/ Boonstra et al. 2011]<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 />
''Patients: 100% squamous cell histology''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 4 hours once on day 1<br />
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup>/day IV over 2 hours once per day on days 1 & 2, then 200 mg/m<sup>2</sup> PO once per day on days 3 & 5<br />
<br />
'''21-day cycle for 2 to 4 cycles'''<br />
<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophageal_cancer_surgery|Surgery]]<br />
<br />
===References===<br />
<br />
#Boonstra JJ, Kok TC, Wijnhoven BP, van Heijl M, van Berge Henegouwen MI, Ten Kate FJ, Siersema PD, Dinjens WN, van Lanschot JJ, Tilanus HW, van der Gaast A. Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial. BMC Cancer. 2011 May 19;11:181. [https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-11-181 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123658/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21595951 PubMed]<br />
<br />
==Cisplatin & Fluorouracil {{#subobject:37e6ba|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CF: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
<br>FP: '''<u>F</u>'''luorouracil, '''<u>P</u>'''latinol (Cisplatin)<br />
===Variant #1, 40/4200 {{#subobject:034277|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/24/24/3953.long Ajani et al. 2006 (RTOG 9904)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma histology. The majority of patients had gastric adenocarcinoma. Although gastroesophageal junction was involved, percentages were not included.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 & 5<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[#Fluorouracil.2C_Paclitaxel.2C_RT|Neoadjuvant fluorouracil, paclitaxel, RT]], then [[Surgery#Esophageal_cancer_surgery|surgery]]<br />
<br />
===Variant #2, 80/4000, 4 day 5-FU infusion {{#subobject:2335c3|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(02)08651-8/fulltext Girling et al. 2002 (UK MRC OE02)]<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 />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585417/ Alderson et al. 2017 (UK MRC OE05)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#ECX|ECX]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: efficacy for UK MRC OE02 is based on the 2009 update.''<br />
''UK MRC OE05 patients: 100% adenocarcinoma of the esophagus (including Siewert types 1 and 2 gastroesophageal junction tumors)''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophageal_cancer_surgery|Surgery]]<br />
<br />
===Variant #3, 80/4000, 5 day 5-FU infusion {{#subobject:4b5879|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://link.springer.com/article/10.1245%2Fs10434-011-2049-9 Ando et al. 2011 (JCOG 9907)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Fluorouracil_3|Adjuvant CF]]<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 over 2 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophageal_cancer_surgery|Surgery]]<br />
<br />
===Variant #4, 100/4000 {{#subobject:ac1485|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://ascopubs.org/doi/full/10.1200/JCO.2010.33.0597 Ychou et al. 2011 (ACCORD 07)]<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 is the neoadjuvant portion of pre-planned perioperative chemotherapy. It 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 />
<br />
''Patients: 100% adenocarcinoma histology (65% esophagogastric junction, 10% lower esophageal, 25% gastric adenocarcinoma)''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycle for 2 or 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophageal_cancer_surgery|Surgery]], then [[#Cisplatin_.26_Fluorouracil_3|adjuvant CF]]<br />
<br />
===Variant #5, 100/5000 {{#subobject:e6fe90|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/NEJM199812313392704 Kelsen et al. 1998 (RTOG 8911)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_neoadjuvant_therapy|Surgery alone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010601%2991%3A11%3C2165%3A%3AAID-CNCR1245%3E3.0.CO%3B2-H Ancona et al. 2001]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_neoadjuvant_therapy|Surgery alone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: it is not entirely clear from Ancona et al. 2001 whether this was a 96-hour or 120-hour infusion; there was option to proceed after the 2nd cycle. In both trials, 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 />
<br />
''Ancona et al. 2001 patients: 100% squamous cell carcinoma histology''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: see note)<br />
<br />
'''28-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*RTOG 8911: [[Surgery#Esophageal_cancer_surgery|Surgery]], then [[#Cisplatin_.26_Fluorouracil_3|adjuvant CF]]<br />
*Ancona et al. 2001: [[Surgery#Esophageal_cancer_surgery|Surgery]], performed 3 to 4 weeks after the last cycle of chemotherapy<br />
<br />
===References===<br />
<br />
#'''RTOG 8911:''' Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med. 1998 Dec 31;339(27):1979-84. [https://www.nejm.org/doi/full/10.1056/NEJM199812313392704 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9869669 PubMed]<br />
##'''Update:''' Kelsen DP, Winter KA, Gunderson LL, Mortimer J, Estes NC, Haller DG, Ajani JA, Kocha W, Minsky BD, Roth JA, Willett CG; Radiation Therapy Oncology Group; USA Intergroup. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol. 2007 Aug 20;25(24):3719-25. [https://ascopubs.org/doi/full/10.1200/JCO.2006.10.4760 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17704421 PubMed]<br />
#Ancona E, Ruol A, Santi S, Merigliano S, Sileni VC, Koussis H, Zaninotto G, Bonavina L, Peracchia A. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer. 2001 Jun 1;91(11):2165-74. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010601%2991%3A11%3C2165%3A%3AAID-CNCR1245%3E3.0.CO%3B2-H link to original article] '''contains partial protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11391598 PubMed]<br />
#'''UK MRC OE02:''' Girling DJ, Bancewicz J, Clark PI, Smith DB, Donnelly RJ, Fayers PM, Weeden S, Hutchinson T, Harvey A, Lyddiard J; Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet. 2002 May 18;359(9319):1727-33. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08651-8/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12049861 PubMed]<br />
##'''Update:''' Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol. 2009 Oct 20;27(30):5062-7. Epub 2009 Sep 21. [https://ascopubs.org/doi/full/10.1200/JCO.2009.22.2083 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19770374 PubMed]<br />
#'''RTOG 9904:''' Ajani JA, Winter K, Okawara GS, Donohue JH, Pisters PW, Crane CH, Greskovich JF, Anne PR, Bradley JD, Willett C, Rich TA. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol. 2006 Aug 20;24(24):3953-8. [http://jco.ascopubs.org/content/24/24/3953.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16921048 PubMed]<br />
#'''ACCORD 07:''' Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. Epub 2011 Mar 28. [https://ascopubs.org/doi/full/10.1200/JCO.2010.33.0597 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21444866 PubMed]<br />
#'''JCOG 9907:''' Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, Nakamura T, Yabusaki H, Aoyama N, Kurita A, Ikeda K, Kanda T, Tsujinaka T, Nakamura K, Fukuda H. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012 Jan;19(1):68-74. Epub 2011 Aug 31. [https://link.springer.com/article/10.1245%2Fs10434-011-2049-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21879261 PubMed]<br />
#'''UK MRC OE05:''' Alderson D, Cunningham D, Nankivell M, Blazeby JM, Griffin SM, Crellin A, Grabsch HI, Langer R, Pritchard S, Okines A, Krysztopik R, Coxon F, Thompson J, Falk S, Robb C, Stenning S, Langley RE. Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial. Lancet Oncol. 2017 Sep;18(9):1249-1260. Epub 2017 Aug 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30447-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585417/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28784312 PubMed]<br />
<br />
==Cisplatin & Irinotecan {{#subobject:500b44|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===Regimen {{#subobject:927613|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.redjournal.org/article/S0360-3016(09)00362-9/abstract Rivera et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.26591/full Ilson et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Rivera et al. patients: 100% adenocarcinoma histology (43% gastroesophageal junction, 57% gastric adenocarcinoma)''<br />
<br />
''Illson et al. patients: 75% adenocarcinoma, 22% squamous cell, 3% poorly differentiated history; 33% gastroesophageal junction.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given first'''<br />
*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given second'''<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once per day on days 1 & 8, prior to chemotherapy<br />
*One of the following:<br />
**[[Granisetron]] 2 mg PO once per day on days 1 & 8, prior to chemotherapy<br />
**[[Ondansetron (Zofran)]] 32 mg IV once per day on days 1 & 8, prior to chemotherapy<br />
*At least 500 mL D5NS or NS as supportive hydration<br />
*[[Atropine (Atropen)]] 0.5 to 1 mg IV prn cholinergic symptoms<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[#Cisplatin.2C_Irinotecan.2C_RT|Neoadjuvant cisplatin, irinotecan, RT]], then [[Surgery#Esophageal_cancer_surgery|surgery]]<br />
<br />
===References===<br />
<br />
#Rivera F, Galán M, Tabernero J, Cervantes A, Vega-Villegas ME, Gallego J, Laquente B, Rodríguez E, Carrato A, Escudero P, Massutí B, Alonso-Orduña V, Cardenal A, Sáenz A, Giralt J, Yuste AL, Antón A, Aranda E; Spanish Cooperative Group for Digestive Tumor Therapy. Phase II trial of preoperative irinotecan-cisplatin followed by concurrent irinotecan-cisplatin and radiotherapy for resectable locally advanced gastric and esophagogastric junction adenocarcinoma. Int J Radiat Oncol Biol Phys. 2009 Dec 1;75(5):1430-6. Epub 2009 Jun 18. [http://www.redjournal.org/article/S0360-3016(09)00362-9/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19540072 PubMed]<br />
#Ilson DH, Minsky BD, Ku GY, Rusch V, Rizk N, Shah M, Kelsen DP, Capanu M, Tang L, Campbell J, Bains M. Phase 2 trial of induction and concurrent chemoradiotherapy with weekly irinotecan and cisplatin followed by surgery for esophageal cancer. Cancer. 2011 Oct 11. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.26591/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21990000 PubMed]<br />
<br />
==CLF {{#subobject:74dca8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CLF: '''<u>C</u>'''isplatin, '''<u>L</u>'''eucovorin (Folinic acid), '''<u>F</u>'''luorouracil<br />
<br>PLF: '''<u>P</u>'''latinol (Cisplatin), '''<u>L</u>'''eucovorin (Folinic acid), '''<u>F</u>'''luorouracil<br />
===Variant #1, 12 weeks {{#subobject:e3d573|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://ascopubs.org/doi/full/10.1200/JCO.2008.17.0506 Stahl et al. 2009 (POET)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#POET|See link]]<br />
|[[Complex_multipart_regimens#POET|See link]]<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma histology. 55% Siewert classification Type I, 45% Siewert classification Types II &III.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 12,000 mg/m<sup>2</sup> )<br />
<br />
'''42-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[#Cisplatin.2C_Etoposide.2C_RT|Cisplatin, Etoposide, RT]], then [[Surgery#Esophageal_cancer_surgery|surgery]]<br />
<br />
===Variant #2, 15 weeks {{#subobject:cf9923|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://ascopubs.org/doi/full/10.1200/JCO.2008.17.0506 Stahl et al. 2009 (POET)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PLF x 12 wk, then [[#Cisplatin.2C_Etoposide.2C_RT|Cisplatin, Etoposide, RT]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
''Note: this regimen is given for 2.5 cycles, which is a highly unusual instruction; total duration of treatment is 15 weeks.''<br />
<br />
''Patients: 100% adenocarcinoma histology. 55% Siewert classification Type I, 45% Siewert classification Types II &III.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 12,000 mg/m<sup>2</sup> )<br />
<br />
'''42-day cycle for 2.5 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophageal_cancer_surgery|Surgery]], in 3 to 4 weeks<br />
<br />
===References===<br />
<br />
#'''POET:''' Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, Riera-Knorrenschild J, Langer P, Engenhart-Cabillic R, Bitzer M, Königsrainer A, Budach W, Wilke H. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol. 2009 Feb 20;27(6):851-6. Epub 2009 Jan 12. [https://ascopubs.org/doi/full/10.1200/JCO.2008.17.0506 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19139439 PubMed]<br />
##'''Update:''' Stahl M, Walz MK, Riera-Knorrenschild J, Stuschke M, Sandermann A, Bitzer M, Wilke H, Budach W. Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): long-term results of a controlled randomised trial. Eur J Cancer. 2017 Aug;81:183-190. [https://www.ncbi.nlm.nih.gov/pubmed/28628843 PubMed]<br />
<br />
==CX {{#subobject:ce2bbb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CX: '''<u>C</u>'''isplatin & '''<u>X</u>'''eloda (Capecitabine)<br />
<br>XP: '''<u>X</u>'''eloda (Capecitabine) & '''<u>P</u>'''latinol (Cisplatin)<br />
===Regimen {{#subobject:1dd767|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://jjco.oxfordjournals.org/content/37/11/829.long Lee et al. 2007<sub>esoph</sub>]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''The study was for patients with stage IV disease.''<br />
<br />
''Patients 97% adenocarcinoma, 3% squamous cell histology; 3% with ECOG PS of 2.''<br />
<br />
*Patients with M1b disease (visceral metastases) received the chemotherapy only part until progression of disease or unacceptable toxicity.<br />
*Patients with M1a or M1b (non-viscertal metastases) received 2 cycles of the chemotherapy only part, underwent treatment with chemoradiation, and then treatment continued with--presumably, but not outright specified in the paper--chemotherapy only until progression of disease or unacceptable toxicity.<br />
<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''<br />
<br />
'''21-day cycles'''<br />
====Subsequent treatment====<br />
<br />
*Patients with M1a or M1b disease: [[#Capecitabine.2C_Cisplatin.2C_RT|Definitive capecitabine, cisplatin, RT]]<br />
<br />
===References===<br />
<br />
#'''Retrospective:''' Lee SS, Kim SB, Park SI, Kim YH, Ryu JS, Song HY, Shin JH, Jung HY, Lee GH, Choi KD, Cho KJ, Kim JH. Capecitabine and cisplatin chemotherapy (XP) alone or sequentially combined chemoradiotherapy containing XP regimen in patients with three different settings of stage IV esophageal cancer. Jpn J Clin Oncol. 2007 Nov;37(11):829-35. Epub 2007 Oct 19. [http://jjco.oxfordjournals.org/content/37/11/829.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17951334 PubMed]<br />
<br />
==ECF {{#subobject:87a09a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:d40982|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/NEJMoa055531 Cunningham et al. 2006 (MAGIC)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Complex_multipart_regimens#MAGIC|See link]]<br />
|[[Complex_multipart_regimens#MAGIC|See link]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2017.35.15_suppl.4004 Al-Batran et al. 2017 (FLOT4-AIO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
|[[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
|-<br />
|}<br />
''This is the neoadjuvant portion of pre-planned perioperative chemotherapy.''<br />
<br />
''Cunningham et al. Patients: 100% adenocarcinoma histology. 75% gastric adenocarcinoma, 15% lower esophagus, 11% gastroesophageal junction.''<br />
<br />
''Al-Batran et. al Patients: 100% adenocarcinoma histology of the gastroesophageal junction (AEG I-III) or the stomach.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup> )<br />
<br />
====Supportive medications====<br />
<br />
*MAGIC: [[Warfarin (Coumadin)]] 1 mg PO once per day recommended for thrombosis prophylaxis<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophageal_cancer_surgery|Surgery]] occurs 3 to 6 weeks after completing cycle 3, then [[#ECF_2|adjuvant ECF]] is started 6 to 12 weeks after surgery<br />
<br />
===References===<br />
<br />
#'''MAGIC:''' Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa055531 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16822992 PubMed]<br />
#'''Abstract:''' Salah-Eddin Al-Batran, Nils Homann, Harald Schmalenberg, Hans-Georg Kopp, Georg Martin Haag, Kim Barbara Luley, Wolff H. Schmiegel, Gunnar Folprecht, Stephan Probst, Nicole Prasnikar, Peter C. Thuss-Patience, Wolfgang Fischbach, Jorg Trojan, Michael Koenigsmann, Claudia Pauligk, Thorsten Oliver Goetze, Elke Jaeger, Johannes Meiler, Martin H. Schuler, and Ralf Hofheinz. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial. Journal of Clinical Oncology 2017 35:15_suppl, 4004-4004 [https://ascopubs.org/doi/full/10.1200/JCO.2017.35.15_suppl.4004 link to abstract]<br />
<br />
==ECX {{#subobject:c8ab0e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECX: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:27f848|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(17)30043-8/fulltext Cunningham et al. 2017 (UK MRC ST03)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ECX & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2017.35.15_suppl.4004 Al-Batran et al. 2017 (FLOT4-AIO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
|[[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
|-<br />
|}<br />
''This is the neoadjuvant portion of pre-planned perioperative chemotherapy.''<br />
<br />
''Cunningham et al. Patients: 100% adenocarcinoma histology (36% gastric, 14% lower esophageal, 50% gastroesophageal junction).''<br />
<br />
''Al-Batran et al.'' ''Patients: 100% adenocarcinoma histology including gastroesophageal junction (AEG I-III) or the stomach.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophageal_cancer_surgery|Surgery]], then [[#ECX_2|adjuvant ECX]]<br />
<br />
===References===<br />
<br />
#Cunningham D, Stenning SP, Smyth EC, Okines AF, Allum WH, Rowley S, Stevenson L, Grabsch HI, Alderson D, Crosby T, Griffin SM, Mansoor W, Coxon FY, Falk SJ, Darby S, Sumpter KA, Blazeby JM, Langley RE. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial. Lancet Oncol. 2017 Mar;18(3):357-370. Epub 2017 Feb 3. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30043-8/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337626/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28163000 PubMed]<br />
#'''Abstract:''' Salah-Eddin Al-Batran, Nils Homann, Harald Schmalenberg, Hans-Georg Kopp, Georg Martin Haag, Kim Barbara Luley, Wolff H. Schmiegel, Gunnar Folprecht, Stephan Probst, Nicole Prasnikar, Peter C. Thuss-Patience, Wolfgang Fischbach, Jorg Trojan, Michael Koenigsmann, Claudia Pauligk, Thorsten Oliver Goetze, Elke Jaeger, Johannes Meiler, Martin H. Schuler, and Ralf Hofheinz. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial. Journal of Clinical Oncology 2017 35:15_suppl, 4004-4004 [https://ascopubs.org/doi/full/10.1200/JCO.2017.35.15_suppl.4004 link to abstract]<br />
<br />
==EOF {{#subobject:ae4e32|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
EOF: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:e532ea|Variant=1}}===<br />
''Note: This regimen is sometimes listed as a perioperative option, but it is not clearly described as one by the primary reference to the REAL-2 study. Study participants could have had either locally advanced or metastatic disease, and the primary reference did not list a uniform policy about what patients underwent surgery and its timing--although a few patients were mentioned to undergo surgery.''<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 8 mg IV once on day 1, prior to chemotherapy, then 4 mg PO three times per day on days 2 & 3<br />
*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] once on day 1, prior to chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10 mg PO three times per day on days 2 to 4<br />
*[[Warfarin (Coumadin)]] 1 mg PO once per day as thrombosis prophylaxis, started on day -1<br />
<br />
'''21-day cycle for up to 8 cycles; for perioperative use per some guidelines, 3 cycles preoperatively and 3 cycles postoperatively would be used'''<br />
<br />
==EOX {{#subobject:891a3e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
EOX: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
<br>EOC: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>C</u>'''apecitabine<br />
===Regimen {{#subobject:6941e|Variant=1}}===<br />
''Note: This regimen is sometimes listed as a perioperative option, but it is not clearly described as one by the primary reference to the REAL-2 study. Study participants could have had either locally advanced or metastatic disease, and the primary reference did not list a uniform policy about what patients underwent surgery and its timing--although a few patients were mentioned to undergo surgery.''<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Capecitabine (Xeloda)]] 500 to 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 8 mg IV once on day 1, prior to chemotherapy, then 4 mg PO three times per day on days 2 & 3<br />
*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] once on day 1, prior to chemotherapy<br />
*[[Metoclopramide (Reglan)]] 10 mg PO three times per day on days 2 to 4<br />
<br />
'''21-day cycle for up to 8 cycles; for perioperative use per some guidelines, 3 cycles preoperatively and 3 cycles postoperatively would be used'''<br />
<br />
==FLEP {{#subobject:78eabc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
FLEP: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>E</u>'''toposide, '''<u>P</u>'''latinol (Cisplatin)<br />
===Regimen {{#subobject:721ee9|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/10.1200/JCO.2005.00.034 Stahl et al. 2005]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''For historic reference.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]]<br />
*[[Folinic acid (Leucovorin)]]<br />
*[[Etoposide (Vepesid)]]<br />
*[[Cisplatin (Platinol)]]<br />
<br />
====Subsequent treatment====<br />
<br />
*PE & RT (40 Gy), then [[Surgery#Esophageal_cancer_surgery|surgery]] versus PE & RT (at least 65 Gy)<br />
<br />
===References===<br />
<br />
#Stahl M, Stuschke M, Lehmann N, Meyer HJ, Walz MK, Seeber S, Klump B, Budach W, Teichmann R, Schmitt M, Schmitt G, Franke C, Wilke H. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol. 2005 Apr 1;23(10):2310-7. Erratum in: J Clin Oncol. 2006 Jan 20;24(3):531. [https://ascopubs.org/doi/10.1200/JCO.2005.00.034 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15800321 PubMed]<br />
<br />
==FLOT {{#subobject:aa7f4f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
FLOT: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>O</u>'''xaliplatin, '''<u>T</u>'''axotere (Docetaxel)<br />
===Regimen {{#subobject:16408e|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://ascopubs.org/doi/full/10.1200/JCO.2017.35.15_suppl.4004 Al-Batran et al. 2017 (FLOT4-AIO)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
|[[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
|-<br />
|}<br />
''This is the neoadjuvant portion of pre-planned perioperative chemotherapy.''<br />
<br />
''Patients: 100% adenocarcinoma histology of the gastroesophageal junction (AEG I-III) or the stomach'' <br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
*[[Docetaxel (Taxotere)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophageal_cancer_surgery|Surgery]], then [[#FLOT_2|adjuvant FLOT]]<br />
<br />
===References===<br />
<br />
#'''Abstract:''' Salah-Eddin Al-Batran, Nils Homann, Harald Schmalenberg, Hans-Georg Kopp, Georg Martin Haag, Kim Barbara Luley, Wolff H. Schmiegel, Gunnar Folprecht, Stephan Probst, Nicole Prasnikar, Peter C. Thuss-Patience, Wolfgang Fischbach, Jorg Trojan, Michael Koenigsmann, Claudia Pauligk, Thorsten Oliver Goetze, Elke Jaeger, Johannes Meiler, Martin H. Schuler, and Ralf Hofheinz. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial. Journal of Clinical Oncology 2017 35:15_suppl, 4004-4004 [https://ascopubs.org/doi/full/10.1200/JCO.2017.35.15_suppl.4004 link to abstract]<br />
<br />
==PCF {{#subobject:747f5e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
PCF: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:2d319e|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.jto.org/article/S1556-0864(15)33583-8/fulltext Zhao et al. 2015]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 2<br />
*[[Fluorouracil (5-FU)]] 700 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3500 mg/m<sup>2</sup>)<br />
<br />
'''2 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophageal_cancer_surgery|Surgery]], then adjuvant PCF x 2 versus no further treatment<br />
<br />
===References===<br />
<br />
#Zhao Y, Dai Z, Min W, Sui X, Kang H, Zhang Y, Ren H, Wang XJ. Perioperative versus Preoperative Chemotherapy with Surgery in Patients with Resectable Squamous Cell Carcinoma of Esophagus: A Phase III Randomized Trial. J Thorac Oncol. 2015 Sep;10(9):1349-1356. [https://www.jto.org/article/S1556-0864(15)33583-8/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26287319 PubMed]<br />
<br />
=Neoadjuvant chemoradiotherapy=<br />
''Note: while these regimens are listed as neoadjuvant (pre-operative), in some cases they are also used as definitive therapy in patients that are not surgical candidates.''<br />
==Capecitabine, Carboplatin, Paclitaxel, RT {{#subobject:79bb5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Capecitabine, Carboplatin, Paclitaxel, RT: Capecitabine, Carboplatin, Paclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:f22688|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.redjournal.org/article/S0360-3016(06)03362-1/abstract Czito et al. 2006]<br />
| style="background-color:#ffffbe" |Pilot, <20 pts<br />
|-<br />
|}<br />
''The primary reference did not specify whether patients were intended to proceed to surgery.''<br />
<br />
''Patients: 77% adenocarcinoma, 23% squamous cell histology. 54% lower thoracic, 23% midthoracic, 23% gastroesophageal junction.''<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 1.5 IV once per day on days 2, 9, 16, 23, 30<br />
*[[Paclitaxel (Taxol)]] 45 mg/m<sup>2</sup> IV over 60 minutes once per day on days 2, 9, 16, 23, 30<br />
*[[Capecitabine (Xeloda)]] 600 mg/m<sup>2</sup> PO twice per day, starting on day 1 and finishing the evening of the last day of radiation therapy<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 28 fractions, for a total dose of 50.4 Gy<br />
<br />
'''6-week course'''<br />
<br />
====Subsequent treatment====<br />
<br />
*Patients were evaluated for [[Surgery#Esophagectomy|surgery]], performed 6 to 8 weeks after chemoradiotherapy completion. Patients could receive adjuvant chemotherapy, beginning 4 to 12 weeks postoperatively<br />
<br />
===References===<br />
<br />
#'''Phase I:''' Czito BG, Kelsey CR, Hurwitz HI, Willett CG, Morse MA, Blobe GC, Fernando NH, D'Amico TA, Harpole DH, Honeycutt W, Yu D, Bendell JC. A Phase I study of capecitabine, carboplatin, and paclitaxel with external beam radiation therapy for esophageal carcinoma. Int J Radiat Oncol Biol Phys. 2007 Mar 15;67(4):1002-7. Epub 2006 Dec 29. [http://www.redjournal.org/article/S0360-3016(06)03362-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17197129 PubMed]<br />
<br />
==Capecitabine, Cisplatin, RT {{#subobject:ae7180|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CX & RT: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine), '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:eccd56|Variant=1}}===<br />
''Note: This study was for patients with stage IV disease. Please reference the original paper, as there were no patients who only received this neoadjuvant treatment, and they did not undergo surgical resection of disease.''<br />
<br />
''Patients: 3% adenocarcinoma, 97% squamous cell histology; 3% with ECOG PS of 2.''<br />
====Preceding treatment====<br />
<br />
*Capecitabine & Cisplatin<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''<br />
*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 5, '''given second'''<br />
<br />
'''7-day cycles until radiation therapy is complete'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], total of 54 Gy given (dose per fraction and total duration of treatment was not specified)<br />
<br />
'''One course'''<br />
<br />
===References===<br />
<br />
#'''Retrospective:''' Lee SS, Kim SB, Park SI, Kim YH, Ryu JS, Song HY, Shin JH, Jung HY, Lee GH, Choi KD, Cho KJ, Kim JH. Capecitabine and cisplatin chemotherapy (XP) alone or sequentially combined chemoradiotherapy containing XP regimen in patients with three different settings of stage IV esophageal cancer. Jpn J Clin Oncol. 2007 Nov;37(11):829-35. Epub 2007 Oct 19. [http://jjco.oxfordjournals.org/content/37/11/829.long link to original article] '''contains verified protocol'''--please see note above, as patients in this study did not undergo surgery [https://www.ncbi.nlm.nih.gov/pubmed/17951334 PubMed]<br />
<br />
==Capecitabine, Docetaxel, RT {{#subobject:ff7031|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Capecitabine, Docetaxel, RT: Capecitabine, Docetaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:d49e8|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/PMC3600150/ Wood et al. 2013]<br />
| style="background-color:#ffffbe" |Phase 1<br />
|-<br />
|}<br />
''Note: Some guidelines recommend different dosing but this is the only publication that we could locate with dosing details. Treatment is assumed to begin on a Monday.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 15 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 3500 mg PO once per day on days 1 to 5, '''given prior to radiation'''<br />
<br />
'''7-day cycle for 5 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] to 50.4 Gy in 28 fractions<br />
<br />
'''5-week course'''<br />
<br />
===References===<br />
<br />
#'''Phase 1:''' Wood MD, Zaki BI, Gordon SR, Sutton JE Jr, Lisovsky M, Gui J, Bubis JA, Dragnev KH, Rigas JR. Trimodality therapy for stage II-III carcinoma of the esophagus: a dose-ranging study of concurrent capecitabine, docetaxel, and thoracic radiotherapy. J Thorac Oncol. 2013 Apr;8(4):487-94. [https://www.jto.org/article/S1556-0864(15)32794-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600150/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23370365 PubMed]<br />
<br />
==Capecitabine, Docetaxel, Oxaliplatin, RT {{#subobject:312400|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Capecitabine, Docetaxel, Oxaliplatin, RT: Capecitabine, Docetaxel, Oxaliplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:e65189|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/28/13/2213.long Spigel et al. 2010]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Patients: 69% adenocarcinoma, 18% squamous cell, 12% not otherwise specified. 69% distal esophagus, 16% midesophagus, 14% gastroesophageal junction.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 7, 15 to 21, 29 to 35<br />
*[[Docetaxel (Taxotere)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29<br />
*[[Oxaliplatin (Eloxatin)]] 40 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 4 mg PO every 12 hours before, at the time of, and after [[Docetaxel (Taxotere)]]; first dose the evening before [[Docetaxel (Taxotere)]]<br />
*"Routine antiemetics"<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions, for a total dose of 45 Gy<br />
<br />
'''5-week course'''<br />
====Subsequent treatment====<br />
<br />
*Endoscopy, CT scan, and--if available--endoscopic ultrasound for restaging 2 to 4 weeks after finishing chemoradiation, with subsequent treatment as follows:<br />
**Appropriate candidates: [[Surgery#Esophagectomy|Surgical resection]] sometime during weeks 9 to 12<br />
**Patients who were no longer surgical candidates: Additional radiation therapy to a total dose of 64.8 Gy<br />
<br />
===References===<br />
<br />
#Spigel DR, Greco FA, Meluch AA, Lane CM, Farley C, Gray JR, Clark BL, Burris HA 3rd, Hainsworth JD. Phase I/II trial of preoperative oxaliplatin, docetaxel, and capecitabine with concurrent radiation therapy in localized carcinoma of the esophagus or gastroesophageal junction. J Clin Oncol. 2010 May 1;28(13):2213-9. Epub 2010 Mar 29. [http://jco.ascopubs.org/content/28/13/2213.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20351330 PubMed]<br />
<br />
==Capecitabine, Oxaliplatin, RT {{#subobject:e958eb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOx & RT: '''<u>Cape</u>'''citabine, '''<u>Ox</u>'''aliplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:69d2ce|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/10.1080/07357900802172093 Javle et al. 2009]<br />
| style="background-color:#ffffbe" |Phase I<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once per day on days 1, 15, 29<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], total dose of 50.4 Gy<br />
<br />
'''5-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophagectomy|Surgery]]<br />
<br />
===References===<br />
<br />
#'''Phase I:''' Javle MM, Yang G, Nwogu CE, Wilding GE, O'Malley L, Vinjamaram S, Schiff MD, Nava HR, LeVea C, Clark KR, Prey JD, Smith PF, Pendyala L. Capecitabine, oxaliplatin and radiotherapy: a phase IB neoadjuvant study for esophageal cancer with gene expression analysis. Cancer Invest. 2009 Feb;27(2):193-200. [https://www.tandfonline.com/doi/full/10.1080/07357900802172093 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19235592 PubMed]<br />
<br />
==Capecitabine, Paclitaxel, RT {{#subobject:17bbec|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Capecitabine, Paclitaxel, RT: Capecitabine, Paclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c6f9f5|Variant=1}}===<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 625 to 825 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33<br />
*[[Paclitaxel (Taxol)]] 45 to 50 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]] not defined<br />
<br />
'''5-week course'''<br />
===References===<br />
<br />
#No primary reference could be found for this regimen.<br />
<br />
==Carboplatin, Fluorouracil, RT {{#subobject:d29415|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Carboplatin, Fluorouracil, RT: Carboplatin, Fluorouracil, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:1c21a7|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.1442-2050.2009.00984.x/full Zemanoa et al. 2009]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
''Patients: 86% squamous cell, 8% adenocarcinoma, 6% other histology. 3% ECOG PS of 2.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)<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, for a total dose of 45 Gy. <br />
**If surgery was contraindicated, total dose was increased to 50.4 to 56.8 Gy.<br />
<br />
'''42-day course'''<br />
====Subsequent treatment====<br />
<br />
*Upper endoscopy and CT chest and abdomen was performed after completion of chemoradiation<br />
*[[Surgery#Esophagectomy|Surgery]] planned to be done 4 to 6 weeks after finishing chemoradiation<br />
<br />
===References===<br />
<br />
#Zemanova M, Petruzelka L, Pazdro A, Kralova D, Smejkal M, Pazdrova G, Honova H. Prospective non-randomized study of preoperative concurrent platinum plus 5-fluorouracil-based chemoradiotherapy with or without paclitaxel in esophageal cancer patients: long-term follow-up. Dis Esophagus. 2010 Feb;23(2):160-7. Epub 2009 Jun 9. [https://onlinelibrary.wiley.com/doi/10.1111/j.1442-2050.2009.00984.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19515190 PubMed]<br />
<br />
==Carboplatin, Paclitaxel, RT {{#subobject:93878b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Carboplatin, Paclitaxel, RT: Carboplatin, Paclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:33b67a|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/PMC2361286 van Meerten et al. 2006]<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/NEJMoa1112088 van Hagen et al. 2012 (CROSS)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_neoadjuvant_therapy|Surgery alone]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''van Meerten et al. Patients: 76% adenocarcinoma, 22% squamous cell, 2% large cell histology. 91% lower esophagus, 9% thoracic esophagus''<br />
<br />
''van Hagen et al. Patients: 75% adenocarcinoma, 23% squamous cell, 2% other. 24% gastroesophageal junction''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15, 22, 29, '''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, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 10 mg IV once per day on days 1, 8, 15, 22, 29; 30 minutes prior to [[Paclitaxel (Taxol)]]<br />
*[[Ranitidine (Zantac)]] 50 mg IV once per day on days 1, 8, 15, 22, 29; 30 minutes prior to [[Paclitaxel (Taxol)]]<br />
*[[Clemastine (Tavist)]] 2 mg IV once per day on days 1, 8, 15, 22, 29; 30 minutes prior to [[Paclitaxel (Taxol)]]<br />
*Between paclitaxel & carboplatin: 100 mL NS given over 30 minutes, then [[Ondansetron (Zofran)]] 8 mg in 100 mL NS given over 30 minutes<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 23 fractions, for a total dose of 41.4 Gy<br />
<br />
'''5-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophagectomy|Surgery]] planned to be done within 6 weeks of finishing chemoradiation; van Hagen et al. 2012 said surgery was done as soon as possible after finishing chemoradiotherapy, preferably within 4 to 6 weeks<br />
<br />
===References===<br />
<br />
#van Meerten E, Muller K, Tilanus HW, Siersema PD, Eijkenboom WM, van Dekken H, Tran TC, van der Gaast A. Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study. Br J Cancer. 2006 May 22;94(10):1389-94. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361286 link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361286/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16670722 PubMed]<br />
#'''CROSS:''' van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ, Busch OR, ten Kate FJ, Creemers GJ, Punt CJ, Plukker JT, Verheul HM, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJ, Rozema T, Biermann K, Beukema JC, Piet AH, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A; CROSS Group. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012 May 31;366(22):2074-84. [https://www.nejm.org/doi/full/10.1056/NEJMoa1112088 link to original article] '''contains verified protocol''' [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1112088/suppl_file/nejmoa1112088_appendix.pdf link to appendix with details about administration] [https://www.ncbi.nlm.nih.gov/pubmed/22646630 PubMed]<br />
##'''Update:''' Shapiro J, van Lanschot JJB, Hulshof MCCM, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch ORC, Ten Kate FJW, Creemers GM, Punt CJA, Plukker JTM, Verheul HMW, Bilgen EJS, van Dekken H, van der Sangen MJC, Rozema T, Biermann K, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, Steyerberg EW, van der Gaast A; CROSS study group. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1090-1098. Epub 2015 Aug 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00040-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26254683 PubMed]<br />
<br />
==Cisplatin, Docetaxel, RT {{#subobject:4231cb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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DC & RT: '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:6c3cc6|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://annonc.oxfordjournals.org/content/20/9/1522.long Ruhstaller et al. 2009 (SAKK 75/02)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 55% adenocarcinoma, 45% squamous cell histology''<br />
<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin_.26_Docetaxel|Cisplatin & Docetaxel]] x 2<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29<br />
*[[Docetaxel (Taxotere)]] 20 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]], 1.8 Gy fractions x 25 fractions, for a total dose of 45 Gy<br />
<br />
'''5-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophagectomy|Surgery]], 3 to 8 weeks after finishing chemoradiation<br />
<br />
===References===<br />
<br />
#Ruhstaller T, Widmer L, Schuller JC, Roth A, Hess V, Mingrone W, von Moos R, Borner M, Pestalozzi BC, Balmermajno S, Köberle D, Terraciano L, Schnider A, Bodis S, Popescu R; Swiss Group for Clinical Cancer Research (SAKK). Multicenter phase II trial of preoperative induction chemotherapy followed by chemoradiation with docetaxel and cisplatin for locally advanced esophageal carcinoma (SAKK 75/02). Ann Oncol. 2009 Sep;20(9):1522-8. Epub 2009 May 22. [http://annonc.oxfordjournals.org/content/20/9/1522.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19465425 PubMed]<br />
<br />
==Cisplatin, Etoposide, RT {{#subobject:88cc36|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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EP & RT: '''<u>E</u>'''toposide, '''<u>P</u>'''latinol (Cisplatin), '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:a9fc90|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://ascopubs.org/doi/full/10.1200/JCO.2008.17.0506 Stahl et al. 2009 (POET)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Complex_multipart_regimens#POET|See link]]<br />
| style="background-color:#d9ef8b" |[[Complex_multipart_regimens#POET|See link]]<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma histology. 55% Siewert classification Type I, 45% Siewert classification Types II &III.''<br />
<br />
====Preceding treatment====<br />
<br />
*[[#CLF|PLF]] x 12 wk<br />
<br />
====Chemotherapy, ''to start 2 weeks after the last day of PLF''====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8<br />
*[[Etoposide (Vepesid)]] 80 mg/m<sup>2</sup> IV over 60 minutes once per day on days 3 to 5<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.0 Gy fractions x 15 fractions (target dose of 30 Gy)<br />
<br />
'''3-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophagectomy|Surgery]], in 3 to 4 weeks<br />
<br />
===References===<br />
<br />
#'''POET:''' Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, Riera-Knorrenschild J, Langer P, Engenhart-Cabillic R, Bitzer M, Königsrainer A, Budach W, Wilke H. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol. 2009 Feb 20;27(6):851-6. Epub 2009 Jan 12. [https://ascopubs.org/doi/full/10.1200/JCO.2008.17.0506 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19139439 PubMed]<br />
##'''Update:''' Stahl M, Walz MK, Riera-Knorrenschild J, Stuschke M, Sandermann A, Bitzer M, Wilke H, Budach W. Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): long-term results of a controlled randomised trial. Eur J Cancer. 2017 Aug;81:183-190. [https://www.ncbi.nlm.nih.gov/pubmed/28628843 PubMed]<br />
<br />
==Cisplatin, Fluorouracil, RT {{#subobject:17919|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CF & RT: '''C'''isplatin, '''<u>F</u>'''luourouracil, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1, 75/3200 x 2 {{#subobject:e20717|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://ascopubs.org/doi/full/10.1200/JCO.2013.53.6532 Mariette et al. 2014 (FFCD 9901)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_neoadjuvant_therapy|Surgery alone]]<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 />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on either day 1 or 2<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3200 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycle for 2 cycles'''<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.80 Gy fractions x 25 fractions, for a total dose of 45 Gy<br />
<br />
'''5-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophagectomy|Surgery]]<br />
<br />
===Variant #2, 75/4000 x 2 {{#subobject:a49842|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/25/10/1160.long Bedenne et al. 2007 (FFCD 9102)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Patients: 89% epidermoid, 11% glandular histology.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*1 liter NS IV over 2 hours before and after [[Cisplatin (Platinol)]]<br />
<br />
'''21-day cycle for 2 cycles''' <br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 23 fractions, for a total dose of 46 Gy<br />
**Earlier in the study, some patients instead received split-course radiation therapy, 3 Gy fractions x 5 fractions given on days 1 to 5. 15 Gy per cycle; total dose after 2 cycles is 30 Gy.<br />
<br />
'''4.5-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[#Cisplatin.2C_Fluorouracil.2C_RT_2|Cisplatin, Fluorouracil, RT (no surgery)]] x 3 (5 cycles total) versus [[Surgery#Esophagectomy|surgery]], 50 to 60 days after start of chemoradiation<br />
<br />
===Variant #3, 80/3200 {{#subobject:b4cc81|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(05)70288-6/fulltext Burmeister et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_neoadjuvant_therapy|Surgery alone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<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 />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose: 3200 mg/m<sup>2</sup>)<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.33 Gy fractions x 15 fractions for a total dose of 35 Gy<br />
<br />
'''3-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophagectomy|Surgery]]<br />
<br />
===Variant #4, 100/4000 x 2 {{#subobject:45f8a2|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/PMC5126644/ Tepper et al. 2008 (CALGB 9781)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_neoadjuvant_therapy|Surgery alone]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Patients: 75% adenocarcinoma, 25% squamous cell histology. 5% with ECOG PS of 2.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1, '''given second''' (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions, then a 5.4 Gy final boost, for a total dose of 50.4 Gy, '''starting within 24 hours of start of chemotherapy'''<br />
<br />
'''5-week course'''<br />
====Subsequent treatment====<br />
<br />
*EGD and CT chest and abdomen done within 4 weeks after finishing radiation therapy. Only patients who still had resectable disease that was stable or responded would proceed to [[Surgery#Esophagectomy|surgery]]. Surgery was planned to be done 3 to 8 weeks after finishing chemoradiation.<br />
<br />
===Variant #5, intermittent 5-FU {{#subobject:213574|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/NEJM199608153350702 Walsh et al. 1996]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_neoadjuvant_therapy|Surgery alone]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: of historic interest only.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]]<br />
*[[Fluorouracil (5-FU)]]<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]]<br />
<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophagectomy|Surgery]]<br />
<br />
===References===<br />
<br />
#Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996 Aug 15;335(7):462-7. Erratum in: N Engl J Med 1999 Jul 29;341(5):384. [https://www.nejm.org/doi/full/10.1056/NEJM199608153350702 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8672151 PubMed]<br />
#Burmeister BH, Smithers BM, Gebski V, Fitzgerald L, Simes RJ, Devitt P, Ackland S, Gotley DC, Joseph D, Millar J, North J, Walpole ET, Denham JW; Trans-Tasman Radiation Oncology Group; Australasian Gastro-Intestinal Trials Group. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol. 2005 Sep;6(9):659-68. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70288-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16129366 PubMed]<br />
#'''FFCD 9102:''' Bedenne L, Michel P, Bouché O, Milan C, Mariette C, Conroy T, Pezet D, Roullet B, Seitz JF, Herr JP, Paillot B, Arveux P, Bonnetain F, Binquet C. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007 Apr 1;25(10):1160-8. [http://jco.ascopubs.org/content/25/10/1160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17401004 PubMed]<br />
#'''CALGB 9781:''' Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, Kiel K, Willett C, Sugarbaker D, Mayer R. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008 Mar 1;26(7):1086-92. [http://jco.ascopubs.org/content/26/7/1086.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126644/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18309943 PubMed]<br />
#'''FFCD 9901:''' Mariette C, Dahan L, Mornex F, Maillard E, Thomas PA, Meunier B, Boige V, Pezet D, Robb WB, Le Brun-Ly V, Bosset JF, Mabrut JY, Triboulet JP, Bedenne L, Seitz JF. Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901. J Clin Oncol. 2014 Aug 10;32(23):2416-22. Epub 2014 Jun 30. [https://ascopubs.org/doi/full/10.1200/JCO.2013.53.6532 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24982463 PubMed]<br />
<br />
==Cisplatin, Irinotecan, RT {{#subobject:4932b1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Cisplatin, Irinotecan, RT: Cisplatin, Irinotecan, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1, 60/130 x 2 + 45 Gy {{#subobject:eac274|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/PMC3563156/ Yoon et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma of the esophagus or gastroesophageal junction (tumor extension < 2cm into gastric cardia)''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV once per day on days 1 & 8<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, starting within 24 hours of the first dose of chemotherapy, for a total dose of 45 Gy.<br />
<br />
'''5-week course'''<br />
====Subsequent treatment====<br />
<br />
*Yoon et al. 2011: [[Surgery#Esophagectomy|surgery]] at least 28 days after finishing chemoradiation, then begin [[#Cisplatin_.26_Irinotecan_2|adjuvant cisplatin & irinotecan]] at least 28 days after surgical resection<br />
<br />
===Variant #2, 60/130 x 2 + 50.4 Gy {{#subobject:927613|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/cncr.26591/full Ilson et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 75% adenocarcinoma, 22% squamous cell, 3% poorly differentiated history; 33% gastroesophageal junction.''<br />
<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin_.26_Irinotecan|Cisplatin & Irinotecan induction]] x 2<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given first'''<br />
*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given second'''<br />
<br />
'''21-day cycle for 2 cycles''' <br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 28 fractions, for a total of 50.4 Gy<br />
<br />
'''5.5-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophagectomy|Surgery]], performed 4 to 8 weeks after chemoradiation<br />
<br />
===Variant #3 {{#subobject:1a3475|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.redjournal.org/article/S0360-3016(09)00362-9/abstract Rivera et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma histology (43% gastroesophageal junction, 57% gastric adenocarcinoma)''<br />
<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin_.26_Irinotecan|Cisplatin & Irinotecan induction]] x 2<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions, starting within 24 hours of the first dose of chemotherapy, for a total dose of 45 Gy.<br />
<br />
'''5-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophagectomy|Surgery]], 5 to 8 weeks after finishing chemoradiation<br />
<br />
===References===<br />
<br />
#Rivera F, Galán M, Tabernero J, Cervantes A, Vega-Villegas ME, Gallego J, Laquente B, Rodríguez E, Carrato A, Escudero P, Massutí B, Alonso-Orduña V, Cardenal A, Sáenz A, Giralt J, Yuste AL, Antón A, Aranda E; Spanish Cooperative Group for Digestive Tumor Therapy. Phase II trial of preoperative irinotecan-cisplatin followed by concurrent irinotecan-cisplatin and radiotherapy for resectable locally advanced gastric and esophagogastric junction adenocarcinoma. Int J Radiat Oncol Biol Phys. 2009 Dec 1;75(5):1430-6. Epub 2009 Jun 18. [http://www.redjournal.org/article/S0360-3016(09)00362-9/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19540072 PubMed]<br />
#Ilson DH, Minsky BD, Ku GY, Rusch V, Rizk N, Shah M, Kelsen DP, Capanu M, Tang L, Campbell J, Bains M. Phase 2 trial of induction and concurrent chemoradiotherapy with weekly irinotecan and cisplatin followed by surgery for esophageal cancer. Cancer. 2011 Oct 11. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.26591/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21990000 PubMed]<br />
#Yoon HH, Catalano P, Gibson MK, Skaar TC, Philips S, Montgomery EA, Hafez MJ, Powell M, Liu G, Forastiere AA, Benson AB, Kleinberg LR, Murphy KM. Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group. Cancer Chemother Pharmacol. 2011 Oct;68(4):863-70. Epub 2011 Feb 1. [http://www.springerlink.com/content/v4g0257025185531/ link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563156/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21286719 PubMed]<br />
<br />
==Cisplatin, Paclitaxel, RT {{#subobject:3d8eaa|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Cisplatin, Paclitaxel, RT: Cisplatin, Paclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1, weekly cisplatin {{#subobject:5a433d|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/PMC3563156/ Yoon et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma of the esophagus or gastroesophageal junction (tumor extension < 2cm into gastric cardia)''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22, 29<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions, starting within 24 hours of the first dose of chemotherapy, for a total dose of 45 Gy.<br />
<br />
'''5-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophagectomy|Surgery]] at least 28 days after finishing chemoradiation, then [[#Cisplatin_.26_Paclitaxel|adjuvant cisplatin & paclitaxel]] at least 28 days after surgical resection<br />
<br />
===Variant #2, q3wk cisplatin {{#subobject:32166d|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/cncr.11759/full Urba et al. 2003]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 83% adenocarcinoma, 14% squamous cell, 3% undifferentiated histology''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Paclitaxel (Taxol)]] 60 mg/m<sup>2</sup> IV over 3 hours once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 20 mg PO twice per day on days 1, 8, 15, 22; 12 and 6 hours before [[Paclitaxel (Taxol)]]<br />
*[[Diphenhydramine (Benadryl)]] 50 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to [[Paclitaxel (Taxol)]]<br />
*[[Cimetidine (Tagamet)]] 300 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to [[Paclitaxel (Taxol)]]<br />
*1 liter D5NS and mannitol 12.5 g bolus IV once on day 1, prior to [[Cisplatin (Platinol)]]<br />
*Mannitol 25 g in 1 liter D5NS IV over 4 hours once on day 1, after [[Cisplatin (Platinol)]]<br />
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 23, continuing until ANC greater than 10,000/uL<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions given twice per day on days 1 to 5, 8 to 12, 15 to 19, with at least 6 hours between fractions, for a total dose of 45 Gy<br />
<br />
'''4-week course'''<br />
====Subsequent treatment====<br />
<br />
*Barium swallow and CT chest and abdomen done about 1 week prior to surgery to rule out metastatic disease. [[Surgery#Esophagectomy|Surgery]] to be done on approximately day 50<br />
<br />
===References===<br />
<br />
#Urba SG, Orringer MB, Ianettonni M, Hayman JA, Satoru H. Concurrent cisplatin, paclitaxel, and radiotherapy as preoperative treatment for patients with locoregional esophageal carcinoma. Cancer. 2003 Nov 15;98(10):2177-83. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.11759/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14601087 PubMed]<br />
#Yoon HH, Catalano P, Gibson MK, Skaar TC, Philips S, Montgomery EA, Hafez MJ, Powell M, Liu G, Forastiere AA, Benson AB, Kleinberg LR, Murphy KM. Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group. Cancer Chemother Pharmacol. 2011 Oct;68(4):863-70. Epub 2011 Feb 1. [http://www.springerlink.com/content/v4g0257025185531/ link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563156/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21286719 PubMed]<br />
<br />
==Cisplatin, Vinorelbine, RT {{#subobject:d72171|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
Cisplatin, Vinorelbine, RT: Cisplatin, Vinorelbine, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1, standard cisplatin {{#subobject:ddf0ee|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/PMC6145832/ Yang et al. 2018 (NEOCRTEC5010)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_neoadjuvant_therapy|No neoadjuvant therapy]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<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 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.0 Gy fractions x 20 fractions, for a total dose of 40 Gy<br />
<br />
'''4-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophagectomy|Surgery]]<br />
<br />
===Variant #2, split-dose cisplatin {{#subobject:672470|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/PMC6145832/ Yang et al. 2018 (NEOCRTEC5010)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#No_neoadjuvant_therapy|No neoadjuvant therapy]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 1 to 4<br />
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.0 Gy fractions x 20 fractions, for a total dose of 40 Gy<br />
<br />
'''4-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophagectomy|Surgery]]<br />
<br />
===References===<br />
<br />
#'''NEOCRTEC5010:''' Yang H, Liu H, Chen Y, Zhu C, Fang W, Yu Z, Mao W, Xiang J, Han Y, Chen Z, Yang H, Wang J, Pang Q, Zheng X, Yang H, Li T, Lordick F, D'Journo XB, Cerfolio RJ, Korst RJ, Novoa NM, Swanson SJ, Brunelli A, Ismail M, Fernando HC, Zhang X, Li Q, Wang G, Chen B, Mao T, Kong M, Guo X, Lin T, Liu M, Fu J; AME Thoracic Surgery Collaborative Group. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): a phase III multicenter, randomized, open-label clinical trial. J Clin Oncol. 2018 Sep 20;36(27):2796-2803. Epub 2018 Aug 8. [https://ascopubs.org/doi/full/10.1200/JCO.2018.79.1483 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145832/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30089078 PubMed]<br />
<br />
==Docetaxel, Fluorouracil, RT {{#subobject:956374|Regimen=1}}==<br />
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Docetaxel, Fluorouracil, RT: Docetaxel, Fluorouracil, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1, 15/4000 x 2 {{#subobject:c112ab|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://ar.iiarjournals.org/content/27/4C/2597.long Hihara et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 86% squamous cell, 14% carcinosarcoma histology''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 7.5 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on days 1, 8, 15 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 8 mg IV once per day on days 1 & 8; 30 minutes prior to [[Docetaxel (Taxotere)]]<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 30 to 33 fractions, for a total dose of 60 to 66 Gy<br />
<br />
'''6- to 6.5-week course'''<br />
===Variant #2 {{#subobject:8dd58b|Variant=1}}===<br />
''Note: No primary reference could be found for this regimen.''<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 20 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 to 300 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] not defined<br />
<br />
'''7-day cycle for 5 cycles'''<br />
<br />
===References===<br />
<br />
#'''Phase I:''' Hihara J, Yoshida K, Hamai Y, Emi M, Yamaguchi Y, Wadasaki K. Phase I study of docetaxel (TXT) and 5-fluorouracil (5-FU) with concurrent radiotherapy in patients with advanced esophageal cancer. Anticancer Res. 2007 Jul-Aug;27(4C):2597-603. [http://ar.iiarjournals.org/content/27/4C/2597.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17695421 PubMed]<br />
<br />
==Fluorouracil, Oxaliplatin, RT {{#subobject:94b79a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Fluorouracil, Oxaliplatin, RT: Fluorouracil, Oxaliplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1, 45 Gy {{#subobject:bbd435|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/PMC2567089 Lorenzen et al. 2008]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''Patients: 100% squamous cell etiology, 65% poor differentiated or undifferentiated''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 225 mg/m<sup>2</sup>/day IV continuous infusion over 33 days, started on day 1 (total dose: 7425 mg/m<sup>2</sup>)<br />
*[[Oxaliplatin (Eloxatin)]] 45 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions, for a total dose of 45 Gy<br />
<br />
'''35-day course'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophagectomy|Surgery]], 4 to 6 weeks after finishing chemoradiation<br />
<br />
===Variant #2, 50.4 Gy, bi-weekly oxaliplatin {{#subobject:ae22de|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/20/12/2844.long Khushalani et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''58% patients were classified as stage IV disease''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29<br />
*[[Fluorouracil (5-FU)]] 180 mg/m<sup>2</sup>/day IV continuous infusion over 35 days, started on day 8 (total dose: 6300 mg/m<sup>2</sup>)<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 20 to 22 fractions, for an initial total dose of 36 to 39.6 Gy, '''started on day 8'''<br />
**Followed by off-cord conformal oblique fields, 5.4 to 9 Gy given to the clinical target volume (CTV). A second off-cord phase to the gross tumor volume (GTV) of 5.4 Gy was then given, for a total dose delivered of 50.4 Gy to the GTV.<br />
<br />
'''6-week course'''<br />
<br />
====Subsequent treatment====<br />
<br />
*Upper GI endoscopy and CT chest, abdomen, and pelvis were done after completion of chemoradiation, and patients without progressive stage II-III disease were offered [[Surgery#Esophagectomy|surgery]] followed by another cycle of oxaliplatin and 5-FU. Patients who could not proceed to surgery were given another 1 to 2 cycles of oxaliplatin and 5-FU within 2 weeks.<br />
<br />
===Variant #3, 50.4 Gy, weekly oxaliplatin {{#subobject:aa7e55|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/PMC3937600/ Ajani et al. 2013]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: it is unclear how long the 5-FU continuous infusions were in this regimen; the authors have been contacted for clarification. Treatment is assumed to start on a Monday.''<br />
====Preceding treatment====<br />
<br />
*Fluorouracil & Oxaliplatin induction versus no induction chemotherapy<br />
<br />
====Chemotherapy====<br />
<br />
*[[Oxaliplatin (Eloxatin)]] 40 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1000 mg/m<sup>2</sup>)<br />
<br />
'''7-day cycle for 5 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 50.4 Gy of proton or photon (intensity modulated) radiation in 28 fractions<br />
<br />
'''5-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophagectomy|Surgery]]<br />
<br />
===References===<br />
<br />
#Khushalani NI, Leichman CG, Proulx G, Nava H, Bodnar L, Klippenstein D, Litwin A, Smith J, Nava E, Pendyala L, Smith P, Greco W, Berdzik J, Douglass H, Leichman L. Oxaliplatin in combination with protracted-infusion fluorouracil and radiation: report of a clinical trial for patients with esophageal cancer. J Clin Oncol. 2002 Jun 15;20(12):2844-50. [http://jco.ascopubs.org/content/20/12/2844.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12065561 PubMed]<br />
#Lorenzen S, Brücher B, Zimmermann F, Geinitz H, Riera J, Schuster T, Roethling N, Höfler H, Ott K, Peschel C, Siewert JR, Molls M, Lordick F. Neoadjuvant continuous infusion of weekly 5-fluorouracil and escalating doses of oxaliplatin plus concurrent radiation in locally advanced oesophageal squamous cell carcinoma: results of a phase I/II trial. Br J Cancer. 2008 Oct 7;99(7):1020-6. Epub 2008 Sep 16. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2567089 link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2567089/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18797462 PubMed]<br />
#Ajani JA, Xiao L, Roth JA, Hofstetter WL, Walsh G, Komaki R, Liao Z, Rice DC, Vaporciyan AA, Maru DM, Lee JH, Bhutani MS, Eid A, Yao JC, Phan AP, Halpin A, Suzuki A, Taketa T, Thall PF, Swisher SG. A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer. Ann Oncol. 2013 Nov;24(11):2844-9. Epub 2013 Aug 23. [https://academic.oup.com/annonc/article/24/11/2844/201894 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937600/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23975663 PubMed]<br />
<br />
==Fluorouracil, Paclitaxel, RT {{#subobject:52e768|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Fluorouracil, Paclitaxel, RT: Fluorouracil, Paclitaxel, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:f8576f|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/24/24/3953.long Ajani et al. 2006 (RTOG 9904)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma histology. The majority of patients had gastric adenocarcinoma. Although gastroesophageal junction was involved, percentages were not included.''<br />
<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin_.26_Fluorouracil|Cisplatin & 5-FU induction]] x 2<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 1500 mg/m<sup>2</sup>)<br />
*[[Paclitaxel (Taxol)]] 45 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycle for 5 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions, for a total dose of 45 Gy<br />
<br />
'''5-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophagectomy|Surgery]]<br />
<br />
===References===<br />
<br />
#'''RTOG 9904:''' Ajani JA, Winter K, Okawara GS, Donohue JH, Pisters PW, Crane CH, Greskovich JF, Anne PR, Bradley JD, Willett C, Rich TA. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol. 2006 Aug 20;24(24):3953-8. [http://jco.ascopubs.org/content/24/24/3953.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16921048 PubMed]<br />
<br />
==No neoadjuvant therapy==<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 />
|[https://www.nejm.org/doi/full/10.1056/NEJM199608153350702 Walsh et al. 1996]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Cisplatin.2C_Fluorouracil.2C_RT|CF & RT]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199707173370304 Bosset et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS60<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199812313392704 Kelsen et al. 1998 (RTOG 8911)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Fluorouracil|CF]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2001.19.2.305 Urba et al. 2001]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Cisplatin, 5-FU, Vinblastine, RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010601%2991%3A11%3C2165%3A%3AAID-CNCR1245%3E3.0.CO%3B2-H Ancona et al. 2001]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Fluorouracil|CF]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08651-8/fulltext Girling et al. 2002 (UK MRC OE02)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Fluorouracil|CF]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|[https://academic.oup.com/annonc/article/15/6/947/129993 Lee et al. 2004]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin.2C_Fluorouracil.2C_RT|CF & RT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70288-6/fulltext Burmeister et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin.2C_Fluorouracil.2C_RT|CF & RT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa055531 Cunningham et al. 2006 (MAGIC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#MAGIC|Perioperative ECF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126644/ Tepper et al. 2008 (CALGB 9781)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin.2C_Fluorouracil.2C_RT|CF & RT]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2010.33.0597 Ychou et al. 2011 (ACCORD 07)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#ACCORD_07|Perioperative CF]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123658/ Boonstra et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Etoposide|EP]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1112088 van Hagen et al. 2012 (CROSS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Carboplatin.2C_Paclitaxel.2C_RT|Carboplatin, Paclitaxel, RT]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2013.53.6532 Mariette et al. 2014 (FFCD 9901)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin.2C_Fluorouracil.2C_RT|CF & RT]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145832/ Yang et al. 2018 (NEOCRTEC5010)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin.2C_Vinorelbine.2C_RT|Cisplatin, Vinorelbine, RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: efficacy for UK MRC OE02 is based on the 2009 update.''<br />
<br />
''Surgery as primary therapy; i.e., no induction chemotherapy or chemoradiotherapy, and no adjuvant therapy.''<br />
<br />
''MAGIC patients: 100% adenocarcinoma of the stomach or lower third of the esophagus. 74% gastric, 15% lower esophagus, 11% gastroesophageal junction.''<br />
<br />
''CALGB 9781 patients: 75% adenocarcinoma, 25% squamous cell histology. 5% with ECOG PS of 2.''<br />
<br />
''CROSS patients: 75% adenocarcinoma, 23% squamous cell, 2% other. 24% gastroesophageal junction.''<br />
====Subsequent treatment====<br />
<br />
*[[Surgery#Esophagectomy|Surgery]]<br />
<br />
===References===<br />
<br />
#Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996 Aug 15;335(7):462-7. Erratum in: N Engl J Med 1999 Jul 29;341(5):384. [https://www.nejm.org/doi/full/10.1056/NEJM199608153350702 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8672151 PubMed]<br />
#Bosset JF, Gignoux M, Triboulet JP, Tiret E, Mantion G, Elias D, Lozach P, Ollier JC, Pavy JJ, Mercier M, Sahmoud T. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med. 1997 Jul 17;337(3):161-7. [https://www.nejm.org/doi/full/10.1056/NEJM199707173370304 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9219702 PubMed]<br />
#'''RTOG 8911:''' Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med. 1998 Dec 31;339(27):1979-84. [https://www.nejm.org/doi/full/10.1056/NEJM199812313392704 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9869669 PubMed]<br />
##'''Update:''' Kelsen DP, Winter KA, Gunderson LL, Mortimer J, Estes NC, Haller DG, Ajani JA, Kocha W, Minsky BD, Roth JA, Willett CG; Radiation Therapy Oncology Group; USA Intergroup. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol. 2007 Aug 20;25(24):3719-25. [https://ascopubs.org/doi/full/10.1200/JCO.2006.10.4760 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17704421 PubMed]<br />
#Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A, Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol. 2001 Jan 15;19(2):305-13. [https://ascopubs.org/doi/full/10.1200/JCO.2001.19.2.305 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11208820 PubMed]<br />
#Ancona E, Ruol A, Santi S, Merigliano S, Sileni VC, Koussis H, Zaninotto G, Bonavina L, Peracchia A. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer. 2001 Jun 1;91(11):2165-74. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010601%2991%3A11%3C2165%3A%3AAID-CNCR1245%3E3.0.CO%3B2-H link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11391598 PubMed]<br />
#'''UK MRC OE02:''' Girling DJ, Bancewicz J, Clark PI, Smith DB, Donnelly RJ, Fayers PM, Weeden S, Hutchinson T, Harvey A, Lyddiard J; Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet. 2002 May 18;359(9319):1727-33. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08651-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12049861 PubMed]<br />
##'''Update:''' Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol. 2009 Oct 20;27(30):5062-7. Epub 2009 Sep 21. [https://ascopubs.org/doi/full/10.1200/JCO.2009.22.2083 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19770374 PubMed]<br />
#Lee JL, Park SI, Kim SB, Jung HY, Lee GH, Kim JH, Song HY, Cho KJ, Kim WK, Lee JS, Kim SH, Min YI. A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol. 2004 Jun;15(6):947-54. [https://academic.oup.com/annonc/article/15/6/947/129993 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15151953 PubMed]<br />
#Burmeister BH, Smithers BM, Gebski V, Fitzgerald L, Simes RJ, Devitt P, Ackland S, Gotley DC, Joseph D, Millar J, North J, Walpole ET, Denham JW; Trans-Tasman Radiation Oncology Group; Australasian Gastro-Intestinal Trials Group. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol. 2005 Sep;6(9):659-68. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70288-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16129366 PubMed]<br />
#'''MAGIC:''' Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa055531 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16822992 PubMed]<br />
#'''CALGB 9781:''' Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, Kiel K, Willett C, Sugarbaker D, Mayer R. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008 Mar 1;26(7):1086-92. [http://jco.ascopubs.org/content/26/7/1086.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126644/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18309943 PubMed]<br />
#'''ACCORD 07:''' Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. Epub 2011 Mar 28. [https://ascopubs.org/doi/full/10.1200/JCO.2010.33.0597 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21444866 PubMed]<br />
#Boonstra JJ, Kok TC, Wijnhoven BP, van Heijl M, van Berge Henegouwen MI, Ten Kate FJ, Siersema PD, Dinjens WN, van Lanschot JJ, Tilanus HW, van der Gaast A. Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial. BMC Cancer. 2011 May 19;11:181. [https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-11-181 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123658/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21595951 PubMed]<br />
#'''CROSS:''' van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ, Busch OR, ten Kate FJ, Creemers GJ, Punt CJ, Plukker JT, Verheul HM, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJ, Rozema T, Biermann K, Beukema JC, Piet AH, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A; CROSS Group. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012 May 31;366(22):2074-84. [https://www.nejm.org/doi/full/10.1056/NEJMoa1112088 link to original article] '''contains verified protocol''' [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1112088/suppl_file/nejmoa1112088_appendix.pdf link to appendix with details about administration] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22646630 PubMed]<br />
##'''Update:''' Shapiro J, van Lanschot JJB, Hulshof MCCM, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch ORC, Ten Kate FJW, Creemers GM, Punt CJA, Plukker JTM, Verheul HMW, Bilgen EJS, van Dekken H, van der Sangen MJC, Rozema T, Biermann K, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, Steyerberg EW, van der Gaast A; CROSS study group. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1090-1098. Epub 2015 Aug 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00040-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26254683 PubMed]<br />
#'''FFCD 9901:''' Mariette C, Dahan L, Mornex F, Maillard E, Thomas PA, Meunier B, Boige V, Pezet D, Robb WB, Le Brun-Ly V, Bosset JF, Mabrut JY, Triboulet JP, Bedenne L, Seitz JF. Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901. J Clin Oncol. 2014 Aug 10;32(23):2416-22. Epub 2014 Jun 30. [https://ascopubs.org/doi/full/10.1200/JCO.2013.53.6532 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982463 PubMed]<br />
#'''NEOCRTEC5010:''' Yang H, Liu H, Chen Y, Zhu C, Fang W, Yu Z, Mao W, Xiang J, Han Y, Chen Z, Yang H, Wang J, Pang Q, Zheng X, Yang H, Li T, Lordick F, D'Journo XB, Cerfolio RJ, Korst RJ, Novoa NM, Swanson SJ, Brunelli A, Ismail M, Fernando HC, Zhang X, Li Q, Wang G, Chen B, Mao T, Kong M, Guo X, Lin T, Liu M, Fu J; AME Thoracic Surgery Collaborative Group. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): a phase III multicenter, randomized, open-label clinical trial. J Clin Oncol. 2018 Sep 20;36(27):2796-2803. Epub 2018 Aug 8. [https://ascopubs.org/doi/full/10.1200/JCO.2018.79.1483 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145832/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30089078 PubMed]<br />
<br />
=Definitive therapy=<br />
<br />
==Capecitabine, Cisplatin, RT {{#subobject:dfe688|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CX & RT: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine), '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1, 1250/60/50 {{#subobject:4beb7f|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(13)70136-0/abstract Crosby et al. 2013 (SCOPE-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Capecitabine, Cisplatin, Cetuximab, RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)<br />
|-<br />
|}<br />
''Note: efficacy is based on the 2017 update.''<br />
<br />
''Patients: 25% adenocarcinoma, 73% squamous cell, 2% undifferentiated histology''<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], total of 50 Gy given in 25 fractions with cycles 3 & 4<br />
<br />
'''5-week course'''<br />
<br />
===Variant #2, 1600/30/54 {{#subobject:f7a6c1|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://jjco.oxfordjournals.org/content/37/11/829.long Lee et al. 2007<sub>esoph</sub>]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Patients: 97% adenocarcinoma, 3% squamous cell histology; 3% with ECOG PS of 2.''<br />
<br />
''The study was for patients with stage IV disease.''<br />
<br />
*Patients with M1b disease (visceral metastases) received the chemotherapy only part until progression of disease or unacceptable toxicity.<br />
*Patients with M1a or M1b (non-visceral metastases) received 2 cycles of the chemotherapy only part, underwent treatment with chemoradiation, and then treatment continued with--presumably, but not outright specified in the paper--chemotherapy only until progression of disease or unacceptable toxicity.<br />
<br />
====Preceding treatment====<br />
<br />
*[[#CX|XP]] x 2<br />
<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 5<br />
*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''<br />
<br />
'''7-day cycles until radiation therapy is complete'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], total of 54 Gy given. Dose per fraction and total duration of treatment were not specified, but based on other regimens, it is suspected to be either 1.8 Gy x 30 fractions or 2 Gy x 27 fractions.<br />
<br />
'''One course'''<br />
===References===<br />
<br />
#'''Retrospective:''' Lee SS, Kim SB, Park SI, Kim YH, Ryu JS, Song HY, Shin JH, Jung HY, Lee GH, Choi KD, Cho KJ, Kim JH. Capecitabine and cisplatin chemotherapy (XP) alone or sequentially combined chemoradiotherapy containing XP regimen in patients with three different settings of stage IV esophageal cancer. Jpn J Clin Oncol. 2007 Nov;37(11):829-35. Epub 2007 Oct 19. [http://jjco.oxfordjournals.org/content/37/11/829.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17951334 PubMed]<br />
#'''SCOPE-1:''' Crosby T, Hurt CN, Falk S, Gollins S, Mukherjee S, Staffurth J, Ray R, Bashir N, Bridgewater JA, Geh JI, Cunningham D, Blazeby J, Roy R, Maughan T, Griffiths G. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial. Lancet Oncol. 2013 Jun;14(7):627-37. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70136-0/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23623280 PubMed]<br />
##'''Update:''' Crosby T, Hurt CN, Falk S, Gollins S, Staffurth J, Ray R, Bridgewater JA, Geh JI, Cunningham D, Blazeby J, Roy R, Maughan T, Griffiths G, Mukherjee S. Long-term results and recurrence patterns from SCOPE-1: a phase II/III randomised trial of definitive chemoradiotherapy +/- cetuximab in oesophageal cancer. Br J Cancer. 2017 Mar 14;116(6):709-716. Epub 2017 Feb 14. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355926/ link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355926/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28196063 PubMed]<br />
<br />
==Cisplatin, Docetaxel, RT {{#subobject:21719f|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 />
===Variant #1, 80/60 x 2 {{#subobject:7b3f9c|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.1442-2050.2009.01003.x/full Li et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% squamous cell histology, 5% gastroesophageal junction. 44% of patients had stage IV disease''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 10 mg IV or PO once on day -1, then once on day 1; 30 minutes prior to [[Docetaxel (Taxotere)]], then once on day 2<br />
*[[Diphenhydramine (Benadryl)]] 40 mg IV once on day 1, prior to chemotherapy<br />
*[[Cimetidine (Tagamet)]] 40 mg IV once on day 1, prior to chemotherapy<br />
*[[Granisetron]] 2 mg IV once on day 1, prior to chemotherapy<br />
*1.5 to 2.0 liters fluids before [[Cisplatin (Platinol)]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 to 2.0 Gy fractions, to start within 24 hours of the start of chemotherapy<br />
**Patients with stage I to III disease received a total dose of 60 to 64 Gy over 4 to 6 weeks<br />
**Patients with stage IV disease (lymph node only) received a total dose of 50 to 56 Gy<br />
<br />
''Note, dose reductions were permitted, see article for specifications'' <br />
<br />
'''One course'''<br />
<br />
===Variant #2 {{#subobject:f4800d|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/PMC3031899 Day et al. 2010]<br />
| style="background-color:#ffffbe" |Phase I<br />
|-<br />
|}<br />
''Patients: 46% squamous cell, 54% adenocarcinoma histology'' <br />
<br />
''Note: some guidelines suggest a wider dose range of 20 to 30 mg/m<sup>2</sup> for both cisplatin and docetaxel. The primary reference also investigated these dose levels, but ultimately recommended 30 mg/m<sup>2</sup> dosages for both cisplatin and docetaxel.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29<br />
<br />
====Supportive medications====<br />
<br />
*"Steroid and anti-emetic pre-medication"<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 25 fractions, for a total dose of 50 Gy, to start within 4 hours after the first dose of chemotherapy.<br />
<br />
'''5-week course'''<br />
<br />
===References===<br />
<br />
#Li QQ, Liu MZ, Hu YH, Liu H, He ZY, Lin HX. Definitive concomitant chemoradiotherapy with docetaxel and cisplatin in squamous esophageal carcinoma. Dis Esophagus. 2010 Apr;23(3):253-9. Epub 2009 Aug 28. [https://onlinelibrary.wiley.com/doi/10.1111/j.1442-2050.2009.01003.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19732130 PubMed]<br />
#'''Phase I:''' Day FL, Leong T, Ngan S, Thomas R, Jefford M, Zalcberg JR, Rischin D, McKendick J, Milner AD, Di Iulio J, Matera A, Michael M. Phase I trial of docetaxel, cisplatin and concurrent radical radiotherapy in locally advanced oesophageal cancer. Br J Cancer. 2011 Jan 18;104(2):265-71. Epub 2010 Dec 14. [https://www.nature.com/articles/6606051 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031899/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21157450 PubMed]<br />
<br />
==Cisplatin, Fluorouracil, RT {{#subobject:2b3dbc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CF & RT: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1, 60/4725 x 4 (50 Gy) {{#subobject:4dab7f|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(13)70136-0/abstract Crosby et al. 2013 (SCOPE-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Capecitabine, Cisplatin, Cetuximab, RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)<br />
|-<br />
|}<br />
''Note: This regimen was an alternative for patients who could not swallow pills. Efficacy is based on the 2017 update.''<br />
<br />
''Patients: 25% adenocarcinoma, 73% squamous cell, 2% undifferentiated histology''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 225 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 4725 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], total of 50 Gy given in 25 fractions with cycles 3 & 4<br />
<br />
'''5-week course'''<br />
===Variant #2, 75/4000 x 2 (50.4 Gy) {{#subobject:3272d5|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/20/5/1167.long Minsky et al. 2002 (RTOG 94-05)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin, 5-FU, high-dose RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS24<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70028-2/abstract Conroy et al. 2014 (PRODIGE5/ACCORD17)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]<br />
| style="background-color:#ffffbf" |[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]<br />
|-<br />
|}<br />
''Patients: RTOG 94-05 included both adenocarcinoma and squamous cell histology''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 30 minutes once on day 1<br />
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] as follows:<br />
**RTOG 94-05: 1.8 Gy fractions x 28 fractions, for a total dose of 50.4 Gy<br />
**PRODIGE5/ACCORD17: 2.0 Gy fractions x 25 fractions, for a total dose of 50 Gy<br />
<br />
'''5- to 5.5-week course'''<br />
<br />
====Subsequent treatment====<br />
<br />
*[[#Cisplatin_.26_Fluorouracil_2|CF consolidation]]<br />
<br />
===Variant #3, 75/4000 x 3 (66 Gy) {{#subobject:0d8520|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/25/10/1160.long Bedenne et al. 2007 (FFCD 9102)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|Surgery<br />
| style="background-color:#eeee01" |Equivalent OS<br />
|-<br />
|}<br />
''Patients: 89% epidermoid, 11% glandular histology. Note that this was not a formal non-inferiority study but the study met its primary endpoint of equivalence.''<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin.2C_Fluorouracil.2C_RT|CF & RT]] x 2<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*1 liter NS IV over 2 hours before and after [[Cisplatin (Platinol)]]<br />
<br />
'''21-day cycle for 1 cycle, then 28-day cycle for 2 cycles''' <br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 10 fractions, for a total dose of 66 Gy (including the initial 46 Gy)<br />
**Earlier in the study, some patients instead received split-course radiation therapy<br />
<br />
'''2-week course'''<br />
===Variant #4, 75/4000 x 4 (50 Gy) {{#subobject:ca1b71|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/NEJM199206113262403 Herskovic et al. 1992 (RTOG 85-01)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Radiation_therapy|Radiation therapy]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Patients: 88% squamous cell, 12% adenocarcinoma histology. 7% karnofsky performance scale of 50-60.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycle for 1 cycle, then 21-day cycle for 3 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 2.0 Gy fractions x 15 fractions, then 2.0 Gy fractions x 10 fractions to the initial tumor length plus a 5 cm margin, for a total dose of 50.0 Gy<br />
<br />
'''5-week course'''<br />
===References===<br />
<br />
#'''RTOG 85-01:''' Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, Cooper J, Byhardt R, Davis L, Emami B. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med. 1992 Jun 11;326(24):1593-8. [https://www.nejm.org/doi/full/10.1056/NEJM199206113262403 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1584260 PubMed]<br />
##'''Update:''' al-Sarraf M, Martz K, Herskovic A, Leichman L, Brindle JS, Vaitkevicius VK, Cooper J, Byhardt R, Davis L, Emami B. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol. 1997 Jan;15(1):277-84. [http://jco.ascopubs.org/content/15/1/277.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8996153 PubMed]<br />
##'''Update:''' Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr, Al-Sarraf M, Byhardt R, Russell AH, Beitler JJ, Spencer S, Asbell SO, Graham MV, Leichman LL; Radiation Therapy Oncology Group. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). JAMA. 1999 May 5;281(17):1623-7. [http://jama.jamanetwork.com/article.aspx?articleid=189737 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10235156 PubMed]<br />
#'''RTOG 94-05:''' Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, Okawara G, Rosenthal SA, Kelsen DP. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol. 2002 Mar 1;20(5):1167-74. [http://jco.ascopubs.org/content/20/5/1167.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11870157 PubMed]<br />
#'''FFCD 9102:''' Bedenne L, Michel P, Bouché O, Milan C, Mariette C, Conroy T, Pezet D, Roullet B, Seitz JF, Herr JP, Paillot B, Arveux P, Bonnetain F, Binquet C. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007 Apr 1;25(10):1160-8. [http://jco.ascopubs.org/content/25/10/1160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17401004 PubMed]<br />
#'''SCOPE-1:''' Crosby T, Hurt CN, Falk S, Gollins S, Mukherjee S, Staffurth J, Ray R, Bashir N, Bridgewater JA, Geh JI, Cunningham D, Blazeby J, Roy R, Maughan T, Griffiths G. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial. Lancet Oncol. 2013 Jun;14(7):627-37. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70136-0/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23623280 PubMed]<br />
##'''Update:''' Crosby T, Hurt CN, Falk S, Gollins S, Staffurth J, Ray R, Bridgewater JA, Geh JI, Cunningham D, Blazeby J, Roy R, Maughan T, Griffiths G, Mukherjee S. Long-term results and recurrence patterns from SCOPE-1: a phase II/III randomised trial of definitive chemoradiotherapy +/- cetuximab in oesophageal cancer. Br J Cancer. 2017 Mar 14;116(6):709-716. Epub 2017 Feb 14. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355926/ link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355926/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28196063 PubMed]<br />
#'''PRODIGE5/ACCORD17:''' Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70028-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24556041 PubMed]<br />
##'''HRQoL analysis:''' Bascoul-Mollevi C, Gourgou S, Galais MP, Raoul JL, Bouché O, Douillard JY, Adenis A, Etienne PL, Juzyna B, Bedenne L, Conroy T. Health-related quality of life results from the PRODIGE 5/ACCORD 17 randomised trial of FOLFOX versus fluorouracil-cisplatin regimen in oesophageal cancer. Eur J Cancer. 2017 Oct;84:239-249. Epub 2017 Aug 19. [https://www.ejcancer.com/article/S0959-8049(17)31158-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28829992 PubMed]<br />
<br />
==Cisplatin, Paclitaxel, RT {{#subobject:5ef1ea|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TP & RT: '''<u>T</u>'''axol (Paclitaxel), '''<u>P</u>'''latinol (Cisplatin), '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1, weekly {{#subobject:8f0c89|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://jamanetwork.com/journals/jamaoncology/fullarticle/2643119 Suntharalingam et al. 2017 (RTOG 0436)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin, Paclitaxel, Cetuximab, RT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
Patients: 62% ''adenocarcinoma, 38% squamous cell histology. 14% with M1a disease. 6% with Zubrod PS score 2.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29<br />
*[[Paclitaxel (Taxol)]] 50 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]], 1.8 Gy fractions x 28 fractions, for a total dose of 50.4 Gy<br />
<br />
'''5-week course'''<br />
<br />
===Variant #2, q3wk {{#subobject:898c89|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.ejcancer.com/article/S0959-8049(18)30119-9/fulltext Wu et al. 2018]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin, Paclitaxel, Erlotinib, ENI<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 3<br />
*[[Paclitaxel (Taxol)]] 135 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''28-day cycle for 2 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]]<br />
<br />
===References===<br />
<br />
#'''RTOG 0436:''' Suntharalingam M, Winter K, Ilson D, Dicker AP, Kachnic L, Konski A, Chakravarthy AB, Anker CJ, Thakrar H, Horiba N, Dubey A, Greenberger JS, Raben A, Giguere J, Roof K, Videtic G, Pollock J, Safran H, Crane CH. Effect of the addition of cetuximab to paclitaxel, cisplatin, and radiation therapy for patients with esophageal cancer: The NRG Oncology RTOG 0436 phase 3 randomized clinical trial. JAMA Oncol. 2017 Nov 1;3(11):1520-1528. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2643119 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28687830 PubMed]<br />
#Wu SX, Wang LH, Luo HL, Xie CY, Zhang XB, Hu W, Zheng AP, Li DJ, Zhang HY, Xie CH, Lian XL, Du DX, Chen M, Bian XH, Tan BX, Jiang H, Zhang HB, Wang JH, Jing Z, Xia B, Zhang N, Zhang P, Li WF, Zhao FJ, Tian ZF, Liu H, Huang KW, Hu J, Xie RF, Du L, Li G. Randomised phase III trial of concurrent chemoradiotherapy with extended nodal irradiation and erlotinib in patients with inoperable oesophageal squamous cell cancer. Eur J Cancer. 2018 Apr;93:99-107. Epub 2018 Mar 20. [https://www.ejcancer.com/article/S0959-8049(18)30119-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29494818 PubMed]<br />
<br />
==FOLFOX4 & RT {{#subobject:1f91c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX4 & RT: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:e2fc30|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(14)70028-2/abstract Conroy et al. 2014 (PRODIGE5/ACCORD17)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]<br />
| style="background-color:#ffffbf" |[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]<br />
|-<br />
|}<br />
''Note: In contrast to the original reference, some guidelines list the dosage of leucovorin as 400 mg/m<sup>2</sup>. Despite being a non-superior experimental arm, this regimen is recommended by some guidelines such as ESMO.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1600 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''14-day cycle for 3 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 25 fractions, for a total dose of 50 Gy<br />
<br />
'''5-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[#FOLFOX4|FOLFOX4]] x 3<br />
<br />
===References===<br />
<br />
#'''PRODIGE5/ACCORD17:''' Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70028-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24556041 PubMed]<br />
##'''HRQoL analysis:''' Bascoul-Mollevi C, Gourgou S, Galais MP, Raoul JL, Bouché O, Douillard JY, Adenis A, Etienne PL, Juzyna B, Bedenne L, Conroy T. Health-related quality of life results from the PRODIGE 5/ACCORD 17 randomised trial of FOLFOX versus fluorouracil-cisplatin regimen in oesophageal cancer. Eur J Cancer. 2017 Oct;84:239-249. Epub 2017 Aug 19. [https://www.ejcancer.com/article/S0959-8049(17)31158-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28829992 PubMed]<br />
<br />
==Fluorouracil, Paclitaxel, RT {{#subobject:52e768|Regimen=1}}==<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://ascopubs.org/doi/full/10.1200/JCO.18.02122 Chen et al. 2019]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Esophageal_cancer#Cisplatin.2C_Fluorouracil.2C_RT_2%7C|Cisplatin, Flourouracil, RT]]<br />
| style="background-color:#eeee01" |Equivalent OS<br />
|-<br />
|}<br />
''Inclusion criteria: Esophageal SCC, stage IIA-IVA (AJCC 6th edition), ECOG 0-2, previously untreated''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1200 mg/m<sup>2</sup>)<br />
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycle for 5 cycles'''<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 34 fractions, for a total dose of 61.2 Gy<br />
<br />
'''7-week course'''<br />
====Subsequent treatment====<br />
<br />
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 1800 mg/m<sup>2</sup>)<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''28-day cycle for 2 cycles'''<br />
<br />
===References===<br />
<br />
#Chen Y, Ye J, Zhu Z, Zhao W, Zhou J, Wu C, Tang H, Fan M, Li L, Lin Q, Xia Y, Li Y, Li J, Jia H, Lu S, Zhang Z, Zhao K. Comparing Paclitaxel Plus Fluorouracil Versus Cisplatin Plus Fluorouracil in Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Cancer: A Randomized, Multicenter, Phase III Clinical Trial. J Clin Oncol. 2019 Jul 10;37(20):1695-1703. Epub 2019 Mar 28. [https://ascopubs.org/action/showCitFormats?doi=10.1200/JCO.18.02122 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30920880 PubMed]<br />
<br />
==Radiation therapy==<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.nejm.org/doi/full/10.1056/NEJM199206113262403 Herskovic et al. 1992 (RTOG 85-01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin.2C_Fluorouracil.2C_RT_2|Cisplatin, 5-FU, RT]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Patients: 88% squamous cell, 12% adenocarcinoma histology. 7% Karnofsky performance scale of 50-60''<br />
<br />
''Radiation as primary therapy; used as a comparator arm and here for reference purposes only.''<br />
====Radiotherapy====<br />
<br />
*[[External beam radiotherapy]] total of 32 fractions in 6.4 weeks: 50 Gy of regional treatment and 14 Gy to the boost field, for total dose of 64 Gy<br />
<br />
===References===<br />
<br />
#'''RTOG 85-01:''' Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, Cooper J, Byhardt R, Davis L, Emami B. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med. 1992 Jun 11;326(24):1593-8. [https://www.nejm.org/doi/full/10.1056/NEJM199206113262403 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1584260 PubMed]<br />
##'''Update:''' al-Sarraf M, Martz K, Herskovic A, Leichman L, Brindle JS, Vaitkevicius VK, Cooper J, Byhardt R, Davis L, Emami B. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol. 1997 Jan;15(1):277-84. [http://jco.ascopubs.org/content/15/1/277.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8996153 PubMed]<br />
##'''Update:''' Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr, Al-Sarraf M, Byhardt R, Russell AH, Beitler JJ, Spencer S, Asbell SO, Graham MV, Leichman LL; Radiation Therapy Oncology Group. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). JAMA. 1999 May 5;281(17):1623-7. [http://jama.jamanetwork.com/article.aspx?articleid=189737 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10235156 PubMed]<br />
<br />
=Consolidation after definitive therapy=<br />
==Cisplatin & Fluorouracil {{#subobject:cf23a6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CF: '''<u>C</u>'''isplatin & '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:ade242|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/20/5/1167.long Minsky et al. 2002 (RTOG 94-05)]<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(14)70028-2/abstract Conroy et al. 2014 (PRODIGE5/ACCORD17)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]<br />
| style="background-color:#ffffbf" |[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]<br />
|-<br />
|}<br />
''Patients: study included both adenocarcinoma and squamous cell histology''<br />
====Preceding treatment====<br />
<br />
*RTOG 94-05: [[#Cisplatin.2C_Fluorouracil.2C_RT_2|Definitive CF & RT]] versus definitive CF & high-dose RT<br />
*PRODIGE5/ACCORD17: [[#Cisplatin.2C_Fluorouracil.2C_RT_2|Definitive CF & RT]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 30 minutes once on day 1<br />
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycle for 2 cycles'''<br />
<br />
===References===<br />
<br />
#'''RTOG 94-05:''' Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, Okawara G, Rosenthal SA, Kelsen DP. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol. 2002 Mar 1;20(5):1167-74. [http://jco.ascopubs.org/content/20/5/1167.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11870157 PubMed]<br />
#'''PRODIGE5/ACCORD17:''' Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70028-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24556041 PubMed]<br />
##'''HRQoL analysis:''' Bascoul-Mollevi C, Gourgou S, Galais MP, Raoul JL, Bouché O, Douillard JY, Adenis A, Etienne PL, Juzyna B, Bedenne L, Conroy T. Health-related quality of life results from the PRODIGE 5/ACCORD 17 randomised trial of FOLFOX versus fluorouracil-cisplatin regimen in oesophageal cancer. Eur J Cancer. 2017 Oct;84:239-249. Epub 2017 Aug 19. [https://www.ejcancer.com/article/S0959-8049(17)31158-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28829992 PubMed]<br />
<br />
==FOLFOX4 {{#subobject:a8048e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin 4<br />
===Regimen {{#subobject:f200f1|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(14)70028-2/abstract Conroy et al. 2014 (PRODIGE5/ACCORD17)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]<br />
| style="background-color:#ffffbf" |[[Complex_multipart_regimens#PRODIGE5.2FACCORD17|See link]]<br />
|-<br />
|}<br />
''Note: In contrast to the original reference, some guidelines list the dosage of leucovorin as 400 mg/m<sup>2</sup>. Despite being a non-superior experimental arm, this regimen is recommended by some guidelines such as ESMO.''<br />
====Preceding treatment====<br />
<br />
*[[#FOLFOX4_.26_RT|FOLFOX4 & RT]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1600 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''14-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''PRODIGE5/ACCORD17:''' Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70028-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24556041 PubMed]<br />
##'''HRQoL analysis:''' Bascoul-Mollevi C, Gourgou S, Galais MP, Raoul JL, Bouché O, Douillard JY, Adenis A, Etienne PL, Juzyna B, Bedenne L, Conroy T. Health-related quality of life results from the PRODIGE 5/ACCORD 17 randomised trial of FOLFOX versus fluorouracil-cisplatin regimen in oesophageal cancer. Eur J Cancer. 2017 Oct;84:239-249. Epub 2017 Aug 19. [https://www.ejcancer.com/article/S0959-8049(17)31158-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28829992 PubMed]<br />
<br />
=Adjuvant therapy=<br />
==FULV/FULV & RT {{#subobject:f6b345|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FULV/FULV & RT: '''<u>F</u>'''luoro'''<u>U</u>'''racil & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid) alternating with '''<u>F</u>'''luoro'''<u>U</u>'''racil, '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid) & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:5cd826|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/NEJMoa010187 Macdonald et al. 2001 (INT-0116)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Esophageal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy, part 1====<br />
<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5 (total dose per cycle: 2125 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
<br />
'''28-day cycle, followed by:'''<br />
<br />
====Chemotherapy, part 2====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 4 and the last 3 days of radiation therapy<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 1.8 Gy x 25 fractions for a total of 45 Gy<br />
<br />
'''35-day course, followed by:'''<br />
<br />
====Chemotherapy, part 3, to start one month after the completion of radiotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5 (total dose per cycle 2125 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
<br />
'''28-day cycle for 2 cycles'''<br />
<br />
===Variant #2 {{#subobject:c3cc1c|Variant=1}}===<br />
''Note: No primary reference could be found for this regimen.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Esophageal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus on EITHER days 1 & 15 OR days 1, 2, 15, 16<br />
*[[Fluorouracil (5-FU)]] 1200 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on days 1, 2, 15, 16 (total dose per cycle: 4800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV on EITHER days 1 & 15 OR days 1, 2, 15, 16<br />
<br />
'''28-day cycle for 3 total cycles (1 cycle given before radiation, and 2 cycles to be given after radiation)'''<br />
<br />
===References===<br />
<br />
#'''INT-0116:''' Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6;345(10):725-30. [https://www.nejm.org/doi/full/10.1056/NEJMoa010187 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11547741 PubMed]<br />
<br />
==Cisplatin & Fluorouracil {{#subobject:e35a6c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CF: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
<br>FP: '''<u>F</u>'''luorouracil, '''<u>P</u>'''latinol<br />
===Variant #1, 75/5000 {{#subobject:fc3c70|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/NEJM199812313392704 Kelsen et al. 1998 (RTOG 8911)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<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. 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 />
<br />
*[[#Cisplatin_.26_Fluorouracil|Neoadjuvant CF]], then [[Surgery#Esophageal_cancer_surgery|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: see note)<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===Variant #2, 80/4000 {{#subobject:e4f654|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://ascopubs.org/doi/full/10.1200/JCO.2003.12.095 Ando et al. 2003 (JCOG 9204)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior DFS<br />
|-<br />
|[https://link.springer.com/article/10.1245%2Fs10434-011-2049-9 Ando et al. 2011 (JCOG 9907)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Fluorouracil|Neoadjuvant CF]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Esophageal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle for 2 cycles'''<br />
<br />
===Variant #3, 100/4000 {{#subobject:d61794|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://ascopubs.org/doi/full/10.1200/JCO.2010.33.0597 Ychou et al. 2011 (ACCORD 07)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''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 />
<br />
''Patients: 100% adenocarcinoma histology (65% gastroesophageal junction, 10% lower esophageal, 25% gastric adenocarcinoma)'' <br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin_.26_Fluorouracil|Neoadjuvant CF]], then [[Surgery#Esophageal_cancer_surgery|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
'''28-day cycle for 3 to 4 cycles for a total of 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''RTOG 8911:''' Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med. 1998 Dec 31;339(27):1979-84. [https://www.nejm.org/doi/full/10.1056/NEJM199812313392704 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9869669 PubMed]<br />
#'''JCOG 9204:''' Ando N, Iizuka T, Ide H, Ishida K, Shinoda M, Nishimaki T, Takiyama W, Watanabe H, Isono K, Aoyama N, Makuuchi H, Tanaka O, Yamana H, Ikeuchi S, Kabuto T, Nagai K, Shimada Y, Kinjo Y, Fukuda H; Japan Clinical Oncology Group. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study--JCOG9204. J Clin Oncol. 2003 Dec 15;21(24):4592-6. [https://ascopubs.org/doi/full/10.1200/JCO.2003.12.095 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14673047 PubMed]<br />
#'''ACCORD 07:''' Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. Epub 2011 Mar 28. [https://ascopubs.org/doi/full/10.1200/JCO.2010.33.0597 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21444866 PubMed]<br />
#'''JCOG 9907:''' Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, Nakamura T, Yabusaki H, Aoyama N, Kurita A, Ikeda K, Kanda T, Tsujinaka T, Nakamura K, Fukuda H. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012 Jan;19(1):68-74. Epub 2011 Aug 31. [https://link.springer.com/article/10.1245%2Fs10434-011-2049-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21879261 PubMed]<br />
<br />
==Cisplatin & Irinotecan {{#subobject:308dd0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===Regimen {{#subobject:507e9f|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/PMC3563156/ Yoon et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma of the esophagus or gastroesophageal junction (tumor extension < 2cm into gastric cardia)''<br />
<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin.2C_Irinotecan.2C_RT|Neoadjuvant cisplatin, irinotecan, RT]], then [[Surgery#Esophageal_cancer_surgery|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Irinotecan (Camptosar)]] 65 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 />
#Yoon HH, Catalano P, Gibson MK, Skaar TC, Philips S, Montgomery EA, Hafez MJ, Powell M, Liu G, Forastiere AA, Benson AB, Kleinberg LR, Murphy KM. Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group. Cancer Chemother Pharmacol. 2011 Oct;68(4):863-70. Epub 2011 Feb 1. [http://www.springerlink.com/content/v4g0257025185531/ link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563156/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21286719 PubMed]<br />
<br />
==Cisplatin & Paclitaxel {{#subobject:b40afb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===Regimen {{#subobject:c15e56|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/PMC3563156/ Yoon et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma of the esophagus or gastroesophageal junction (tumor extension < 2cm into gastric cardia)''<br />
<br />
====Preceding treatment====<br />
<br />
*[[#Cisplatin.2C_Paclitaxel.2C_RT|Neoadjuvant cisplatin, paclitaxel, RT]], then [[Surgery#Esophageal_cancer_surgery|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 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 3 cycles'''<br />
<br />
===References===<br />
<br />
#Yoon HH, Catalano P, Gibson MK, Skaar TC, Philips S, Montgomery EA, Hafez MJ, Powell M, Liu G, Forastiere AA, Benson AB, Kleinberg LR, Murphy KM. Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group. Cancer Chemother Pharmacol. 2011 Oct;68(4):863-70. Epub 2011 Feb 1. [http://www.springerlink.com/content/v4g0257025185531/ link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563156/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21286719 PubMed]<br />
<br />
==ECF {{#subobject:87a09a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:d40982|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/NEJMoa055531 Cunningham et al. 2006 (MAGIC)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Complex_multipart_regimens#MAGIC|See link]]<br />
|[[Complex_multipart_regimens#MAGIC|See link]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2017.35.15_suppl.4004 Al-Batran et al. 2017 (FLOT4-AIO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
|[[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
|-<br />
|}<br />
''This is the adjuvant portion of pre-planned perioperative chemotherapy.''<br />
<br />
''Cunningham et al. Patients: 100% adenocarcinoma histology (75% gastric adenocarcinoma, 15% lower esophagus, 11% gastroesophageal junction).''<br />
<br />
''Al-Batran et. al Patients: 100% adenocarcinoma histology of the gastroesophageal junction (AEG I-III) or the stomach.''<br />
<br />
====Preceding treatment====<br />
<br />
*[[#ECF|Neoadjuvant ECF]] x 3, then [[Surgery#Esophageal_cancer_surgery|surgery]]<br />
<br />
====Chemotherapy, to start 6 to 12 weeks after surgery====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*MAGIC: [[Warfarin (Coumadin)]] 1 mg PO once per day recommended for thrombosis prophylaxis<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''MAGIC:''' Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa055531 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16822992 PubMed]<br />
#'''Abstract:''' Salah-Eddin Al-Batran, Nils Homann, Harald Schmalenberg, Hans-Georg Kopp, Georg Martin Haag, Kim Barbara Luley, Wolff H. Schmiegel, Gunnar Folprecht, Stephan Probst, Nicole Prasnikar, Peter C. Thuss-Patience, Wolfgang Fischbach, Jorg Trojan, Michael Koenigsmann, Claudia Pauligk, Thorsten Oliver Goetze, Elke Jaeger, Johannes Meiler, Martin H. Schuler, and Ralf Hofheinz. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial. Journal of Clinical Oncology 2017 35:15_suppl, 4004-4004 [https://ascopubs.org/doi/full/10.1200/JCO.2017.35.15_suppl.4004 link to abstract]<br />
<br />
==ECF/5-FU & RT {{#subobject:7f3e93|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECF/5-FU & RT: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil alternating with '''<u>5</u>'''-'''<u>F</u>'''luoro'''<u>U</u>'''racil & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:53c380|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.redjournal.org/article/S0360-3016(09)03613-X/abstract Leong et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: In contrast to the primary reference, some guidelines list this regimen without ECF cycles 1, 3, 4.''<br />
<br />
''Patients: 100% adenocarcinoma (6% gastroesophageal junction, 94% gastric origin).''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Esophageal_cancer_surgery|Surgery]], within 10 weeks<br />
<br />
====Chemotherapy, part 1====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose: 4200 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle, followed 1 to 3 weeks later by:'''<br />
<br />
====Chemotherapy, part 2====<br />
<br />
*[[Fluorouracil (5-FU)]] 225 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose: 7875 mg/m<sup>2</sup>)<br />
<br />
====Radiotherapy====<br />
<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions for a total dose of 45 Gy<br />
<br />
'''5-week course, followed 1 month later by:'''<br />
<br />
====Chemotherapy, part 3====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycle for 2 cycles'''<br />
<br />
===References===<br />
<br />
#Leong T, Joon DL, Willis D, Jayamoham J, Spry N, Harvey J, Di Iulio J, Milner A, Mann GB, Michael M. Adjuvant chemoradiation for gastric cancer using epirubicin, cisplatin, and 5-fluorouracil before and after three-dimensional conformal radiotherapy with concurrent infusional 5-fluorouracil: a multicenter study of the Trans-Tasman Radiation Oncology Group. Int J Radiat Oncol Biol Phys. 2011 Mar 1;79(3):690-5. Epub 2010 May 14. [http://www.redjournal.org/article/S0360-3016(09)03613-X/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20472363 PubMed]<br />
<br />
==ECX {{#subobject:c8ab0e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECX: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:27f848|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(17)30043-8/fulltext Cunningham et al. 2017 (UK MRC ST03)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|ECX & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2017.35.15_suppl.4004 Al-Batran et al. 2017 (FLOT4-AIO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
|[[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
|-<br />
|}<br />
''This is the adjuvant portion of pre-planned perioperative chemotherapy.''<br />
<br />
''Cunningham et al. Patients: 100% adenocarcinoma histology (36% gastric, 14% lower esophageal, 50% gastroesophageal junction).''<br />
<br />
''Al-Batran et al.'' ''Patients: 100% adenocarcinoma histology including gastroesophageal junction (AEG I-III) or the stomach.''<br />
<br />
====Preceding treatment====<br />
<br />
*[[#ECX|Neoadjuvant ECX]] x 3, then [[Surgery#Esophageal_cancer_surgery|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21<br />
<br />
'''21-day cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''UK MRC ST03:''' Cunningham D, Stenning SP, Smyth EC, Okines AF, Allum WH, Rowley S, Stevenson L, Grabsch HI, Alderson D, Crosby T, Griffin SM, Mansoor W, Coxon FY, Falk SJ, Darby S, Sumpter KA, Blazeby JM, Langley RE. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial. Lancet Oncol. 2017 Mar;18(3):357-370. Epub 2017 Feb 3. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30043-8/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337626/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28163000 PubMed]<br />
#'''Abstract:''' Salah-Eddin Al-Batran, Nils Homann, Harald Schmalenberg, Hans-Georg Kopp, Georg Martin Haag, Kim Barbara Luley, Wolff H. Schmiegel, Gunnar Folprecht, Stephan Probst, Nicole Prasnikar, Peter C. Thuss-Patience, Wolfgang Fischbach, Jorg Trojan, Michael Koenigsmann, Claudia Pauligk, Thorsten Oliver Goetze, Elke Jaeger, Johannes Meiler, Martin H. Schuler, and Ralf Hofheinz. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial. Journal of Clinical Oncology 2017 35:15_suppl, 4004-4004 [https://ascopubs.org/doi/full/10.1200/JCO.2017.35.15_suppl.4004 link to abstract]<br />
<br />
==FLOT {{#subobject:3ad093|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FLOT: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>O</u>'''xaliplatin, '''<u>T</u>'''axotere (Docetaxel)<br />
===Regimen {{#subobject:e6d646|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://ascopubs.org/doi/full/10.1200/JCO.2017.35.15_suppl.4004 Al-Batran et al. 2017 (FLOT4-AIO)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
| style="background-color:#91cf60" |[[Complex_multipart_regimens#FLOT4-AIO|See link]]<br />
|-<br />
|}<br />
''This is the adjuvant portion of pre-planned perioperative chemotherapy.''<br />
<br />
''Patients: 100% adenocarcinoma histology including gastroesophageal junction (AEG I-III) or the stomach.''<br />
====Preceding treatment====<br />
<br />
*[[#FLOT|Neoadjuvant FLOT]] x 4, then [[Surgery#Esophageal_cancer_surgery|surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
*[[Docetaxel (Taxotere)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<br />
#'''Abstract:''' Salah-Eddin Al-Batran, Nils Homann, Harald Schmalenberg, Hans-Georg Kopp, Georg Martin Haag, Kim Barbara Luley, Wolff H. Schmiegel, Gunnar Folprecht, Stephan Probst, Nicole Prasnikar, Peter C. Thuss-Patience, Wolfgang Fischbach, Jorg Trojan, Michael Koenigsmann, Claudia Pauligk, Thorsten Oliver Goetze, Elke Jaeger, Johannes Meiler, Martin H. Schuler, and Ralf Hofheinz. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial. Journal of Clinical Oncology 2017 35:15_suppl, 4004-4004 [https://ascopubs.org/doi/full/10.1200/JCO.2017.35.15_suppl.4004 link to abstract]<br />
<br />
==Observation==<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 />
|[https://www.jtcvs.org/article/S0022-5223(97)70146-6/fulltext Ando et al. 1997 (JCOG8806)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Cisplatin & Vindesine<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS60<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa010187 Macdonald et al. 2001 (INT-0116)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FULV.2FFULV_.26_RT|FULV/FULV & RT]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2003.12.095 Ando et al. 2003 (JCOG 9204)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Fluorouracil_3|CF]]<br />
| style="background-color:#fc8d59" |Seems to have inferior DFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa055531 Cunningham et al. 2006 (MAGIC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#MAGIC|Perioperative ECF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2010.33.0597 Ychou et al. 2011 (ACCORD 07)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#ACCORD_07|Perioperative CF]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Surgery as primary therapy; i.e., no induction chemotherapy or chemoradiotherapy, and no adjuvant therapy.''<br />
<br />
''McDonald et al. patients: 100% adenocarcinoma histology, originating from the stomach or gastroesophageal junction.'' <br />
''MAGIC patients: 100% adenocarcinoma of the stomach or lower third of the esophagus. 74% gastric, 15% lower esophagus, 11% gastroesophageal junction.''<br />
<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Esophageal_cancer_surgery|Surgery]]<br />
<br />
===References===<br />
<br />
#'''JCOG8806:''' Ando N, Iizuka T, Kakegawa T, Isono K, Watanabe H, Ide H, Tanaka O, Shinoda M, Takiyama W, Arimori M, Ishida K, Tsugane S. A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: the Japan Clinical Oncology Group Study. J Thorac Cardiovasc Surg. 1997 Aug;114(2):205-9. [https://www.jtcvs.org/article/S0022-5223(97)70146-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9270637 PubMed]<br />
#'''INT-0116:''' Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6;345(10):725-30. [https://www.nejm.org/doi/full/10.1056/NEJMoa010187 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11547741 PubMed]<br />
#'''JCOG 9204:''' Ando N, Iizuka T, Ide H, Ishida K, Shinoda M, Nishimaki T, Takiyama W, Watanabe H, Isono K, Aoyama N, Makuuchi H, Tanaka O, Yamana H, Ikeuchi S, Kabuto T, Nagai K, Shimada Y, Kinjo Y, Fukuda H; Japan Clinical Oncology Group. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study--JCOG9204. J Clin Oncol. 2003 Dec 15;21(24):4592-6. [https://ascopubs.org/doi/full/10.1200/JCO.2003.12.095 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14673047 PubMed]<br />
#'''MAGIC:''' Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa055531 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16822992 PubMed]<br />
#'''ACCORD 07:''' Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. Epub 2011 Mar 28. [https://ascopubs.org/doi/full/10.1200/JCO.2010.33.0597 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21444866 PubMed]<br />
<br />
=Metastatic or locally advanced disease, first-line=<br />
==CapeOx {{#subobject:c699c3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
CapeOx: '''<u>Cape</u>'''citabine and '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:d1aac0|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://ascopubs.org/doi/full/10.1200/JCO.2015.62.6598 Hecht et al. 2015 (LOGiC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CapeOx & Lapatinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''100% adenocarcinoma histology (4% esophagus, 9% gastroesophageal junction, 87% gastric origin). 9% with ECOG PS of 2.'' <br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 850 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for up to 8 cycles'''<br />
<br />
===References===<br />
<br />
#'''LOGiC:''' Hecht JR, Bang YJ, Qin SK, Chung HC, Xu JM, Park JO, Jeziorski K, Shparyk Y, Hoff PM, Sobrero A, Salman P, Li J, Protsenko SA, Wainberg ZA, Buyse M, Afenjar K, Houé V, Garcia A, Kaneko T, Huang Y, Khan-Wasti S, Santillana S, Press MF, Slamon D. Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC--a randomized phase III trial. J Clin Oncol. 2016 Feb 10;34(5):443-51. Epub 2015 Nov 30. [https://ascopubs.org/doi/full/10.1200/JCO.2015.62.6598 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26628478 PubMed]<br />
<br />
==CAPIRI {{#subobject:c701c3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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CapeIRI: '''<u>Cape</u>'''citabine and '''<u>IRI</u>'''notecan<br />
<br>CAPIRI: '''<u>CAP</u>'''ecitabine and '''<u>IRI</u>'''notecan<br />
<br>XELIRI: '''<u>XEL</u>'''ox (Capecitabine) and '''<u>IRI</u>'''notecan<br />
<br>XI: '''<u>X</u>'''eloda (Capecitabine) and '''<u>I</u>'''rinotecan<br />
===Regimen {{#subobject:d62c90|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://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mdp269 Moehler et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#CX_2|XP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
''Patients: 45% esophageal, 38% gastroesophageal junction, 17% gastric origin. 93% adenocarcinoma, 7% squamous cell histology. 86% metastatic disease. 14% ECOG PS of 2.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[Atropine (Atropen)]] 0.25 mg SC once on day 1, given before [[Irinotecan (Camptosar)]]<br />
*[[Loperamide (Imodium)]] 4 mg PO prn first unformed stool, then 2 mg PO Q2H x at least 12 hours, or for 12 hours after last liquid stool<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day prn diarrhea lasting longer than 24 hours despite loperamide<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#Moehler M, Kanzler S, Geissler M, Raedle J, Ebert MP, Daum S, Flieger D, Seufferlein T, Galle PR, Hoehler T; Arbeitsgemeinschaft Internistische Onkologie. A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2010 Jan;21(1):71-7. Epub 2009 Jul 15. [https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mdp269 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19605504 PubMed]<br />
<br />
==Carboplatin & Paclitaxel {{#subobject:4df570|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===Regimen {{#subobject:9725d8|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/9427274 Philip et al. 1997]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: In contrast to the original reference, some guidelines list the dosage of carboplatin as AUC 6.''<br />
<br />
''Philip et al. Patients: locally advanced metastatic or recurrent esophageal or gastric cancer'' <br />
====Chemotherapy====<br />
<br />
*[[Carboplatin (Paraplatin)]] AUC 5 IV 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 cycles'''<br />
<br />
===References===<br />
<br />
#Philip PA, Zalupski MM, Gadgeel S, Hussain M, Shields A. A phase II study of carboplatin and paclitaxel in the treatment of patients with advanced esophageal and gastric cancer. Semin Oncol. 1997 Dec;24(6 Suppl 19):S19-86-S19-88. '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9427274 PubMed]<br />
<br />
==Cisplatin & Docetaxel {{#subobject:724868|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
DC: '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin<br />
<br>TC: '''<u>T</u>'''axotere (Docetaxel), '''<u>C</u>'''isplatin<br />
===Regimen {{#subobject:6adc30|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.springerlink.com/content/e131402311p276x0/ Kim et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% squamous cell histology. 5% with ECOG PS of 2.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Docetaxel (Taxotere)]] 70 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given 3 hours before cisplatin'''<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 8 mg PO twice per day x 1 day, starting 1 day before [[Docetaxel (Taxotere)]] administration<br />
*At least 3 liters hydration (with mannitol, magnesium, and potassium chloride)<br />
*"Antiemetic treatment"<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Kim JY, Do YR, Park KU, Kim MK, Lee KH, Bae SH, Ryoo HM, Baek JH, Song HS. A multi-center phase II study of docetaxel plus cisplatin as first-line therapy in patients with metastatic squamous cell esophageal cancer. Cancer Chemother Pharmacol. 2010 May;66(1):31-6. Epub 2009 Sep 18. [http://www.springerlink.com/content/e131402311p276x0/ link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19763571 PubMed]<br />
<br />
==Cisplatin & Fluorouracil {{#subobject:4d9936|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
CF: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
<br>FP: '''<u>F</u>'''luorouracil, '''<u>P</u>'''latinol<br />
===Variant #1 {{#subobject:10f0c6|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/24/31/4991.long Van Cutsem et al. 2006 (TAX 325)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#DCF|DCF]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://annonc.oxfordjournals.org/content/19/8/1450.long Dank et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRI|IF]]<br />
| style="background-color:#fee08b" |Might have inferior TTP<br />
|-<br />
|}<br />
''Van Cutsem et al Patients: 100% adenocarcinoma histology (22% gastroesophageal junction, 88% gastric origin). 97% with metastatic disease. 1% with Karnosky PS of 70.'' <br />
<br />
''Dank et al Patients: 100% adenocarcinoma histology (20% gastroesophageal junction, 80% gastric origin). 96% with metastatic disease. 1% with Karnofsky PS of 70.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 1 to 3 hours once on day 1, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1, '''given second''' (total dose per cycle: 5000 mg/m<sup>2</sup> )<br />
<br />
====Supportive medications====<br />
<br />
*As described in Dank et al. 2008:<br />
*"Hyperhydration" for 2 to 3 days with each infusion<br />
*[[Ondansetron (Zofran)]] IV for antiemetic prophylaxis<br />
*[[Dexamethasone (Decadron)]] IV for antiemetic prophylaxis, then PO for 2 to 3 days<br />
*[[Metoclopramide (Reglan)]] for antiemetic prophylaxis<br />
*[[Filgrastim (Neupogen)]] (dose not specified) SC once per day, starting on day 4, to be continued until ANC greater than 1000/uL for grade 3 to 4 neutropenia, febrile neutropenia, or neutropenic infection<br />
*[[Atropine (Atropen)]] prn cholinergic symptoms<br />
*[[Loperamide (Imodium)]] prn delayed diarrhea<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:fe6c13|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://annonc.oxfordjournals.org/content/20/10/1667.long Lorenzen et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Cisplatin.2C_Fluorouracil.2C_Cetuximab|CF & Cetuximab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
''Patients: 100% squamous cell histology. 87% with metastatic disease. No patients with ECOG PS greater than 1.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1, '''given second''' (total dose per cycle: 5000 mg/m<sup>2</sup> )<br />
<br />
====Supportive medications====<br />
<br />
*"Standard antiemetic prophylaxis and pre- and post- [[Cisplatin (Platinol)]] hydration"<br />
<br />
'''29-day cycle for up to 6 cycles'''<br />
<br />
===Variant #3 {{#subobject:782e95|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%2810%2961121-X/fulltext Bang et al. 2010 (ToGA)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CF_.26_Trastuzumab|CF & Trastuzumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Patients in '''ToGA''' had overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation.''<br />
<br />
''ToGA Patients: 100% adenocarcinoma (19% gastroesophageal junction, 81% gastric). 10% with ECOG of 2.'' <br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*"Hyperhydration" for [[Cisplatin (Platinol)]]<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''TAX 325:''' Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006 Nov 1;24(31):4991-7. [http://jco.ascopubs.org/content/24/31/4991.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17075117 PubMed]<br />
#Dank M, Zaluski J, Barone C, Valvere V, Yalcin S, Peschel C, Wenczl M, Goker E, Cisar L, Wang K, Bugat R. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2008 Aug;19(8):1450-7. Epub 2008 Jun 16. [http://annonc.oxfordjournals.org/content/19/8/1450.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18558665 PubMed]<br />
#Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, Moehler M, Grabowski P, Arnold D, Greten T, Müller L, Röthling N, Peschel C, Langer R, Lordick F. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009 Oct;20(10):1667-73. Epub 2009 Jun 23. [http://annonc.oxfordjournals.org/content/20/10/1667.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19549707 PubMed]<br />
#'''ToGA:''' Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961121-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20728210 PubMed]<br />
<br />
==Cisplatin, Fluorouracil, Cetuximab {{#subobject:717dc4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CF-C: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil, '''<u>C</u>'''etuximab<br />
===Regimen {{#subobject:54b7fe|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://annonc.oxfordjournals.org/content/20/10/1667.long Lorenzen et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Cisplatin_.26_Fluorouracil_4|CF]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
''Patients: 100% squamous cell histology. 87% with metastatic disease. No patients with ECOG PS greater than 1.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m<sup>2</sup> )<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, 22<br />
**Cycles 2 to 6: 250 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
<br />
*"Standard antiemetic prophylaxis and pre- and post- [[Cisplatin (Platinol)]] hydration"<br />
<br />
'''29-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, Moehler M, Grabowski P, Arnold D, Greten T, Müller L, Röthling N, Peschel C, Langer R, Lordick F. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009 Oct;20(10):1667-73. Epub 2009 Jun 23. [http://annonc.oxfordjournals.org/content/20/10/1667.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19549707 PubMed]<br />
<br />
==CF & Trastuzumab {{#subobject:ca9cd1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CF: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
<br />
===Regimen {{#subobject:b2731|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%2810%2961121-X/fulltext Bang et al. 2010 (ToGA)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Cisplatin_.26_Fluorouracil_4|CF]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Patients had overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation.''<br />
<br />
''Patients: 100% adenocarcinoma (19% gastroesophageal junction, 81% gastric). 10% with ECOG of 2.'' <br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 800 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Subsequent cycles: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ToGA:''' Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961121-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20728210 PubMed]<br />
<br />
==Cisplatin, Doxorubicin liposomal, Fluorouracil {{#subobject:f31fcc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1b58a0|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.springerlink.com/content/n8477v3g21081103 Cascinu et al. 2010]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#MCF|MCF]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Patients: 11% gastroesophageal junction, 89% gastric origin. 90% metastatic. 6% with ECOG PS of 2.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Pegylated liposomal doxorubicin (Doxil)]] 20 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup> IV continuous infusion over 22 hours (total dose per cycle: 1600 mg/m<sup>2</sup> )<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#Cascinu S, Galizia E, Labianca R, Ferraù F, Pucci F, Silva RR, Luppi G, Beretta GD, Berardi R, Scartozzi M. Pegylated liposomal doxorubicin, 5-fluorouracil and cisplatin versus mitomycin-C, 5-fluorouracil and cisplatin for advanced gastric cancer: a randomized phase II trial. Cancer Chemother Pharmacol. 2011 Jul;68(1):37-43. Epub 2010 Sep 7. [http://www.springerlink.com/content/n8477v3g21081103/ link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20821330 PubMed]<br />
<br />
==Cisplatin & Irinotecan {{#subobject:ec60da|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CI: '''<u>C</u>'''isplatin & '''<u>I</u>'''rinotecan<br />
===Variant #1 {{#subobject:8f624d|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.cancernetwork.com/esophageal-cancer/phase-ii-trial-weekly-irinotecancisplatin-advanced-esophageal-cancer Ilson 2004]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: In contrast to the original reference, some guidelines list cisplatin 25 mg/m<sup>2</sup> as an alternate dosage.''<br />
<br />
''Patients: 26% squamous cell, 74% adenocarcinoma histology. 85% metastatic disease.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2 {{#subobject:219a1|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/17/10/3270.full Ilson et al. 1999]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 66% adenocarcinoma, 34% squamous cell histology. Did not receive any prior chemotherapy. 97% with metastatic disease.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22<br />
*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 20 mg IV once per day on days 1, 8, 15, 22, prior to chemotherapy<br />
*[[Granisetron]] 2 mg PO once per day on days 1, 8, 15, 22, prior to chemotherapy<br />
*At least 500 mL D5NS IV over 30 to 60 minutes once per day on days 1, 8, 15, 22, prior to [[Cisplatin (Platinol)]]<br />
*[[Atropine (Atropen)]] used as pretreatment medication if there was diarrhea or abdominal cramps within 1 hour of [[Irinotecan (Camptosar)]]<br />
<br />
'''42-day cycles''' <br />
<br />
===References===<br />
<br />
#Ilson DH, Saltz L, Enzinger P, Huang Y, Kornblith A, Gollub M, O'Reilly E, Schwartz G, DeGroff J, Gonzalez G, Kelsen DP. Phase II trial of weekly irinotecan plus cisplatin in advanced esophageal cancer. J Clin Oncol. 1999 Oct;17(10):3270-5. [http://jco.ascopubs.org/content/17/10/3270.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10506629 PubMed]<br />
#Ilson DH. Phase II trial of weekly irinotecan/cisplatin in advanced esophageal cancer. Oncology (Williston Park). 2004 Dec;18(14 Suppl 14):22-5. [http://www.cancernetwork.com/esophageal-cancer/phase-ii-trial-weekly-irinotecancisplatin-advanced-esophageal-cancer link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15685830 PubMed]<br />
<br />
==Cisplatin & Paclitaxel {{#subobject:5d50ee|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:c401a9|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://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2008&issue=02000&article=00005&type=abstract Zhang et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% squamous cell carcinoma with advanced or metastatic disease. 18% ECOG PS of 2.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2 {{#subobject:ffaa05|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/11079171 Ilson et al. 2000]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: In contrast to the original reference, some guidelines list the paclitaxel dose as 135 mg/m<sup>2</sup>. No primary reference could be found for the 135 mg/m<sup>2</sup> dosage. The protocol reported here was amended to change the original dose of 250 mg/m<sup>2</sup> to 200 mg/m<sup>2</sup> based on toxicity and treatment-related deaths.''<br />
<br />
''Patients: 87% adenocarcinoma, 13% squamous cell histology. Included both gastroesophageal junction and esophageal patients. 95% with metastatic disease. None had received prior chemotherapy.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 2, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1<br />
<br />
====Supportive medications====<br />
<br />
*"Granulocyte colony stimulating factor support"<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #3 {{#subobject:a5b523|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/PMC2063082 Petrasch et al. 1998]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 25% adenocarcinoma, 75% squamous cell histology. Consisting of unresectable stage III disease, recurrent or metastatic tumors of esophageal origin.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given second'''<br />
*[[Paclitaxel (Taxol)]] 90 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 20 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 />
*[[Clemastine (Tavist)]] 2 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]<br />
*[[Ondansetron (Zofran)]] 8 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]<br />
*"Adequate pre- and posthydration" for [[Cisplatin (Platinol)]]<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#Petrasch S, Welt A, Reinacher A, Graeven U, König M, Schmiegel W. Chemotherapy with cisplatin and paclitaxel in patients with locally advanced, recurrent or metastatic oesophageal cancer. Br J Cancer. 1998 Aug;78(4):511-4. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063082 link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9716036 PubMed]<br />
#Ilson DH, Forastiere A, Arquette M, Costa F, Heelan R, Huang Y, Kelsen DP. A phase II trial of paclitaxel and cisplatin in patients with advanced carcinoma of the esophagus. Cancer J. 2000 Sep-Oct;6(5):316-23. '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11079171 PubMed]<br />
#Zhang X, Shen L, Li J, Li Y, Li J, Jin M. A phase II trial of paclitaxel and cisplatin in patients with advanced squamous-cell carcinoma of the esophagus. Am J Clin Oncol. 2008 Feb;31(1):29 to 33. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2008&issue=02000&article=00005&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18376224 PubMed]<br />
<br />
==CX {{#subobject:c58325|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CX: '''<u>C</u>'''isplatin & '''<u>X</u>'''eloda (Capecitabine)<br />
<br>XP: '''<u>X</u>'''eloda (Capecitabine) & '''<u>P</u>'''latinol (Cisplatin)<br />
===Regimen {{#subobject:130681|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://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mdp269 Moehler et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|[[#CAPIRI|XI]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961121-X/fulltext Bang et al. 2010 (ToGA)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CX_.26_Trastuzumab|CX & Trastuzumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70102-5/abstract Lordick et al. 2013 (EXPAND)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CX-C|CX & Cetuximab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''Patients in '''ToGA''' had overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Patients:100% adenocarcinoma (19% gastroesophageal junction, 81% gastric). 10% with ECOG of 2.'' <br />
<br />
''Lordick Patients: 100% adenocarcinoma (stomach or gastroesophageal junction) locally advanced unresectable (M0) or metastatic (M1).''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
**Lordick et al. 2013: 1000 mg/m<sup>2</sup> PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)<br />
<br />
====Supportive medications====<br />
<br />
*per Kang et al. 2009:<br />
*"Hyperhydration" for [[Cisplatin (Platinol)]]<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Moehler M, Kanzler S, Geissler M, Raedle J, Ebert MP, Daum S, Flieger D, Seufferlein T, Galle PR, Hoehler T; Arbeitsgemeinschaft Internistische Onkologie. A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2010 Jan;21(1):71-7. Epub 2009 Jul 15. [https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mdp269 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19605504 PubMed]<br />
#'''ToGA:''' Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961121-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20728210 PubMed]<br />
#'''EXPAND:''' Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V, Park JO, Sawaki A, Celik I, Götte H, Melezínková H, Moehler M; Arbeitsgemeinschaft Internistische Onkologie (AIO) and EXPAND Investigators. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013 May;14(6):490-9. Epub 2013 Apr 15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70102-5/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23594786 PubMed]<br />
<br />
==CX-C {{#subobject:318959|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CX-C: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine), '''<u>C</u>'''etuximab<br />
===Regimen {{#subobject:afe6a1|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(13)70102-5/abstract Lordick et al. 2013 (EXPAND)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#CX_2|CX]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''Lordick Patients: 100% adenocarcinoma (stomach or gastroesophageal junction) locally advanced unresectable (M0) or metastatic (M1).''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**Cycle 1: 400 mg/m<sup>2</sup> IV once on day 1<br />
**Subsequently: 250 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''EXPAND:''' Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V, Park JO, Sawaki A, Celik I, Götte H, Melezínková H, Moehler M; Arbeitsgemeinschaft Internistische Onkologie (AIO) and EXPAND Investigators. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013 May;14(6):490-9. Epub 2013 Apr 15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70102-5/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23594786 PubMed]<br />
<br />
==CX & Trastuzumab {{#subobject:7cbb79|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CX & Trastuzumab: '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine), Trastuzumab<br />
===Variant #1 {{#subobject:cdee6d|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://ascopubs.org/doi/full/10.1200/JCO.2016.71.6852 Shah et al. 2017 (HELOISE)]<br />
| style="background-color:#1a9851" |Phase IIIb (C)<br />
|CX & HD-Trastuzumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Patients had overexpression of HER2 protein by immunohistochemistry AND gene amplification by in-situ hybridisation. Patients: 100% metastatic adenocarcinoma (gastroesophageal junction or gastric)''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Subsequent cycles: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*Trastuzumab alone continued indefinitely<br />
<br />
===Variant #2 {{#subobject:27adc6|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%2810%2961121-X/fulltext Bang et al. 2010 (ToGA)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#CX_2|CX]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Patients had overexpression of HER2 protein by immunohistochemistry OR gene amplification by fluorescence in-situ hybridisation. Patients: 100% adenocarcinoma (19% gastroesophageal junction, 81% gastric). 10% with ECOG of 2.''<br />
====Chemotherapy====<br />
<br />
*[[Cisplatin (Platinol)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Trastuzumab (Herceptin)]] as follows:<br />
**Cycle 1: 8 mg/kg IV once on day 1<br />
**Subsequent cycles: 6 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ToGA:''' Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961121-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20728210 PubMed]<br />
#'''HELOISE:''' Shah MA, Xu RH, Bang YJ, Hoff PM, Liu T, Herráez-Baranda LA, Xia F, Garg A, Shing M, Tabernero J. HELOISE: Phase IIIb randomized multicenter study comparing standard-of-care and higher-dose trastuzumab regimens combined with chemotherapy as first-line therapy in patients with human epidermal growth factor receptor 2-positive metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol. 2017 Aug 1;35(22):2558-2567. Epub 2017 Jun 2. [https://ascopubs.org/doi/full/10.1200/JCO.2016.71.6852 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28574779 PubMed]<br />
<br />
==Docetaxel & Irinotecan {{#subobject:96e013|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:38cdd0|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/PMC2699385/ Burtness et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 79% adenocarcinoma, 21% squamous cell histology. All patients ECOG PS of 0 or 1, and unresectable/metastatic disease.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8, '''given first'''<br />
*[[Irinotecan (Camptosar)]] 50 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given second'''<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**8 mg PO once per day on days 1 & 8; 12 hours before [[Docetaxel (Taxotere)]]<br />
**10 mg IV once per day on days 1 & 8, within 1 hour of chemotherapy<br />
**8 mg PO once per day on days 1 & 8; 12 hour afters chemotherapy<br />
*[[:Category:Serotonin 5-HT3 antagonists|Serotonin 5-HT3 antagonist]] IV once per day on days 1 & 8, within 1 hour before chemotherapy<br />
*"Oral antiemetic therapy prescribed"<br />
*[[Loperamide (Imodium)]] as needed<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Burtness B, Gibson M, Egleston B, Mehra R, Thomas L, Sipples R, Quintanilla M, Lacy J, Watkins S, Murren JR, Forastiere AA. Phase II trial of docetaxel-irinotecan combination in advanced esophageal cancer. Ann Oncol. 2009 Jul;20(7):1242-8. Epub 2009 May 8. [http://annonc.oxfordjournals.org/content/20/7/1242.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699385/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19429872 PubMed]<br />
<br />
==ECF {{#subobject:6325cb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:e5ede0|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/20/8/1996.long Ross et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MCF|MCF]]<br />
| style="background-color:#eeee01" |Seems to have non-inferior OS<br />
|-<br />
| rowspan="3" |[https://www.nejm.org/doi/full/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#ECX_2|ECX]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|2. [[#EOF_2|EOF]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|3. [[#EOX_2|EOX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
<br />
''Ross et al. Patients: adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma histology, all advanced esophagogastric cancer.''<br />
<br />
''REAL-2 Patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 4 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*(varied depending on reference):<br />
*3 liters per day "hyperhydration"<br />
*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]] for emesis prophylaxis<br />
*Growth factor support allowed, such as with [[Filgrastim (Neupogen)]]<br />
*[[Warfarin (Coumadin)]] 1 mg PO once per day for catheter thrombosis prophylaxis<br />
<br />
'''21-day cycle for up to 8 cycles'''<br />
<br />
===References===<br />
<br />
#Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, Price T, Anderson H, Iveson T, Hickish T, Lofts F, Norman A. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol. 2002 Apr 15;20(8):1996-2004. [http://jco.ascopubs.org/content/20/8/1996.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11956258 PubMed]<br />
#'''REAL-2:''' Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. [https://www.nejm.org/doi/full/10.1056/NEJMoa073149 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18172173 PubMed]<br />
<br />
==ECX {{#subobject:bb95b5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
ECX: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
===Variant #1, 50/60/625 x 8 {{#subobject:e965c5|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.nejm.org/doi/full/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#ECF_2|ECF]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|2. [[#EOF_2|EOF]]<br> 3. [[#EOX_2|EOX]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
''REAL-2 patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 4 hours once on day 1<br />
*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21<br />
<br />
'''21-day cycle for up to 8 cycles'''<br />
<br />
===Variant #2, 50/60/625, indefinite {{#subobject:eab855|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(14)70023-3/fulltext Iveson et al. 2014 (Amgen 20060317)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|ECX & Rilotumumab<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 4 hours once on day 1<br />
*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #3, 50/60/1000 {{#subobject:2f83d2|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://ascopubs.org/doi/full/10.1200/JCO.2013.54.1011 Guimbaud et al. 2014 (FFCD 03-07)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRI|FOLFIRI]]<br />
| style="background-color:#d73027" |Inferior TTF<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV over 15 minutes once on day 1<br />
**Maximum cumulative dose allowed was 900 mg/m<sup>2</sup><br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 2 to 15<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''REAL-2:''' Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. [https://www.nejm.org/doi/full/10.1056/NEJMoa073149 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18172173 PubMed]<br />
#'''Amgen 20060317:''' Iveson T, Donehower RC, Davidenko I, Tjulandin S, Deptala A, Harrison M, Nirni S, Lakshmaiah K, Thomas A, Jiang Y, Zhu M, Tang R, Anderson A, Dubey S, Oliner KS, Loh E. Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study. Lancet Oncol. 2014 Aug;15(9):1007-18. Epub 2014 Jun 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70023-3/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24965569 PubMed]<br />
#'''FFCD 03-07:''' Guimbaud R, Louvet C, Ries P, Ychou M, Maillard E, André T, Gornet JM, Aparicio T, Nguyen S, Azzedine A, Etienne PL, Boucher E, Rebischung C, Hammel P, Rougier P, Bedenne L, Bouché O. Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French intergroup (Fédération Francophone de Cancérologie Digestive, Fédération Nationale des Centres de Lutte Contre le Cancer, and Groupe Coopérateur Multidisciplinaire en Oncologie) study. J Clin Oncol. 2014 Nov 1;32(31):3520-6. Epub 2014 Oct 6. Erratum in: J Clin Oncol. 2015 Apr 20;33(12):1416. [https://ascopubs.org/doi/full/10.1200/JCO.2013.54.1011 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25287828 PubMed]<br />
<br />
==EOF {{#subobject:a6390c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
EOF: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:abf19f|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.nejm.org/doi/full/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#ECF_2|ECF]]<br> 2. [[#ECX_2|ECX]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|3. [[#EOX_2|EOX]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
''Patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*[[Warfarin (Coumadin)]] 1 mg PO once per day for catheter thrombosis prophylaxis<br />
<br />
'''21-day cycle for up to 8 cycles'''<br />
<br />
===References===<br />
<br />
#'''REAL-2:''' Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. [https://www.nejm.org/doi/full/10.1056/NEJMoa073149 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18172173 PubMed]<br />
<br />
==EOX {{#subobject:438182|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
EOX: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>X</u>'''eloda (Capecitabine)<br />
<br>EOC: '''<u>E</u>'''pirubicin, '''<u>O</u>'''xaliplatin, '''<u>C</u>'''apecitabine<br />
===Regimen {{#subobject:339609|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="3" |[https://www.nejm.org/doi/full/10.1056/NEJMoa073149 Cunningham et al. 2008 (REAL-2)]<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#ECF_2|ECF]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|2. [[#ECX_2|ECX]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|3. [[#EOF_2|EOF]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669518/ Waddell et al. 2013 (REAL3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|mEOC+P<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''REAL-2 patients: 35% esophageal, 25% gastroesophageal junction, 40% gastric. 11% ECOG PS of 2.''<br />
<br />
''REAL3 patients: 99% adenocarcinoma, 1% undifferentiated histology. 39% esophagus, 31% ''gastroesophageal'' junction, 30% gastric. 6% ECOF PS of 2. 89% metastatic disease.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 21<br />
<br />
'''21-day cycle for up to 8 cycles'''<br />
<br />
===References===<br />
<br />
#'''REAL-2:''' Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. [https://www.nejm.org/doi/full/10.1056/NEJMoa073149 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18172173 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
#'''REAL3:''' Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AF, Okines C, Wotherspoon A, Saffery C, Middleton G, Wadsley J, Ferry D, Mansoor W, Crosby T, Coxon F, Smith D, Waters J, Iveson T, Falk S, Slater S, Peckitt C, Barbachano Y. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 2013 May;14(6):481-9. Epub 2013 Apr 15. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669518/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23594787 PubMed]<br />
<br />
==Erlotinib monotherapy {{#subobject:50cjcd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:yac7de|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/24/30/4922.long Dragovich et al. 2006 (SWOG 0127)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma (63% gastroesophageal junction, 37% gastric origin). All with ECOG PS of 0 or 1.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day, at least 1 hour before a meal, or 2 hours after a meal<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''SWOG 0127:''' Dragovich T, McCoy S, Fenoglio-Preiser CM, Wang J, Benedetti JK, Baker AF, Hackett CB, Urba SG, Zaner KS, Blanke CD, Abbruzzese JL. Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol. 2006 Oct 20;24(30):4922-7. [http://jco.ascopubs.org/content/24/30/4922.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17050876 PubMed]<br />
<br />
==Etoposide monotherapy {{#subobject:344c29|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:bdcf31|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://link.springer.com/article/10.1007%2FBF00685952 Harstrick et al. 1992]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: this is higher than the dose usually employed in modern settings.''<br />
<br />
''Patients: metastatic 100% squamous cell carcinoma of the esophagus, with ECOG PS range 1-2.''<br />
====Chemotherapy====<br />
<br />
*[[Etoposide (Vepesid)]] 200 mg/m<sup>2</sup> (route not specified) once per day on days 1 to 3<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Harstrick A, Bokemeyer C, Preusser P, Köhne-Wömpner CH, Meyer HJ, Stahl M, Knipp H, Schmoll HJ, Wilke H. Phase II study of single-agent etoposide in patients with metastatic squamous-cell carcinoma of the esophagus. Cancer Chemother Pharmacol. 1992;29(4):321-2. [https://link.springer.com/article/10.1007%2FBF00685952 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1537080 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:5aad1e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:2d601|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/22/21/4319.long Bouché et al. 2004 (FFCD 9803)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-de-esc)<br />
|1. [[#CLF_2|LV5FU2 & Cisplatin]]<br> 2. [[#FOLFIRI|LV5FU2 & Irinotecan]]<br />
| style="background-color:#d3d3d3" |Not powered to draw conclusions<br />
|-<br />
|}<br />
''Note: the primary reference said every cycle was 15 days, but also said that medications were given every 14 days, so the assumption was made that this more typical schedule was used.''<br />
<br />
''Patients: 100% adenocarcinoma (70% gastric origin, 30% cardia)''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup> IV continuous infusion over 22 hours (total dose per cycle: 1600 mg/m<sup>2</sup>)<br />
<br />
'''14-day cycle for at least 4 cycles'''<br />
<br />
===References===<br />
<br />
#'''FFCD 9803:''' Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, Arsène D, Paitel JF, Guérin-Meyer V, Mitry E, Buecher B, Kaminsky MC, Seitz JF, Rougier P, Bedenne L, Milan C; Fédération Francophone de Cancérologie Digestive Group. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1;22(21):4319-28. [http://jco.ascopubs.org/content/22/21/4319.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15514373 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, Gemcitabine {{#subobject:876cd7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:173a91|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.karger.com/Article/Abstract/87815 Morgan-Meadows et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% esophageal cancer (both squamous and adenocarcinoma histology). Patients received no prior therapy.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1, 8, 15 (total dose per cycle: 1800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<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 />
<!-- # Michelle Pipp, Daniel Mulkerin, Deb Warren, Wesley Hotchkis, Jordan Berlin, James P Thomas. A Phase II Trial of Gemcitabine and 5-Fluoruracil in Advanced Esophageal Cancer. 2001 ASCO Annual Meeting abstract 630. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=10&abstractID=630 link to abstract] --><br />
<br />
#Morgan-Meadows S, Mulkerin D, Berlin JD, Kim K, Bailey H, Saphner T, Jumonville A, Hansen R, Ahuja H, McFarland T, Thomas JP. A phase II trial of gemcitabine, 5-fluorouracil and leucovorin in advanced esophageal carcinoma. Oncology. 2005;69(2):130-4. Epub 2005 Aug 23. [http://www.karger.com/Article/Abstract/87815 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16118509 PubMed]<br />
<br />
==FLOT {{#subobject:b427b1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FLOT: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>O</u>'''xaliplatin, '''<u>T</u>'''axotere (Docetaxel)<br />
===Regimen {{#subobject:bb5eb6|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://annonc.oxfordjournals.org/content/19/11/1882.long Al-Batran et al. 2008a]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma histology (44% gastroesophageal junction, 56% gastric origin). 93% metastatic disease. 15% with ECOG 2-3.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1, '''given fourth'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 1 to 2 hours once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 1 to 2 hours once on day 1<br />
*[[Docetaxel (Taxotere)]] 50 mg/m<sup>2</sup> IV over 1 to 2 hours once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 8 mg PO once per day on days 0 to 3<br />
<br />
'''14-day cycle for up to 8 (or more) cycles'''<br />
<br />
===References===<br />
<br />
#Al-Batran SE, Hartmann JT, Hofheinz R, Homann N, Rethwisch V, Probst S, Stoehlmacher J, Clemens MR, Mahlberg R, Fritz M, Seipelt G, Sievert M, Pauligk C, Atmaca A, Jäger E. Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2008 Nov;19(11):1882-7. Epub 2008 Jul 31. [http://annonc.oxfordjournals.org/content/19/11/1882.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669868 PubMed]<br />
<br />
==FOLFIRI {{#subobject:ba35aa|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br>IF: '''<u>I</u>'''rinotecan & 5-'''<u>F</u>'''luorouracil<br />
===Variant #1, 6 out of 7 weeks ("AIO regimen") {{#subobject:cec083|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://annonc.oxfordjournals.org/content/19/8/1450.long Dank et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Cisplatin_.26_Fluorouracil_4|CF]]<br />
| style="background-color:#d9ef8b" |Might have superior TTP<br />
|-<br />
|[http://journals.lww.com/anti-cancerdrugs/pages/articleviewer.aspx?year=2009&issue=03000&article=00002&type=abstract Wolff et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma histology (20% gastroesophageal junction, 80% gastric origin). 96% with metastatic disease.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous infusion over 22 hours, started on days 1, 8, 15, 22, 29, 36, '''given third''' (total dose per cycle: 12,000 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, '''given second'''<br />
*[[Irinotecan (Camptosar)]] 80 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*[[Ondansetron (Zofran)]] for antiemetic prophylaxis<br />
*[[Dexamethasone (Decadron)]] for antiemetic prophylaxis<br />
*[[Filgrastim (Neupogen)]] (dose not specified) SC once per day, starting on day 4, to be continued until ANC greater than 1000/uL for grade 3 to 4 neutropenia, febrile neutropenia, or neutropenic infection<br />
*[[Atropine (Atropen)]] prn cholinergic symptoms<br />
*[[Loperamide (Imodium)]] prn delayed diarrhea<br />
<br />
'''7-week cycles'''<br />
<br />
===Variant #2, LV5FU2 & Irinotecan (200/1600/180) {{#subobject:56018a|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/22/21/4319.long Bouché et al. 2004 (FFCD 9803)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|1. [[#Fluorouracil_.26_Folinic_acid|LV5FU2]]<br> 2. [[#CLF_2|LV5FU2 & Cisplatin]]<br />
| style="background-color:#d3d3d3" |Not powered to draw conclusions<br />
|-<br />
|}<br />
''Patients: 100% adenocarcinoma (70% gastric origin, 30% cardia).'' <br />
<br />
''Note: the primary reference said every cycle was 15 days, but also said that medications were given every 14 days, so the assumption was made that this more typical schedule was used.''<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup> IV continuous infusion over 22 hours (total dose per cycle: 1600 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
'''14-day cycle for at least 4 cycles'''<br />
<br />
===Variant #3, 400/2800/180 {{#subobject:6526d0|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://ascopubs.org/doi/full/10.1200/JCO.2013.54.1011 Guimbaud et al. 2014 (FFCD 03-07)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#ECX_3|ECX]]<br />
| style="background-color:#1a9850" |Superior TTF<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
'''14-day cycles''' <br />
<br />
===References===<br />
<br />
#'''FFCD 9803:''' Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, Arsène D, Paitel JF, Guérin-Meyer V, Mitry E, Buecher B, Kaminsky MC, Seitz JF, Rougier P, Bedenne L, Milan C; Fédération Francophone de Cancérologie Digestive Group. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1;22(21):4319-28. [http://jco.ascopubs.org/content/22/21/4319.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15514373 PubMed]<br />
#Dank M, Zaluski J, Barone C, Valvere V, Yalcin S, Peschel C, Wenczl M, Goker E, Cisar L, Wang K, Bugat R. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2008 Aug;19(8):1450-7. Epub 2008 Jun 16. [http://annonc.oxfordjournals.org/content/19/8/1450.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18558665 PubMed]<br />
#Wolff K, Wein A, Reulbach U, Männlein G, Brückl V, Meier C, Ostermeier N, Schwab SA, Horbach T, Hohenberger W, Hahn EG, Boxberger F. Weekly high-dose 5-fluorouracil as a 24-h infusion and sodium folinic acid (AIO regimen) plus irinotecan in patients with locally advanced nonresectable and metastatic adenocarcinoma or squamous cell carcinoma of the oesophagus: a phase II trial. Anticancer Drugs. 2009 Mar;20(3):165-73. [http://journals.lww.com/anti-cancerdrugs/pages/articleviewer.aspx?year=2009&issue=03000&article=00002&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19125117 PubMed]<br />
#'''FFCD 03-07:''' Guimbaud R, Louvet C, Ries P, Ychou M, Maillard E, André T, Gornet JM, Aparicio T, Nguyen S, Azzedine A, Etienne PL, Boucher E, Rebischung C, Hammel P, Rougier P, Bedenne L, Bouché O. Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French intergroup (Fédération Francophone de Cancérologie Digestive, Fédération Nationale des Centres de Lutte Contre le Cancer, and Groupe Coopérateur Multidisciplinaire en Oncologie) study. J Clin Oncol. 2014 Nov 1;32(31):3520-6. Epub 2014 Oct 6. Erratum in: J Clin Oncol. 2015 Apr 20;33(12):1416. [https://ascopubs.org/doi/full/10.1200/JCO.2013.54.1011 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25287828 PubMed]<br />
<br />
==mFOLFOX6 & Cetuximab {{#subobject:e51095|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOX6 & Cetuximab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Cetuximab<br />
<br>FOLFOX-C: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>C</u>'''etuximab<br />
===Regimen {{#subobject:2a9d10|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/PMC5019745/ Enziger et al. 2016 (CALGB 80403/ECOG E1206)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|1. ECF-C<br> 2. IC-C<br />
| style="background-color:#d3d3d3" |Not powered to draw conclusions<br />
|-<br />
|}<br />
''Patients: 91% adenocarcinoma, 9% squamous cell histology. 56% esophageal, 43% gastroesophageal tumors.'' <br />
<br />
''To receive full-dose therapy in this trial, patients were required to have an absolute neutrophil count of 1,000/µL or greater, platelets of 75,000/µL or greater, and no other grade 2 or higher treatment-related toxicity.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, with oxaliplatin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, with leucovorin'''<br />
*[[Cetuximab (Erbitux)]] as follows, '''given first''':<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 on day 8<br />
**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<!--<br />
# P. C. Enzinger, B. Burtness, D. Hollis, D. Niedzwiecki, D. Ilson, A. B. Benson, R. J. Mayer, R. M. Goldberg. CALGB 80403/ECOG 1206: A randomized phase II study of three standard chemotherapy regimens (ECF, IC, FOLFOX) plus cetuximab in metastatic esophageal and GE junction cancer. 2010 ASCO Annual Meeting abstract 4006. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=44487 link to abstract] --><br />
<br />
#'''CALGB 80403/ECOG E1206:''' Enzinger PC, Burtness BA, Niedzwiecki D, Ye X, Douglas K, Ilson DH, Villaflor VM, Cohen SJ, Mayer RJ, Venook A, Benson AB 3rd, Goldberg RM. CALGB 80403 (Alliance)/E1206: a randomized phase II study of three chemotherapy regimens plus cetuximab in metastatic esophageal and gastroesophageal junction cancers. J Clin Oncol. 2016 Aug 10;34(23):2736-42. Epub 2016 Jul 5. [http://jco.ascopubs.org/content/34/23/2736.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019745/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27382098 PubMed]<br />
<br />
==Irinotecan monotherapy {{#subobject:69cjc0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9fb982|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://link.springer.com/article/10.1007%2Fs10620-005-3038-2 Enzinger et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: In contrast to the primary reference, some guidelines list a dosing schedule of 125 mg/m<sup>2</sup> IV once per day on days 1 & 8, with 21-day cycles.''<br />
<br />
''Patients: 100% adenocarcinoma histology, both gastric and esophageal''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<br />
#Enzinger PC, Kulke MH, Clark JW, Ryan DP, Kim H, Earle CC, Vincitore MM, Michelini AL, Mayer RJ, Fuchs CS. A phase II trial of irinotecan in patients with previously untreated advanced esophageal and gastric adenocarcinoma. Dig Dis Sci. 2005 Dec;50(12):2218-23. [http://link.springer.com/article/10.1007%2Fs10620-005-3038-2 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16416165 PubMed]<br />
<br />
==Irinotecan & Mitomycin {{#subobject:dfcjc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:87100a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 33%" |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/PMC3641556/ Lustberg et al. 2010]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|Irinotecan & Mitomycin (alternate schedule)<br />
|-<br />
|}<br />
''Patients: 56% lower esophageal, 44% gastroesophageal junction. 100% adenocarcinoma histology. 100% previously untreated 6% with ECOG PS = 2. 77% stage four disease.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV once per day on days 2 & 9<br />
*[[Mitomycin (Mutamycin)]] 6 mg/m<sup>2</sup> IV once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[Ondansetron (Zofran)]] or [[Granisetron]] and [[Dexamethasone (Decadron)]] premedication<br />
*[[Loperamide (Imodium)]] started with first episode of diarrhea<br />
*Erythropoietin for hemoglobin less than 10 g/dL permitted<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
<br />
#Lustberg MB, Bekaii-Saab T, Young D, Otterson G, Burak W, Abbas A, McCracken-Bussa B, Lustberg ME, Villalona-Calero MA. Phase II randomized study of two regimens of sequentially administered mitomycin C and irinotecan in patients with unresectable esophageal and gastroesophageal adenocarcinoma. J Thorac Oncol. 2010 May;5(5):713-8. [https://www.jto.org/article/S1556-0864(15)32147-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641556/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20354452 PubMed]<br />
<br />
==MCF {{#subobject:d3775b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MCF: '''<u>M</u>'''itomycin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil<br />
===Regimen {{#subobject:47b99f|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/20/8/1996.long Ross et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#ECF_2|ECF]]<br />
| style="background-color:#eeee01" |Seems to have non-inferior OS<br />
|-<br />
|[http://www.springerlink.com/content/n8477v3g21081103 Cascinu et al. 2010]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Cisplatin.2C_Doxorubicin_liposomal.2C_Fluorouracil|Cisplatin, Doxorubicin liposomal, Fluorouracil]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Cascinu Patients: 11% gastroesophageal junction, 89% gastric origin. 90% metastatic. 6% with ECOG PS of 2.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Mitomycin (Mutamycin)]] 7 mg/m<sup>2</sup> (maximum dose of 14 mg) IV once on day 1<br />
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once per day on days 1 & 22<br />
*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion, started on day 1 (total dose per cycle: 12,600 mg/m<sup>2</sup>)<br />
<br />
====Supportive medications====<br />
<br />
*[[Warfarin (Coumadin)]] 1 mg PO once per day for catheter thrombosis prophylaxis<br />
<br />
'''42-day cycle for up to 5 cycles (6 months)'''<br />
<br />
===References===<br />
<br />
#Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, Price T, Anderson H, Iveson T, Hickish T, Lofts F, Norman A. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol. 2002 Apr 15;20(8):1996-2004. [http://jco.ascopubs.org/content/20/8/1996.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11956258 PubMed]<br />
#Cascinu S, Galizia E, Labianca R, Ferraù F, Pucci F, Silva RR, Luppi G, Beretta GD, Berardi R, Scartozzi M. Pegylated liposomal doxorubicin, 5-fluorouracil and cisplatin versus mitomycin-C, 5-fluorouracil and cisplatin for advanced gastric cancer: a randomized phase II trial. Cancer Chemother Pharmacol. 2011 Jul;68(1):37-43. Epub 2010 Sep 7. [http://www.springerlink.com/content/n8477v3g21081103/ link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20821330 PubMed]<br />
<br />
==Paclitaxel monotherapy {{#subobject:ed008a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, weekly {{#subobject:dd30a4|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://annonc.oxfordjournals.org/content/18/5/898.long Ilson et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% esophageal cancers. 66% adenocarcinoma, 34% squamous cell. Median ECOG PS 1, ranging 0-2.'' <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, 22<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 20 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to [[Paclitaxel (Taxol)]]<br />
*[[Cimetidine (Tagamet)]] 300 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to [[Paclitaxel (Taxol)]]<br />
*[[Diphenhydramine (Benadryl)]] 50 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to [[Paclitaxel (Taxol)]]<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, CI {{#subobject:1d24a4|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://jnci.oxfordjournals.org/content/86/14/1086.long Ajani et al. 1994]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: In contrast to the original reference, some guidelines list the dosage of paclitaxel as 135 to 175 mg/m<sup>2</sup>.''<br />
<br />
''Patients: 100% esophageal cancer. 36% squamous cell, 64% adenocarcinoma histology.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 250 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1<br />
**Dosage adjusted based on toxicity down to 150 or 200 mg/m<sup>2</sup>, or up to 280 mg/m<sup>2</sup><br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 20 mg PO for 2 doses on day 1; 14 hours and 7 hours prior to [[Paclitaxel (Taxol)]]<br />
*[[Cimetidine (Tagamet)]] 300 mg IV once on day 1; 60 minutes prior to [[Paclitaxel (Taxol)]]<br />
*[[Diphenhydramine (Benadryl)]] 50 mg IV once on day 1; 60 minutes prior to [[Paclitaxel (Taxol)]]<br />
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 hours after the [[Paclitaxel (Taxol)]] infusion finishes<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Ajani JA, Ilson DH, Daugherty K, Pazdur R, Lynch PM, Kelsen DP. Activity of taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus. J Natl Cancer Inst. 1994 Jul 20;86(14):1086-91. [http://jnci.oxfordjournals.org/content/86/14/1086.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7912736 PubMed]<br />
#Ilson DH, Wadleigh RG, Leichman LP, Kelsen DP. Paclitaxel given by a weekly 1-h infusion in advanced esophageal cancer. Ann Oncol. 2007 May;18(5):898-902. Epub 2007 Mar 9. [http://annonc.oxfordjournals.org/content/18/5/898.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17351256 PubMed]<br />
<br />
=Metastatic or locally advanced disease, subsequent lines of therapy=<br />
==Apatinib monotherapy {{#subobject:c701c3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d1dde0|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/34/13/1448.full Li et al. 2016]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Apatinib (Aitan)]] 850 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#Li J, Qin S, Xu J, Xiong J, Wu C, Bai Y, Liu W, Tong J, Liu Y, Xu R, Wang Z, Wang Q, Ouyang X, Yang Y, Ba Y, Liang J, Lin X, Luo D, Zheng R, Wang X, Sun G, Wang L, Zheng L, Guo H, Wu J, Xu N, Yang J, Zhang H, Cheng Y, Wang N, Chen L, Fan Z, Sun P, Yu H. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol. 2016 May 1;34(13):1448-54. Epub 2016 Feb 16. [http://jco.ascopubs.org/content/34/13/1448.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26884585 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 />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70549-7/fulltext Ford et al. 2013 (COUGAR-02)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Docetaxel_monotherapy|Docetaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''COUGAR-02 patients: 100% adenocarcinoma histology (20% esophageal, 35% gastroesophageal'' ''junction, 45% stomach) that progressed on or within 6 months of treatment with a platinum-fluoropyrimidine combination. 15% ECOG PS of 2. 12% locally advanced, 88% metastatic disease. Supportive care only.'' <br />
<br />
===References===<br />
<br />
#'''COUGAR-02:''' Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA; COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):78-86. Epub 2013 Dec 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70549-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24332238 PubMed]<br />
<br />
==CAPIRI {{#subobject:c699c3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeIRI: '''<u>Cape</u>'''citabine and '''<u>IRI</u>'''notecan<br />
<br>CAPIRI: '''<u>CAP</u>'''ecitabine and '''<u>IRI</u>'''notecan<br />
<br>XELIRI: '''<u>XEL</u>'''ox (Capecitabine) and '''<u>IRI</u>'''notecan<br />
<br>XI: '''<u>X</u>'''eloda (Capecitabine) and '''<u>I</u>'''rinotecan<br />
===Regimen {{#subobject:d233c0|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.springerlink.com/content/8051q1q431p22662/ Leary et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*[[Atropine (Atropen)]] 0.25 mg SC once on day 1, given before [[Irinotecan (Camptosar)]]<br />
*[[Loperamide (Imodium)]] 4 mg PO prn first unformed stool, then 2 mg PO Q2H x at least 12 hours, or for 12 hours after last liquid stool<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day prn diarrhea lasting longer than 24 hours despite loperamide<br />
<br />
'''21-day cycle for up to 8 cycles'''<br />
<br />
===References===<br />
<br />
#Leary A, Assersohn L, Cunningham D, Norman AR, Chong G, Brown G, Ross PJ, Costello C, Higgins L, Oates J. A phase II trial evaluating capecitabine and irinotecan as second line treatment in patients with oesophago-gastric cancer who have progressed on, or within 3 months of platinum-based chemotherapy. Cancer Chemother Pharmacol. 2009 Aug;64(3):455-62. Epub 2008 Dec 23. [http://www.springerlink.com/content/8051q1q431p22662/ link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19104814 PubMed]<br />
<br />
==Cetuximab monotherapy {{#subobject:5aca6d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b11ea0|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/PMC2928397 Gold et al. 2010 (SWOG S0415)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% metastatic esophageal adenocarcinoma who failed one prior chemotherapy regimen. 10% had ECOG PS of 2.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**Cycle 1: 400 mg/m<sup>2</sup> IV over 2 hours on day 1, then 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 8, 15, 22<br />
**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
<br />
*[[Diphenhydramine (Benadryl)]] 50 mg IV or PO once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to [[Cetuximab (Erbitux)]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Gold PJ, Goldman B, Iqbal S, Leichman LP, Zhang W, Lenz HJ, Blanke CD. Cetuximab as second-line therapy in patients with metastatic esophageal adenocarcinoma: a phase II Southwest Oncology Group Study (S0415). J Thorac Oncol. 2010 Sep;5(9):1472-6. [https://www.jto.org/article/S1556-0864(15)30627-4/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928397/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20631636 PubMed]<br />
<br />
==Docetaxel monotherapy {{#subobject:421f5e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 75 mg/m<sup>2</sup> x 6 {{#subobject:044193|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(13)70549-7/fulltext Ford et al. 2013 (COUGAR-02)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Best_supportive_care|Active symptom control]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''COUGAR-02 patients: 100% adenocarcinoma histology (20% esophageal, 35% gastroesophageal'' ''junction, 45% stomach) that progressed on or within 6 months of treatment with a platinum-fluoropyrimidine combination. 15% ECOG PS of 2. 12% locally advanced, 88% metastatic disease.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
'''21-day cycle for up to 6 cycles'''<br />
<br />
===Variant #2, 75 mg/m<sup>2</sup>, indefinite {{#subobject:abe193|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://annonc.oxfordjournals.org/content/24/6/1567.long Roy et al. 2013 (PEP0206)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|1. [[#Irinotecan_monotherapy_2|Irinotecan]]<br> 2. [[#Irinotecan_liposomal_monotherapy|Irinotecan liposomal]]<br />
| style="background-color:#d3d3d3" |Not powered to draw conclusions<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.4_suppl.2 Kojima et al. 2019 (KEYNOTE-181)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior 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 />
'''21-day cycles'''<br />
<br />
===Variant #3, 100 mg/m<sup>2</sup> {{#subobject:b279a5|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://link.springer.com/article/10.1007/s12032-007-0028-6 Albertsson et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: squamous cell or adenocarcinoma histology of the esophagus or gastric cardia.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Albertsson M, Johansson B, Friesland S, Kadar L, Letocha H, Frykholm G, Wagenius G. Phase II studies on docetaxel alone every third week, or weekly in combination with gemcitabine in patients with primary locally advanced, metastatic, or recurrent esophageal cancer. Med Oncol. 2007;24(4):407-12. [http://link.springer.com/article/10.1007/s12032-007-0028-6 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17917090 PubMed]<br />
#'''PEP0206:''' Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. [https://annonc.oxfordjournals.org/content/24/6/1567.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23406728 PubMed]<br />
#'''COUGAR-02:''' Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA; COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):78-86. Epub 2013 Dec 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70549-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24332238 PubMed]<br />
#'''Abstract:''' Kojima et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study. Journal of Clinical Oncology 37, no. 4_suppl (February 1 2019) 2-2. [https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.4_suppl.2 link to abstract]<br />
<br />
==Docetaxel & Irinotecan {{#subobject:96f053|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:38cff0|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/PMC2699385/ Burtness et al. 2009]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts in this subgroup<br />
|-<br />
|}<br />
''Patients: 79% adenocarcinoma, 21% squamous cell histology. All patients ECOG PS of 0 or 1, and unresectable/metastatic disease.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8, '''given first'''<br />
*[[Irinotecan (Camptosar)]] 50 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given second'''<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**8 mg PO once per day on days 1 & 8; 12 hours before [[Docetaxel (Taxotere)]]<br />
**10 mg IV once per day on days 1 & 8, within 1 hour of chemotherapy<br />
**8 mg PO once per day on days 1 & 8; 12 hour afters chemotherapy<br />
*[[:Category:Serotonin 5-HT3 antagonists|Serotonin 5-HT3 antagonist]] IV once per day on days 1 & 8, within 1 hour before chemotherapy<br />
*"Oral antiemetic therapy prescribed"<br />
*[[Loperamide (Imodium)]] as needed<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Burtness B, Gibson M, Egleston B, Mehra R, Thomas L, Sipples R, Quintanilla M, Lacy J, Watkins S, Murren JR, Forastiere AA. Phase II trial of docetaxel-irinotecan combination in advanced esophageal cancer. Ann Oncol. 2009 Jul;20(7):1242-8. Epub 2009 May 8. [http://annonc.oxfordjournals.org/content/20/7/1242.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699385/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19429872 PubMed]<br />
<br />
==Erlotinib monotherapy {{#subobject:5efb4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:eaf7de|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/PMC3116987/ Ilson et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 57% adenocarcinoma, 43% squamous cell histology. 6% proximal esophagus, 35% distal esophagus, 59% gastroesophageal junction.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day, at least 1 hour before a meal, or 2 hours after a meal<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Ilson DH, Kelsen D, Shah M, Schwartz G, Levine DA, Boyd J, Capanu M, Miron B, Klimstra D. A phase 2 trial of erlotinib in patients with previously treated squamous cell and adenocarcinoma of the esophagus. Cancer. 2011 Apr 1;117(7):1409-14. Epub 2010 Nov 8. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.25602/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116987/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21425140 PubMed]<br />
<br />
==Irinotecan monotherapy {{#subobject:6df2c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 14-day cycles {{#subobject:9b9303|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://ascopubs.org/doi/abs/10.1200/JCO.2019.37.4_suppl.2 Kojima et al. 2019 (KEYNOTE-181)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, 21-day cycles {{#subobject:9b9808|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://annonc.oxfordjournals.org/content/24/6/1567.long Roy et al. 2013 (PEP0206)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. [[#Irinotecan_liposomal_monotherapy|Irinotecan liposomal]]<br />
| style="background-color:#d3d3d3" |Not powered to draw conclusions<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 300 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #3, 4 out of 6 weeks {{#subobject:9fb427|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://link.springer.com/article/10.1007/s00384-002-0464-x Mühr-Wilkenshoff et al. 2003]<br />
| style="background-color:#ffffbe" |Phase II, <20 patients<br />
|-<br />
|}<br />
''Note: In contrast to the primary reference, some guidelines list a dosing schedule of 125 mg/m<sup>2</sup> IV once per day on days 1 & 8, with 21-day cycles.''<br />
<br />
''Patients: Ten with esophageal squamous cell carcinoma, three with esophageal adenocarcinoma''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<br />
#Mühr-Wilkenshoff F, Hinkelbein W, Ohnesorge I, Wolf KJ, Riecken EO, Zeitz M, Scherübl H. A pilot study of irinotecan (CPT-11) as single-agent therapy in patients with locally advanced or metastatic esophageal carcinoma. Int J Colorectal Dis. 2003 Jul;18(4):330-4. Epub 2003 Feb 1. [https://link.springer.com/article/10.1007/s00384-002-0464-x link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12774248 PubMed]<br />
#'''PEP0206:''' Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. [https://annonc.oxfordjournals.org/content/24/6/1567.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23406728 PubMed]<br />
#'''Abstract:''' Kojima et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study. Journal of Clinical Oncology 37, no. 4_suppl (February 1 2019) 2-2. [https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.4_suppl.2 link to abstract]<br />
<br />
==Irinotecan liposomal monotherapy {{#subobject:9a99c8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c50e15|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://annonc.oxfordjournals.org/content/24/6/1567.long Roy et al. 2013 (PEP0206)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)<br />
|1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. [[#Irinotecan_monotherapy_2|Irinotecan]]<br />
| style="background-color:#d3d3d3" |Not powered to draw conclusions<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan liposome (Onivyde)]] 120 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''PEP0206:''' Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun;24(6):1567-73. Epub 2013 Feb 13. [https://annonc.oxfordjournals.org/content/24/6/1567.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23406728 PubMed]<br />
<br />
==Irinotecan & Mitomycin {{#subobject:dfc95f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 125/5 {{#subobject:3213a7|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.jchemother.it/cgi-bin/digisuite.exe/product?ID=252&IDCategory=30 Bamias et al. 2003a]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: Advanced gastric and colorectal cancers. All previously received 5-fluorouracil-based chemotherapy.''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV once on day 1<br />
*[[Mitomycin (Mutamycin)]] 5 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, 300/8 {{#subobject:4a905|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://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2005&issue=12000&article=00009&type=abstract Giuliani et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% gastric adenocarcinoma. Treatment given as second-line chemotherapy for pretreated patients with advanced or metastatic disease.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV once per day on days 1 & 15<br />
*[[Mitomycin (Mutamycin)]] 8 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Bamias A, Papamichael D, Syrigos K, Pavlidis N. Phase II study of irinotecan and mitomycin C in 5-fluorouracil-pretreated patients with advanced colorectal and gastric cancer. J Chemother. 2003 Jun;15(3):275-81. [http://www.jchemother.it/cgi-bin/digisuite.exe/product?ID=252&IDCategory=30 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12868555 PubMed]<br />
#Giuliani F, Molica S, Maiello E, Battaglia C, Gebbia V, Di Bisceglie M, Vinciarelli G, Gebbia N, Colucci G; Gruppo Oncologico dell' Italia Meridionale. Irinotecan (CPT-11) and mitomycin-C (MMC) as second-line therapy in advanced gastric cancer: a phase II study of the Gruppo Oncologico dell' Italia Meridionale (prot 2106). Am J Clin Oncol. 2005 Dec;28(6):581-5. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2005&issue=12000&article=00009&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16317268 PubMed]<br />
<br />
==Irinotecan & S-1 {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cdcc15|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/PMC6444575/ Huang et al. 2019 (ESWN 01)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 160 mg/m<sup>2</sup> IV once on day 1, '''given first'''<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 10<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 10<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 10<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ESWN 01:''' Huang J, Xu B, Liu Y, Huang J, Lu P, Ba Y, Wu L, Bai Y, Zhang S, Feng J, Cheng Y, Li J, Wen L, Yuan X, Ma C, Hu C, Fan Q, Wang X. Irinotecan plus S-1 versus S-1 in patients with previously treated recurrent or metastatic esophageal cancer (ESWN 01): a prospective randomized, multicenter, open-labeled phase 3 trial. Cancer Commun (Lond). 2019 Apr 2;39(1):16. [https://cancercommun.biomedcentral.com/articles/10.1186/s40880-019-0359-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444575/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30940189 PubMed]<br />
<br />
==Nivolumab monotherapy {{#subobject:10ee99|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d18acj2|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30626-6/fulltext Kato et al. 2019 (ATTRACTION-3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[Esophageal_cancer#Docetaxel_monotherapy|Docetaxel monotherapy]] <br> 2. [[Esophageal_cancer#Paclitaxel_monotherapy_2|Paclitaxel monotherapy]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|} <br />
''Inclusion Criteria: Unresectable advanced or recurrent esophageal SCC regardless of PDL1 expression, ECOG 0-1, refractory or intolerance to one prior 5-FU or platinum-based chemotherapy''<br />
====Immunotherapy====<br />
<br />
*[[Nivolumab (Opdivo)]] 240 mg IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ATTRACTION-3.''' Kato K, Cho BC, Takahashi M, Okada M, Lin CY, Chin K, Kadowaki S, Ahn MJ, Hamamoto Y, Doki Y, Yen CC, Kubota Y, Kim SB, Hsu CH, Holtved E, Xynos I, Kodani M, Kitagawa Y. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Nov;20(11):1506-1517. Epub 2019 Sep 30. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30626-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31582355 PubMed]<br />
<br />
==Paclitaxel monotherapy {{#subobject:ec998a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, weekly {{#subobject:aa30a4|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://annonc.oxfordjournals.org/content/18/5/898.long Ilson et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients: 100% esophageal cancers. 66% adenocarcinoma, 34% squamous cell. Median ECOG PS 1, ranging 0-2.'' <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, 22<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]] 20 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to [[Paclitaxel (Taxol)]]<br />
*[[Cimetidine (Tagamet)]] 300 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to [[Paclitaxel (Taxol)]]<br />
*[[Diphenhydramine (Benadryl)]] 50 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to [[Paclitaxel (Taxol)]]<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 80 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:cc40a4|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2970420-6/fulltext Wilke et al. 2014 (RAINBOW)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Paclitaxel_.26_Ramucirumab|Paclitaxel & Ramucirumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.4_suppl.2 Kojima et al. 2019 (KEYNOTE-181)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: this is the lower bound of dosing specified in KEYNOTE-181.''<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 100 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:99h0a4|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.4_suppl.2 Kojima et al. 2019 (KEYNOTE-181)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: this is the upper bound of dosing specified in the protocol.''<br />
====Chemotherapy====<br />
<br />
*[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
===References===<br />
<br />
#Ilson DH, Wadleigh RG, Leichman LP, Kelsen DP. Paclitaxel given by a weekly 1-h infusion in advanced esophageal cancer. Ann Oncol. 2007 May;18(5):898-902. Epub 2007 Mar 9. [http://annonc.oxfordjournals.org/content/18/5/898.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17351256 PubMed]<br />
#'''RAINBOW:''' Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2970420-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25240821 PubMed]<br />
#'''Abstract:''' Kojima et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study. Journal of Clinical Oncology 37, no. 4_suppl (February 1 2019) 2-2. [https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.4_suppl.2 link to abstract]<br />
<br />
==Paclitaxel & Ramucirumab {{#subobject:fdd93f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f66446|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2970420-6/fulltext Wilke et al. 2014 (RAINBOW)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Paclitaxel_monotherapy_2|Paclitaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|28% (95% CI 23-33%)<br />
|16% (95% CI 13-20%)<br />
|-<br />
|}<br />
''Eligibility criteria for patients in RAINBOW included: "documented objective radiological or clinical disease progression during or within 4 months of the last dose of first-line platinum and fluoropyrimidine doublet with or without anthracycline."''<br />
<br />
''Patients: 100% adenocarcinoma histology, 20% gastroesophageal junction, 80% gastric origin.'' <br />
<br />
====Chemotherapy====<br />
<br />
*[[Ramucirumab (Cyramza)]] 8 mg/kg IV once per day on days 1 & 15<br />
*[[Paclitaxel (Taxol)]] 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 />
#'''RAINBOW:''' Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2970420-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25240821 PubMed]<br />
<br />
==Pembrolizumab monotherapy {{#subobject:c798a3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d18acj2|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%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.4_suppl.2 Kojima et al. 2019 (KEYNOTE-181)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)<br />
|Investigator's choice of:<br> 1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. [[#Irinotecan_monotherapy_2|Irinotecan]]<br> 3. [[#Paclitaxel_monotherapy_2|Paclitaxel]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2718411 Shah et al. 2019 (KEYNOTE-180)]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test,<br />
<br />
''100% squamous histology.'' <br />
====Immunotherapy====<br />
<br />
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1<br />
<br />
'''21-day cycle for up to 35 cycles (2 years)'''<br />
<br />
===References===<br />
<br />
#'''Abstract:''' Kojima et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study. Journal of Clinical Oncology 37, no. 4_suppl (February 1 2019) 2-2. [https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.4_suppl.2 link to abstract]<br />
#'''KEYNOTE-180:''' Shah MA, Kojima T, Hochhauser D, Enzinger P, Raimbourg J, Hollebecque A, Lordick F, Kim SB, Tajika M, Kim HT, Lockhart AC, Arkenau HT, El-Hajbi F, Gupta M, Pfeiffer P, Liu Q, Lunceford J, Kang SP, Bhagia P, Kato K. Efficacy and Safety of Pembrolizumab for Heavily Pretreated Patients With Advanced, Metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus: The Phase 2 KEYNOTE-180 Study. JAMA Oncol. 2019 Apr 1;5(4):546-550. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2718411 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30570649 PubMed]<br />
<br />
==Placebo==<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 />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961719-5/fulltext Fuchs et al. 2013 (REGARD)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ramucirumab_monotherapy|Ramucirumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70024-5/fulltext Dutton et al. 2014 (COG)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gefitinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[http://jco.ascopubs.org/content/34/13/1448.full Li et al. 2016]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Apatinib_monotherapy|Apatinib]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31827-5/fulltext Kang et al. 2017 (ATTRACTION-2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Nivolumab<br />
| style="background-color:#d73027" |Inferior OS<br />
|}<br />
''Patients in REGARD previously had "disease progression within 4 months of the last dose of first-line platinum-containing or fluoropyrimidine-containing chemotherapy for metastatic disease, or within 6 months of the last dose of platinum-containing or fluoropyrimidine-containing adjuvant treatment."''<br />
<br />
''No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.''<br />
<br />
''Fuchs patients: 100% adenocarcinoma histology (25% gastroesophageal junction, 75% gastric origin).'' <br />
<br />
''Dutton patients: 24% squamous cell, 76% adenocarcinoma histology. 78% esophageal, 22% gastroesophageal junction''<br />
<br />
''Li patients: 100% adenocarcinoma histology (70% gastric origin, 22% gastroesophageal junction, 8% unknown). All patients with at least two prior lines of treatment.''<br />
<br />
''ATTRACTION-2: 100% adenocarcinoma. Patients had progression on two prior lines of systemic treatment.'' <br />
<br />
===References===<br />
<br />
#'''REGARD:''' Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9. Epub 2013 Oct 3. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961719-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24094768 PubMed]<br />
#'''COG:''' Dutton SJ, Ferry DR, Blazeby JM, Abbas H, Dahle-Smith A, Mansoor W, Thompson J, Harrison M, Chatterjee A, Falk S, Garcia-Alonso A, Fyfe DW, Hubner RA, Gamble T, Peachey L, Davoudianfar M, Pearson SR, Julier P, Jankowski J, Kerr R, Petty RD. Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol. 2014 Jul;15(8):894-904. Epub 2014 Jun 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70024-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24950987 PubMed]<br />
#Li J, Qin S, Xu J, Xiong J, Wu C, Bai Y, Liu W, Tong J, Liu Y, Xu R, Wang Z, Wang Q, Ouyang X, Yang Y, Ba Y, Liang J, Lin X, Luo D, Zheng R, Wang X, Sun G, Wang L, Zheng L, Guo H, Wu J, Xu N, Yang J, Zhang H, Cheng Y, Wang N, Chen L, Fan Z, Sun P, Yu H. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol. 2016 May 1;34(13):1448-54. Epub 2016 Feb 16. [http://jco.ascopubs.org/content/34/13/1448.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26884585 PubMed]<br />
#'''ATTRACTION-2:''' Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Dec 2;390(10111):2461-2471. Epub 2017 Oct 6. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31827-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28993052 PubMed]<br />
##'''Subgroup analysis:''' Kato K, Satoh T, Muro K, Yoshikawa T, Tamura T, Hamamoto Y, Chin K, Minashi K, Tsuda M, Yamaguchi K, Machida N, Esaki T, Goto M, Komatsu Y, Nakajima TE, Sugimoto N, Yoshida K, Oki E, Nishina T, Tsuji A, Fujii H, Kunieda K, Saitoh S, Omuro Y, Azuma M, Iwamoto Y, Taku K, Fushida S, Chen LT, Kang YK, Boku N. A subanalysis of Japanese patients in a randomized, double-blind, placebo-controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2). Gastric Cancer. 2019 Mar;22(2):344-354. Epub 2018 Dec 1. [https://link.springer.com/article/10.1007%2Fs10120-018-0899-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394726/ link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30506519 PubMed]<br />
<br />
==Ramucirumab monotherapy {{#subobject:425b15|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:813cff|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Overall response rate|'''ORR''']]<br />
!Comparator [[Overall response rate|'''ORR''']]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961719-5/fulltext Fuchs et al. 2013 (REGARD)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|3%<br />
|3%<br />
|-<br />
|}<br />
''Patients in REGARD previously had "disease progression within 4 months of the last dose of first-line platinum-containing or fluoropyrimidine-containing chemotherapy for metastatic disease, or within 6 months of the last dose of platinum-containing or fluoropyrimidine-containing adjuvant treatment."''<br />
<br />
''Patients: 100% adenocarcinoma histology (25% gastroesophageal junction, 75% gastric origin)''<br />
<br />
====Chemotherapy====<br />
<br />
*[[Ramucirumab (Cyramza)]] 8 mg/kg IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''REGARD:''' Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9. Epub 2013 Oct 3. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961719-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24094768 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:387c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cdff15|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/PMC6444575/ Huang et al. 2019 (ESWN 01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Irinotecan_.26_S-1|Irinotecan & S-1]]<br />
| style="background-color:#d73027" |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 />
<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 14<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 14<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ESWN 01:''' Huang J, Xu B, Liu Y, Huang J, Lu P, Ba Y, Wu L, Bai Y, Zhang S, Feng J, Cheng Y, Li J, Wen L, Yuan X, Ma C, Hu C, Fan Q, Wang X. Irinotecan plus S-1 versus S-1 in patients with previously treated recurrent or metastatic esophageal cancer (ESWN 01): a prospective randomized, multicenter, open-labeled phase 3 trial. Cancer Commun (Lond). 2019 Apr 2;39(1):16. [https://cancercommun.biomedcentral.com/articles/10.1186/s40880-019-0359-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444575/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30940189 PubMed]<br />
<br />
[[Category:Esophageal cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Dweeraratnehttps://hemonc.org/w/index.php?title=Colorectal_cancer,_HER2-positive&diff=41808Colorectal cancer, HER2-positive2020-01-08T23:17:33Z<p>Dweeraratne: /* Regimen #subobject:98buya */</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:RyanNguyen.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Ryannguyen|Ryan Nguyen, DO]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br>[https://www.linkedin.com/in/ryan-nguyen-0b12a432/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br />
|-<br />
|}<br />
<big>Note: the page has regimens specific to Her2-amplified colon cancer. <br />
<br />
*See the [[Colon_cancer|'''main colon cancer page''']] for general regimens.</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 />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2016:''' Van Cutsem et al. [https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Management-of-Patients-with-Metastatic-Colorectal-Cancer ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.] [https://www.ncbi.nlm.nih.gov/pubmed/27380959 PubMed]<br />
<br />
===Older===<br />
<br />
*'''2013:''' Labianca et al. [http://annonc.oxfordjournals.org/content/24/suppl_6/vi64.full.pdf+html Early Colon Cancer: ESMO Clinical Practice Guidelines] [https://www.ncbi.nlm.nih.gov/pubmed/24078664 PubMed]<br />
*'''2013:''' Balmaña et al. [http://annonc.oxfordjournals.org/content/24/suppl_6/vi73.full.pdf+html Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines.] [https://www.ncbi.nlm.nih.gov/pubmed/23813931 PubMed]<br />
<br />
==[http://www.jsccr.jp/en/index.html Japanese Society for Cancer of the Colon and Rectum]==<br />
<br />
*'''2016:''' Watanabe et al. [https://link.springer.com/article/10.1007%2Fs10147-017-1101-6 Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer] [https://www.ncbi.nlm.nih.gov/pubmed/28349281 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf NCCN Guidelines - Colon Cancer]<br />
<br />
==[http://www.siog.org/ SIOG]==<br />
<br />
*'''2014:''' Papamichael et al. [https://academic.oup.com/annonc/article/26/3/463/222917 Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013]<br />
<br />
=Advanced or metastatic disease, second or third-line therapy=<br />
==Pertuzumab & Trastuzumab {{#subobject:ea894c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:98buya|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(18)30904-5/fulltext Meric-Bernstam et al. 2019 (MyPathway)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#6e016b; color:white" |ORR: 32% (95% CI 20-45%)<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
HER2 amplification<br />
<br />
''Patients enrolled in MyPathway had ECOG 0-2''<br />
<br />
''Diagnostic criteria for Her2 positivity in MyPathway:''<br />
<br />
*Patients with solid tumors that have HER2 overexpression, amplification, or HER2-activating mutation as identified by assays performed at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. <br />
**Assays using in situ hybridization (fluorescence in situ hybridization [FISH] or chromogenic in situ hybridization [CISH]) must indicate the presence of gene amplification with a HER2/CEP17 ratio of ≥ 2.0 or HER2 gene copy number > 6.0.<br />
**Assays using IHC must indicate a score of 3 +.<br />
**Assays using next generation sequencing (NGS) of genes with known or potentially clinically relevant alterations or analysis by real-time polymerase chain reaction (RT-PCR) must identify clinically activating mutations (those with major coding disruptions resulting in an amino acid change that is likely to be detrimental to protein function, including premature stop codons or frameshift mutations early in the coding region) or copy number gain.<br />
**In cases where multiple assays are done, HER2 positivity by any of the testing methodologies would make the patient eligible as long as eligibility criteria are fulfilled.<br />
<br />
====Chemotherapy====<br />
<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 />
<br />
#'''MyPathway:''' Meric-Bernstam F, Hurwitz H, Raghav KPS, MCwilliams RR, Fakih M, VanderWalde A, Swanton C, Kurzrock R, Burris H, Sweeney C, Bose R, Spigel DR, Beattie MS, Blotner S, Stone A, Schulze K, Cuchelkar V, Hainsworth J. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2019 Apr;20(4):518-530. Epub 2019 Mar 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30904-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30857956 PubMed]<br />
<br />
==Lapatinib & Trastuzumab {{#subobject:e17gbc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:9817cz|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(16)00150-9/fulltext Sartore-Bianchi et al. 2016 (HERACLES)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#6e016b; color:white" |ORR: 30% (95% CI 14-50%)<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
KRAS wild-type, HER2 amplification<br />
<br />
''Patients enrolled in HERACLES had ECOG 0-1''<br />
<br />
''Diagnostic criteria for Her2 positivity in HERACLES:''<br />
<br />
*Tumours with 3+ HER2 score in more than 50% of cells by immunohistochemistry<br />
<br />
or<br />
<br />
*2+ HER2 score and a HER2:CEP17 ratio higher than two in more than 50% of cells by FISH<br />
<br />
====Chemotherapy====<br />
<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<br />
**Cycle 2 onwards: 2 mg/kg IV once on day 1<br />
<br />
'''7-day cycles'''<br />
<br />
===References===<br />
<br />
#'''HERACLES:''' Sartore-Bianchi A, Trusolino L, Martino C, Bencardino K, Lonardi S, Bergamo F, Zagonel V, Leone F, Depetris I, Martinelli E, Troiani T, Ciardiello F, Racca P, Bertotti A, Siravegna G, Torri V, Amatu A, Ghezzi S, Marrapese G, Palmeri L, Valtorta E, Cassingena A, Lauricella C, Vanzulli A, Regge D, Veronese S, Comoglio PM, Bardelli A, Marsoni S, Siena S. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016 Jun;17(6):738-746. Epub 2016 Apr 20. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00150-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27108243 PubMed]<br />
<br />
[[Category:Colon cancer regimens]]<br />
[[Category:Biomarker-specific pages]]<br />
[[Category:Colorectal cancers]]</div>Dweeraratnehttps://hemonc.org/w/index.php?title=Colorectal_cancer,_BRAF-mutated&diff=41802Colorectal cancer, BRAF-mutated2020-01-08T23:11:44Z<p>Dweeraratne: /* Regimen #subobject:9134b2 */</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:RyanNguyen.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Ryannguyen|Ryan Nguyen, DO]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br>[https://www.linkedin.com/in/ryan-nguyen-0b12a432/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br />
|-<br />
|}<br />
<big>Note: the page has regimens specific to BRAF-mutated colon cancer. <br />
<br />
*See the [[Colon_cancer|'''main colon cancer page''']] for general regimens.</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 />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2016:''' Van Cutsem et al. [https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Management-of-Patients-with-Metastatic-Colorectal-Cancer ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.] [https://www.ncbi.nlm.nih.gov/pubmed/27380959 PubMed]<br />
<br />
===Older===<br />
<br />
*'''2013:''' Labianca et al. [http://annonc.oxfordjournals.org/content/24/suppl_6/vi64.full.pdf+html Early Colon Cancer: ESMO Clinical Practice Guidelines] [https://www.ncbi.nlm.nih.gov/pubmed/24078664 PubMed]<br />
*'''2013:''' Balmaña et al. [http://annonc.oxfordjournals.org/content/24/suppl_6/vi73.full.pdf+html Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines.] [https://www.ncbi.nlm.nih.gov/pubmed/23813931 PubMed]<br />
<br />
==[http://www.jsccr.jp/en/index.html Japanese Society for Cancer of the Colon and Rectum]==<br />
<br />
*'''2016:''' Watanabe et al. [https://link.springer.com/article/10.1007%2Fs10147-017-1101-6 Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer] [https://www.ncbi.nlm.nih.gov/pubmed/28349281 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf NCCN Guidelines - Colon Cancer]<br />
<br />
==[http://www.siog.org/ SIOG]==<br />
<br />
*'''2014:''' Papamichael et al. [https://academic.oup.com/annonc/article/26/3/463/222917 Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013]<br />
<br />
=Advanced or metastatic disease, second or third-line therapy=<br />
==Binimetinib, Encorafenib, Cetuximab {{#subobject:ea894c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9134b2|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1908075 Kopetz et al. 2019 (BEACON)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|1. Irinotecan & Cetuximab <br> 2. FOLFIRI & Cetuximab<br />
| style="background-color:#1a9851" |Superior OS<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
BRAF V600E<br />
<br />
====Chemotherapy====<br />
<br />
*[[Binimetinib (Mektovi)]] 45 mg PO twice per day<br />
*[[Encorafenib (Braftovi)]] 300 mg PO once per day<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**Cycle 1: 400 mg/m<sup>2</sup> IV over 120 minutes once on day 1, then 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 8, 15, 22<br />
**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''BEACON:''' Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, Wasan H, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Pfeiffer P, Orlov S, Lonardi S, Elez E, Kim TW, Schellens JHM, Guo C, Krishnan A, Dekervel J, Morris V, Calvo Ferrandiz A, Tarpgaard LS, Braun M, Gollerkeri A, Keir C, Maharry K, Pickard M, Christy-Bittel J, Anderson L, Sandor V, Tabernero J. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer. N Engl J Med. 2019 Oct 24;381(17):1632-1643. Epub 2019 Sep 30. [https://www.nejm.org/doi/full/10.1056/NEJMoa1908075 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31566309 PubMed]<br />
<br />
==Irinotecan, Vemurafenib, Cetuximab {{#subobject:aab14c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:98buya|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.2017.35.4_suppl.520 Kopetz et al. 2017 (SWOG 1406)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|Irinotecan & Cetuximab<br />
| style="background-color:#1a9851" |Superior PFS<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
BRAF V600<br />
<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vemurafenib (Zelboraf)]] 960 mg PO twice per day<br />
*[[Cetuximab (Erbitux)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Abstract:''' Kopetz S, McDonough S, Morris V, Lenz HJ, Magliocco A, Atreya C, Diaz L, Allegra C, Lieu C, Wang S, Eckhardt SG, Semrad T, Kaberle K, Guthrie K, Hochster H. Randomized phase II study of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG1406). Journal of Clinical Oncology 35, no. 4_suppl (February 01, 2017) 520-520. Published online March 21, 2017. [https://ascopubs.org/doi/abs/10.1200/JCO.2017.35.4_suppl.520 link to abstract]<br />
<br />
==Dabrafenib, Trametinib, Panitumumab{{#subobject:abca4c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:98bhza|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://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.103 Atreya et al. 2017 (Study 116833)]<br />
| style="background-color:#91cf61" |Phase I/II<br />
| style="background-color:#6e016b; color:white" |ORR: 26%<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
BRAF V600E<br />
<br />
====Chemotherapy====<br />
<br />
*[[Dabrafenib (Tafinlar)]] 150 mg PO twice per day<br />
*[[Trametinib (Mekinist)]] 2 mg PO once per day<br />
*[[Panitumumab (Vectibix)]] 6 mg/kg IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Abstract:''' Chloe EA, Van Cutsem E, Bendell JC, Andre T, Schellens JHM, Gordon MS, McRee AJ, O'Dwyer PJ, Muro K, Tabernero J, Van Geel R, Sidhu R, Greger JG, Rangwala FA, Motwani M, Wu Y, Orford KW, and Corcoran RB. Journal of Clinical Oncology 2015 33:15_suppl, 103-103. Published online January 31, 2017. [https://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.103 link to abstract] <br />
<br />
[[Category:Colon cancer regimens]]<br />
[[Category:Biomarker-specific pages]]<br />
[[Category:Colorectal cancers]]</div>Dweeraratnehttps://hemonc.org/w/index.php?title=Colon_cancer,_RAS_wild-type&diff=41792Colon cancer, RAS wild-type2020-01-08T23:03:11Z<p>Dweeraratne: /* Variant #1, 250 mg/m2 weekly #subobject:a72650 */</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:RyanNguyen.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Ryannguyen|Ryan Nguyen, DO]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br>[https://www.linkedin.com/in/ryan-nguyen-0b12a432/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br />
|-<br />
|}<br />
<big>Note: the page has adjuvant and perioperative regimens specific to KRAS wild-type colon cancer as well as systemic regimens for the more general category of KRAS wild-type colorectal cancer. <br />
<br />
*See the [[Colon_cancer|'''main colon cancer page''']] for general regimens.</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 />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2016:''' [http://annonc.oxfordjournals.org/content/27/8/1386.full.pdf+html ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.] [https://www.ncbi.nlm.nih.gov/pubmed/27380959 PubMed]<br />
*'''2013:''' [http://annonc.oxfordjournals.org/content/24/suppl_6/vi64.full.pdf+html Early Colon Cancer: ESMO Clinical Practice Guidelines] [https://www.ncbi.nlm.nih.gov/pubmed/24078664 PubMed]<br />
*'''2013:''' [http://annonc.oxfordjournals.org/content/24/suppl_6/vi73.full.pdf+html Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines.] [https://www.ncbi.nlm.nih.gov/pubmed/23813931 PubMed]<br />
<br />
==[http://www.jsccr.jp/en/index.html Japanese Society for Cancer of the Colon and Rectum]==<br />
<br />
*'''2016:''' [https://link.springer.com/article/10.1007%2Fs10147-017-1101-6 Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer] [https://www.ncbi.nlm.nih.gov/pubmed/28349281 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf NCCN Guidelines - Colon Cancer]<br />
<br />
=Adjuvant therapy=<br />
==mFOLFOX6 {{#subobject:32d6c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:30juz2|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jama.jamanetwork.com/article.aspx?articleid=1148329 Alberts et al. 2012 (N0147)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#mFOLFOX6_.26_Cetuximab|mFOLFOX6 & Cetuximab]]<br />
| style="background-color:#d9ef8b" |Might have superior DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]], within 10 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''<br />
<br />
'''14-day cycle for 12 cycles'''<br />
<br />
===References===<br />
<br />
#'''N0147:''' Alberts SR, Sargent DJ, Nair S, Mahoney MR, Mooney M, Thibodeau SN, Smyrk TC, Sinicrope FA, Chan E, Gill S, Kahlenberg MS, Shields AF, Quesenberry JT, Webb TA, Farr GH Jr, Pockaj BA, Grothey A, Goldberg RM. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA. 2012 Apr 4;307(13):1383-93. [http://jama.jamanetwork.com/article.aspx?articleid=1148329 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442260/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22474202 PubMed]<br />
<br />
==mFOLFOX6 & Cetuximab {{#subobject:e4c5e0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOX6 & Cetuximab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Cetuximab<br />
===Regimen {{#subobject:7abe3e|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jama.jamanetwork.com/article.aspx?articleid=1148329 Alberts et al. 2012 (N0147)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#mFOLFOX6|mFOLFOX6]]<br />
| style="background-color:#fee08b" |Might have inferior DFS<br />
|-<br />
|}<br />
''Some guidelines do not recommend using cetuximab as adjuvant therapy outside of a clinical trial.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]], within 10 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1<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 on day 8<br />
**Cycles 2 to 12: 250 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 8<br />
<br />
'''14-day cycle for 12 cycles'''<br />
<br />
===References===<br />
<br />
#'''N0147:''' Alberts SR, Sargent DJ, Nair S, Mahoney MR, Mooney M, Thibodeau SN, Smyrk TC, Sinicrope FA, Chan E, Gill S, Kahlenberg MS, Shields AF, Quesenberry JT, Webb TA, Farr GH Jr, Pockaj BA, Grothey A, Goldberg RM. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA. 2012 Apr 4;307(13):1383-93. [http://jama.jamanetwork.com/article.aspx?articleid=1148329 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442260/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22474202 PubMed]<br />
<br />
=Perioperative therapy for oligometastatic disease=<br />
==FOLFIRI {{#subobject:a051ec|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br />
===Regimen {{#subobject:49d215|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRI_.26_Cetuximab|FOLFIRI & Cetuximab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles until lesions deemed resectable or up to 12 cycles'''<br />
<br />
===References===<br />
<br />
#'''Fudan 2012-03:''' Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. [https://ascopubs.org/doi/full/10.1200/JCO.2012.44.8308 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23569301 PubMed]<br />
<br />
==FOLFIRI & Cetuximab {{#subobject:a051ec|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI & Cetuximab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Cetuximab<br />
===Variant #1, weekly cetuximab {{#subobject:8f47f9|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#FOLFIRI|FOLFIRI]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Wild-type KRAS, Wild-type NRAS<br />
<br />
''Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cetuximab (Erbitux)]] as follows, '''given first''':<br />
**Cycle 1: 400 mg/m<sup>2</sup> IV once on day 1, then 250 mg/m<sup>2</sup> IV once on day 8<br />
**Subsequent cycles: 250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''14-day cycles until lesions deemed resectable or up to 12 cycles'''<br />
<br />
===Variant #2, bi-weekly cetuximab {{#subobject:49d215|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#FOLFIRI|FOLFIRI]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cetuximab (Erbitux)]] 500 mg/m<sup>2</sup> IV once on day 1, '''given first'''<br />
<br />
'''14-day cycles until lesions deemed resectable or up to 12 cycles'''<br />
<br />
===References===<br />
<br />
#'''Fudan 2012-03:''' Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. [https://ascopubs.org/doi/full/10.1200/JCO.2012.44.8308 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23569301 PubMed]<br />
<br />
==mFOLFOX6 {{#subobject:8fcd39|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Variant #1, 400/2800/85, resectable or suboptimally resectable {{#subobject:17252e|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70105-6/fulltext Primrose et al. 2014 (New EPOC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#mFOLFOX6_.26_Cetuximab|mFOLFOX6 & Cetuximab]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
''Note: this trial was only open to KRAS wild-type patients with resectable or suboptimally resectable colorectal liver metastases.''<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycle for 6 cycles, then surgery, then 14-day cycle for 6 cycles'''<br />
<br />
===Variant #2, 400/2800/85, unresectable {{#subobject:e190fa|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#mFOLFOX6_.26_Cetuximab|mFOLFOX6 & Cetuximab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.''<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles until lesions deemed resectable or up to 12 cycles'''<br />
<br />
===References===<br />
<br />
#'''Fudan 2012-03:''' Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. [https://ascopubs.org/doi/full/10.1200/JCO.2012.44.8308 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23569301 PubMed]<br />
#'''New EPOC:''' Primrose J, Falk S, Finch-Jones M, Valle J, O'Reilly D, Siriwardena A, Hornbuckle J, Peterson M, Rees M, Iveson T, Hickish T, Butler R, Stanton L, Dixon E, Little L, Bowers M, Pugh S, Garden OJ, Cunningham D, Maughan T, Bridgewater J. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol. 2014 May;15(6):601-11. Epub 2014 Apr 7. Erratum in: Lancet Oncol. 2014 Jun;15(7):e253. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70105-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24717919 PubMed]<br />
<br />
==mFOLFOX6 & Cetuximab {{#subobject:8fcd39|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOX6 & Cetuximab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Cetuximab<br />
===Variant #1, weekly cetuximab {{#subobject:dcf5ee|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#mFOLFOX6|mFOLFOX6]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Wild-type KRAS, Wild-type NRAS<br />
<br />
''Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cetuximab (Erbitux)]] as follows, '''given first''':<br />
**Cycle 1: 400 mg/m<sup>2</sup> IV once on day 1, then 250 mg/m<sup>2</sup> IV once on day 8<br />
**Subsequent cycles: 250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''14-day cycles until lesions deemed resectable or up to 12 cycles'''<br />
<br />
===Variant #2, bi-weekly cetuximab {{#subobject:e190fa|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|mFOLFOX6<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cetuximab (Erbitux)]] 500 mg/m<sup>2</sup> IV once on day 1, '''given first'''<br />
<br />
'''14-day cycles until lesions deemed resectable or up to 12 cycles'''<br />
<br />
===References===<br />
<br />
#'''Fudan 2012-03:''' Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. [https://ascopubs.org/doi/full/10.1200/JCO.2012.44.8308 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23569301 PubMed]<br />
<br />
=Advanced or metastatic disease, first-line=<br />
==CapeOx & Panitumumab {{#subobject:22cf7b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOx & Panitumumab: '''<u>Cape</u>'''citabine, '''<u>Ox</u>'''aliplatin, Panitumumab<br />
===Regimen {{#subobject:944ac6|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://link.springer.com/article/10.1007%2Fs12032-018-1160-1 Papaxoinis et al. 2018 (HE 6A/09)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Wild-type KRAS, Wild-type NRAS<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
*[[Panitumumab (Vectibix)]] 9 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
===References===<br />
<br />
#'''HE 6A/09:''' Papaxoinis G, Kotoula V, Giannoulatou E, Koliou GA, Karavasilis V, Lakis S, Koureas A, Bobos M, Chalaralambous E, Daskalaki E, Chatzopoulos K, Tsironis G, Pazarli E, Chrisafi S, Samantas E, Kaklamanos IG, Varthalitis I, Konstantara A, Syrigos KN, Pentheroudakis G, Pectasides D, Fountzilas G. Phase II study of panitumumab combined with capecitabine and oxaliplatin as first-line treatment in metastatic colorectal cancer patients: clinical results including extended tumor genotyping. Med Oncol. 2018 May 31;35(7):101. [https://link.springer.com/article/10.1007%2Fs12032-018-1160-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29855806 PubMed]<br />
<br />
==FOLFIRI & Bevacizumab {{#subobject:80d6b8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI & Bevacizumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Bevacizumab<br />
===Regimen {{#subobject:28b67a|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70330-4/fulltext Heinemann et al. 2014 (FIRE-3)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#FOLFIRI_.26_Cetuximab_2|FOLFIRI & Cetuximab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first, with leucovorin'''<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given second'''<br />
**In FIRE-3, initial infusion is over 90 minutes, next over 60 minutes, and subsequently over 30 minutes<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''FIRE-3:''' Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31.[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70330-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25088940 PubMed]<br />
<br />
==FOLFIRI & Cetuximab {{#subobject:11cf7b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI & Cetuximab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Cetuximab<br />
===Regimen {{#subobject:921ac6|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%" |[[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/NEJMoa0805019 Van Cutsem et al. 2009 (CRYSTAL)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#FOLFIRI|FOLFIRI]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70330-4/fulltext Heinemann et al. 2014 (FIRE-3)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Wild-type KRAS, Wild-type NRAS<br />
<br />
''Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.''<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, 1 hour after completion of cetuximab, with irinotecan'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given second, 1 hour after completion of cetuximab, with leucovorin'''<br />
*[[Cetuximab (Erbitux)]] as follows, '''given first and completed at least 1 hour before FOLFIRI begins''':<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 on day 8<br />
**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''CRYSTAL:''' Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. [https://www.nejm.org/doi/full/10.1056/NEJMoa0805019 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19339720 PubMed]<br />
<!-- ## '''Update: Abstract:''' E. Van Cutsem, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D. Cunningham, I. Celik, C. Kohne. Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome. 2010 ASCO Annual Meeting abstract 3570. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=54429 link to abstract] --><br />
##'''Update:''' Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. [http://jco.ascopubs.org/content/29/15/2011.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21502544 PubMed]<br />
##'''Pooled update:''' Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://www.ejcancer.com/article/S0959-8049(12)00209-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22446022 PubMed]<br />
##'''Biomarker analysis:''' Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. [https://ascopubs.org/doi/full/10.1200/JCO.2014.59.4812 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25605843 PubMed]<br />
#'''FIRE-3:''' Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70330-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25088940 PubMed]<br />
<br />
==FOLFIRI & Cetuximab (L-Leucovorin) {{#subobject:22bf7b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI & Cetuximab: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Cetuximab<br />
===Regimen {{#subobject:8ugac6|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%" |[[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/NEJMoa0805019 Van Cutsem et al. 2009 (CRYSTAL)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#FOLFIRI|FOLFIRI]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70330-4/fulltext Heinemann et al. 2014 (FIRE-3)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Wild-type KRAS, Wild-type NRAS<br />
<br />
''Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.''<br />
====Chemotherapy====<br />
<br />
*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, 1 hour after completion of cetuximab, with irinotecan'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given second, 1 hour after completion of cetuximab, with L-leucovorin'''<br />
*[[Cetuximab (Erbitux)]] as follows, '''given first and completed at least 1 hour before FOLFIRI begins''':<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 on day 8<br />
**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''CRYSTAL:''' Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. [https://www.nejm.org/doi/full/10.1056/NEJMoa0805019 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19339720 PubMed]<br />
<!-- ## '''Update: Abstract:''' E. Van Cutsem, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D. Cunningham, I. Celik, C. Kohne. Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome. 2010 ASCO Annual Meeting abstract 3570. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=54429 link to abstract] --><br />
##'''Update:''' Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. [http://jco.ascopubs.org/content/29/15/2011.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21502544 PubMed]<br />
##'''Pooled update:''' Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://www.ejcancer.com/article/S0959-8049(12)00209-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22446022 PubMed]<br />
##'''Biomarker analysis:''' Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. [https://ascopubs.org/doi/full/10.1200/JCO.2014.59.4812 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25605843 PubMed]<br />
#'''FIRE-3:''' Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70330-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25088940 PubMed]<br />
<br />
==FOLFOX4 {{#subobject:7239a0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:ab483a|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2008.20.8397 Bokemeyer et al. 2008 (OPUS)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#FOLFOX4_.26_Cetuximab|FOLFOX4 & Cetuximab]]<br />
| style="background-color:#d73027" |Inferior OS (*)<br />
|-<br />
|[http://jco.ascopubs.org/content/28/31/4697.long Douillard et al. 2010 (PRIME)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFOX4_.26_Panitumumab|FOLFOX4 & Panitumumab]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS (*)<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2018.78.3183 Qin et al. 2018 (TAILOR-CRC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFOX4_.26_Cetuximab|FOLFOX4 & Cetuximab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: in PRIME, patients with KRAS wild-type tumors receiving this regimen seem to have inferior OS, based on the 2014 update. Conversely, in KRAS mutants, this regimen seems to have superior PFS. Reported efficacy for OPUS is based on the 2012 pooled update and is only for KRAS wild-type tumors. TAILOR required RAS wild-type (not just KRAS). Note that there is another trial named TAILOR in non-small cell lung cancer, so this one has been dubbed TAILOR-CRC.''<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''OPUS:''' Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29. [https://ascopubs.org/doi/full/10.1200/JCO.2008.20.8397 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19114683 PubMed]<br />
##'''Update:''' Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011 Jul;22(7):1535-46. Epub 2011 Jan 12. [https://academic.oup.com/annonc/article/22/7/1535/187254 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21228335 PubMed]<br />
##'''Pooled Update:''' Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://www.ejcancer.com/article/S0959-8049(12)00209-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22446022 PubMed]<br />
#'''PRIME:''' Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010 Nov 1;28(31):4697-705. Epub 2010 Oct 4. [http://jco.ascopubs.org/content/28/31/4697.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20921465 PubMed]<br />
##'''Biomarker analysis:''' Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013 Sep 12;369(11):1023-34. [https://www.nejm.org/doi/full/10.1056/NEJMoa1305275 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24024839 PubMed]<br />
##'''Update:''' Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jul;25(7):1346-55. Epub 2014 Apr 8. [https://academic.oup.com/annonc/article/25/7/1346/2801199 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24718886 PubMed]<br />
#'''TAILOR:''' Qin S, Li J, Wang L, Xu J, Cheng Y, Bai Y, Li W, Xu N, Lin LZ, Wu Q, Li Y, Yang J, Pan H, Ouyang X, Qiu W, Wu K, Xiong J, Dai G, Liang H, Hu C, Zhang J, Tao M, Yao Q, Wang J, Chen J, Eggleton SP, Liu T. Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer: the open-label, randomized, phase III TAILOR trial. J Clin Oncol. 2018 Oct 20;36(30):3031-9. Epub 2018 Sep 10. [https://ascopubs.org/doi/full/10.1200/JCO.2018.78.3183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30199311 PubMed]<br />
<br />
==FOLFOX4 & Cetuximab {{#subobject:5e5bf3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX4 & Cetuximab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Cetuximab<br />
<br />
===Regimen {{#subobject:9ec84d|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2008.20.8397 Bokemeyer et al. 2008 (OPUS)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#FOLFOX4|FOLFOX4]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2018.78.3183 Qin et al. 2018 (TAILOR-CRC)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#FOLFOX4|FOLFOX4]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Wild-type KRAS, Wild-type NRAS<br />
<br />
''Reported efficacy for OPUS is based on the 2012 pooled update and is only for KRAS wild-type tumors. TAILOR required RAS wild-type (not just KRAS). Note that there is another trial named TAILOR in non-small cell lung cancer, so this one has been dubbed TAILOR-CRC.''<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given second, with oxaliplatin on day 1'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given third''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<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 on day 8, '''given first'''<br />
**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''OPUS:''' Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29. [https://ascopubs.org/doi/full/10.1200/JCO.2008.20.8397 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19114683 PubMed]<br />
##'''Update:''' Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011 Jul;22(7):1535-46. Epub 2011 Jan 12. [https://academic.oup.com/annonc/article/22/7/1535/187254 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21228335 PubMed]<br />
##'''Pooled Update:''' Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://www.ejcancer.com/article/S0959-8049(12)00209-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22446022 PubMed]<br />
#'''TAILOR:''' Qin S, Li J, Wang L, Xu J, Cheng Y, Bai Y, Li W, Xu N, Lin LZ, Wu Q, Li Y, Yang J, Pan H, Ouyang X, Qiu W, Wu K, Xiong J, Dai G, Liang H, Hu C, Zhang J, Tao M, Yao Q, Wang J, Chen J, Eggleton SP, Liu T. Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer: the open-label, randomized, phase III TAILOR trial. J Clin Oncol. 2018 Oct 20;36(30):3031-9. Epub 2018 Sep 10. [https://ascopubs.org/doi/full/10.1200/JCO.2018.78.3183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30199311 PubMed]<br />
<br />
==FOLFOX4 & Panitumumab {{#subobject:486271|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX4 & Panitumumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Panitumumab<br />
===Regimen {{#subobject:d862a3|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/28/31/4697.long Douillard et al. 2010 (PRIME)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#FOLFOX4|FOLFOX4]]<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Wild-type KRAS, Wild-type NRAS<br />
<br />
''Note: in KRAS wild-type patients, this regimen seems to have superior OS, based on the 2014 update.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Panitumumab (Vectibix)]] 6 mg/kg IV once on day 1, '''given first'''<br />
**Infusion times are 1 hour for cycle 1, then if tolerated, 30 minutes for cycle 2 and later<br />
<br />
'''14-day cycles'''<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; the 2008 Gastrointestinal Cancers Symposium, January 25-27, 2008, Orlando, FL; the joint 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology, September 20-24, 2009, Berlin, Germany; the 6th Annual Meeting of the International Society of Gastrointestinal Oncology, October 1-3, 2009, Philadelphia, PA; the 2009 National Cancer Research Institute Cancer Conference, October 4-7, 2009, Birmingham, United Kingdom; and the 2010 Gastrointestinal Cancers Symposium, January 22-24, 2010, Orlando, FL. --><br />
<br />
#'''PRIME:''' Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010 Nov 1;28(31):4697-705. Epub 2010 Oct 4. [http://jco.ascopubs.org/content/28/31/4697.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20921465 PubMed]<br />
##'''Biomarker analysis:''' Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013 Sep 12;369(11):1023-34. [https://www.nejm.org/doi/full/10.1056/NEJMoa1305275 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24024839 PubMed]<br />
##'''Update:''' Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jul;25(7):1346-55. Epub 2014 Apr 8. [https://academic.oup.com/annonc/article/25/7/1346/2801199 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24718886 PubMed]<br />
<br />
==mFOLFOX6 & Cetuximab {{#subobject:12d786|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOX6 & Cetuximab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Cetuximab<br />
===Regimen {{#subobject:8baf2c|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545896/ Venook et al. 2017 (CALGB 80405)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|mFOLFOX6 & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(18)30938-9/fulltext Aranda et al. 2018 (MACRO-2)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Wild-type KRAS, Wild-type NRAS<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cetuximab (Erbitux)]] as follows, '''given first''':<br />
**Cycle 1: 400 mg/m<sup>2</sup> IV once on day 1, then 250 mg/m<sup>2</sup> IV once on day 8<br />
**Subsequent cycles: 250 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
'''14-day cycles (see below)'''<br />
====Subsequent treatment====<br />
<br />
*MACRO-2, after 8 cycles: continued mFOLFOX6 & Cetuximab until progression versus [[#Cetuximab_monotherapy|cetuximab maintenance]]<br />
<br />
===References===<br />
<br />
#'''CALGB 80405:''' Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O'Neil BH, Atkins JN, Berry S, Polite BN, O'Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, El-Khoueiry AB, Watson P, Benson AB 3rd, Mulkerin DL, Mayer RJ, Blanke C. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2017 Jun 20;317(23):2392-2401. [https://jamanetwork.com/journals/jama/fullarticle/2632502 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545896/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28632865 PubMed]<br />
#'''MACRO-2:''' Aranda E, García-Alfonso P, Benavides M, Sánchez Ruiz A, Guillén-Ponce C, Safont MJ, Alcaide J, Gómez A, López R, Manzano JL, Méndez Ureña M, Sastre J, Rivera F, Grávalos C, García T, Martín-Valadés JI, Falcó E, Navalón M, González Flores E, Ma García Tapiador A, Ma López Muñoz A, Barrajón E, Reboredo M, García Teijido P, Viudez A, Cárdenas N, Díaz-Rubio E; Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD). First-line mFOLFOX plus cetuximab followed by mFOLFOX plus cetuximab or single-agent cetuximab as maintenance therapy in patients with metastatic colorectal cancer: phase II randomised MACRO2 TTD study. Eur J Cancer. 2018 Sep;101:263-272. Epub 2018 Jul 24. [https://www.ejcancer.com/article/S0959-8049(18)30938-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30054049 PubMed]<br />
<br />
==mFOLFOXIRI & Cetuximab (L-Leucovorin){{#subobject:9bf7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOXIRI & Cetuximab: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>IRI</u>'''notecan, Cetuximab<br />
===Regimen {{#subobject:19365|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/PMC5885260/ Cremolini et al. 2018 (MACBETH)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Wild-type KRAS, Wild-type NRAS<br />
<br />
''Note: 5-FU instructions are unusual in that no bolus is given.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 1200 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1, '''given fourth''' (total dose per cycle: 2400 mg/m<sup>2</sup>)<br />
*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given third, with oxaliplatin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given third, with L-leucovorin'''<br />
*[[Irinotecan (Camptosar)]] 130 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given second'''<br />
*[[Cetuximab (Erbitux)]] 500 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''<br />
<br />
'''14-day cycle for 8 cycles'''<br />
====Subsequent treatment====<br />
<br />
*If deemed resectable: [[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
*If deemed unresectable: [[#Cetuximab_monotherapy|Cetuximab]] versus Bevacizumab maintenance<br />
<br />
===References===<br />
<br />
#'''MACBETH:''' Cremolini C, Antoniotti C, Lonardi S, Aprile G, Bergamo F, Masi G, Grande R, Tonini G, Mescoli C, Cardellino GG, Coltelli L, Salvatore L, Corsi DC, Lupi C, Gemma D, Ronzoni M, Dell'Aquila E, Marmorino F, Di Fabio F, Mancini ML, Marcucci L, Fontanini G, Zagonel V, Boni L, Falcone A. Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial. JAMA Oncol. 2018 Apr 1;4(4):529-536. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2672387 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885260/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29450468 PubMed]<br />
<br />
==FOLFOXIRI & Panitumumab {{#subobject:9bf7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOXIRI & Panitumumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>IRI</u>'''notecan, Panitumumab<br />
===Regimen {{#subobject:19365|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01340 Modest et al. 2019 (VOLFI)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#FOLFIRINOX|FOLFOXIRI]]<br />
| style="background-color:#1a9850" |Superior ORR<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Wild-type KRAS, Wild-type NRAS<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 6000 mg/m<sup>2</sup>)<br />
*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Panitumumab (Vectibix)]] 6 mg/kg<sup>2</sup> IV over 60 minutes once on day 1<br />
<br />
'''14-day cycle until POD or resectability or to max 12 cycles'''<br />
<br />
===References===<br />
<br />
#'''VOLFI:''' Modest DP, Martens UM, Riera-Knorrenschild J, Greeve J, Florschütz A, Wessendorf S, Ettrich T, Kanzler S, Nörenberg D, Ricke J, Seidensticker M, Held S, Buechner-Steudel P, Atzpodien J, Heinemann V, Seufferlein T, Tannapfel A, Reinacher-Schick AC, Geissler M. FOLFOXIRI Plus Panitumumab As First-Line Treatment of RAS Wild-Type Metastatic Colorectal Cancer: The Randomized, Open-Label, Phase II VOLFI Study (AIO KRK0109). J Clin Oncol. 2019 Dec 10;37(35):3401-3411. Epub 2019 Oct 14. [https://ascopubs.org/doi/full/10.1200/JCO.19.01340 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31609637 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Cetuximab monotherapy {{#subobject:afad4f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 250 mg/m<sup>2</sup> weekly {{#subobject:a72650|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(18)30938-9/fulltext Aranda et al. 2018 (MACRO-2)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-de-esc)<br />
|[[#mFOLFOX6_.26_Cetuximab_3|mFOLFOX6 & Cetuximab]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Wild-type KRAS, Wild-type NRAS<br />
<br />
''Note: regimen details were not available in the abstract.''<br />
====Preceding treatment====<br />
<br />
*[[#mFOLFOX6_.26_Cetuximab_3|mFOLFOX6 & Cetuximab]] x 8<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cetuximab (Erbitux)]] 250 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycles'''<br />
<br />
===Variant #2, 500 mg/m<sup>2</sup> q2wk {{#subobject:3d7e64|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/PMC5885260/ Cremolini et al. 2018 (MACBETH)]<br />
| style="background-color:#91cf61" |Randomized Phase II (*)<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Wild-type KRAS, Wild-type NRAS<br />
<br />
''Note: this was a non-comparative study.''<br />
====Preceding treatment====<br />
<br />
*[[#mFOLFOXIRI_.26_Cetuximab_.28L-Leucovorin.29|mFOLFOXIRI & Cetuximab]] x 8<br />
<br />
====Chemotherapy====<br />
<br />
*[[Cetuximab (Erbitux)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''MACBETH:''' Cremolini C, Antoniotti C, Lonardi S, Aprile G, Bergamo F, Masi G, Grande R, Tonini G, Mescoli C, Cardellino GG, Coltelli L, Salvatore L, Corsi DC, Lupi C, Gemma D, Ronzoni M, Dell'Aquila E, Marmorino F, Di Fabio F, Mancini ML, Marcucci L, Fontanini G, Zagonel V, Boni L, Falcone A. Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial. JAMA Oncol. 2018 Apr 1;4(4):529-536. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2672387 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885260/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29450468 PubMed]<br />
#'''MACRO-2:''' Aranda E, García-Alfonso P, Benavides M, Sánchez Ruiz A, Guillén-Ponce C, Safont MJ, Alcaide J, Gómez A, López R, Manzano JL, Méndez Ureña M, Sastre J, Rivera F, Grávalos C, García T, Martín-Valadés JI, Falcó E, Navalón M, González Flores E, Ma García Tapiador A, Ma López Muñoz A, Barrajón E, Reboredo M, García Teijido P, Viudez A, Cárdenas N, Díaz-Rubio E; Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD). First-line mFOLFOX plus cetuximab followed by mFOLFOX plus cetuximab or single-agent cetuximab as maintenance therapy in patients with metastatic colorectal cancer: phase II randomised MACRO2 TTD study. Eur J Cancer. 2018 Sep;101:263-272. Epub 2018 Jul 24. [https://www.ejcancer.com/article/S0959-8049(18)30938-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30054049 PubMed]<br />
<br />
=Advanced or metastatic disease, second-line=<br />
==FOLFIRI & Panitumumab {{#subobject:8c0093|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI & Panitumumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Panitumumab<br />
<br />
===Regimen {{#subobject:ebf6e5|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/28/31/4706.long Peeters et al. 2010 (20050181)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#FOLFIRI|FOLFIRI]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS (*)<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
Wild-type KRAS, Wild-type NRAS<br />
<br />
''Note: reported efficacy is for wild-type KRAS, only, and is based on the 2014 update.''<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, with irinotecan'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given second, with leucovorin'''<br />
*[[Panitumumab (Vectibix)]] 6 mg/kg IV over 60 minutes once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''20050181:''' Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010 Nov 1;28(31):4706-13. Epub 2010 Oct 4. [http://jco.ascopubs.org/content/28/31/4706.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20921462 PubMed]<br />
##'''Update:''' Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tian Y, Sidhu R. Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jan;25(1):107-16. Erratum in: Ann Oncol. 2014 Mar;25(3):757. [https://academic.oup.com/annonc/article/25/1/107/166332 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24356622 PubMed]<br />
<br />
==Irinotecan monotherapy {{#subobject:d4d4f9|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 Irinotecan (Camptosar) in colon cancer]]<br />
<br />
===Variant #1, 300 mg/m<sup>2</sup> q3wk {{#subobject:190e25|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70163-3/fulltext Seymour et al. 2013 (PICCOLO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Irinotecan & Panitumumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: In some trials, this starting dose was intended for patients who were at least 70 years old, had [[Performance status|ECOG performance status]] 2 or more, or had prior pelvic radiation. Patients in N9841 had not previously received irinotecan or oxaliplatin.''<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 300 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2, 350 mg/m<sup>2</sup> q3wk {{#subobject:627110|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70163-3/fulltext Seymour et al. 2013 (PICCOLO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Irinotecan & Cyclosporine<br> 2. Irinotecan & Panitumumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 350 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*(varied depending on reference):<br />
*"Standard regimens of [[:Category:Emesis_prevention|antiemetics]], [[Atropine (Atropen)]], and intensive [[Loperamide (Imodium)]]," but no prophylactic [[Atropine (Atropen)]] allowed on cycle 1 day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''PICCOLO:''' Seymour MT, Brown SR, Middleton G, Maughan T, Richman S, Gwyther S, Lowe C, Seligmann JF, Wadsley J, Maisey N, Chau I, Hill M, Dawson L, Falk S, O'Callaghan A, Benstead K, Chambers P, Oliver A, Marshall H, Napp V, Quirke P. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013 Jul;14(8):749-59. Epub 2013 May 29. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70163-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699713/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23725851 PubMed]<br />
<br />
==Irinotecan & Cetuximab {{#subobject:c912ee|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b7315f|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/26/14/2311.long Sobrero et al. 2008 (EPIC)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Colon_cancer#Irinotecan_monotherapy_2|Irinotecan]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 350 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
**If aged 70 years old or more, [[Performance status|ECOG performance status]] 2 or more, or prior pelvic radiation: 300 mg/m<sup>2</sup> IV over 90 minutes once on day 1<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 />
**Subsequent cycles: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Antihistamines|Antihistamine]] prior to at least the first infusion of [[Cetuximab (Erbitux)]]<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<!-- Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, June 2005; the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2006; safety and efficacy results from this study were presented at the Annual Meeting of the American Association for Cancer Research, April 14-18, 2007, Los Angeles, CA; and the quality of life results from this study were presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 2007. --><br />
<br />
#'''EPIC:''' Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kröning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008 May 10;26(14):2311-9. Epub 2008 Apr 7. [http://jco.ascopubs.org/content/26/14/2311.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18390971 PubMed]<br />
<br />
=Advanced or metastatic disease, subsequent lines of therapy=<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/13/1658.long Van Cutsem et al. 2007 (20020408)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Panitumumab_monotherapy|Panitumumab]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa071834 Jonker et al. 2007 (NCIC CTG CO.17)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cetuximab_monotherapy_2|Cetuximab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104888/ Kim et al. 2016 (20100007)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Panitumumab_monotherapy|Panitumumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''No treatment except for supportive care.''<br />
<br />
===References===<br />
<!-- Presented at the 97th Annual Meeting of the American Association for Cancer Research, April 1-5, 2006, Washington, DC; 2nd Annual Conference of the Hematology/Oncology Pharmacy Association, June 15-18, 2006, Orlando, FL; 8th Annual Conference of the World Congress on Gastrointestinal Cancer, June 28-July 1, 2006, Barcelona, Spain; and at the 31st European Society of Medical Oncology Congress, September 29-October 3, 2006, Istanbul, Turkey. --><br />
<br />
#'''20020408:''' Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1;25(13):1658-64. [http://jco.ascopubs.org/content/25/13/1658.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17470858 PubMed]<br />
<!-- # Bristol-Myers Squibb and ImClone. A Phase III Randomized Study of Cetuximab (Erbitux, C225) and Best Supportive Care Versus Best Supportive Care in Patients with Pretreated Metastatic Epidermal Growth Factor Receptor (EGFR)-Positive Colorectal Carcinoma. Final Clinical Study Report for CA225025. 2007 Mar 5. [http://ctr.bms.com/pdf//CA225025.pdf link to original report] '''contains verified protocol''' --><br />
#'''NCIC CTG CO.17:''' Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007 Nov 15;357(20):2040-8. [https://www.nejm.org/doi/full/10.1056/NEJMoa071834 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18003960 PubMed]<br />
##'''Subgroup analysis:''' Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008 Oct 23;359(17):1757-65. [https://www.nejm.org/doi/10.1056/NEJMoa0804385 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18946061 PubMed]<br />
##'''Subgroup analysis:''' Asmis TR, Powell E, Karapetis CS, Jonker DJ, Tu D, Jeffery M, Pavlakis N, Gibbs P, Zhu L, Dueck DA, Whittom R, Langer C, O'Callaghan CJ. Comorbidity, age and overall survival in cetuximab-treated patients with advanced colorectal cancer (ACRC)--results from NCIC CTG CO.17: a phase III trial of cetuximab versus best supportive care. Ann Oncol. 2011 Jan;22(1):118-26. Epub 2010 Jul 5. [http://annonc.oxfordjournals.org/content/22/1/118.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20603436 PubMed]<br />
#'''20100007:''' Kim TW, Elme A, Kusic Z, Park JO, Udrea AA, Kim SY, Ahn JB, Valencia RV, Krishnan S, Bilic A, Manojlovic N, Dong J, Guan X, Lofton-Day C, Jung AS, Vrdoljak E. A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer. Br J Cancer. 2016 Nov 8;115(10):1206-1214. Epub 2016 Oct 13. [https://www.nature.com/bjc/journal/v115/n10/full/bjc2016309a.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104888/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27736842 PubMed]<br />
<br />
==Cetuximab monotherapy {{#subobject:a41ec2|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 Cetuximab (Erbitux) in colon cancer]]<br />
<br />
===Variant #1, weekly {{#subobject:e4f241|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%" |[[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/NEJMoa033025 Cunningham et al. 2004 (BOND)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Irinotecan_.26_Cetuximab_2|Irinotecan & Cetuximab]]<br />
| style="background-color:#d73027" |Inferior TTP<br />
|-<br />
|[http://jco.ascopubs.org/content/24/30/4914.long Lenz et al. 2006 (SALVAGE)]<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/NEJMoa071834 Jonker et al. 2007 (NCIC CTG CO.17)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2012.46.0543 Siu et al. 2013 (NCIC CTG/AGITG CO.20)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Brivanib & Cetuximab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70118-4/fulltext Price et al. 2014 (ASPECCT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Panitumumab_monotherapy|Panitumumab]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<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, 22<br />
**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
<br />
*Varies depending on reference<br />
*[[:Category:Antihistamines|Antihistamine]] (such as [[Diphenhydramine (Benadryl)]] 50 mg IV) prior to at least the first infusion of [[Cetuximab (Erbitux)]]<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, bi-weekly {{#subobject:315dde|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://academic.oup.com/annonc/article/21/7/1537/164079 Tabernero et al. 2009]<br />
| style="background-color:#ffffbe" |Phase I<br />
|-<br />
|}<br />
''Note: no primary reference could be found for this exact dosing in monotherapy; in the phase I trial it is described as "the most convenient and feasible dose".''<br />
====Chemotherapy====<br />
<br />
*[[Cetuximab (Erbitux)]] 500 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**If tolerated, subsequent doses can be given over 1 hour<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Antihistamines|Antihistamine]] prior to [[Cetuximab (Erbitux)]]<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''BOND:''' Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22;351(4):337-45. [https://www.nejm.org/doi/full/10.1056/NEJMoa033025 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15269313 PubMed]<br />
#'''SALVAGE:''' Lenz HJ, Van Cutsem E, Khambata-Ford S, Mayer RJ, Gold P, Stella P, Mirtsching B, Cohn AL, Pippas AW, Azarnia N, Tsuchihashi Z, Mauro DJ, Rowinsky EK. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol. 2006 Oct 20;24(30):4914-21. [http://jco.ascopubs.org/content/24/30/4914.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17050875 PubMed]<br />
<!-- # Bristol-Myers Squibb and ImClone. A Phase III Randomized Study of Cetuximab (Erbitux, C225) and Best Supportive Care Versus Best Supportive Care in Patients with Pretreated Metastatic Epidermal Growth Factor Receptor (EGFR)-Positive Colorectal Carcinoma. Final Clinical Study Report for CA225025. 2007 Mar 5. [http://ctr.bms.com/pdf//CA225025.pdf link to original report] '''contains verified protocol''' --><br />
#'''NCIC CTG CO.17:''' Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007 Nov 15;357(20):2040-8. [https://www.nejm.org/doi/full/10.1056/NEJMoa071834 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18003960 PubMed]<br />
##'''Subgroup analysis:''' Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008 Oct 23;359(17):1757-65. [https://www.nejm.org/doi/10.1056/NEJMoa0804385 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18946061 PubMed]<br />
##'''Subgroup analysis:''' Asmis TR, Powell E, Karapetis CS, Jonker DJ, Tu D, Jeffery M, Pavlakis N, Gibbs P, Zhu L, Dueck DA, Whittom R, Langer C, O'Callaghan CJ. Comorbidity, age and overall survival in cetuximab-treated patients with advanced colorectal cancer (ACRC)--results from NCIC CTG CO.17: a phase III trial of cetuximab versus best supportive care. Ann Oncol. 2011 Jan;22(1):118-26. Epub 2010 Jul 5. [http://annonc.oxfordjournals.org/content/22/1/118.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20603436 PubMed]<br />
#'''Phase I:''' Tabernero J, Ciardiello F, Rivera F, Rodriguez-Braun E, Ramos FJ, Martinelli E, Vega-Villegas ME, Roselló S, Liebscher S, Kisker O, Macarulla T, Baselga J, Cervantes A. Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/pharmacodynamic phase I dose-escalation study. Ann Oncol. 2010 Jul;21(7):1537-45. Epub 2009 Nov 25. [https://academic.oup.com/annonc/article/21/7/1537/164079 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19940007 PubMed]<br />
#'''NCIC CTG/AGITG CO.20:''' Siu LL, Shapiro JD, Jonker DJ, Karapetis CS, Zalcberg JR, Simes J, Couture F, Moore MJ, Price TJ, Siddiqui J, Nott LM, Charpentier D, Liauw W, Sawyer MB, Jefford M, Magoski NM, Haydon A, Walters I, Ringash J, Tu D, O'Callaghan CJ. Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: the NCIC Clinical Trials Group and AGITG CO.20 Trial. J Clin Oncol. 2013 Jul 1;31(19):2477-84. Epub 2013 May 20. [https://ascopubs.org/doi/full/10.1200/JCO.2012.46.0543 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23690424 PubMed]<br />
#'''ASPECCT:''' Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Zhang K, Murugappan S, Sidhu R. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014 May;15(6):569-79. Epub 2014 Apr 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70118-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24739896 PubMed]<br />
##'''Update:''' Price T, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Guan X, Peeters M. Final results and outcomes by prior bevacizumab exposure, skin toxicity, and hypomagnesaemia from ASPECCT: randomized phase 3 non-inferiority study of panitumumab versus cetuximab in chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer. Eur J Cancer. 2016 Nov;68:51-59. Epub 2016 Oct 5. [https://www.sciencedirect.com/science/article/pii/S0959804916323838 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/27716478 PubMed]<br />
<br />
==Irinotecan & Cetuximab {{#subobject:5d7e80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 125/250, irinotecan 2 weeks on, 1 week off {{#subobject:e734bb|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
''Note: In contrast to BOND, some guidelines list irinotecan as being given on days 1 & 8 of a 21-day cycle. No primary reference could be found for this. Note also that the FDA-recommended dosing is for the cetuximab component; no comment is made about irinotecan dosing.''<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 8<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 />
**Subsequent cycles: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Antihistamines|Antihistamine]] prior to at least the first infusion of [[Cetuximab (Erbitux)]]<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2, 125/250, irinotecan 4 weeks on, 2 weeks off {{#subobject:a4d073|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%" |[[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/NEJMoa033025 Cunningham et al. 2004 (BOND)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Cetuximab_monotherapy_2|Cetuximab]]<br />
| style="background-color:#1a9850" |Superior TTP<br />
|-<br />
|}<br />
''Note that the FDA-recommended dosing is for the cetuximab component; no comment is made about irinotecan dosing.''<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22<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, 22, 29, 36<br />
**Subsequent cycles: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Antihistamines|Antihistamine]] prior to at least the first infusion of [[Cetuximab (Erbitux)]]<br />
<br />
'''42-day cycles'''<br />
<br />
===Variant #3, 150/500, bi-weekly {{#subobject:c0c538|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/PMC6113428/ Osumi et al. 2018]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV once on day 1<br />
*[[Cetuximab (Erbitux)]] 500 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**Subsequent doses are given over 60 minutes<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Antihistamines|Antihistamine]] prior to [[Cetuximab (Erbitux)]]<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #4, 180/250, bi-weekly, with response adaptation {{#subobject:7c9e16|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://ascopubs.org/doi/full/10.1200/JCO.2011.40.9243 Van Cutsem et al. 2012 (EVEREST)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15<br />
*[[Cetuximab (Erbitux)]] 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 />
<br />
'''21-day course'''<br />
====Subsequent treatment====<br />
<br />
*Grade 0 or 1 skin reaction: Continue standard dose versus escalate dose of cetuximab to 500 mg/m<sup>2</sup><br />
*Grade 2 or worse skin reaction: Continue standard dose<br />
<br />
===Variant #5, 180/500, bi-weekly {{#subobject:3062ba|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/PMC2527794/ Martín-Martorell et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 minutes once on day 1<br />
*[[Cetuximab (Erbitux)]] 500 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**If tolerated, subsequent doses can be given over 1 hour<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Antihistamines|Antihistamine]] prior to [[Cetuximab (Erbitux)]]<br />
*[[Dexamethasone (Decadron)]] & [[Ondansetron (Zofran)]] prior to [[Irinotecan (Camptosar)]]<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #6, 350/250, q3wk irinotecan {{#subobject:ada904|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%" |[[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/NEJMoa033025 Cunningham et al. 2004 (BOND)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Cetuximab_monotherapy_2|Cetuximab]]<br />
| style="background-color:#1a9850" |Superior TTP<br />
|-<br />
|}<br />
''Note that the FDA-recommended dosing is for the cetuximab component; no comment is made about irinotecan dosing.''<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 350 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
**If aged 70 years old or more, [[Performance status|ECOG performance status]] 2 or more, or prior pelvic radiation: 300 mg/m<sup>2</sup> IV over 90 minutes once on day 1<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 />
**Subsequent cycles: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
<br />
*[[:Category:Antihistamines|Antihistamine]] prior to at least the first infusion of [[Cetuximab (Erbitux)]]<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''BOND:''' Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22;351(4):337-45. [https://www.nejm.org/doi/full/10.1056/NEJMoa033025 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15269313 PubMed]<br />
#Martín-Martorell P, Roselló S, Rodríguez-Braun E, Chirivella I, Bosch A, Cervantes A. Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial. Br J Cancer. 2008 Aug 5;99(3):455-8. [https://www.nature.com/bjc/journal/v99/n3/full/6604530a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2527794/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18665167 PubMed]<br />
#'''EVEREST:''' Van Cutsem E, Tejpar S, Vanbeckevoort D, Peeters M, Humblet Y, Gelderblom H, Vermorken JB, Viret F, Glimelius B, Gallerani E, Hendlisz A, Cats A, Moehler M, Sagaert X, Vlassak S, Schlichting M, Ciardiello F. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol. 2012 Aug 10;30(23):2861-8. Epub 2012 Jul 2. [https://ascopubs.org/doi/full/10.1200/JCO.2011.40.9243 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22753904 PubMed]<br />
#Osumi H, Shinozaki E, Mashima T, Wakatsuki T, Suenaga M, Ichimura T, Ogura M, Ota Y, Nakayama I, Takahari D, Chin K, Miki Y, Yamaguchi K. Phase II trial of biweekly cetuximab and irinotecan as third-line therapy for pretreated KRAS exon 2 wild-type colorectal cancer. Cancer Sci. 2018 Aug;109(8):2567-2575. Epub 2018 Jul 13. [https://onlinelibrary.wiley.com/doi/full/10.1111/cas.13698 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113428/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29908105 PubMed]<br />
<br />
==Panitumumab monotherapy {{#subobject:5a3eb5|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 Panitumumab (Vectibix) in colon cancer]]<br />
<br />
===Regimen {{#subobject:fa978e|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/13/1658.long Van Cutsem et al. 2007 (20020408)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70118-4/fulltext Price et al. 2014 (ASPECCT)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Cetuximab_monotherapy_2|Cetuximab]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104888/ Kim et al. 2016 (20100007)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|}<br />
''Note: reported efficacy for 20100007 is based on the 2018 update.''<br />
====Chemotherapy====<br />
<br />
*[[Panitumumab (Vectibix)]] 6 mg/kg IV over 60 minutes once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<!-- Presented at the 97th Annual Meeting of the American Association for Cancer Research, April 1-5, 2006, Washington, DC; 2nd Annual Conference of the Hematology/Oncology Pharmacy Association, June 15-18, 2006, Orlando, FL; 8th Annual Conference of the World Congress on Gastrointestinal Cancer, June 28-July 1, 2006, Barcelona, Spain; and at the 31st European Society of Medical Oncology Congress, September 29-October 3, 2006, Istanbul, Turkey. --><br />
<br />
#'''20020408:''' Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1;25(13):1658-64. [http://jco.ascopubs.org/content/25/13/1658.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17470858 PubMed]<br />
#'''ASPECCT:''' Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Zhang K, Murugappan S, Sidhu R. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014 May;15(6):569-79. Epub 2014 Apr 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70118-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24739896 PubMed]<br />
##'''Update:''' Price T, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Guan X, Peeters M. Final results and outcomes by prior bevacizumab exposure, skin toxicity, and hypomagnesaemia from ASPECCT: randomized phase 3 non-inferiority study of panitumumab versus cetuximab in chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer. Eur J Cancer. 2016 Nov;68:51-59. Epub 2016 Oct 5. [https://www.sciencedirect.com/science/article/pii/S0959804916323838 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/27716478 PubMed]<br />
#'''20100007:''' Kim TW, Elme A, Kusic Z, Park JO, Udrea AA, Kim SY, Ahn JB, Valencia RV, Krishnan S, Bilic A, Manojlovic N, Dong J, Guan X, Lofton-Day C, Jung AS, Vrdoljak E. A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer. Br J Cancer. 2016 Nov 8;115(10):1206-1214. Epub 2016 Oct 13. [https://www.nature.com/bjc/journal/v115/n10/full/bjc2016309a.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104888/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27736842 PubMed]<br />
##'''Update:''' Kim TW, Elme A, Park JO, Udrea AA, Kim SY, Ahn JB, Valencia RV, Krishnan S, Manojlovic N, Guan X, Lofton-Day C, Jung AS, Vrdoljak E. Final Analysis of Outcomes and RAS/BRAF Status in a Randomized Phase 3 Study of Panitumumab and Best Supportive Care in Chemorefractory Wild Type KRAS Metastatic Colorectal Cancer. Clin Colorectal Cancer. 2018 Sep;17(3):206-214. Epub 2018 Mar 21. [https://www.clinical-colorectal-cancer.com/article/S1533-0028(17)30529-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29703606 PubMed]<br />
<br />
[[Category:Colon cancer regimens]]<br />
[[Category:Biomarker-specific pages]]<br />
[[Category:Colorectal cancers]]</div>Dweeraratnehttps://hemonc.org/w/index.php?title=Colon_cancer&diff=41766Colon cancer2020-01-08T22:40:58Z<p>Dweeraratne: /* Regimen #subobject:91abt2 */</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:RyanNguyen.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Ryannguyen|Ryan Nguyen, DO]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br>[https://www.linkedin.com/in/ryan-nguyen-0b12a432/ LinkedIn]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>University of Illinois at Chicago<br>Chicago, IL</big><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 [[Colon_cancer_-_historical|historical regimens 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 colon cancer as well as systemic regimens for the more general category of colorectal cancer. <br />
<br />
*See the [[Rectal_cancer|'''rectal cancer page''']] for regimens specific to rectal cancer.<br />
*See the [[Colon cancer, BRAF-mutated|'''BRAF-mutated page''']] for biomarker-specific regimens.<br />
*See the [[Colon cancer, Her2-amplified|'''HER2+ page''']] for biomarker-specific regimens.<br />
*See the [[Colon_cancer,_KRAS_wild-type|'''KRAS wild-type page''']] for biomarker-specific regimens.</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 />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[http://www.asco.org/ ASCO]==<br />
<br />
*'''2019:''' Lieu et al. [https://ascopubs.org/doi/full/10.1200/JCO.19.00281 Duration of oxaliplatin-containing adjuvant therapy for stage III colon cancer: ASCO Clinical Practice Guideline]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
<br />
*'''2019:''' Stjepanovic et al. [https://academic.oup.com/annonc/article/30/10/1558/5543095 Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
*'''2016:''' Van Cutsem et al. [https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Management-of-Patients-with-Metastatic-Colorectal-Cancer ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.] [https://www.ncbi.nlm.nih.gov/pubmed/27380959 PubMed]<br />
<br />
===Older===<br />
<br />
*'''2013:''' Labianca et al. [http://annonc.oxfordjournals.org/content/24/suppl_6/vi64.full.pdf+html Early Colon Cancer: ESMO Clinical Practice Guidelines] [https://www.ncbi.nlm.nih.gov/pubmed/24078664 PubMed]<br />
*'''2013:''' Balmaña et al. [http://annonc.oxfordjournals.org/content/24/suppl_6/vi73.full.pdf+html Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines.] [https://www.ncbi.nlm.nih.gov/pubmed/23813931 PubMed]<br />
<br />
==[http://www.jsccr.jp/en/index.html Japanese Society for Cancer of the Colon and Rectum]==<br />
<br />
*'''2016:''' Watanabe et al. [https://link.springer.com/article/10.1007%2Fs10147-017-1101-6 Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer] [https://www.ncbi.nlm.nih.gov/pubmed/28349281 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf NCCN Guidelines - Colon Cancer]<br />
<br />
==[http://www.siog.org/ SIOG]==<br />
<br />
*'''2014:''' Papamichael et al. [https://academic.oup.com/annonc/article/26/3/463/222917 Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013]<br />
<br />
=Adjuvant therapy=<br />
==Capecitabine monotherapy {{#subobject:7b50df|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ed4e3f|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa043116 Twelves et al. 2005 (X-ACT)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30172-3/fulltext Kerr et al. 2016 (QUASAR 2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Capecitabine & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36<br />
|-<br />
|[https://www.thelancet.com/journals/langas/article/PIIS2468-1253(17)30297-2/fulltext Hamaguchi et al. 2017 (JCOG0910)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|S-1<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior DFS<br />
|-<br />
|[https://www.nature.com/articles/s41416-019-0410-0 Tomita et al. 2019 (JFMC37-0801)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Capecitabine x 12 mo<br />
| style="background-color:#fee08b" |Might have inferior DFS<br />
|-<br />
|}<br />
''Note: reported efficacy for X-ACT is based on the 2011 update.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for 8 cycles'''<br />
<br />
===References===<br />
<br />
#'''X-ACT:''' Twelves C, Wong A, Nowacki MP, Abt M, Burris HA 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005 Jun 30;352(26):2696-704. [https://www.nejm.org/doi/full/10.1056/NEJMoa043116 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15987918 PubMed]<br />
##'''Update:''' Twelves C, Scheithauer W, McKendrick J, Seitz JF, Van Hazel G, Wong A, Díaz-Rubio E, Gilberg F, Cassidy J. Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy. Ann Oncol. 2012 May;23(5):1190-7. Epub 2011 Sep 6. [https://academic.oup.com/annonc/article/23/5/1190/192299 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21896539 PubMed]<br />
#'''QUASAR 2:''' Kerr RS, Love S, Segelov E, Johnstone E, Falcon B, Hewett P, Weaver A, Church D, Scudder C, Pearson S, Julier P, Pezzella F, Tomlinson I, Domingo E, Kerr DJ. Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial. Lancet Oncol. 2016 Nov;17(11):1543-1557. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30172-3/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27660192 PubMed]<br />
#'''JCOG0910:''' Hamaguchi T, Shimada Y, Mizusawa J, Kinugasa Y, Kanemitsu Y, Ohue M, Fujii S, Takiguchi N, Yatsuoka T, Takii Y, Ojima H, Masuko H, Kubo Y, Mishima H, Yamaguchi T, Bando H, Sato T, Kato T, Nakamura K, Fukuda H, Moriya Y. Capecitabine versus S-1 as adjuvant chemotherapy for patients with stage III colorectal cancer (JCOG0910): an open-label, non-inferiority, randomised, phase 3, multicentre trial. Lancet Gastroenterol Hepatol. 2018 Jan;3(1):47-56. Epub 2017 Oct 24. [https://www.thelancet.com/journals/langas/article/PIIS2468-1253(17)30297-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29079411 PubMed]<br />
#'''JFMC37-0801:''' Tomita N, Kunieda K, Maeda A, Hamada C, Yamanaka T, Sato T, Yoshida K, Boku N, Nezu R, Yamaguchi S, Mishima H, Sadahiro S, Muro K, Ishiguro M, Sakamoto J, Saji S, Maehara Y. Phase III randomised trial comparing 6 vs 12-month of capecitabine as adjuvant chemotherapy for patients with stage III colon cancer: final results of the JFMC37-0801 study. Br J Cancer. 2019 Apr;120(7):689-696. Epub 2019 Mar 5. [https://www.nature.com/articles/s41416-019-0410-0 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30833647 PubMed]<br />
<br />
==CapeOx {{#subobject:cf9acc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOx: '''<u>Cape</u>'''citabine & '''<u>Ox</u>'''aliplatin<br />
<br>CAPOX: '''<u>CAP</u>'''ecitabine & '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine) & '''<u>OX</u>'''aliplatin<br />
===Example orders===<br />
<br />
*[[Example orders for CapeOx (XELOX) in colon cancer]]<br />
<br />
===Variant #1, 3 months {{#subobject:205ad6|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext Iveson et al. 2018 (SCOT)]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#CapeOx|CapeOx]] x 6 mo<br />
| style="background-color:#eeee01" |Seems to have non-inferior DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycle for 4 cycles'''<br />
<br />
===Variant #2, 6 months {{#subobject:1ef938|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/1/102.long Schmoll et al. 2007 (XELOXA)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445286/ Pectasides et al. 2015]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#mFOLFOX6|mFOLFOX6]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237801/ Snoeren et al. 2017 (HEPATICA)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CapeOx & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext Iveson et al. 2018 (SCOT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CapeOx|CapeOx]] x 3 mo<br />
| style="background-color:#eeee01" |Seems to have non-inferior DFS<br />
|-<br />
|}<br />
''Note: HEPATICA enrolled patients with resected colorectal liver metastases. Reported efficacy for XELOXA is based on the 2015 update.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
**Some references specify from the evening of day 1 to the morning of day 15 (28 doses per cycle)<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycle for 8 cycles'''<br />
<br />
===References===<br />
<br />
#'''XELOXA:''' Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A, Maroun J, Price T, Lim R, Van Cutsem E, Park YS, McKendrick J, Topham C, Soler-Gonzalez G, de Braud F, Hill M, Sirzén F, Haller DG. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007 Jan 1;25(1):102-9. [http://jco.ascopubs.org/content/25/1/102.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17194911 PubMed]<br />
##'''Update:''' Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011 Apr 10;29(11):1465-71. Epub 2011 Mar 7. [http://jco.ascopubs.org/content/29/11/1465.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21383294 PubMed]<br />
##'''Update:''' Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: Final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015 Nov 10;33(32):3733-40. Epub 2015 Aug 31. [http://jco.ascopubs.org/content/33/32/3733.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26324362 PubMed]<br />
#Pectasides D, Karavasilis V, Papaxoinis G, Gourgioti G, Makatsoris T, Raptou G, Vrettou E, Sgouros J, Samantas E, Basdanis G, Papakostas P, Bafaloukos D, Kotoula V, Kalofonos HP, Scopa CD, Pentheroudakis G, Fountzilas G. Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or stage III colorectal cancer. BMC Cancer. 2015 May 10;15:384. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1406-7 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25956750 PubMed]<br />
#'''HEPATICA:''' Snoeren N, van Hillegersberg R, Schouten SB, Bergman AM, van Werkhoven E, Dalesio O, Tollenaar RA, Verheul HM, van der Sijp J, Borel Rinkes IH, Voest EE; Hepatica study group. Randomized phase III study to assess efficacy and safety of adjuvant CAPOX with or without bevacizumab in patients after resection of colorectal liver metastases: HEPATICA study. Neoplasia. 2017 Feb;19(2):93-99. Epub 2017 Jan 12. [https://www.clinicalkey.com/#!/content/playContent/1-s2.0-S1476558616301701 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237801/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28088688 PubMed]<br />
#'''IDEA:''' Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018 Mar 29;378(13):1177-1188. [https://www.nejm.org/doi/full/10.1056/NEJMoa1713709 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29590544 PubMed]<br />
##'''Subgroup analysis:''' Souglakos J, Boukovinas I, Kakolyris S, Xynogalos S, Ziras N, Athanasiadis A, Androulakis N, Christopoulou A, Vaslamatzis M, Ardavanis A, Emmanouilides C, Bompolaki I, Kourousis C, Makrantonakis P, Christofyllakis C, Athanasiadis E, Kentepozidis N, Karampeazis A, Katopodi U, Anagnosopoulos A, Papadopoulos G, Prinarakis E, Kalisperi A, Mavroudis D, Georgoulias V. Three versus six months adjuvant FOLFOX or CAPOX for high risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project. Ann Oncol. 2019 Aug 1;30(8):1304-1310. Epub 2019 Jun 22. [https://academic.oup.com/annonc/article/30/8/1304/5522015 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31228203 PubMed]<br />
#'''SCOT:''' Iveson TJ, Kerr RS, Saunders MP, Cassidy J, Hollander NH, Tabernero J, Haydon A, Glimelius B, Harkin A, Allan K, McQueen J, Scudder C, Boyd KA, Briggs A, Waterston A, Medley L, Wilson C, Ellis R, Essapen S, Dhadda AS, Harrison M, Falk S, Raouf S, Rees C, Olesen RK, Propper D, Bridgewater J, Azzabi A, Farrugia D, Webb A, Cunningham D, Hickish T, Weaver A, Gollins S, Wasan HS, Paul J. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2018 Apr;19(4):562-578. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29611518 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:a93a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FULV: 5-'''<u>FU</u>''' & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid)<br />
<br>LV5FU2: '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid) & '''<u>5-FU</u>''' for '''<u>2</u>''' days<br />
===Example orders===<br />
<br />
*[[Example orders for 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV) in colon cancer]]<br />
*[[Example orders for 5-FU & high-dose Leucovorin (Roswell Park regimen/HDLV) in colon cancer]]<br />
<br />
===Variant #1, 500/200, 6 out of 8 weeks {{#subobject:2c3f1b|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038965/ Papadimitriou et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|IFL<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
'''8-week cycle for 4 cycles'''<br />
<br />
===Variant #2, 500/500, 6 out of 8 weeks {{#subobject:489be0|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.1993.11.10.1879 Wolmark et al. 1993 (NSABP C-03)]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[Colon_cancer_-_historical#MOF|MOF]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/JCO.1999.17.11.3553 Wolmark et al. 1999 (NSABP C-04)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|1. [[Colon_cancer_-_historical#Fluorouracil_.26_Levamisole|5-FU & Levamisole]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|2. 5-FU, Leucovorin, Levamisole<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS/OS<br />
|-<br />
| rowspan="3" |[http://jco.ascopubs.org/content/23/34/8671.long Haller et al. 2005 (Intergroup 0089)]<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Fluorouracil_.26_Folinic_acid|5-FU & LV]]; low-dose<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. LDLV & Levamisole<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|3. 5-FU & Levamisole<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[http://jco.ascopubs.org/content/24/13/2059.long Lembersky et al. 2006 (NSABP C-06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Tegafur.2C_Uracil.2C_Folinic_acid|Tegafur, Uracil, Folinic acid]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS/OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/1/102.long Schmoll et al. 2007 (XELOXA)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CapeOx|CapeOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2198.full Kuebler et al. 2007 (NSABP C-07)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FLOX|FLOX]]<br />
| style="background-color:#d73027" |Inferior DFS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2007.11.2144 Saltz et al. 2007 (CALGB 89803)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|IFL<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS/OS<br />
|-<br />
|}<br />
''Note: this is often called the "Roswell Park regimen" but the original regimen described by Petrelli et al. 1987 & 1989 used a 5-FU dose of 600 mg/m<sup>2</sup>.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, 29, 36, '''given second, 1 hour after start of leucovorin'''<br />
*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, '''given first'''<br />
<br />
'''8-week cycle for 3 to 6 cycles'''<br />
<br />
===Variant #3, 600/500, 6 out of 8 weeks ("Roswell Park regimen") {{#subobject:50ybe0|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.karger.com/Article/Abstract/12105 Fountzilas et al. 2000]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FULV & IFN alfa-2a<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, 29, 36, '''given second, 1 hour after start of leucovorin'''<br />
*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, '''given first'''<br />
<br />
'''8-week cycle for 4 cycles'''<br />
<br />
===Variant #4, 1850/1000 {{#subobject:588afe|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140673695906967/fulltext Marsoni et al. 1995 (IMPACT<sub>CRC</sub>)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: this was the lower bound of 5-FU dose for the three included RCTs. This study should not be confused with the studies of the same name in breast cancer and prostate cancer.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #5, 1850/2500 ("NCI schedule") {{#subobject:7cc2b9|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/jnci/article/90/23/1810/2520545 Wolmark et al. 1998 (NSABP C-05)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FULV & Interferon alfa<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS/OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #6, 2000/400 ("de Gramont regimen"/LV5FU2) {{#subobject:685f89|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2003.10.065 André et al. 2003 (GERCOR C96.1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid|FULV]]; monthly<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa032709 André et al. 2004 (MOSAIC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFOX4|FOLFOX4]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|[https://academic.oup.com/annonc/article/20/4/674/205923 Ychou et al. 2009 (FFCD 9802)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|IFL<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2008.21.6663 Van Cutsem et al. 2009 (PETACC-3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|IFL<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|}<br />
''Reported efficacy for MOSAIC is based on the 2009 update.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first'''<br />
<br />
'''14-day cycle for 12 cycles'''<br />
<br />
===Variant #7, 2125/100 ("Mayo Clinic regimen") {{#subobject:4bd336|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
||[https://www.nejm.org/doi/full/10.1056/NEJMoa043116 Twelves et al. 2005 (X-ACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_monotherapy|Capecitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|[http://jco.ascopubs.org/content/25/1/102.long Schmoll et al. 2007 (XELOXA)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CapeOx|XELOX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(08)00535-2/fulltext Popov et al. 2008 (PETACC-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Raltitrexed<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior RFS/OS<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(13)00094-4/fulltext Köhne et al. 2013 (PETACC-2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. LV5FU2<br> 2. AIO regimen<br> 3. TTD regimen<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS60<br />
|-<br />
|}<br />
''Note: efficacy for X-ACT is based on the 2011 update. Dosing details for PETACC-1 could not be confirmed from the abstract.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #8, 2125/100, with cycle elongation ("Mayo Clinic regimen") {{#subobject:e24014|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/1/246.long O'Connell et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140673602098367/fulltext Punt et al. 2002 (Study 157-002)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. FULV & Edrecolomab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. [[Colon_cancer_-_historical#Edrecolomab_monotherapy|Edrecolomab]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
| rowspan="3" |[http://jco.ascopubs.org/content/23/34/8671.long Haller et al. 2005 (Intergroup 0089)]<br />
| rowspan="3" style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|1. [[#Fluorouracil_.26_Folinic_acid|5-FU & LV]]; high-dose<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. LDLV & Levamisole<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|3. 5-FU & Levamisole<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2008.18.5710 Fields et al. 2009 (Study 157-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FULV & Edrecolomab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 3 cycles, then 35-day cycle for 3 cycles'''<br />
<br />
===Variant #9, 2800/400 (LV5FUs) {{#subobject:476348|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/20/12/1964/210839 Ychou et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FOLFIRI<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Complete surgical resection of colorectal liver metastases]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycle for 12 cycles'''<br />
<br />
===References===<br />
<br />
#'''NSABP C-03:''' Wolmark N, Rockette H, Fisher B, Wickerham DL, Redmond C, Fisher ER, Jones J, Mamounas EP, Ore L, Petrelli NJ, Spurr CL, Dimitrov N, Romond EH, Sutherland CM, Kardinal CG, DeFusco PA, Jochimsen P. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol. 1993 Oct;11(10):1879-87. [https://ascopubs.org/doi/full/10.1200/JCO.1993.11.10.1879 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8410113 PubMed]<br />
##'''Pooled update:''' Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. [https://link.springer.com/article/10.1245%2Fs10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20082144 PubMed]<br />
#'''IMPACT:''' Marsoni S, Labianca R, Pancera G, Torri V, Zaniboni A, Erlichman C, Pater J, Shepherd L, Zee B, Seitz JF, Milan C, Pignon JP; International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet. 1995 Apr 15;345(8955):939-44. [https://www.thelancet.com/journals/lancet/article/PIIS0140673695906967/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7715291 PubMed]<br />
#O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, Wieand HS. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997 Jan;15(1):246-50. [http://jco.ascopubs.org/content/15/1/246.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8996149 PubMed]<br />
##'''Pooled update:''' Erlichman C, O'Connell M, Kahn M, Marsoni S, Torri V, Tardio B, Zaniboni A, Pancera G, Martignoni G, Labianca R, Barni A, Seitz JF, Milan C, Bedenne L, Giovannini M, Letreut YP, Skillings J, Shepard L, Zee B, Petrioli R, Francini G; International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol. 1999 May;17(5):1356-63. [https://ascopubs.org/doi/full/10.1200/JCO.1999.17.5.1356 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10334519 PubMed]<br />
#'''NSABP C-05:''' Wolmark N, Bryant J, Smith R, Grem J, Allegra C, Hyams D, Atkins J, Dimitrov N, Oishi R, Prager D, Fehrenbacher L, Romond E, Colangelo L, Fisher B. Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst. 1998 Dec 2;90(23):1810-6. [https://academic.oup.com/jnci/article/90/23/1810/2520545 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9839521 PubMed]<br />
##'''Pooled update:''' Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. [https://link.springer.com/article/10.1245%2Fs10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20082144 PubMed]<br />
#'''NSABP C-04:''' Wolmark N, Rockette H, Mamounas E, Jones J, Wieand S, Wickerham DL, Bear HD, Atkins JN, Dimitrov NV, Glass AG, Fisher ER, Fisher B. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol. 1999 Nov;17(11):3553-9. [https://ascopubs.org/doi/full/10.1200/JCO.1999.17.11.3553 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10550154 PubMed]<br />
##'''Pooled update:''' Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. [https://link.springer.com/article/10.1245%2Fs10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20082144 PubMed]<br />
#Fountzilas G, Zisiadis A, Dafni U, Konstantaras C, Hatzitheoharis G, Papavramidis S, Bousoulegas A, Basdanis G, Giannoulis E, Dokmetzioglou J, Katsohis C, Nenopoulou E, Karvounis N, Briassoulis E, Aravantinos G, Kosmidis P, Skarlos D, Pavlidis N. Fluorouracil and leucovorin with or without interferon alfa-2a as adjuvant treatment, in patients with high-risk colon cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Oncology. 2000 Apr;58(3):227-36. [https://www.karger.com/Article/Abstract/12105 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10765125 PubMed]<br />
#'''Study 157-002:''' Punt CJ, Nagy A, Douillard JY, Figer A, Skovsgaard T, Monson J, Barone C, Fountzilas G, Riess H, Moylan E, Jones D, Dethling J, Colman J, Coward L, MacGregor S. Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study. Lancet. 2002 Aug 31;360(9334):671-7. [https://www.thelancet.com/journals/lancet/article/PIIS0140673602098367/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12241873 PubMed]<br />
#'''GERCOR C96.1:''' Andre T, Colin P, Louvet C, Gamelin E, Bouche O, Achille E, Colbert N, Boaziz C, Piedbois P, Tubiana-Mathieu N, Boutan-Laroze A, Flesch M, Buyse M, de Gramont A. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol. 2003 Aug 1;21(15):2896-903. [https://ascopubs.org/doi/full/10.1200/JCO.2003.10.065 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12885807 PubMed]<br />
##'''Update:''' André T, Quinaux E, Louvet C, Colin P, Gamelin E, Bouche O, Achille E, Piedbois P, Tubiana-Mathieu N, Boutan-Laroze A, Flesch M, Lledo G, Raoul Y, Debrix I, Buyse M, de Gramont A. Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1. J Clin Oncol. 2007 Aug 20;25(24):3732-8. [https://ascopubs.org/doi/full/10.1200/JCO.2007.12.2234 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17704423 PubMed]<br />
#'''MOSAIC:''' André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004 Jun 3;350(23):2343-51. [https://www.nejm.org/doi/full/10.1056/NEJMoa032709 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15175436 PubMed]<br />
##'''Update:''' André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009 Jul 1;27(19):3109-16. Epub 2009 May 18. [https://ascopubs.org/doi/full/10.1200/JCO.2008.20.6771 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19451431 PubMed]<br />
##'''Update:''' André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, Scriva A, Hickish T, Tabernero J, Van Laethem JL, Banzi M, Maartense E, Shmueli E, Carlsson GU, Scheithauer W, Papamichael D, Möehler M, Landolfi S, Demetter P, Colote S, Tournigand C, Louvet C, Duval A, Fléjou JF, de Gramont A. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol. 2015 Dec 10;33(35):4176-87. Epub 2015 Nov 2. [https://ascopubs.org/doi/full/10.1200/JCO.2015.63.4238 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26527776 PubMed]<br />
#'''X-ACT:''' Twelves C, Wong A, Nowacki MP, Abt M, Burris HA 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005 Jun 30;352(26):2696-704. [https://www.nejm.org/doi/full/10.1056/NEJMoa043116 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15987918 PubMed]<br />
##'''Update:''' Twelves C, Scheithauer W, McKendrick J, Seitz JF, Van Hazel G, Wong A, Díaz-Rubio E, Gilberg F, Cassidy J. Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy. Ann Oncol. 2012 May;23(5):1190-7. Epub 2011 Sep 6. [https://academic.oup.com/annonc/article/23/5/1190/192299 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21896539 PubMed]<br />
<!-- Presented in part at the 33rd Annual Meeting of the American Society of Clinical Oncology, Denver, CO, May 20, 1997. --><br />
#'''Intergroup 0089:''' Haller DG, Catalano PJ, Macdonald JS, O'Rourke MA, Frontiera MS, Jackson DV, Mayer RJ. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 2005 Dec 1;23(34):8671-8. [http://jco.ascopubs.org/content/23/34/8671.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16314627 PubMed]<br />
<!-- Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 13-17, 2004. --><br />
#Lembersky BC, Wieand HS, Petrelli NJ, O'Connell MJ, Colangelo LH, Smith RE, Seay TE, Giguere JK, Marshall ME, Jacobs AD, Colman LK, Soran A, Yothers G, Wolmark N. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 2006 May 1;24(13):2059-64. [http://jco.ascopubs.org/content/24/13/2059.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16648506 PubMed]<br />
#'''XELOXA:''' Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A, Maroun J, Price T, Lim R, Van Cutsem E, Park YS, McKendrick J, Topham C, Soler-Gonzalez G, de Braud F, Hill M, Sirzén F, Haller DG. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007 Jan 1;25(1):102-9. [http://jco.ascopubs.org/content/25/1/102.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17194911 PubMed]<br />
##'''Update:''' Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011 Apr 10;29(11):1465-71. Epub 2011 Mar 7. [http://jco.ascopubs.org/content/29/11/1465.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21383294/ PubMed]<br />
##'''Update:''' Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: Final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015 Nov 10;33(32):3733-40. Epub 2015 Aug 31. [http://jco.ascopubs.org/content/33/32/3733.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26324362 PubMed]<br />
#'''NSABP C-07:''' Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, Zapas JL, Goodwin JW, Fehrenbacher L, Ramanathan RK, Conley BA, Flynn PJ, Soori G, Colman LK, Levine EA, Lanier KS, Wolmark N. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007 Jun 1;25(16):2198-204. Epub 2007 Apr 30. [http://jco.ascopubs.org/content/25/16/2198.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17470851 PubMed]<br />
##'''Update:''' Yothers G, O'Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, Wolmark N. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011 Oct 1;29(28):3768-74. Epub 2011 Aug 22. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.4539 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188282/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21859995 PubMed]<br />
#'''CALGB 89803:''' Saltz LB, Niedzwiecki D, Hollis D, Goldberg RM, Hantel A, Thomas JP, Fields AL, Mayer RJ. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol. 2007 Aug 10;25(23):3456-61. [https://ascopubs.org/doi/full/10.1200/JCO.2007.11.2144 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17687149 PubMed]<br />
#'''PETACC-1:''' Popov I, Carrato A, Sobrero A, Vincent M, Kerr D, Labianca R, Raffaele Bianco A, El-Serafi M, Bedenne L, Paillot B, Mini E, Sanches E, Welch J, Collette L, Praet M, Wils J. Raltitrexed (Tomudex) versus standard leucovorin-modulated bolus 5-fluorouracil: Results from the randomised phase III Pan-European Trial in Adjuvant Colon Cancer 01 (PETACC-1). Eur J Cancer. 2008 Oct;44(15):2204-11. Epub 2008 Aug 15. [https://www.ejcancer.com/article/S0959-8049(08)00535-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18707870 PubMed]<br />
#'''FFCD 9802:''' Ychou M, Raoul JL, Douillard JY, Gourgou-Bourgade S, Bugat R, Mineur L, Viret F, Becouarn Y, Bouché O, Gamelin E, Ducreux M, Conroy T, Seitz JF, Bedenne L, Kramar A. A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). Ann Oncol. 2009 Apr;20(4):674-80. Epub 2009 Jan 29. [https://academic.oup.com/annonc/article/20/4/674/205923 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19179549 PubMed]<br />
#'''Study 157-001:''' Fields AL, Keller A, Schwartzberg L, Bernard S, Kardinal C, Cohen A, Schulz J, Eisenberg P, Forster J, Wissel P. Adjuvant therapy with the monoclonal antibody edrecolomab plus fluorouracil-based therapy does not improve overall survival of patients with stage III colon cancer. J Clin Oncol. 2009 Apr 20;27(12):1941-7. Epub 2009 Mar 9. [https://ascopubs.org/doi/full/10.1200/JCO.2008.18.5710 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19273708 PubMed]<br />
#'''PETACC-3:''' Van Cutsem E, Labianca R, Bodoky G, Barone C, Aranda E, Nordlinger B, Topham C, Tabernero J, André T, Sobrero AF, Mini E, Greil R, Di Costanzo F, Collette L, Cisar L, Zhang X, Khayat D, Bokemeyer C, Roth AD, Cunningham D. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol. 2009 Jul 1;27(19):3117-25. Epub 2009 May 18. [https://ascopubs.org/doi/full/10.1200/JCO.2008.21.6663 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19451425 PubMed]<br />
#Ychou M, Hohenberger W, Thezenas S, Navarro M, Maurel J, Bokemeyer C, Shacham-Shmueli E, Rivera F, Kwok-Keung Choi C, Santoro A. A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer. Ann Oncol. 2009 Dec;20(12):1964-70. Epub 2009 Jun 30. [https://academic.oup.com/annonc/article/20/12/1964/210839 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19567451 PubMed]<br />
#Papadimitriou CA, Papakostas P, Karina M, Malettou L, Dimopoulos MA, Pentheroudakis G, Samantas E, Bamias A, Miliaras D, Basdanis G, Xiros N, Klouvas G, Bafaloukos D, Kafiri G, Papaspirou I, Pectasides D, Karanikiotis C, Economopoulos T, Efstratiou I, Korantzis I, Pisanidis N, Makatsoris T, Matsiakou F, Aravantinos G, Kalofonos HP, Fountzilas G. A randomized phase III trial of adjuvant chemotherapy with irinotecan, leucovorin and fluorouracil versus leucovorin and fluorouracil for stage II and III colon cancer: a Hellenic Cooperative Oncology Group study. BMC Med. 2011 Jan 31;9:10. [https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-10 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038965/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21281463 PubMed]<br />
#'''PETACC-2:''' Köhne CH, Bedenne L, Carrato A, Bouché O, Popov I, Gaspà L, Valladares M, Rougier P, Gog C, Reichardt P, Wils J, Pignatti F, Biertz F. A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: the Pan-European Trial in Adjuvant Colon Cancer 2 study. Eur J Cancer. 2013 May;49(8):1868-75. Epub 2013 Apr 6. [https://www.ejcancer.com/article/S0959-8049(13)00094-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23571150 PubMed]<br />
<br />
==Fluorouracil & Levoleucovorin {{#subobject:a93a7t|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 370/25, weekly {{#subobject:1d257d|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02214-5/fulltext Gray et al. 2000 (QUASAR)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. 5-FU & HDLV<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. 5-FU, LDLV, Levamisole<br> 3. 5-FU, HDLV, Levamisole<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Levoleucovorin (Fusilev)]] 25 mg/m<sup>2</sup> IV bolus once on day 1<br />
<br />
'''7-day cycle for 30 cycles'''<br />
<br />
===Variant #2, 1850/125, q4wk {{#subobject:acc8d1|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02214-5/fulltext Gray et al. 2000 (QUASAR)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. 5-FU & HDLV<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. 5-FU, LDLV, Levamisole<br> 3. 5-FU, HDLV, Levamisole<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
*[[Levoleucovorin (Fusilev)]] 25 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''QUASAR:''' Gray RG, Kerr DJ, McConkey CC, Williams NS, Hills RK; QUASAR Collaborative Group. Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. Lancet. 2000 May 6;355(9215):1588-96. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02214-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10821362 PubMed]<br />
##'''Update:''' Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ; Quasar Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007 Dec 15;370(9604):2020-9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61866-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18083404 PubMed]<br />
<br />
==FLOX {{#subobject:617cc1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FLOX: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>OX</u>'''aliplatin<br />
<br />
===Example orders===<br />
<br />
*[[Example orders for FLOX in colon cancer]]<br />
<br />
===Regimen {{#subobject:c80e20|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2198.full Kuebler et al. 2007 (NSABP C-07)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, 29, 36, '''given third, 1 hour after start of leucovorin'''<br />
*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, '''given second'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29, '''given first'''<br />
<br />
'''8-week cycle for 3 cycles'''<br />
<br />
===References===<br />
<br />
#'''NSABP C-07:''' Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, Zapas JL, Goodwin JW, Fehrenbacher L, Ramanathan RK, Conley BA, Flynn PJ, Soori G, Colman LK, Levine EA, Lanier KS, Wolmark N. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007 Jun 1;25(16):2198-204. Epub 2007 Apr 30. [http://jco.ascopubs.org/content/25/16/2198.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17470851 PubMed]<br />
##'''Update:''' Yothers G, O'Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, Wolmark N. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011 Oct 1;29(28):3768-74. Epub 2011 Aug 22. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.4539 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188282/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21859995 PubMed]<br />
<br />
==FOLFOX4 {{#subobject:f61339|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin <br />
===Regimen {{#subobject:671bbe|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa032709 André et al. 2004 (MOSAIC)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Folinic acid]]<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70509-0/fulltext de Gramont et al. 2012 (AVANT)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. FOLFOX4 & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|2. XELOX & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70227-X/fulltext Taieb et al. 2014 (PETACC-8)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FOLFOX4 & Cetuximab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1713709 Grothey et al. 2018 (IDEA)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FOLFOX4 x 6<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior DFS36<br />
|-<br />
|}<br />
''Note: Reported efficacy for MOSAIC is based on the 2009 update. IDEA is a pooled analysis of six phase III RCTs.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with leucovorin'''<br />
<br />
'''14-day cycle for 12 cycles'''<br />
<br />
===References===<br />
<br />
#'''MOSAIC:''' André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004 Jun 3;350(23):2343-51. [https://www.nejm.org/doi/full/10.1056/NEJMoa032709 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15175436 PubMed]<br />
##'''Update:''' André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009 Jul 1;27(19):3109-16. Epub 2009 May 18. [https://ascopubs.org/doi/full/10.1200/JCO.2008.20.6771 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19451431 PubMed]<br />
##'''Update:''' André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, Scriva A, Hickish T, Tabernero J, Van Laethem JL, Banzi M, Maartense E, Shmueli E, Carlsson GU, Scheithauer W, Papamichael D, Möehler M, Landolfi S, Demetter P, Colote S, Tournigand C, Louvet C, Duval A, Fléjou JF, de Gramont A. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol. 2015 Dec 10;33(35):4176-87. Epub 2015 Nov 2. [https://ascopubs.org/doi/full/10.1200/JCO.2015.63.4238 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26527776 PubMed]<br />
#'''AVANT:''' de Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, Cunningham D, Cartwright TH, Hecht JR, Rivera F, Im SA, Bodoky G, Salazar R, Maindrault-Goebel F, Shacham-Shmueli E, Bajetta E, Makrutzki M, Shang A, André T, Hoff PM. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012 Dec;13(12):1225-33. Epub 2012 Nov 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70509-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23168362 PubMed]<br />
#'''PETACC-8:''' Taieb J, Tabernero J, Mini E, Subtil F, Folprecht G, Van Laethem JL, Thaler J, Bridgewater J, Petersen LN, Blons H, Collette L, Van Cutsem E, Rougier P, Salazar R, Bedenne L, Emile JF, Laurent-Puig P, Lepage C; PETACC-8 Study Investigators. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Jul;15(8):862-73. Epub 2014 Jun 11. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70227-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24928083 PubMed]<br />
#'''IDEA:''' Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018 Mar 29;378(13):1177-1188. [https://www.nejm.org/doi/full/10.1056/NEJMoa1713709 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29590544 PubMed]<br />
##'''Subgroup analysis:''' Souglakos J, Boukovinas I, Kakolyris S, Xynogalos S, Ziras N, Athanasiadis A, Androulakis N, Christopoulou A, Vaslamatzis M, Ardavanis A, Emmanouilides C, Bompolaki I, Kourousis C, Makrantonakis P, Christofyllakis C, Athanasiadis E, Kentepozidis N, Karampeazis A, Katopodi U, Anagnosopoulos A, Papadopoulos G, Prinarakis E, Kalisperi A, Mavroudis D, Georgoulias V. Three versus six months adjuvant FOLFOX or CAPOX for high risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project. Ann Oncol. 2019 Aug 1;30(8):1304-1310. Epub 2019 Jun 22. [https://academic.oup.com/annonc/article/30/8/1304/5522015 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31228203 PubMed]<br />
<br />
==mFOLFOX6 {{#subobject:32d6c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Example orders===<br />
<br />
*[[Example orders for mFOLFOX 6 in colon cancer]]<br />
<br />
===Variant #1, 3 months {{#subobject:205ad6|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext Iveson et al. 2018 (SCOT)]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|mFOLFOX6 x 6 mo<br />
| style="background-color:#eeee01" |Seems to have non-inferior DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 350 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''<br />
<br />
'''14-day cycle for 6 cycles'''<br />
<br />
===Variant #2, 6 months (LCV 200 mg/m<sup>2</sup>) {{#subobject:30b6e7|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445286/ Pectasides et al. 2015]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CapeOx|CAPOX]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]], within 10 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''<br />
<br />
'''14-day cycle for 12 cycles'''<br />
<br />
===Variant #3, 6 months (LCV 350 mg/m<sup>2</sup>) {{#subobject:308ic7|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext Iveson et al. 2018 (SCOT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|mFOLFOX6 x 3 mo<br />
| style="background-color:#eeee01" |Seems to have non-inferior DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]], within 10 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 350 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''<br />
<br />
'''14-day cycle for 12 cycles'''<br />
<br />
===Variant #4, 6 months (LCV 400 mg/m<sup>2</sup>) {{#subobject:30juz2|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717026/ Allegra et al. 2009 (NSABP C-08)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Colon_cancer_-_historical#mFOLFOX6_.26_Bevacizumab|mFOLFOX6 & Bevacizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1713709 Grothey et al. 2018 (IDEA)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|mFOLFOX6 x 3 mo<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior DFS36<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2017.76.0355 André et al. 2018 (IDEA France)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|mFOLFOX6 x 3 mo<br />
| style="background-color:#91cf60" |Seems to have superior DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]], within 10 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''<br />
<br />
'''14-day cycle for 12 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. --><br />
<br />
#'''NSABP C-08:''' Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Colangelo LH, Lopa SH, Petrelli NJ, Goldberg RM, Atkins JN, Seay TE, Fehrenbacher L, O'Reilly S, Chu L, Azar CA, Wolmark N. Initial safety report of NSABP C-08: A randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol. 2009 Jul 10;27(20):3385-90. Epub 2009 May 4. [http://jco.ascopubs.org/content/27/20/3385.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717026/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19414665 PubMed]<br />
##'''Update:''' Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Colangelo LH, Atkins JN, Seay TE, Fehrenbacher L, Goldberg RM, O'Reilly S, Chu L, Azar CA, Lopa S, Wolmark N. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011 Jan 1;29(1):11-6. [https://ascopubs.org/doi/full/10.1200/JCO.2010.30.0855 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055856/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20940184 PubMed]<br />
##'''Update:''' Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Lopa SH, Wolmark N. Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J Clin Oncol. 2013 Jan 20;31(3):359-64. [https://ascopubs.org/doi/full/10.1200/JCO.2012.44.4711 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732014/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23233715 PubMed]<br />
#Pectasides D, Karavasilis V, Papaxoinis G, Gourgioti G, Makatsoris T, Raptou G, Vrettou E, Sgouros J, Samantas E, Basdanis G, Papakostas P, Bafaloukos D, Kotoula V, Kalofonos HP, Scopa CD, Pentheroudakis G, Fountzilas G. Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or stage III colorectal cancer. BMC Cancer. 2015 May 10;15:384. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1406-7 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25956750 PubMed]<br />
#'''IDEA:''' Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018 Mar 29;378(13):1177-1188. [https://www.nejm.org/doi/full/10.1056/NEJMoa1713709 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29590544 PubMed]<br />
##'''Subgroup analysis:''' Souglakos J, Boukovinas I, Kakolyris S, Xynogalos S, Ziras N, Athanasiadis A, Androulakis N, Christopoulou A, Vaslamatzis M, Ardavanis A, Emmanouilides C, Bompolaki I, Kourousis C, Makrantonakis P, Christofyllakis C, Athanasiadis E, Kentepozidis N, Karampeazis A, Katopodi U, Anagnosopoulos A, Papadopoulos G, Prinarakis E, Kalisperi A, Mavroudis D, Georgoulias V. Three versus six months adjuvant FOLFOX or CAPOX for high risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project. Ann Oncol. 2019 Aug 1;30(8):1304-1310. Epub 2019 Jun 22. [https://academic.oup.com/annonc/article/30/8/1304/5522015 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31228203 PubMed]<br />
#'''IDEA France:''' André T, Vernerey D, Mineur L, Bennouna J, Desrame J, Faroux R, Fratte S, Hug de Larauze M, Paget-Bailly S, Chibaudel B, Bez J, Dauba J, Louvet C, Lepere C, Dupuis O, Becouarn Y, Mabro M, Egreteau J, Bouche O, Deplanque G, Ychou M, Galais MP, Ghiringhelli F, Dourthe LM, Bachet JB, Khalil A, Bonnetain F, de Gramont A, Taieb J; PRODIGE investigators, GERCOR, Fédération Française de Cancérologie Digestive, UNICANCER. Three versus 6 months of oxaliplatin-based adjuvant chemotherapy for patients with stage III colon cancer: disease-free survival results from a randomized, open-label, International Duration Evaluation of Adjuvant (IDEA) France, phase III trial. J Clin Oncol. 2018 May 20;36(15):1469-1477. Epub 2018 Apr 5. [https://ascopubs.org/doi/full/10.1200/JCO.2017.76.0355 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29620995 PubMed]<br />
#'''SCOT:''' Iveson TJ, Kerr RS, Saunders MP, Cassidy J, Hollander NH, Tabernero J, Haydon A, Glimelius B, Harkin A, Allan K, McQueen J, Scudder C, Boyd KA, Briggs A, Waterston A, Medley L, Wilson C, Ellis R, Essapen S, Dhadda AS, Harrison M, Falk S, Raouf S, Rees C, Olesen RK, Propper D, Bridgewater J, Azzabi A, Farrugia D, Webb A, Cunningham D, Hickish T, Weaver A, Gollins S, Wasan HS, Paul J. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2018 Apr;19(4):562-578. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29611518 PubMed]<br />
<br />
==mFOLFOX6 (L-Leucovorin) {{#subobject:32d6c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOX6: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Example orders===<br />
<br />
*[[Example orders for mFOLFOX 6 in colon cancer]]<br />
<br />
===Variant #1, 3 months {{#subobject:205ad6|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext Iveson et al. 2018 (SCOT)]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|mFOLFOX6 x 6 mo<br />
| style="background-color:#eeee01" |Seems to have non-inferior DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Levoleucovorin (Fusilev)]] 175 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with L-folinic acid'''<br />
<br />
'''14-day cycle for 6 cycles'''<br />
<br />
===Variant #2, 6 months {{#subobject:372bh7|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext Iveson et al. 2018 (SCOT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|mFOLFOX6 x 3 mo<br />
| style="background-color:#eeee01" |Seems to have non-inferior DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]], within 10 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Levoleucovorin (Fusilev)]] 175 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''<br />
<br />
'''14-day cycle for 12 cycles'''<br />
===References===<br />
<br />
#'''SCOT:''' Iveson TJ, Kerr RS, Saunders MP, Cassidy J, Hollander NH, Tabernero J, Haydon A, Glimelius B, Harkin A, Allan K, McQueen J, Scudder C, Boyd KA, Briggs A, Waterston A, Medley L, Wilson C, Ellis R, Essapen S, Dhadda AS, Harrison M, Falk S, Raouf S, Rees C, Olesen RK, Propper D, Bridgewater J, Azzabi A, Farrugia D, Webb A, Cunningham D, Hickish T, Weaver A, Gollins S, Wasan HS, Paul J. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2018 Apr;19(4):562-578. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29611518 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen, stage II disease===<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/10.1200/jco.1995.13.12.2936 Moertel et al. 1995 (INT-0035)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & Levamisole<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02214-5/fulltext Gray et al. 2000 (QUASAR)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.karger.com/Article/Abstract/84595 Hartung et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Colon_cancer_-_historical#Edrecolomab_monotherapy|Edrecolomab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360441/ Schippinger et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00384-008-0543-8 Laffer et al. 2008 (SAKK 40/87)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Portal venous 5-FU & Mitomycin<br> 2. 5-FU & Mitomycin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157980/ Niedzwiecki et al. 2011 (CALGB 9581)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Colon_cancer_-_historical#Edrecolomab_monotherapy|Edrecolomab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''No systemic treatment after surgery for stage II colon cancer.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
===Regimen, stage III disease===<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM198403223101201 Lessner et al. 1984]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. 5-FU & Semustine<br> 2. 5-FU, Semustine, BCG<br> 3. BCG<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://academic.oup.com/jnci/article-abstract/80/1/30/886027 Wolmark et al. 1988 (NSABP C-01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[Colon_cancer_-_historical#MOF|MOF]]<br> 2. BCG<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1988.6.6.947 Panettiere et al. 1988 (SWOG S7510)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. 5-FU & Semustine<br> 2. 5-FU, Semustine, BCG<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1990.8.9.1466 Wolmark et al. 1990 (NSABP C-02)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Portal venous chemotherapy<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PII0140-6736(92)91708-G/fulltext Fielding et al. 1992 (AXIS-CRC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Portal venous chemotherapy<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(94)92398-1/fulltext Riethmüller et al. 1994]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Colon_cancer_-_historical#Edrecolomab_monotherapy|Edrecolomab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140673695903402/fulltext Laffer et al. 1995 (SAKK 40/81)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Portal venous chemotherapy<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140673695906967/fulltext Marsoni et al. 1995 (IMPACT<sub>CRC</sub>)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/15/1/246.long O'Connell et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)08169-5/fulltext Rougier et al. 1998]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Portal venous chemotherapy<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1421018/ Vaillant et al. 2000]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|IP 5-FU<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS60/OS60<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00384-008-0543-8 Laffer et al. 2008 (SAKK 40/87)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Portal venous 5-FU & Mitomycin<br> 2. 5-FU & Mitomycin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010179/ Hasegawa et al. 2016]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Tegafur.2C_Uracil.2C_Folinic_acid|Tegafur, Uracil, Leucovorin]]<br />
| style="background-color:#d73027" |Inferior RFS<br />
|-<br />
|}<br />
''No systemic treatment after surgery. The AXIS trial is named "AXIS-CRC" here so as not to confuse it with the AXIS trial in renal cell carcinoma. IMPACT should not be confused with the studies of the same name in breast cancer and prostate cancer. Reported efficacy for NSABP C-01 is based on the 2004 update.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
===References===<br />
<br />
#Lessner HE, Mayer RJ, Ellenberg SS, Holyoke ED; Gastrointestinal Tumor Study Group. Adjuvant therapy of colon cancer--results of a prospectively randomized trial. N Engl J Med. 1984 Mar 22;310(12):737-43. [https://www.nejm.org/doi/full/10.1056/NEJM198403223101201 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6366550 PubMed]<br />
#'''NSABP C-01:''' Wolmark N, Fisher B, Rockette H, Redmond C, Wickerham DL, Fisher ER, Jones J, Glass A, Lerner H, Lawrence W, Prager D, Wexler M, Evans J, Cruz A, Dimitrov N, Jochimsen P; Other NSABP Investigators. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst. 1988 Mar 2;80(1):30-6. [https://academic.oup.com/jnci/article-abstract/80/1/30/886027 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3276901 PubMed]<br />
##'''Update:''' Smith RE, Colangelo L, Wieand HS, Begovic M, Wolmark N. Randomized trial of adjuvant therapy in colon carcinoma: 10-year results of NSABP protocol C-01. J Natl Cancer Inst. 2004 Aug 4;96(15):1128-32. [https://academic.oup.com/jnci/article/96/15/1128/2520926 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15292384 PubMed]<br />
##'''Pooled update:''' Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. [https://link.springer.com/article/10.1245%2Fs10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20082144 PubMed]<br />
#'''SWOG S7510:''' Panettiere FJ, Goodman PJ, Costanzi JJ, Cruz AB Jr, Vaitkevicius VK, McCracken JD, Brownlee RW, Laufman L, Stephens RL, Bonnet J, Bottomley R, Rivkin S, Fletcher W, Oishi N, Chen TT. Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study. J Clin Oncol. 1988 Jun;6(6):947-54. [https://ascopubs.org/doi/abs/10.1200/JCO.1988.6.6.947 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3286830 PubMed]<br />
#Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, Veeder MH, Mailliard JA. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990 Feb 8;322(6):352-8. [https://www.nejm.org/doi/full/10.1056/NEJM199002083220602 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2300087 PubMed]<br />
##'''Update:''' Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Tangen CM, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, Veeder MH, Mailliard JA. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med. 1995 Mar 1;122(5):321-6. [http://annals.org/aim/article-abstract/708455/fluorouracil-plus-levamisole-effective-adjuvant-therapy-after-resection-stage-iii link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7847642 PubMed]<br />
#'''NSABP C-02:''' Wolmark N, Rockette H, Wickerham DL, Fisher B, Redmond C, Fisher ER, Potvin M, Davies RJ, Jones J, Robidoux A, Wexler M, Gordon P, Cruz AB, Horsley S, Nims TA, Thirlwell M, Phillips WA, Prager D, Stern HS, Lerner HJ, Frazier TG. Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: preliminary results of National Surgical Adjuvant Breast and Bowel Project protocol C-02. J Clin Oncol. 1990 Sep;8(9):1466-75. [https://ascopubs.org/doi/abs/10.1200/JCO.1990.8.9.1466 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2202789 PubMed]<br />
##'''Pooled update:''' Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. [https://link.springer.com/article/10.1245%2Fs10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20082144 PubMed]<br />
#'''AXIS-CRC:''' Fielding LP, Hittinger R, Grace RH, Fry JS. Randomised controlled trial of adjuvant chemotherapy by portal-vein perfusion after curative resection for colorectal adenocarcinoma. Lancet. 1992 Aug 29;340(8818):502-6. [https://www.thelancet.com/journals/lancet/article/PII0140-6736(92)91708-G/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1354275 PubMed]<br />
#Riethmüller G, Schneider-Gädicke E, Schlimok G, Schmiegel W, Raab R, Höffken K, Gruber R, Pichlmaier H, Hirche H, Pichlmayr R, Buggisch P, Witte J; German Cancer Aid 17-1A Study Group. Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes' C colorectal carcinoma. Lancet. 1994 May 14;343(8907):1177-83. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(94)92398-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7909866 PubMed]<br />
#'''SAKK 40/81:''' Laffer U, Metzger U, Aeberhard P, Maibach R, Castiglione M, Goldhirsch A; Swiss Group for Clinical Cancer Research (SAKK). Long-term results of single course of adjuvant intraportal chemotherapy for colorectal cancer. Lancet. 1995 Feb 11;345(8946):349-53. [https://www.thelancet.com/journals/lancet/article/PIIS0140673695903402/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7845115 PubMed]<br />
#'''IMPACT:''' Marsoni S, Labianca R, Pancera G, Torri V, Zaniboni A, Erlichman C, Pater J, Shepherd L, Zee B, Seitz JF, Milan C, Pignon JP; International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet. 1995 Apr 15;345(8955):939-44. [https://www.thelancet.com/journals/lancet/article/PIIS0140673695906967/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7715291 PubMed]<br />
#'''INT-0035:''' Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Tangen CM, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, Veeder MH, Mailliard JA; North Central Cancer Treatment Group; Southwest Oncology Group; Eastern Cooperative Oncology Group. Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes' B2 colon cancer. J Clin Oncol. 1995 Dec;13(12):2936-43. [https://ascopubs.org/doi/10.1200/jco.1995.13.12.2936 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8523058 PubMed]<br />
#O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, Wieand HS. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997 Jan;15(1):246-50. [http://jco.ascopubs.org/content/15/1/246.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8996149 PubMed]<br />
##'''Pooled update:''' Erlichman C, O'Connell M, Kahn M, Marsoni S, Torri V, Tardio B, Zaniboni A, Pancera G, Martignoni G, Labianca R, Barni A, Seitz JF, Milan C, Bedenne L, Giovannini M, Letreut YP, Skillings J, Shepard L, Zee B, Petrioli R, Francini G; International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol. 1999 May;17(5):1356-63. [https://ascopubs.org/doi/full/10.1200/JCO.1999.17.5.1356 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10334519 PubMed]<br />
#Rougier P, Sahmoud T, Nitti D, Curran D, Doci R, De Waele B, Nakajima T, Rauschecker H, Labianca R, Pector JC, Marsoni S, Apolone G, Lasser P, Couvreur ML, Wils J; European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group and the Gruppo Interdisciplinare Valutazione Interventi in Oncologia and the Japanese Foundation for Cancer Research. Adjuvant portal-vein infusion of fluorouracil and heparin in colorectal cancer: a randomised trial. Lancet. 1998 Jun 6;351(9117):1677-81. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)08169-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9734883 PubMed]<br />
#Vaillant JC, Nordlinger B, Deuffic S, Arnaud JP, Pelissier E, Favre JP, Jaeck D, Fourtanier G, Grandjean JP, Marre P, Letoublon C. Adjuvant intraperitoneal 5-fluorouracil in high-risk colon cancer: a multicenter phase III trial. Ann Surg. 2000 Apr;231(4):449-56. [https://insights.ovid.com/pubmed?pmid=10749603 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1421018/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/10749603 PubMed]<br />
#'''QUASAR:''' Gray RG, Kerr DJ, McConkey CC, Williams NS, Hills RK; QUASAR Collaborative Group. Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. Lancet. 2000 May 6;355(9215):1588-96. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02214-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10821362 PubMed]<br />
##'''Update:''' Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ; Quasar Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007 Dec 15;370(9604):2020-9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61866-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18083404 PubMed]<br />
#Hartung G, Hofheinz RD, Dencausse Y, Sturm J, Kopp-Schneider A, Dietrich G, Fackler-Schwalbe I, Bornbusch D, Gonnermann M, Wojatschek C, Lindemann W, Eschenburg H, Jost K, Edler L, Hochhaus A, Queisser W. Adjuvant therapy with edrecolomab versus observation in stage II colon cancer: a multicenter randomized phase III study. Onkologie. 2005 Jun;28(6-7):347-50. Epub 2005 Jun 2. [https://www.karger.com/Article/Abstract/84595 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15933423 PubMed]<br />
#Schippinger W, Samonigg H, Schaberl-Moser R, Greil R, Thödtmann R, Tschmelitsch J, Jagoditsch M, Steger GG, Jakesz R, Herbst F, Hofbauer F, Rabl H, Wohlmuth P, Gnant M, Thaler J; Austrian Breast and Colorectal Cancer Study Group. A prospective randomised phase III trial of adjuvant chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer. Br J Cancer. 2007 Oct 22;97(8):1021-7. Epub 2007 Sep 25. [https://www.nature.com/articles/6604011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360441/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/17895886 PubMed]<br />
#'''SAKK 40/87:''' Laffer U, Metzger U, Aeberhard P, Lorenz M, Harder F, Maibach R, Zuber M, Herrmann R. Adjuvant perioperative portal vein or peripheral intravenous chemotherapy for potentially curative colorectal cancer: long-term results of a randomized controlled trial. Int J Colorectal Dis. 2008 Dec;23(12):1233-41. Epub 2008 Aug 8. [https://link.springer.com/article/10.1007%2Fs00384-008-0543-8 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18688620 PubMed]<br />
#'''CALGB 9581:''' Niedzwiecki D, Bertagnolli MM, Warren RS, Compton CC, Kemeny NE, Benson AB 3rd, Eckhardt SG, Alberts S, Porjosh GN, Kerr DJ, Fields A, Rougier P, Pipas JM, Schwartz JH, Atkins J, O'Rourke M, Perry MC, Goldberg RM, Mayer RJ, Colacchio TA. Documenting the natural history of patients with resected stage II adenocarcinoma of the colon after random assignment to adjuvant treatment with edrecolomab or observation: results from CALGB 9581. J Clin Oncol. 2011 Aug 10;29(23):3146-52. Epub 2011 Jul 11. [https://ascopubs.org/doi/full/10.1200/JCO.2010.32.5357 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157980/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21747085 PubMed]<br />
#Hasegawa K, Saiura A, Takayama T, Miyagawa S, Yamamoto J, Ijichi M, Teruya M, Yoshimi F, Kawasaki S, Koyama H, Oba M, Takahashi M, Mizunuma N, Matsuyama Y, Watanabe T, Makuuchi M, Kokudo N. Adjuvant oral uracil-tegafur with leucovorin for colorectal cancer liver metastases: A randomized controlled trial. PLoS One. 2016 Sep 2;11(9):e0162400. eCollection 2016. [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162400 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010179/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27588959 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" 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://ascopubs.org/doi/full/10.1200/JCO.2010.29.6244 Midgley et al. 2010 (VICTOR)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Rofecoxib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
===References===<br />
<br />
#'''VICTOR:''' Midgley RS, McConkey CC, Johnstone EC, Dunn JA, Smith JL, Grumett SA, Julier P, Iveson C, Yanagisawa Y, Warren B, Langman MJ, Kerr DJ. Phase III randomized trial assessing rofecoxib in the adjuvant setting of colorectal cancer: final results of the VICTOR trial. J Clin Oncol. 2010 Oct 20;28(30):4575-80. Epub 2010 Sep 13. [https://ascopubs.org/doi/full/10.1200/JCO.2010.29.6244 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20837956 PubMed]<br />
<br />
==SOX {{#subobject:617cc1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
SOX: '''<u>S</u>'''-1, '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:c80e20|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.clinical-colorectal-cancer.com/article/S1533-0028(19)30449-9/abstract Sunami et al. 2019 (ACTS-CC 02)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[Colon_cancer#Tegafur.2C_Uracil.2C_Folinic_acid|Tegafur, Uracil, Folinic Acid]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Colorectal_cancer_surgery|Surgery]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for 8 cycles'''<br />
<br />
===References===<br />
<br />
#'''ACTS-CC 02:''' Sunami E, Kusumoto T, Ota M, SakamotoY, Yoshida K, Tomita N, Maeda A, Teshima J, Okabe M, Tanaka C, Yamauchi J, Itabashi M, Kotake K, Takahashi K, Baba H, Boku N, Aiba K, Ishiguro M, Morita S, Takenaka N, Okude R, Sugihara K. S-1 and oxaliplatin versus tegafur-uracil and leucovorin as postoperative adjuvant chemotherapy in patients with high-risk stage III colon cancer (ACTS-CC 02): a randomized, open-label, multicenter, phase 3, superiority trial. Clinical Colorectal Cancer (2019). Epub Oct 2019. [https://www.clinical-colorectal-cancer.com/article/S1533-0028(19)30449-9/fulltext link to original article]<br />
<br />
==Tegafur, Uracil, Folinic acid {{#subobject:5ed2aa|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
UFT + LV: '''<u>UFT</u>''' (Tegafur and uracil) & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid)<br />
===Variant #1, 300/75 {{#subobject:8cc7d8|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143094/ Yoshida et al. 2014 (ACTS-CC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|S-1<br />
| style="background-color:#eeee01" |Non-inferior DFS<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(14)00724-2/fulltext Shimada et al. 2014 (JCOG0205)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#eeee01" |Non-inferior DFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621030/ Sadahiro et al. 2015 (JFMC33-0502)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|UFT + LV weekly x 18 mo<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010179/ Hasegawa et al. 2016]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior RFS<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00595-017-1555-1 Miyake et al. 2018]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|UFT/PSK<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior DFS36<br />
|-<br />
|}<br />
''Note: Miyake et al. 2018 does not contain treatment details in the abstract.''<br />
====Preceding treatment====<br />
<br />
*JCOG0205: [[Surgery#Colorectal_cancer_surgery|Surgery]] with D2/D3 lymph node dissection<br />
*Hasegawa et al. 2016: [[Surgery#Metastasectomy|Surgical resection of colorectal cancer liver metastases]], within 8 weeks<br />
<br />
====Chemotherapy====<br />
<br />
*[[Tegafur and uracil (UFT)]] 100 mg/m<sup>2</sup> PO every 8 hours on days 1 to 28<br />
*[[Folinic acid (Leucovorin)]] 25 mg PO every 8 hours on days 1 to 28<br />
<br />
'''35-day cycle for 5 cycles'''<br />
<br />
===Variant #2, 300/90 {{#subobject:643dbb|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/13/2059.long Lembersky et al. 2006 (NSABP C-06)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS/OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*A potentially curative [[Surgery#Colorectal_cancer_surgery|resection]] of stage II or stage III colon cancer<br />
<br />
====Chemotherapy====<br />
<br />
*[[Tegafur and uracil (UFT)]] 100 mg/m<sup>2</sup> PO every 8 hours on days 1 to 28<br />
*[[Folinic acid (Leucovorin)]] 30 mg PO every 8 hours on days 1 to 28<br />
*No food for 1 hour before and after each dose of medication.<br />
<br />
'''35-day cycle for 5 cycles'''<br />
<br />
===References===<br />
<!-- Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 13-17, 2004. --><br />
<br />
#'''NSABP C-06:''' Lembersky BC, Wieand HS, Petrelli NJ, O'Connell MJ, Colangelo LH, Smith RE, Seay TE, Giguere JK, Marshall ME, Jacobs AD, Colman LK, Soran A, Yothers G, Wolmark N. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 2006 May 1;24(13):2059-64. [http://jco.ascopubs.org/content/24/13/2059.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16648506 PubMed]<br />
#'''ACTS-CC:''' Yoshida M, Ishiguro M, Ikejiri K, Mochizuki I, Nakamoto Y, Kinugasa Y, Takagane A, Endo T, Shinozaki H, Takii Y, Mochizuki H, Kotake K, Kameoka S, Takahashi K, Watanabe T, Watanabe M, Boku N, Tomita N, Nakatani E, Sugihara K; ACTS-CC study group. S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial). Ann Oncol. 2014 Sep;25(9):1743-9. Epub 2014 Jun 18. [https://academic.oup.com/annonc/article/25/9/1743/2801231 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143094/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24942277 PubMed]<br />
#'''JCOG0205:''' Shimada Y, Hamaguchi T, Mizusawa J, Saito N, Kanemitsu Y, Takiguchi N, Ohue M, Kato T, Takii Y, Sato T, Tomita N, Yamaguchi S, Akaike M, Mishima H, Kubo Y, Nakamura K, Fukuda H, Moriya Y. Randomised phase III trial of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients with stage III colorectal cancer who have undergone Japanese D2/D3 lymph node dissection: final results of JCOG0205. Eur J Cancer. 2014 Sep;50(13):2231-40. Epub 2014 Jun 20. [https://www.ejcancer.com/article/S0959-8049(14)00724-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24958736 PubMed]<br />
#'''JFMC33-0502:''' Sadahiro S, Tsuchiya T, Sasaki K, Kondo K, Katsumata K, Nishimura G, Kakeji Y, Baba H, Sato S, Koda K, Yamaguchi Y, Morita T, Matsuoka J, Usuki H, Hamada C, Kodaira S. Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502. Ann Oncol. 2015 Nov;26(11):2274-80. Epub 2015 Sep 7. [https://academic.oup.com/annonc/article/26/11/2274/263547 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621030/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26347106 PubMed]<br />
#Hasegawa K, Saiura A, Takayama T, Miyagawa S, Yamamoto J, Ijichi M, Teruya M, Yoshimi F, Kawasaki S, Koyama H, Oba M, Takahashi M, Mizunuma N, Matsuyama Y, Watanabe T, Makuuchi M, Kokudo N. Adjuvant oral uracil-tegafur with leucovorin for colorectal cancer liver metastases: A randomized controlled trial. PLoS One. 2016 Sep 2;11(9):e0162400. eCollection 2016. [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162400 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010179/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27588959 PubMed]<br />
#Miyake Y, Nishimura J, Kato T, Ikeda M, Tsujie M, Hata T, Takemasa I, Mizushima T, Yamamoto H, Sekimoto M, Nezu R, Doki Y, Mori M; Multi-center Clinical Study Group of Osaka, Colorectal Cancer Treatment Group (MCSGO). Phase III trial comparing UFT + PSK to UFT + LV in stage IIB, III colorectal cancer (MCSGO-CCTG). Surg Today. 2018 Jan;48(1):66-72. Epub 2017 Jun 20. [https://link.springer.com/article/10.1007%2Fs00595-017-1555-1 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28634730 PubMed]<br />
<br />
=Therapy for oligometastatic disease, including perioperative therapy and hyperthermic intra-peritoneal chemotherapy=<br />
==Fluorouracil & Folinic acid {{#subobject:e9bcc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:12cfb6|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2006.06.8353 Portier et al. 2006 (FFCD 9002)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation_2|Observation]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS (*)<br />
|-<br />
|}<br />
''Reported efficacy is based on the 2008 pooled update.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Surgical_resection|Surgical resection of oligometastatic disease]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
<br />
#'''FFCD 9002:''' Portier G, Elias D, Bouche O, Rougier P, Bosset JF, Saric J, Belghiti J, Piedbois P, Guimbaud R, Nordlinger B, Bugat R, Lazorthes F, Bedenne L. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol. 2006 Nov 1;24(31):4976-82. [https://ascopubs.org/doi/full/10.1200/JCO.2006.06.8353 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17075115 PubMed]<br />
##'''Pooled update:''' Mitry E, Fields AL, Bleiberg H, Labianca R, Portier G, Tu D, Nitti D, Torri V, Elias D, O'Callaghan C, Langer B, Martignoni G, Bouché O, Lazorthes F, Van Cutsem E, Bedenne L, Moore MJ, Rougier P. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol. 2008 Oct 20;26(30):4906-11. Epub 2008 Sep 15. [https://ascopubs.org/doi/full/10.1200/JCO.2008.17.3781 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18794541 PubMed]<br />
<br />
==FOLFIRI {{#subobject:a051ec|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
===Regimen {{#subobject:0e95b6|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://ar.iiarjournals.org/content/32/4/1387.long Fiorentini et al. 2012]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|DEBIRI<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second on day 1''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 100 mg/m<sup>2</sup> IV over 120 minutes once on day 1, '''given first, with irinotecan'''<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 120 minutes once on day 1, '''given first, with leucovorin'''<br />
<br />
'''14-day cycle for 8 cycles'''<br />
<br />
===References===<br />
<br />
#Fiorentini G, Aliberti C, Tilli M, Mulazzani L, Graziano F, Giordani P, Mambrini A, Montagnani F, Alessandroni P, Catalano V, Coschiera P. Intra-arterial infusion of irinotecan-loaded drug-eluting beads (DEBIRI) versus intravenous therapy (FOLFIRI) for hepatic metastases from colorectal cancer: final results of a phase III study. Anticancer Res. 2012 Apr;32(4):1387-95. Erratum in: Anticancer Res. 2013 Nov;33(11):5211. [http://ar.iiarjournals.org/content/32/4/1387.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22493375 PubMed]<br />
<br />
==FOLFOX4 {{#subobject:58d3ec|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:dfc57d|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277487/ Nordlinger et al. 2008 (EORTC 40983)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation_2|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://academic.oup.com/annonc/article/26/2/340/2800608 Hebbar et al. 2014 (MIROX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FOLFOX7-FOLFIRI<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS24<br />
|-<br />
|}<br />
''Note: this is the regimen as described by de Gramont et al. 2000; EORTC 40983 refers to this protocol. In MIROX, the treatment could be given perioperatively or postoperatively.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Surgical_resection|Surgical resection of oligometastatic disease]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with leucovorin'''<br />
<br />
'''14-day cycle for 6 cycles before surgery, and 6 cycles after surgery (12 cycles total)'''<br />
<br />
===References===<br />
<br />
#'''EORTC 40983:''' Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008 Mar 22;371(9617):1007-16. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60455-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277487/ link to PMC article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18358928 PubMed]<br />
##'''Update:''' Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Mauer M, Tanis E, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und–tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectalcancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1208-15. Epub 2013 Oct 11. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70447-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24120480 PubMed]<br />
#'''MIROX:''' Hebbar M, Chibaudel B, André T, Mineur L, Smith D, Louvet C, Dutel JL, Ychou M, Legoux JL, Mabro M, Faroux R, Auby D, Brusquant D, Khalil A, Truant S, Hadengue A, Dalban C, Gayet B, Paye F, Pruvot FR, Bonnetain F, Landi B, Flesch M, Carola E, Martin P, Vaillant E, de Gramont A; Group Coopérateur Multidisciplinaire en Oncologie (GERCOR) Group. FOLFOX4 versus sequential dose-dense FOLFOX7 followed by FOLFIRI in patients with resectable metastatic colorectal cancer (MIROX): a pragmatic approach to chemotherapy timing with perioperative or postoperative chemotherapy from an open-label, randomized phase III trial. Ann Oncol. 2015 Feb;26(2):340-7. Epub 2014 Nov 17. Erratum in: Ann Oncol. 2015 May;26(5):1040. Taieb, J [removed]; Brucker, P [removed]. [https://academic.oup.com/annonc/article/26/2/340/2800608 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25403578 PubMed]<br />
<br />
==mFOLFOX6 (L-Leucovorin) {{#subobject:8fig59|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOX6: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e300fa|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0959804915008631 Cashin et al. 2016 (SPS-1)]<br />
| style="background-color:#1a9851" |Randomized (C)<br />
|[[#Intraperitoneal_5-FU|IP 5-FU & LV]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycle for 12 cycles'''<br />
<br />
===References===<br />
<br />
#'''SPS-1:''' Cashin PH, Mahteme H, Spång N, Syk I, Frödin JE, Torkzad M, Glimelius B, Graf W. Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial. Eur J Cancer. 2016 Jan;53:155-62. Epub 2016 Jan 2. [https://www.sciencedirect.com/science/article/pii/S0959804915008631 link to SD article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26751236 PubMed]<br />
<br />
==Hepatic arterial chemotherapy==<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140673694907501/fulltext Allen-Mersh et al. 1994]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|Best supportive care<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199912303412702 Kemeny et al. 1999]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation_2|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Of historic interest; unlikely to be completed.''<br />
====Preceding treatment====<br />
<br />
*[[Surgery#Surgical_resection|Surgical resection of oligometastatic disease]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Floxuridine (FUDR)]]<br />
<br />
====Supportive medications====<br />
<br />
*[[Dexamethasone (Decadron)]]<br />
<br />
===References===<br />
<br />
#Allen-Mersh TG, Earlam S, Fordy C, Abrams K, Houghton J. Quality of life and survival with continuous hepatic-artery floxuridine infusion for colorectal liver metastases. Lancet. 1994 Nov 5;344(8932):1255-60. [https://www.thelancet.com/journals/lancet/article/PIIS0140673694907501/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7526096 PubMed]<br />
#Kemeny N, Huang Y, Cohen AM, Shi W, Conti JA, Brennan MF, Bertino JR, Turnbull AD, Sullivan D, Stockman J, Blumgart LH, Fong Y. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med. 1999 Dec 30;341(27):2039-48. [https://www.nejm.org/doi/full/10.1056/NEJM199912303412702 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10615075 PubMed]<br />
<br />
==Intraperitoneal 5-FU {{#subobject:581aec|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:1ac57d|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0959804915008631 Cashin et al. 2016 (SPS-1)]<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#mFOLFOX6_2|mFOLFOX6]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Cytoreductive surgery<br />
<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 550 mg/m<sup>2</sup>/day IP continuous infusion over 6 days, started on day 1 (total dose per cycle: 3300 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 30 mg/m<sup>2</sup>/day IV once on day 1, '''given 60 minutes after start of 5-FU IP infusion'''<br />
<br />
'''1-month cycle for 6 cycles'''<br />
===References===<br />
<br />
#'''SPS-1:''' Cashin PH, Mahteme H, Spång N, Syk I, Frödin JE, Torkzad M, Glimelius B, Graf W. Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial. Eur J Cancer. 2016 Jan;53:155-62. Epub 2016 Jan 2. [https://www.sciencedirect.com/science/article/pii/S0959804915008631 link to SD article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26751236 PubMed]<br />
<br />
==Intraperitoneal hyperthermic mitomycin {{#subobject:c049cb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f86ab6|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2003.04.187 Verwaal et al. 2003]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|[[#Fluorouracil_.26_Folinic_acid_3|5-FU & LV (modified Laufman regimen)]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Cytoreductive surgery<br />
<br />
====Chemotherapy====<br />
<br />
*Hyperthermic [[Mitomycin (Mutamycin)]] 17.5 mg/m<sup>2</sup> IP once, then 8.8 mg/m<sup>2</sup> every 30 minutes (maximum dose of 70 mg)<br />
<br />
'''One treatment'''<br />
<br />
===References===<br />
<br />
#Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003 Oct 15;21(20):3737-43. [https://ascopubs.org/doi/full/10.1200/JCO.2003.04.187 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14551293 PubMed]<br />
<br />
==Observation==<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM199912303412702 Kemeny et al. 1999]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Hepatic_arterial_chemotherapy|Hepatic arterial chemotherapy]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2006.06.8353 Portier et al. 2006 (FFCD 9002)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid_2|5-FU & LV]]<br />
| style="background-color:#fee08b" |Might have inferior PFS (*)<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277487/ Nordlinger et al. 2008 (EORTC 40983)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFOX4_2|FOLFOX4]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|}<br />
''No treatment other than surgical resection of oligometastatic disease. Reported efficacy for FFCD 9002 is based on the 2008 pooled update.''<br />
===References===<br />
<br />
#Kemeny N, Huang Y, Cohen AM, Shi W, Conti JA, Brennan MF, Bertino JR, Turnbull AD, Sullivan D, Stockman J, Blumgart LH, Fong Y. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med. 1999 Dec 30;341(27):2039-48. [https://www.nejm.org/doi/full/10.1056/NEJM199912303412702 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10615075 PubMed]<br />
#'''FFCD 9002:''' Portier G, Elias D, Bouche O, Rougier P, Bosset JF, Saric J, Belghiti J, Piedbois P, Guimbaud R, Nordlinger B, Bugat R, Lazorthes F, Bedenne L. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol. 2006 Nov 1;24(31):4976-82. [https://ascopubs.org/doi/full/10.1200/JCO.2006.06.8353 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17075115 PubMed]<br />
##'''Pooled update:''' Mitry E, Fields AL, Bleiberg H, Labianca R, Portier G, Tu D, Nitti D, Torri V, Elias D, O'Callaghan C, Langer B, Martignoni G, Bouché O, Lazorthes F, Van Cutsem E, Bedenne L, Moore MJ, Rougier P. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol. 2008 Oct 20;26(30):4906-11. Epub 2008 Sep 15. [https://ascopubs.org/doi/full/10.1200/JCO.2008.17.3781 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18794541 PubMed]<br />
#'''EORTC 40983:''' Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008 Mar 22;371(9617):1007-16. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60455-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277487/ link to PMC article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18358928 PubMed]<br />
##'''Update:''' Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Mauer M, Tanis E, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und–tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectalcancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1208-15. Epub 2013 Oct 11. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70447-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24120480 PubMed]<br />
<br />
=Advanced or metastatic disease, first-line=<br />
<br />
==Capecitabine monotherapy {{#subobject:6816ee|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
C: '''<u>C</u>'''apecitabine<br />
===Variant #1, 2000 mg/m<sup>2</sup>/day {{#subobject:b1642a|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#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://academic.oup.com/annonc/article-abstract/28/6/1288/3102942 Kwakman et al. 2017 (SALTO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints (*)<br />
| style="background-color:#d73027" |Higher incidence of hand-foot syndrome<br />
|-<br />
|}<br />
''Note: this trial had a primary toxicity endpoint; this dose was intended for patients at least 70 years old; reported efficacy is based on the 2019 update.'' <br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2, 2500 mg/m<sup>2</sup>/day {{#subobject:303fab|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#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[http://jco.ascopubs.org/content/19/8/2282.long Hoff et al. 2001]<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Fluorouracil_.26_Folinic_acid_3|5-FU + Folinic acid]]<br />
| style="background-color:#1a9850" |Superior ORR<br />
|<br />
|-<br />
|[http://jco.ascopubs.org/content/19/21/4097.long Van Cutsem et al. 2001]<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Fluorouracil_.26_Folinic_acid_3|5-FU + Folinic acid]]<br />
| style="background-color:#eeee01" |Equivalent ORR<br />
|<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext Koopman et al. 2007 (CAIRO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#CAIRO|See link]]<br />
| style="background-color:#ffffbf" |[[Complex_multipart_regimens#CAIRO|See link]]<br />
|<br />
|-<br />
| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/JCO.2009.27.7723 Tebbutt et al. 2010 (AGITG MAX)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|<br />
|-<br />
|2. CBM<br />
| style="background-color:#d73027" |Inferior PFS<br />
|<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70154-2/fulltext Cunningham et al. 2013 (AVEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|<br />
|-<br />
|[https://academic.oup.com/annonc/article-abstract/28/6/1288/3102942 Kwakman et al. 2017 (SALTO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints (*)<br />
| style="background-color:#d73027" |Higher incidence of hand-foot syndrome<br />
|-<br />
|}<br />
''Note: SALTO had a primary toxicity endpoint; this dose was intended for patients less than 70 years old; reported efficacy is based on the 2019 update.'' <br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
====Subsequent treatment====<br />
<br />
*CAIRO, upon progression: [[#Irinotecan_monotherapy_2|Irinotecan]]<br />
<br />
===References===<br />
<!-- Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, Georgia, May 15-18, 1999. --><br />
<br />
#Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001 Apr 15;19(8):2282-92. [http://jco.ascopubs.org/content/19/8/2282.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11304782 PubMed]<br />
##'''Pooled update:''' Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. [https://www.nature.com/articles/6601676 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409640/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/15026800 PubMed]<br />
<!-- This study was presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999. --><br />
#Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P; Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001 Nov 1;19(21):4097-106. [http://jco.ascopubs.org/content/19/21/4097.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11689577 PubMed]<br />
##'''Pooled update:''' Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. [https://www.nature.com/articles/6601676 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409640/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/15026800 PubMed]<br />
#'''CAIRO:''' Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. [https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17630036 PubMed]<br />
#'''AGITG MAX:''' Tebbutt NC, Wilson K, Gebski VJ, Cummins MM, Zannino D, van Hazel GA, Robinson B, Broad A, Ganju V, Ackland SP, Forgeson G, Cunningham D, Saunders MP, Stockler MR, Chua Y, Zalcberg JR, Simes RJ, Price TJ. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group randomized phase III MAX study. J Clin Oncol. 2010 Jul 1;28(19):3191-8. Epub 2010 Jun 1. [https://ascopubs.org/doi/full/10.1200/JCO.2009.27.7723 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20516443 PubMed]<br />
<!--<br />
# '''Abstract:''' David Cunningham, Istvan Lang, Vito Lorusso, Janja Ocvirk, Dongbok Shin, Derek J. Jonker, Stuart Osborne, Niko Alexander Andre, Daniel Waterkamp, Mark P. Saunders. Bevacizumab (bev) in combination with capecitabine (cape) for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): Results of a randomized international phase III trial (AVEX). 2013 ASCO Gastrointestinal Cancers Symposium abstract 337. [http://meetinglibrary.asco.org/content/106233-133 link to abstract] --><br />
#'''AVEX:''' Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, Jonker D, Osborne S, Andre N, Waterkamp D, Saunders MP; AVEX study investigators. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label,randomised phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1077-85. Epub 2013 Sep 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70154-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24028813 PubMed]<br />
#'''SALTO:''' Kwakman JJM, Simkens LHJ, van Rooijen JM, van de Wouw AJ, Ten Tije AJ, Creemers GJM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, van Werkhoven E, Punt CJA. Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group. Ann Oncol. 2017 Jun 1;28(6):1288-1293. [https://academic.oup.com/annonc/article-abstract/28/6/1288/3102942 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28383633 PubMed]<br />
##'''Update:''' Kwakman JJM, van Werkhoven E, Simkens LHJ, van Rooijen JM, van de Wouw YAJ, Tije AJT, Creemers GM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, Punt CJA. Updated Survival Analysis of the Randomized Phase III Trial of S-1 Versus Capecitabine in the First-Line Treatment of Metastatic Colorectal Cancer by the Dutch Colorectal Cancer Group. Clin Colorectal Cancer. 2019 Jun;18(2):e229-e230. Epub 2019 Jan 29. [https://www.clinical-colorectal-cancer.com/article/S1533-0028(18)30531-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30782413 PubMed]<br />
<br />
==Capecitabine & Bevacizumab {{#subobject:408d3d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CB: '''<u>C</u>'''apecitabine & '''<u>B</u>'''evacizumab<br />
===Variant #1, 1000/7.5 {{#subobject:f9f237|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70154-2/fulltext Cunningham et al. 2013 (AVEX)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Capecitabine_monotherapy_2|Capecitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2, 1250/7.5 {{#subobject:94ef02|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
||[https://ascopubs.org/doi/full/10.1200/JCO.2009.27.7723 Tebbutt et al. 2010 (AGITG MAX)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Capecitabine_monotherapy_2|Capecitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''AGITG MAX:''' Tebbutt NC, Wilson K, Gebski VJ, Cummins MM, Zannino D, van Hazel GA, Robinson B, Broad A, Ganju V, Ackland SP, Forgeson G, Cunningham D, Saunders MP, Stockler MR, Chua Y, Zalcberg JR, Simes RJ, Price TJ. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group randomized phase III MAX study. J Clin Oncol. 2010 Jul 1;28(19):3191-8. Epub 2010 Jun 1. [https://ascopubs.org/doi/full/10.1200/JCO.2009.27.7723 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20516443 PubMed]<br />
<!--<br />
# '''Abstract:''' David Cunningham, Istvan Lang, Vito Lorusso, Janja Ocvirk, Dongbok Shin, Derek J. Jonker, Stuart Osborne, Niko Alexander Andre, Daniel Waterkamp, Mark P. Saunders. Bevacizumab (bev) in combination with capecitabine (cape) for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): Results of a randomized international phase III trial (AVEX). 2013 ASCO Gastrointestinal Cancers Symposium abstract 337. [http://meetinglibrary.asco.org/content/106233-133 link to abstract] --><br />
#'''AVEX:''' Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, Jonker D, Osborne S, Andre N, Waterkamp D, Saunders MP; AVEX study investigators. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label,randomised phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1077-85. Epub 2013 Sep 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70154-2/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24028813 PubMed]<br />
#'''XELAVIRI:''' Modest DP, Fischer von Weikersthal L, Decker T, Vehling-Kaiser U, Uhlig J, Schenk M, Freiberg-Richter J, Peuser B, Denzlinger C, Peveling Genannt Reddemann C, Graeven U, Schuch G, Schwaner I, Stahler A, Jung A, Kirchner T, Held S, Stintzing S, Giessen-Jung C, Heinemann V; XELAVIRI/AIO KRK0110 Investigators. Sequential Versus Combination Therapy of Metastatic Colorectal Cancer Using Fluoropyrimidines, Irinotecan, and Bevacizumab: A Randomized, Controlled Study-XELAVIRI (AIO KRK0110). J Clin Oncol. 2019 Jan 1;37(1):22-32. Epub 2018 Nov 2. [https://ascopubs.org/doi/full/10.1200/JCO.18.00052 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30388045 PubMed]<br />
<br />
==CapeOx {{#subobject:b4a5f5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine & '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda & '''<u>OX</u>'''aliplatin<br />
<br>COX: '''<u>C</u>'''apecitabine & '''<u>OX</u>'''aliplatin<br />
===Example orders===<br />
<br />
*[[Example orders for CapeOx (XELOX) in colon cancer]]<br />
<br />
===Variant #1, 850/130 {{#subobject:d1897d|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[http://jco.ascopubs.org/content/26/21/3523.full Hochster et al. 2008 (TREE-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. bFOL<br />
| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints<br />
|-<br />
|2. [[#mFOLFOX6_3|mFOLFOX6]]<br />
| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints<br />
|-<br />
|}<br />
''Note: TREE-1 did not have any primary endpoints.''<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 850 mg/m<sup>2</sup> PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)<br />
**In TREE-2, based on safety data from TREE-1, the initial dose was decreased to 850 mg/m<sup>2</sup> PO twice per day. Patients with a CrCl of 30 to 50 mL/min/1.73m<sup>2</sup> received 650 mg/m<sup>2</sup> PO twice per day<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2, 1000/70 {{#subobject:b301d1|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/27/4217.long Porschen et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|FUFOX<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] 70 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #3, 1000/130 {{#subobject:162a54|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/27/4224.long Díaz-Rubio et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#FUOX|FUOX]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP<br />
|-<br />
| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 Cassidy et al. 2008 (NO16966)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#FOLFOX4_2|FOLFOX4]]<br> 2. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|3. [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
| rowspan="2" |[http://jco.ascopubs.org/content/26/12/2013.long Saltz et al. 2008 (NO16966)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]<br> 2. [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|3. [[#FOLFOX4_2|FOLFOX4]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.25369 Ducreux et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#mFOLFOX6_3|mFOLFOX6]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159415/ Maughan et al. 2011 (UK MRC COIN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CapeOx & Cetuximab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)<br />
|-<br />
|[http://jco.ascopubs.org/content/30/29/3596.long Hoff et al. 2012 (HORIZON II)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. CAPOX & Cediranib<br> 2. FOLFOX4 & Cediranib<br> 3. mFOLFOX6 & Cediranib<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext Hong et al. 2012 (SMC 2008-03-012)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#SOX_2|SOX]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|}<br />
''Note: Ducreux et al. 2011 gave up to 8 cycles of treatment. NO16966 said that initial treatment could be given up to 16 cycles, but then could continue beyond that for patients who did not have progression of disease. Efficacy for UK MRC COIN is as reported for KRAS wild-type patients.''<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)<br />
**Note: In Saltz et al. 2008 and SMC 2008-03-012 capecitabine was described as being given 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles (see note)''' <br />
====Subsequent treatment====<br />
<br />
*SMC 2008-03-012: Optional [[#Capecitabine_monotherapy|capecitabine maintenance]] after 9 cycles<br />
<br />
===References===<br />
<br />
#Porschen R, Arkenau HT, Kubicka S, Greil R, Seufferlein T, Freier W, Kretzschmar A, Graeven U, Grothey A, Hinke A, Schmiegel W, Schmoll HJ; AIO Colorectal Study Group. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol. 2007 Sep 20;25(27):4217-23. Epub 2007 Jun 4. [http://jco.ascopubs.org/content/25/27/4217.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17548840 PubMed]<br />
<!-- Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2005, Atlanta, GA; and the Annual Meeting of the European Society for Medical Oncology, Istanbul, Turkey, September 29-October 3, 2006. --><br />
#Díaz-Rubio E, Tabernero J, Gómez-España A, Massutí B, Sastre J, Chaves M, Abad A, Carrato A, Queralt B, Reina JJ, Maurel J, González-Flores E, Aparicio J, Rivera F, Losa F, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol. 2007 Sep 20;25(27):4224-30. Epub 2007 Jun 4. [http://jco.ascopubs.org/content/25/27/4224.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17548839 PubMed]<br />
<!-- Presented in part at the 31st European Society of Medical Oncology Congress, Istanbul, Turkey, September 29- October 3, 2006; the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Orlando, FL, January 19-21, 2007; and the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007. --><br />
#'''NO16966:''' Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. [https://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18421053 PubMed]<br />
##'''Update:''' Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. [http://jco.ascopubs.org/content/26/12/2013.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18421054 PubMed]<br />
##'''Update:''' Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64. Epub 2011 Jun 14. [https://www.nature.com/articles/bjc2011201 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137415/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21673685 PubMed]<br />
#'''TREE:''' Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. [http://jco.ascopubs.org/content/26/21/3523.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18640933 PubMed]<br />
#Ducreux M, Bennouna J, Hebbar M, Ychou M, Lledo G, Conroy T, Adenis A, Faroux R, Rebischung C, Bergougnoux L, Kockler L, Douillard JY; GI Group of the French Anti-Cancer Centers. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer. Int J Cancer. 2011 Feb 1;128(3):682-90. [https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.25369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20473862 PubMed]<br />
#'''UK MRC COIN:''' Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP; MRC COIN Trial Investigators. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011 Jun 18;377(9783):2103-14. Epub 2011 Jun 5. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60613-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159415/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21641636 PubMed]<br />
##'''Update:''' Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, Kenny SL, Kay E, Hodgkinson E, Pope M, Rogers P, Wasan H, Falk S, Gollins S, Hickish T, Bessell EM, Propper D, Kennedy MJ, Kaplan R, Maughan TS; MRC COIN Trial Investigators. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011 Jul;12(7):642-53. Epub 2011 Jun 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70102-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159416/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21641867 PubMed]<br />
#'''HORIZON II:''' Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. [http://jco.ascopubs.org/content/30/29/3596.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22965965 PubMed]<br />
#'''SMC 2008-03-012:''' Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23062232 PubMed]<br />
##'''Update:''' Kim ST, Hong YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Lee JW, Jo SJ, Park YS. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: updated results from a phase 3 trial. BMC Cancer. 2014 Nov 26;14:883. [https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-14-883 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289339/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25424120 PubMed]<br />
<br />
==CapeOx & Bevacizumab {{#subobject:62d39f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX & Bevacizumab: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin, Bevacizumab<br />
<br>CAPOX-B: '''<u>CAP</u>'''ecitabine, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab<br />
<br>XELOX & Bevacizumab: '''<u>XEL</u>'''oda, '''<u>OX</u>'''aliplatin, Bevacizumab<br />
===Variant #1, 850/130/7.5 {{#subobject:618554|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#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
| rowspan="2" |[http://jco.ascopubs.org/content/26/21/3523.full Hochster et al. 2008 (TREE-2)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. bFOL & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints<br />
| style="background-color:#ffffbf" |Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment<br />
|-<br />
|2. [[#mFOLFOX6_.26_Bevacizumab|mFOLFOX6 & Bevacizumab]]<br />
| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints<br />
| style="background-color:#ffffbf" |Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 850 mg/m<sup>2</sup> PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)<br />
**In TREE-2, patients with a CrCl of 30 to 50 mL/min/1.73m<sup>2</sup> received 650 mg/m<sup>2</sup> PO twice per day<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2, 1000/130/7.5 x 6 {{#subobject:e7bd8e|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0808268 Tol et al. 2009 (CAIRO2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|CapeOx, Bevacizumab, Cetuximab<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267817/ Díaz-Rubio et al. 2012 (MACRO)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://academic.oup.com/annonc/article/24/9/2335/202863 Johnsson et al. 2013 (Nordic ACT)]<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(14)62004-3/fulltext Simkens et al. 2015 (CAIRO3)]<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 />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*CAIRO2: [[#Capecitabine_.26_Bevacizumab_2|Capecitabine & Bevacizumab maintenance]]<br />
*MACRO: [[#Bevacizumab_monotherapy|Bevacizumab]] versus XELOX & Bevacizumab maintenance<br />
*Nordic ACT: [[#Bevacizumab_monotherapy|Bevacizumab]] versus Erlotinib & Bevacizumab maintenance<br />
*CAIRO3: [[#Capecitabine_.26_Bevacizumab_2|Capecitabine & Bevacizumab maintenance]] versus [[#Observation_3|Observation]]<br />
<br />
===Variant #3, 1000/130/7.5, indefinite {{#subobject:e7bd8e|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 Cassidy et al. 2008 (NO16966)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#FOLFOX4_2|FOLFOX4]]<br> 2. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|3. [[#CapeOx_2|XELOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
| rowspan="2" |[http://jco.ascopubs.org/content/26/12/2013.long Saltz et al. 2008 (NO16966)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#FOLFOX4_3|FOLFOX4]]<br> 2. [[#CapeOx_2|XELOX]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|3. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[https://academic.oup.com/annonc/article/29/3/624/4779925 Yamada et al. 2018 (TRICOLORE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#IRIS_.26_Bevacizumab|IRIS & Bevacizumab]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|[http://theoncologist.alphamedpress.org/content/23/8/919.long Nakayama 2018 (CCOG-1201)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#CAPIRI-Bev|CAPIRI & Bevacizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
''Note: N016966 specified that initial treatment could be given up to 16 cycles, but then could continue beyond that for patients who did not have progression of disease.''<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)<br />
**Note: In Saltz et al. 2008--the same study as Cassidy et al. 2008--capecitabine was described as being given 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV over 30 to 90 minutes once on day 1, '''given first'''<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<!-- Presented in part at the 31st European Society of Medical Oncology Congress, Istanbul, Turkey, September 29- October 3, 2006; the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Orlando, FL, January 19-21, 2007; and the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007. --><br />
<br />
#'''NO16966:''' Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. [https://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18421053 PubMed]<br />
##'''Update:''' Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. [http://jco.ascopubs.org/content/26/12/2013.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18421054 PubMed]<br />
##'''Update:''' Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64. Epub 2011 Jun 14. [https://www.nature.com/articles/bjc2011201 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137415/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21673685 PubMed]<br />
#'''TREE-2:''' Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. [http://jco.ascopubs.org/content/26/21/3523.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18640933 PubMed]<br />
#'''CAIRO2:''' Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, Erdkamp FL, Vos AH, van Groeningen CJ, Sinnige HA, Richel DJ, Voest EE, Dijkstra JR, Vink-Börger ME, Antonini NF, Mol L, van Krieken JH, Dalesio O, Punt CJ. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009 Feb 5;360(6):563-72. Erratum in: N Engl J Med. 2010 Dec 23;363(26):2573. [https://www.nejm.org/doi/full/10.1056/NEJMoa0808268 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19196673 PubMed]<br />
##'''Subgroup analysis:''' Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009 Jul 2;361(1):98-9. Erratum in: N Engl J Med. 2011 Sep 1;365(9):869. [https://www.nejm.org/doi/10.1056/NEJMc0904160 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19571295 PubMed]<br />
#'''MACRO:''' Díaz-Rubio E, Gómez-España A, Massutí B, Sastre J, Abad A, Valladares M, Rivera F, Safont MJ, Martínez de Prado P, Gallén M, González E, Marcuello E, Benavides M, Fernández-Martos C, Losa F, Escudero P, Arrivi A, Cervantes A, Dueñas R, López-Ladrón A, Lacasta A, Llanos M, Tabernero JM, Antón A, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors. First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study. Oncologist. 2012;17(1):15-25. Epub 2012 Jan 10. [http://theoncologist.alphamedpress.org/content/17/1/15.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267817/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22234633 PubMed]<br />
#'''Nordic ACT:''' Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. [https://academic.oup.com/annonc/article/24/9/2335/202863 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23788755 PubMed]<br />
#'''CAIRO3:''' Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoeven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, Honkoop AH, Mol L, Punt CJ, Koopman M. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015 May 9;385(9980):1843-52. Epub 2015 Apr 7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62004-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25862517 PubMed]<br />
##'''Update:''' Goey KKH, Elias SG, van Tinteren H, Laclé MM, Willems SM, Offerhaus GJA, de Leng WWJ, Strengman E, Ten Tije AJ, Creemers GM, van der Velden A, de Jongh FE, Erdkamp FLG, Tanis BC, Punt CJA, Koopman M. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann Oncol. 2017 Sep 1;28(9):2128-2134. [https://academic.oup.com/annonc/article/28/9/2128/3884600 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28911067 PubMed]<br />
#'''TRICOLORE:''' Yamada Y, Denda T, Gamoh M, Iwanaga I, Yuki S, Shimodaira H, Nakamura M, Yamaguchi T, Ohori H, Kobayashi K, Tsuda M, Kobayashi Y, Miyamoto Y, Kotake M, Shimada K, Sato A, Morita S, Takahashi S, Komatsu Y, Ishioka C. S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized, open-label, phase III, noninferiority trial. Ann Oncol. 2018 Mar 1;29(3):624-631. [https://academic.oup.com/annonc/article/29/3/624/4779925 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29293874 PubMed]<br />
#'''CCOG-1201:''' Nakayama G, Mitsuma A, Sunagawa Y, Ishigure K, Yokoyama H, Matsui T, Nakayama H, Nakata K, Ishiyama A, Asada T, Umeda S, Ezaka K, Hattori N, Takami H, Kobayashi D, Tanaka C, Kanda M, Yamada S, Koike M, Fujiwara M, Fujii T, Murotani K, Ando Y, Kodera Y. Randomized phase II trial of CapOX plus bevacizumab and capIRI plus bevacizumab as first-line treatment for Japanese patients with metastatic colorectal cancer (CCOG-1201 study). Oncologist. 2018 Aug;23(8):919-927. Epub 2018 Jul 26. [http://theoncologist.alphamedpress.org/content/23/8/919.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30049885 PubMed]<br />
<br />
==CAPIRI {{#subobject:793efd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeIRI: '''<u>Cape</u>'''citabine and '''<u>IRI</u>'''notecan<br />
<br>CAPIRI: '''<u>CAP</u>'''ecitabine and '''<u>IRI</u>'''notecan<br />
<br>XELIRI: '''<u>XEL</u>'''ox (Capecitabine) and '''<u>IRI</u>'''notecan<br />
===Regimen {{#subobject:0ec52b|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext Koopman et al. 2007 (CAIRO)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Complex_multipart_regimens#CAIRO|See link]]<br />
| style="background-color:#ffffbf" |[[Complex_multipart_regimens#CAIRO|See link]]<br />
|-<br />
| rowspan="2" |[http://jco.ascopubs.org/content/25/30/4779.long Fuchs et al. 2007 (BICC-C)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#FOLFIRI_2|FOLFIRI]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|2. [[#IFL|mIFL]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://academic.oup.com/annonc/article/19/5/920/167346 Köhne et al. 2007 (EORTC 40015)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#FOLFIRI_2|FOLFIRI]] +/- Celecoxib<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366 Moehler et al. 2009a]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: EORTC 40015 was closed prematurely.''<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
====Subsequent treatment====<br />
<br />
*CAIRO, with progression: [[#CapeOx_3|CapeOx]]<br />
<br />
===References===<br />
<br />
#'''CAIRO:''' Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. [https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17630036 PubMed]<br />
<!-- Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA. --><br />
#'''BICC-C:''' Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. [http://jco.ascopubs.org/content/25/30/4779.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947725 PubMed]<br />
##'''Update:''' Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. [http://jco.ascopubs.org/content/26/4/689.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18235136 PubMed]<br />
#'''EORTC 40015:''' Köhne CH, De Greve J, Hartmann JT, Lang I, Vergauwe P, Becker K, Braumann D, Joosens E, Müller L, Janssens J, Bokemeyer C, Reimer P, Link H, Späth-Schwalbe E, Wilke HJ, Bleiberg H, Van Den Brande J, Debois M, Bethe U, Van Cutsem E. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer: EORTC study 40015. Ann Oncol. 2008 May;19(5):920-6. Epub 2007 Dec 6. [https://academic.oup.com/annonc/article/19/5/920/167346 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18065406 PubMed]<br />
#Moehler M, Sprinzl MF, Abdelfattah M, Schimanski CC, Adami B, Godderz W, Majer K, Flieger D, Teufel A, Siebler J, Hoehler T, Galle PR, Kanzler S. Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients. World J Gastroenterol. 2009 Jan 28;15(4):449-56. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366 link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19152449 PubMed]<br />
<br />
==CAPIRI-Bev {{#subobject:cd6750|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CAPIRI-Bev: '''<u>CAP</u>'''ecitabine, '''<u>IRI</u>'''notecan, '''<u>Bev</u>'''acizumab<br />
<br>XELIRI-Bev: '''<u>XEL</u>'''oda (Capecitabine), '''<u>IRI</u>'''notecan, '''<u>Bev</u>'''acizumab<br />
===Variant #1, 750/150/7.5 {{#subobject:ed3172|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://academic.oup.com/annonc/article/24/9/2335/202863 Johnsson et al. 2013 (Nordic ACT)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
''This dose was recommended for patients older than 65 years.''<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV once on day 1<br />
*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[#Bevacizumab_monotherapy|Bevacizumab]] versus Erlotinib & Bevacizumab maintenance<br />
<br />
===Variant #2, 800/200/7.5 {{#subobject:f6bf78|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.18.00052 Modest et al. 2018 (XELAVIRI)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Capecitabine_.26_Bevacizumab|Cape-Bev]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior TFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV once on day 1<br />
*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #3, 1000/180/7.5 {{#subobject:852626|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://academic.oup.com/annonc/article/24/9/2335/202863 Johnsson et al. 2013 (Nordic ACT)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*[[#Bevacizumab_monotherapy|Bevacizumab]] versus Erlotinib & Bevacizumab maintenance<br />
<br />
===Variant #4, 1000/200/7.5 {{#subobject:88c136|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/PMC2653366 Moehler et al. 2009a]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV once on day 1<br />
*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #5, 1000/240/7.5 {{#subobject:a19b6d|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466131/ Pectasides et al. 2012]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI-Bev]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Irinotecan (Camptosar)]] 240 mg/m<sup>2</sup> IV once on day 1<br />
*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1<br />
<br />
'''21-day cycle for 6 cycles'''<br />
<br />
===References===<br />
<br />
#Moehler M, Sprinzl MF, Abdelfattah M, Schimanski CC, Adami B, Godderz W, Majer K, Flieger D, Teufel A, Siebler J, Hoehler T, Galle PR, Kanzler S. Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients. World J Gastroenterol. 2009 Jan 28;15(4):449-56. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366 link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19152449 PubMed]<br />
#Pectasides D, Papaxoinis G, Kalogeras KT, Eleftheraki AG, Xanthakis I, Makatsoris T, Samantas E, Varthalitis I, Papakostas P, Nikitas N, Papandreou CN, Pentheroudakis G, Timotheadou E, Koutras A, Sgouros J, Bafaloukos D, Klouvas G, Economopoulos T, Syrigos KN, Fountzilas G. XELIRI-bevacizumab versus FOLFIRI-bevacizumab as first-line treatment in patients with metastatic colorectal cancer: a Hellenic Cooperative Oncology Group phase III trial with collateral biomarker analysis. BMC Cancer. 2012 Jun 29;12:271. [https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-12-271 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466131/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22748098 PubMed]<br />
#'''Nordic ACT:''' Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. [https://academic.oup.com/annonc/article/24/9/2335/202863 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23788755 PubMed]<br />
#'''XELAVIRI:''' Modest DP, Fischer von Weikersthal L, Decker T, Vehling-Kaiser U, Uhlig J, Schenk M, Freiberg-Richter J, Peuser B, Denzlinger C, Peveling Genannt Reddemann C, Graeven U, Schuch G, Schwaner I, Stahler A, Jung A, Kirchner T, Held S, Stintzing S, Giessen-Jung C, Heinemann V; XELAVIRI/AIO KRK0110 Investigators. Sequential Versus Combination Therapy of Metastatic Colorectal Cancer Using Fluoropyrimidines, Irinotecan, and Bevacizumab: A Randomized, Controlled Study-XELAVIRI (AIO KRK0110). J Clin Oncol. 2019 Jan 1;37(1):22-32. Epub 2018 Nov 2. [https://ascopubs.org/doi/full/10.1200/JCO.18.00052 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30388045 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:a3995f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 400 mg/m<sup>2</sup> intermittent bolus {{#subobject:323429|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/9/5/535/142141 Borner et al. 1998]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid_3|5-FU & LV]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
<br />
'''1-month cycles'''<br />
<br />
===Variant #2, 450 mg/m<sup>2</sup> intermittent bolus {{#subobject:54acz9|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/2667324 Molinaro et al. 1989]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Epirubicin<br />
| style="background-color:#1a9850" |Superior ORR<br />
|-<br />
|}<br />
''Note: this dose was used for those who had previously been exposed to radiotherapy.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 450 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 500 mg/m<sup>2</sup> intermittent bolus {{#subobject:545429|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.4.425 Lokich et al. 1989]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PVI 5-FU<br />
| style="background-color:#d73027" |Inferior ORR<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pubmed/2667324 Molinaro et al. 1989]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Epirubicin<br />
| style="background-color:#1a9850" |Superior ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
<br />
'''4- to 5-week cycles'''<br />
<br />
===Variant #4, 600 mg/m<sup>2</sup>/week {{#subobject:768cajb|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/6/9/948/141837 Smyth et al. 1995 (F-trial)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|TCNU<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoint<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycles'''<br />
<br />
===Variant #5, 600 mg/m<sup>2</sup>/week, 6 out of 8 weeks {{#subobject:76acae|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1986.4.4.565 Richards et al. 1986]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MMF<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
|-<br />
|[https://journals.lww.com/amjclinicaloncology/Fulltext/2002/02000/A_Phase_III_Study_of_5_Fluorouracil_Versus.4.aspx Kalofonos et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. 5-FU & IFN alfa<br> 2. [[#Fluorouracil_.26_Folinic_acid_3|5-FU & LV]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
'''8-week cycles'''<br />
<br />
===Variant #6, weekly bolus with CI lead-in {{#subobject:b3b13d|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1995.13.6.1297 Hill et al. 1995]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & IFN alfa-2b<br />
| style="background-color:#ffffbf" |Did not meet efficacy endpoints<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.10.2674 Greco et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & IFN alfa-2a<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] as follows:<br />
**Cycle 1: 750 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose: 3750 mg/m<sup>2</sup>)<br />
**Cycle 2 onwards: 750 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycles'''<br />
<br />
===Variant #7, weekly CI {{#subobject:cbf24c|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/9/7/727/274760 Aranda et al. 1998]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Fluorouracil_.26_Folinic_acid_3|Mayo Clinic regimen]]<br />
| style="background-color:#91cf60" |Seems to have superior ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 1750 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 3500 mg/m<sup>2</sup>)<br />
<br />
'''7-day cycles'''<br />
<br />
===Variant #8, PVI ("Lokich regimen") {{#subobject:88b2a1|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.4.425 Lokich et al. 1989]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|Bolus 5-FU<br />
| style="background-color:#1a9850" |Superior ORR<br />
|-<br />
|[https://academic.oup.com/jnci/article/88/10/668/894396 Hansen et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|Bolus 5-FU<br />
| style="background-color:#1a9850" |Superior TTP<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08514-8/fulltext Maughan et al. 2002]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Fluorouracil_.26_Folinic_acid_3|de Gramont regimen]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. Raltitrexed<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #9, load to toxicity {{#subobject:31493b|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010301%2991%3A5%3C1020%3A%3AAID-CNCR1093%3E3.0.CO%3B2-V Witte et al. 2001]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & Levamisole<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] as follows:<br />
**Cycle 1: 480 mg/m<sup>2</sup> IV once per day on days 1 to 5, then 240 mg/m<sup>2</sup> every other day to toxicity or six additional doses<br />
**Cycle 2 onwards: 480 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''6-week cycle for 1 cycle, then 5-week cycles'''<br />
<br />
===References===<br />
<br />
#Richards F 2nd, Case LD, White DR, Muss HB, Spurr CL, Jackson DV, Cooper MR, Zekan P, Cruz J, Stuart JJ, Capizzi RL, McCulloch JH, McFarland JA, Kincaid WR, Harding RW, Pope E, McMahan R, Wellls HB. Combination chemotherapy (5-fluorouracil, methyl-CCNU, mitomycin C) versus 5-fluorouracil alone for advanced previously untreated colorectal carcinoma: a phase III study of the Piedmont Oncology Association. J Clin Oncol. 1986 Apr;4(4):565-70. [https://ascopubs.org/doi/abs/10.1200/JCO.1986.4.4.565 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3514806 PubMed]<br />
#Lokich JJ, Ahlgren JD, Gullo JJ, Philips JA, Fryer JG. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol. 1989 Apr;7(4):425-32. [https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.4.425 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2926468 PubMed]<br />
#Molinaro P, Lafleur F, Blum RH. A phase III randomized trial of epirubicin versus 5-fluorouracil in metastatic rectal/sigmoid adenocarcinoma. Am J Clin Oncol. 1989 Aug;12(4):332-4. [https://www.ncbi.nlm.nih.gov/pubmed/2667324 PubMed]<br />
#Hill M, Norman A, Cunningham D, Findlay M, Nicolson V, Hill A, Iveson A, Evans C, Joffe J, Nicolson M, Hickish T. Royal Marsden phase III trial of fluorouracil with or without interferon alfa-2b in advanced colorectal cancer. J Clin Oncol. 1995 Jun;13(6):1297-302. [https://ascopubs.org/doi/abs/10.1200/JCO.1995.13.6.1297 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7751874 PubMed]<br />
#Smyth JF, Hardcastle JD, Denton G, Alderson D, Grace RH, Mansi JL, Yosef HM, Nordle O, Lauri H, Wählby S. Two phase III trials of tauromustine (TCNU) in advanced colorectal cancer. Ann Oncol. 1995 Nov;6(9):948-9. [https://academic.oup.com/annonc/article/6/9/948/141837 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8624301 PubMed]<br />
#Hansen RM, Ryan L, Anderson T, Krzywda B, Quebbeman E, Benson A 3rd, Haller DG, Tormey DC. Phase III study of bolus versus infusion fluorouracil with or without cisplatin in advanced colorectal cancer. J Natl Cancer Inst. 1996 May 15;88(10):668-74. [https://academic.oup.com/jnci/article/88/10/668/894396 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8627643 PubMed]<br />
#Greco FA, Figlin R, York M, Einhorn L, Schilsky R, Marshall EM, Buys SS, Froimtchuk MJ, Schuller J, Schuchter L, Buyse M, Ritter L, Man A, Yap AK. Phase III randomized study to compare interferon alfa-2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer. J Clin Oncol. 1996 Oct;14(10):2674-81. [https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.10.2674 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8874326 PubMed]<br />
#Aranda E, Díaz-Rubio E, Cervantes A, Antón-Torres A, Carrato A, Massutí T, Tabernero JM, Sastre J, Trés A, Aparicio J, López-Vega JM, Barneto I, García-Conde J. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol. 1998 Jul;9(7):727-31. [https://academic.oup.com/annonc/article/9/7/727/274760 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9739438 PubMed]<br />
#Witte RS, Cnaan A, Mansour EG, Barylak E, Harris JE, Schutt AJ. Comparison of 5-fluorouracil alone, 5-fluorouracil with levamisole, and 5-fluorouracil with hepatic irradiation in the treatment of patients with residual, nonmeasurable, intra-abdominal metastasis after undergoing resection for colorectal carcinoma. Cancer. 2001 Mar 1;91(5):1020-8. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010301%2991%3A5%3C1020%3A%3AAID-CNCR1093%3E3.0.CO%3B2-V link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11251955 PubMed]<br />
#Kalofonos HP, Nicolaides C, Samantas E, Mylonakis N, Aravantinos G, Dimopoulos MA, Gennatas C, Kouvatseas G, Giannoulis E, Dervenis C, Basdanis G, Pavlidis N, Androulakis I, Fountzilas G; Hellenic Cooperative Oncology Group (HeCOG). A phase III study of 5-fluorouracil versus 5-fluorouracil plus interferon alpha 2b versus 5-fluorouracil plus leucovorin in patients with advanced colorectal cancer: a Hellenic Cooperative Oncology Group (HeCOG) study. Am J Clin Oncol. 2002 Feb;25(1):23-30. [https://journals.lww.com/amjclinicaloncology/Fulltext/2002/02000/A_Phase_III_Study_of_5_Fluorouracil_Versus.4.aspx link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11823690 PubMed]<br />
#Maughan TS, James RD, Kerr DJ, Ledermann JA, McArdle C, Seymour MT, Cohen D, Hopwood P, Johnston C, Stephens RJ; British MRC Colorectal Cancer Working Party. Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2002 May 4;359(9317):1555-63. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08514-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12047964 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:e9add2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
LV5FU2: '''<u>L</u>'''euco'''<u>V</u>'''orin and '''<u>5-FU</u>''', two days out of the month<br />
<br>sLV5FU2: '''<u>s</u>'''implified '''<u>L</u>'''euco'''<u>V</u>'''orin and '''<u>5-FU</u>''', two days out of the month<br />
===Example orders===<br />
<br />
*[[Example orders for 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV) in colon cancer]]<br />
*[[Example orders for 5-FU & high-dose Leucovorin (Roswell Park regimen/HDLV) in colon cancer]]<br />
*[[Example orders for weekly 5-FU & Leucovorin in colon cancer]]<br />
*[[Example orders for simplified biweekly 5-FU & leucovorin (sLV5FU2) in colon cancer]]<br />
<br />
===Variant #1, 400/80 ("modified Laufman regimen") {{#subobject:8f214e|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2003.04.187 Verwaal et al. 2003]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Intraperitoneal_hyperthermic_mitomycin|HIPEC]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Folinic acid (Leucovorin)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycle for up to 26 cycles (6 months)'''<br />
<br />
===Variant #2, 450/200 {{#subobject:24e32a|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.10.2682 Kosmidis et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FULV & IFN alfa-2b<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 450 mg/m<sup>2</sup> IV bolus once on day 1, '''given halfway through'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''7-day cycles'''<br />
<br />
===Variant #3, 500/20 {{#subobject:a1523|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/14/8/2274.long Jäger et al. 1996]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid_3|FULV]]; high-dose<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once on day 1, '''given second, 1 hour after start of leucovorin'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''7-day cycles'''<br />
<br />
===Variant #4, 500/200, 6 out of 8 weeks {{#subobject:f7ed72|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/13/1/87/143714 Blanke et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FULV & Trimetrexate<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
'''8-week cycles'''<br />
<br />
===Variant #5, 600/500 ("Roswell Park regimen") {{#subobject:3f90af|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1987.5.10.1559 Petrelli et al. 1987]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Fluorouracil_monotherapy|5-FU]]<br> 2. 5-FU & MTX<br />
| style="background-color:#1a9850" |Superior ORR<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.10.1419 Petrelli et al. 1989]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Fluorouracil_monotherapy|5-FU]]<br> 2. 5-FU & LDLV<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1994.12.1.14 Buroker et al. 1994]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Fluorouracil_.26_Folinic_acid_3|FULV]]; Mayo Clinic regimen<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19951115)76:10%3C1709::AID-CNCR2820761006%3E3.0.CO;2-5 Jones et al. 1995]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MFL<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[http://jco.ascopubs.org/content/21/1/60.full Kabbinavar et al. 2003 (AVF0780)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|FULV & Bevacizumab<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
''Note: the original regimen described by Petrelli et al. 1987 & 1989 used a 5-FU dose of 600 mg/m<sup>2</sup>.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 500 to 600 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, 29, 36, '''given second, 1 hour after start of leucovorin'''<br />
*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, '''given first'''<br />
<br />
'''8-week cycles'''<br />
<br />
===Variant #6, 1500/400 {{#subobject:be5dfd|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2007.13.3934 Gamelin et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid_3|FULV]]; PK-guided<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 1500 mg/m<sup>2</sup> IV over 8 hours once on day 1<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus every 4 hours on day 1, '''given before and 4 hours into 5-FU infusion''' (total dose per cycle: 400 mg/m<sup>2</sup>)<br />
<br />
'''7-day cycles'''<br />
<br />
===Variant #7, 1850/1000 {{#subobject:566afe|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1995.13.4.921 Man et al. 1995 (Corfu-A)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ooc)<br />
|5-FU & IFN alfa-2a<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.11.3320 Goldberg et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Fluorouracil_.26_Levoleucovorin|FULV]]; low-dose LV<br> 2. [[#Fluorouracil_.26_Folinic_acid_3|FULV]]; oral LV<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycles'''<br />
<br />
===Variant #8, 2000/100 {{#subobject:d429aa|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/9/5/535/142141 Borner et al. 1998]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''1-month cycles'''<br />
<br />
===Variant #9, 2000/400 (LV5FU2 aka "de Gramont regimen") {{#subobject:66012|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.1997.15.2.808 de Gramont et al. 1997 (FFCD 9101)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Fluorouracil_.26_Folinic_acid_3|FULV]]; Mayo Clinic regimen<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext Douillard et al. 2000]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#IFL|IFL]]<br> 2. [[#FOLFIRI_2|FOLFIRI]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/18/16/2938.long de Gramont et al. 2000]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFOX4_3|FOLFOX4]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08514-8/fulltext Maughan et al. 2002]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Fluorouracil_monotherapy|Lokich regimen]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|2. Raltitrexed<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)12388-4/fulltext Kerr et al. 2003]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|IHA LV5FU2<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)12461-0/fulltext Maughan et al. 2003]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Intermittent LV5FU2<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
| rowspan="2" |[https://www.karger.com/Article/Abstract/94357 Ducreux et al. 2006 (FFCD 9601)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. ldLV5FU2<br> 2. [[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|2. Raltitrexed<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|[https://academic.oup.com/annonc/article/20/2/244/165904 Cunningham et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFOX4_3|FOLFOX4]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
| rowspan="2" |[https://academic.oup.com/annonc/article/27/1/121/2196319 Aparicio et al. 2015 (FFCD 2001-02)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#FOLFIRI_2|"Classic" FOLFIRI]]<br> 2. [[#FOLFIRI_2|"Simplified" FOLFIRI]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|3. sLV5FU2<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''Note: Maughan et al. 2003 randomized patients to 12 weeks of treatment with re-treatment upon progression, versus continuous treatment. There was no difference in outcome between the two arms. FFCD 2001-02 enrolled elderly (75 or older) patients.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first'''<br />
<br />
'''14-day cycles (see note)'''<br />
<br />
===Variant #10, 2000/1000 {{#subobject:d539aa|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article-abstract/2/9/673/229114 Labianca et al. 1991]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#91cf60" |Seems to have superior ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV over 15 minutes once per day on days 1 to 5<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #11, 2125/100 ("Mayo Clinic regimen") {{#subobject:ad7e77|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19890315)63:6%2B%3C1026::AID-CNCR2820631307%3E3.0.CO;2-R O'Connell 1989]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[[#Fluorouracil_.26_Folinic_acid_3|FULV]]; HDLV<br />
| style="background-color:#ffffbf" |Did not meet primary efficacy endpoint<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.10.1407 Poon et al. 1989]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1994.12.1.14 Buroker et al. 1994]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#Fluorouracil_.26_Folinic_acid_3|FULV]]; Roswell Park regimen<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.1997.15.2.808 de Gramont et al. 1997 (FFCD 9101)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid_3|FULV]]; LV5FU2<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://academic.oup.com/annonc/article/9/7/727/274760 Aranda et al. 1998]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_monotherapy|High-dose 5-FU]]<br />
| style="background-color:#fc8d59" |Seems to have inferior ORR<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 Saltz et al. 2000]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#IFL|IFL]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|2. [[#Irinotecan_monotherapy|Irinotecan]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[http://jco.ascopubs.org/content/19/8/2282.long Hoff et al. 2001]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_monotherapy_2|Capecitabine]]<br />
| style="background-color:#d73027" |Inferior ORR<br />
|-<br />
|[http://jco.ascopubs.org/content/19/21/4097.long Van Cutsem et al. 2001]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_monotherapy_2|Capecitabine]]<br />
| style="background-color:#eeee01" |Equivalent ORR<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2002.20.6.1519 Schilsky et al. 2002 (FUMA3008)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Eniluracil & 5-FU<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2002.04.123 Douillard et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|UFT & Leucovorin<br />
| style="background-color:#eeee01" |Seems to have equivalent OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2002.10.129 Carmichael et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|UFT & Leucovorin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2003.11.122 Köhne et al. 2003 (EORTC 40952)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. FU24h<br> 2. FU24h + LV<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/17/3/437/146088 Chong et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FULV & 3H1<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/17/3/443/146259 Hospers et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FOLFOX6<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|}<br />
''Note: not all manuscripts explicitly describe the timing described here; O'Connell 1989 is the clearest.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 3 cycles, then 35-day cycle for 3 cycles (see note)'''<br />
<br />
===Variant #12, 2560/175 (reduced-dose sLV5FU2) {{#subobject:d246ce|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#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109515/ Seymour et al. 2011 (MRC FOCUS2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Capecitabine_monotherapy_2|Capecitabine]]<br> 2. [[#CapeOx_2|CapeOx]]<br> 3. OxFU<br />
| style="background-color:#fee08b" |Might have inferior PFS (see note)<br />
| style="background-color:#ffffbf" |Similar QoL (see note)<br />
|-<br />
|}<br />
''Note: efficacy comparison was to oxaliplatin-containing regimens; QoL comparison was to capecitabine-containing regimens.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 320 mg/m<sup>2</sup> IV bolus once on day 1, then 2240 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2560 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 175 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #13, 2600/500 {{#subobject:f4d2e9|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext Douillard et al. 2000]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#IFL|IFL]]<br> 2. [[#FOLFIRI_2|FOLFIRI]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1<br />
*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycles'''<br />
<br />
===Variant #14, 2800/350 ("modified de Gramont regimen") {{#subobject:a28e0a|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/PMC2376131/ Cheeseman et al. 2002]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61087-3/fulltext Seymour et al. 2007 (MRC FOCUS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|-<br />
|}<br />
''Note: it is not completely clear from the abstract whether this was the protocol used in MRC FOCUS, although it is alluded to in the Cheeseman et al. 2002 publication. Also, efficacy results for MRC FOCUS are complex and will be added in the future (to be completed).''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>), '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 350 mg IV over 2 hours once on day 1, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*No routine prophylactic [[:Category:Emesis_prevention|antiemetics]] and [[:Category:Anti-diarrheals|antidiarrheal]] medications were used, but patients could use [[Metoclopramide (Reglan)]] prn nausea and [[Loperamide (Imodium)]] prn diarrhea.<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #15, 2800/400 (sLV5FU2) {{#subobject:9bdfa8|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancetonc/article/PIIS1470204511701991/fulltext Ducreux et al. 2011 (FFCD 2000-05)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#FFCD_2000-05|See link]]<br />
| style="background-color:#ffffbf" |[[Complex_multipart_regimens#FFCD_2000-05|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''14-day cycles'''<br />
====Subsequent treatment====<br />
<br />
*Upon progression: [[#mFOLFOX6_4|mFOLFOX6]]<br />
<br />
===Variant #16, other {{#subobject:8f03e1|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/0959-8049(94)00360-H/pdf Heys et al. 1995]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FULV & rIL2<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(98)00397-9/fulltext Hausmaninger et al. 1999]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FULV & IFN alfa-2c<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2000.18.1.136 Giacchetti et al. 2000]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Chronomodulated FOLFOX<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|}<br />
''See papers for details.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]]<br />
*[[Folinic acid (Leucovorin)]]<br />
<br />
===References===<br />
<br />
#Petrelli N, Herrera L, Rustum Y, Burke P, Creaven P, Stulc J, Emrich LJ, Mittelman A. A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol. 1987 Oct;5(10):1559-65. [https://ascopubs.org/doi/abs/10.1200/JCO.1987.5.10.1559 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2443619 PubMed]<br />
#O'Connell MJ. A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer: a Mayo Clinic/North Central Cancer Treatment Group study. Cancer. 1989 Mar 15;63(6 Suppl):1026-30. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19890315)63:6%2B%3C1026::AID-CNCR2820631307%3E3.0.CO;2-R link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2465076 PubMed]<br />
#Poon MA, O'Connell MJ, Moertel CG, Wieand HS, Cullinan SA, Everson LK, Krook JE, Mailliard JA, Laurie JA, Tschetter LK, Wiesenfeld M. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol. 1989 Oct;7(10):1407-18. [https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.10.1407 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2476530 PubMed]<br />
##'''Update:''' Poon MA, O'Connell MJ, Wieand HS, Krook JE, Gerstner JB, Tschetter LK, Levitt R, Kardinal CG, Mailliard JA. Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol. 1991 Nov;9(11):1967-72. [https://ascopubs.org/doi/abs/10.1200/JCO.1991.9.11.1967 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1941055 PubMed]<br />
#Petrelli N, Douglass HO Jr, Herrera L, Russell D, Stablein DM, Bruckner HW, Mayer RJ, Schinella R, Green MD, Muggia FM, Megibow A, Greenwald ES, Bukowski RM, Harris J, Levin B, Gaynor E, Loutfi A, Kaiser MH, Barkin JS, Benedetto P, Woolley PV, Nauta R, Weaver DW, Leichman LP; Gastrointestinal Tumor Study Group. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. J Clin Oncol. 1989 Oct;7(10):1419-26. Erratum in: J Clin Oncol 1990 Jan;8(1):185. [https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.10.1419 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2674331 PubMed]<br />
#Labianca R, Pancera G, Aitini E, Barni S, Beretta A, Beretta GD, Cesana B, Comella G, Cozzaglio L, Cristoni M, Spagnolli P, Frontini L, Gottardi O, Martignoni G, Scapaticci R, Smerieri F, Vinci M, Zadro A, Zaniboni A, Luporini G. Folinic acid + 5-fluorouracil (5-FU) versus equidose 5-FU in advanced colorectal cancer: phase III study of 'GISCAD' (Italian Group for the Study of Digestive Tract Cancer). Ann Oncol. 1991 Oct;2(9):673-9. [https://academic.oup.com/annonc/article-abstract/2/9/673/229114 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1742223 PubMed]<br />
#Buroker TR, O'Connell MJ, Wieand HS, Krook JE, Gerstner JB, Mailliard JA, Schaefer PL, Levitt R, Kardinal CG, Gesme DH Jr. Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol. 1994 Jan;12(1):14-20. [https://ascopubs.org/doi/abs/10.1200/JCO.1994.12.1.14 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7677801 PubMed]<br />
#'''Corfu-A:''' Man A, Levi J, Weinerman B, Kjaer M, Yap AKL; Corfu-A Study Group. Phase III randomized study of two fluorouracil combinations with either interferon alfa-2a or leucovorin for advanced colorectal cancer. J Clin Oncol. 1995 Apr;13(4):921-8. [https://ascopubs.org/doi/abs/10.1200/JCO.1995.13.4.921 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7707120 PubMed]<br />
#Jones DV Jr, Winn RJ, Brown BW, Levy LB, Pugh RP, Wade JL 3rd, Gross HM, Pendergrass KB, Levin B, Abbruzzese JL. Randomized phase III study of 5-fluorouracil plus high dose folinic acid versus 5-fluorouracil plus folinic acid plus methyl-lomustine for patients with advanced colorectal cancer. Cancer. 1995 Nov 15;76(10):1709-14. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19951115)76:10%3C1709::AID-CNCR2820761006%3E3.0.CO;2-5 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8625038 PubMed]<br />
#Heys SD, Eremin O, Ruggeri EM, Pein F, Rainer H, Oskam R, de Peuter RA, Palmer PA, Franks CR. A phase III study of recombinant interleukin-2, 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in patients with unresectable or metastatic colorectal carcinoma. Eur J Cancer. 1995;31A(1):19-25. [https://www.ejcancer.com/article/0959-8049(94)00360-H/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7695972 PubMed]<br />
#Jäger E, Heike M, Bernhard H, Klein O, Bernhard G, Lautz D, Michaelis J, Meyer zum Büschenfelde KH, Knuth Al; Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. J Clin Oncol. 1996 Aug;14(8):2274-9. [http://jco.ascopubs.org/content/14/8/2274.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8708717 PubMed]<br />
#Kosmidis PA, Tsavaris N, Skarlos D, Theocharis D, Samantas E, Pavlidis N, Briassoulis E, Fountzilas G; Hellenic Cooperative Oncology Group. Fluorouracil and leucovorin with or without interferon alfa-2b in advanced colorectal cancer: analysis of a prospective randomized phase III trial. J Clin Oncol. 1996 Oct;14(10):2682-7. [https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.10.2682 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8874327 PubMed]<br />
#'''FFCD 9101:''' de Gramont A, Bosset JF, Milan C, Rougier P, Bouché O, Etienne PL, Morvan F, Louvet C, Guillot T, François E, Bedenne L. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol. 1997 Feb;15(2):808-15. [https://ascopubs.org/doi/full/10.1200/JCO.1997.15.2.808 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9053508 PubMed]<br />
#Goldberg RM, Hatfield AK, Kahn M, Sargent DJ, Knost JA, O'Connell MJ, Krook JE, Maillard JA, Wiesenfeld M, Schaefer PL, Tirona MT, Moertel CG. Prospectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. J Clin Oncol. 1997 Nov;15(11):3320-9. [https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.11.3320 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9363861 PubMed]<br />
#Borner MM, Castiglione M, Bacchi M, Weber W, Herrmann R, Fey MF, Pagani O, Leyvraz S, Morant R, Pestalozzi B, Hanselmann S, Goldhirsch A; Swiss Group for Clinical Cancer Research (SAKK). The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: results of a phase III trial. Ann Oncol. 1998 May;9(5):535-41. [https://academic.oup.com/annonc/article/9/5/535/142141 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9653495 PubMed]<br />
#Aranda E, Díaz-Rubio E, Cervantes A, Antón-Torres A, Carrato A, Massutí T, Tabernero JM, Sastre J, Trés A, Aparicio J, López-Vega JM, Barneto I, García-Conde J. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol. 1998 Jul;9(7):727-31. [https://academic.oup.com/annonc/article/9/7/727/274760 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9739438 PubMed]<br />
#Hausmaninger H, Moser R, Samonigg H, Mlineritsch B, Schmidt H, Pecherstorfer M, Fridrik M, Kopf C, Nitsche D, Kaider A, Ludwig H. Biochemical modulation of 5-fluorouracil by leucovorin with or without interferon-alpha-2c in patients with advanced colorectal cancer: final results of a randomised phase III study. Eur J Cancer. 1999 Mar;35(3):380-5. [https://www.ejcancer.com/article/S0959-8049(98)00397-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10448286 PubMed]<br />
#Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet P, Llory JF, Letourneau Y, Coudert B, Bertheaut-Cvitkovic F, Larregain-Fournier D, Le Rol A, Walter S, Adam R, Misset JL, Lévi F. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2000 Jan;18(1):136-47. [https://ascopubs.org/doi/full/10.1200/JCO.2000.18.1.136 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10623704 PubMed]<br />
#Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10744089 PubMed]<br />
#de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. [http://jco.ascopubs.org/content/18/16/2938.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10944126 PubMed]<br />
#Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. [https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11006366 PubMed]<br />
<!-- Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, Georgia, May 15-18, 1999. --><br />
#Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001 Apr 15;19(8):2282-92. [http://jco.ascopubs.org/content/19/8/2282.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11304782 PubMed]<br />
##'''Pooled update:''' Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. [https://www.nature.com/articles/6601676 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409640/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/15026800 PubMed]<br />
<!-- This study was presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999. --><br />
#Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P; Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001 Nov 1;19(21):4097-106. [http://jco.ascopubs.org/content/19/21/4097.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11689577 PubMed]<br />
##'''Pooled update:''' Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. [https://www.nature.com/articles/6601676 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409640/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/15026800 PubMed]<br />
#Blanke CD, Shultz J, Cox J, Modiano M, Isaacs R, Kasimis B, Schilsky R, Fleagle J, Moore M, Kemeny N, Carlin D, Hammershaimb L, Haller D. A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer. Ann Oncol. 2002 Jan;13(1):87-91. [https://academic.oup.com/annonc/article/13/1/87/143714 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11863117 PubMed]<br />
#'''FUMA3008:''' Schilsky RL, Levin J, West WH, Wong A, Colwell B, Thirlwell MP, Ansari RH, Bell WN, White RL, Yates BB, McGuirt PV, Pazdur R. Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. J Clin Oncol. 2002 Mar 15;20(6):1519-26. [https://ascopubs.org/doi/full/10.1200/JCO.2002.20.6.1519 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11896100 PubMed]<br />
#Maughan TS, James RD, Kerr DJ, Ledermann JA, McArdle C, Seymour MT, Cohen D, Hopwood P, Johnston C, Stephens RJ; British MRC Colorectal Cancer Working Party. Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2002 May 4;359(9317):1555-63. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08514-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12047964 PubMed]<br />
#Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12;87(4):393-9. [https://www.nature.com/bjc/journal/v87/n4/full/6600467a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376131/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/12177775 PubMed]<br />
#Douillard JY, Hoff PM, Skillings JR, Eisenberg P, Davidson N, Harper P, Vincent MD, Lembersky BC, Thompson S, Maniero A, Benner SE. Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2002 Sep 1;20(17):3605-16. [https://ascopubs.org/doi/full/10.1200/JCO.2002.04.123 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12202661 PubMed]<br />
#Carmichael J, Popiela T, Radstone D, Falk S, Borner M, Oza A, Skovsgaard T, Munier S, Martin C. Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2002 Sep 1;20(17):3617-27. [https://ascopubs.org/doi/full/10.1200/JCO.2002.10.129 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12202662 PubMed]<br />
#'''AVF0780:''' Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, Griffing S, Bergsland E. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003 Jan 1;21(1):60-5. [http://jco.ascopubs.org/content/21/1/60.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506171 PubMed]<br />
#Kerr DJ, McArdle CS, Ledermann J, Taylor I, Sherlock DJ, Schlag PM, Buckels J, Mayer D, Cain D, Stephens RJ; Medical Research Council's colorectal cancer study group; European Organisation for Research and Treatment of Cancer colorectal cancer study group. Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. Lancet. 2003 Feb 1;361(9355):368-73. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)12388-4/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12573372 PubMed]<br />
#Maughan TS, James RD, Kerr DJ, Ledermann JA, Seymour MT, Topham C, McArdle C, Cain D, Stephens RJ; Medical Research Council Colorectal Cancer Group. Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial. Lancet. 2003 Feb 8;361(9356):457-64. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)12461-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12583944 PubMed]<br />
#'''EORTC 40952:''' Köhne CH, Wils J, Lorenz M, Schöffski P, Voigtmann R, Bokemeyer C, Lutz M, Kleeberg C, Ridwelski K, Souchon R, El-Serafi M, Weiss U, Burkhard O, Rückle H, Lichnitser M, Langenbuch T, Scheithauer W, Baron B, Couvreur ML, Schmoll HJ; European Organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952. Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952. J Clin Oncol. 2003 Oct 15;21(20):3721-8. Epub 2003 Sep 8. [https://ascopubs.org/doi/full/10.1200/JCO.2003.11.122 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12963704 PubMed]<br />
#Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003 Oct 15;21(20):3737-43. [https://ascopubs.org/doi/full/10.1200/JCO.2003.04.187 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14551293 PubMed]<br />
#Chong G, Bhatnagar A, Cunningham D, Cosgriff TM, Harper PG, Steward W, Bridgewater J, Moore M, Cassidy J, Coleman R, Coxon F, Redfern CH, Jones JJ, Hawkins R, Northfelt D, Sreedharan S, Valone F, Carmichael J. Phase III trial of 5-fluorouracil and leucovorin plus either 3H1 anti-idiotype monoclonal antibody or placebo in patients with advanced colorectal cancer. Ann Oncol. 2006 Mar;17(3):437-42. Epub 2005 Nov 25. [https://academic.oup.com/annonc/article/17/3/437/146088 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16311275 PubMed]<br />
#Hospers GA, Schaapveld M, Nortier JW, Wils J, van Bochove A, de Jong RS, Creemers GJ, Erjavec Z, de Gooyer DJ, Slee PH, Gerrits CJ, Smit JM, Mulder NH. Randomised Phase III study of biweekly 24-h infusion of high-dose 5FU with folinic acid and oxaliplatin versus monthly plus 5-FU/folinic acid in first-line treatment of advanced colorectal cancer. Ann Oncol. 2006 Mar;17(3):443-9. [https://academic.oup.com/annonc/article/17/3/443/146259 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16500914 PubMed]<br />
#'''FFCD 9601:''' Ducreux M, Bouche O, Pignon JP, Mousseau M, Raoul JL, Cassan P, Leduc B, Berger C, Dunant A, Fournet J, Bedenne L; FFCD 9601 Collaborative Group. Randomised trial comparing three different schedules of infusional 5FU and raltitrexed alone as first-line therapy in metastatic colorectal cancer: final results of the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 trial. Oncology. 2006;70(3):222-30. Epub 2006 Jun 30. [https://www.karger.com/Article/Abstract/94357 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16816536 PubMed]<br />
#'''MRC FOCUS:''' Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, Smith DB, Shepherd S, Maraveyas A, Ferry DR, Meade AM, Thompson L, Griffiths GO, Parmar MK, Stephens RJ; FOCUS Trial Investigators; National Cancer Research Institute Colorectal Clinical Studies Group. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007 Jul 14;370(9582):143-52. Erratum in: Lancet. 2007 Aug 18;370(9587):566. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61087-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17630037 PubMed]<br />
#Gamelin E, Delva R, Jacob J, Merrouche Y, Raoul JL, Pezet D, Dorval E, Piot G, Morel A, Boisdron-Celle M. Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer. J Clin Oncol. 2008 May 1;26(13):2099-105. Erratum in: J Clin Oncol. 2013 Oct 1;31(28):3612. [https://ascopubs.org/doi/full/10.1200/JCO.2007.13.3934 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18445839 PubMed]<br />
#Cunningham D, Sirohi B, Pluzanska A, Utracka-Hutka B, Zaluski J, Glynne-Jones R, Koralewski P, Bridgewater J, Mainwaring P, Wasan H, Wang JY, Szczylik C, Clingan P, Chan RT, Tabah-Fisch I, Cassidy J. Two different first-line 5-fluorouracil regimens with or without oxaliplatin in patients with metastatic colorectal cancer. Ann Oncol. 2009 Feb;20(2):244-50. Epub 2008 Oct 14. [https://academic.oup.com/annonc/article/20/2/244/165904 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18854549 PubMed]<br />
#'''MRC FOCUS2:''' Seymour MT, Thompson LC, Wasan HS, Middleton G, Brewster AE, Shepherd SF, O'Mahony MS, Maughan TS, Parmar M, Langley RE; FOCUS2 Investigators; National Cancer Research Institute Colorectal Cancer Clinical Studies Group. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. Lancet. 2011 May 21;377(9779):1749-59. Epub 2011 May 11. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60399-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109515/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21570111 PubMed]<br />
#'''FFCD 2000-05:''' Ducreux M, Malka D, Mendiboure J, Etienne PL, Texereau P, Auby D, Rougier P, Gasmi M, Castaing M, Abbas M, Michel P, Gargot D, Azzedine A, Lombard-Bohas C, Geoffroy P, Denis B, Pignon JP, Bedenne L, Bouché O; Fédération Francophone de Cancérologie Digestive (FFCD) 2000–05 Collaborative Group. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol. 2011 Oct;12(11):1032-44. Epub 2011 Sep 6. [https://www.thelancet.com/journals/lancetonc/article/PIIS1470204511701991/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21903473 PubMed]<br />
#'''FFCD 2001-02:''' Aparicio T, Lavau-Denes S, Phelip JM, Maillard E, Jouve JL, Gargot D, Gasmi M, Locher C, Adhoute X, Michel P, Khemissa F, Lecomte T, Provençal J, Breysacher G, Legoux JL, Lepère C, Charneau J, Cretin J, Chone L, Azzedine A, Bouché O, Sobhani I, Bedenne L, Mitry E; FFCD investigators. Randomized phase III trial in elderly patients comparing LV5FU2 with or without irinotecan for first-line treatment of metastatic colorectal cancer (FFCD 2001-02). Ann Oncol. 2016 Jan;27(1):121-7. Epub 2015 Oct 20. [https://academic.oup.com/annonc/article/27/1/121/2196319 link to original article] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/26487578 PubMed]<br />
<br />
==Fluorouracil & Levoleucovorin {{#subobject:e9bgg2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 1870/50 {{#subobject:138u06|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/8/2/169/214080 Labianca et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Levoleucovorin_2|FULV]]; HDLV<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV over 15 minutes once per day on days 1 to 5<br />
*[[Levoleucovorin (Fusilev)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 1875/500 {{#subobject:13cd06|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819990201%2985%3A3%3C535%3A%3AAID-CNCR4%3E3.0.CO%3B2-7 Colucci et al. 1999]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU, LV, IFN alfa-2b<br />
| style="background-color:#ffffbf" |Did not meet primary efficacy endpoints<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 375 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second'''<br />
*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given first'''<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #3, 2800/350 ("modified de Gramont regimen") {{#subobject:a9juza|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/PMC2376131/ Cheeseman et al. 2002]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61087-3/fulltext Seymour et al. 2007 (MRC FOCUS)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|-<br />
|}<br />
''Note: it is not completely clear from the abstract whether this was the protocol used in MRC FOCUS, although it is alluded to in the Cheeseman et al. 2002 publication. Also, efficacy results for MRC FOCUS are complex and will be added in the future (to be completed).''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>), '''given second'''<br />
*[[Levoleucovorin (Fusilev)]] 175 mg IV over 2 hours once on day 1, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*No routine prophylactic [[:Category:Emesis_prevention|antiemetics]] and [[:Category:Anti-diarrheals|antidiarrheal]] medications were used, but patients could use [[Metoclopramide (Reglan)]] prn nausea and [[Loperamide (Imodium)]] prn diarrhea.<br />
<br />
'''14-day cycles'''<br />
===References===<br />
<br />
#Labianca R, Cascinu S, Frontini L, Barni S, Fiorentini G, Comella G, Zaniboni A, Gottardi O, Arnoldi E, Oliani C, Duro M, Pavanato G, Martignoni G, Raina A, Piazza E, Dallavalle G, Valsecchi R, Pancera G, Luporini G; Italian Group for the Study of Digestive Tract Cancer. High-versus low-dose levo-leucovorin as a modulator of 5-fluorouracil in advanced colorectal cancer: a 'GISCAD' phase III study. Ann Oncol. 1997 Feb;8(2):169-74. [https://academic.oup.com/annonc/article/8/2/169/214080 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9093726 PubMed]<br />
#Colucci G, Maiello E, Gebbia V, Giuliani F, Serravezza G, Lelli G, Leo S, Filippelli G, Nicolella G, Brandi M. 5-fluorouracil and levofolinic acid with or without recombinant interferon-2b in patients with advanced colorectal carcinoma: a randomized multicenter study with stratification for tumor burden and liver involvement by the Southern Italy Oncology Group. Cancer. 1999 Feb 1;85(3):535-45. [https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819990201%2985%3A3%3C535%3A%3AAID-CNCR4%3E3.0.CO%3B2-7 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10091727 PubMed]<br />
#Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12;87(4):393-9. [https://www.nature.com/bjc/journal/v87/n4/full/6600467a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376131/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/12177775 PubMed]<br />
#'''MRC FOCUS:''' Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, Smith DB, Shepherd S, Maraveyas A, Ferry DR, Meade AM, Thompson L, Griffiths GO, Parmar MK, Stephens RJ; FOCUS Trial Investigators; National Cancer Research Institute Colorectal Clinical Studies Group. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007 Jul 14;370(9582):143-52. Erratum in: Lancet. 2007 Aug 18;370(9587):566. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61087-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17630037 PubMed]<br />
<br />
==FOLFIRI {{#subobject:ebcf30|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br>FUFIRI: 5-'''<u>FU</u>''' (Fluorouracil), '''<u>F</u>'''olinic acid, '''<u>IRI</u>'''notecan<br />
===Example orders===<br />
<br />
*[[Example orders for FOLFIRI in colon cancer]]<br />
<br />
===Variant #1, 400/2000/180, bi-weekly ("Lv5FU2-Iri") {{#subobject:048237|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext Douillard et al. 2000]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Fluorouracil_.26_Folinic_acid_3|5-FU & LV]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361370/ Souglakos et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFOXIRI]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/19/5/920/167346 Köhne et al. 2007 (EORTC 40015)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CAPIRI|CAPIRI]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS<br />
|-<br />
|[https://academic.oup.com/annonc/article/19/5/909/168102 Glimelius et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FLIRI<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://academic.oup.com/annonc/article/20/2/251/164564 Aranda et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FUIRI|FUIRI]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR (*)<br />
|-<br />
|[https://academic.oup.com/annonc/article/26/6/1201/161806 Passardi et al. 2015 (ITACa)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''Note: EORTC 40015 was closed prematurely. Aranda et al. 2008 is described by the authors as a non-inferiority trial but the statistics used are superiority-based.''<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 120 minutes once per day on days 1 & 2, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given third''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, 400/2800/180 {{#subobject:abe1bd|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/13/1670.long Falcone et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFOXIRI]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
| rowspan="2" |[http://jco.ascopubs.org/content/25/30/4779.long Fuchs et al. 2007 (BICC-C)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#CAPIRI|CapeIRI]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|2. [[#IFL|mIFL]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0805019 Van Cutsem et al. 2009 (CRYSTAL)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Colon_cancer,_KRAS_wild-type#FOLFIRI_.26_Cetuximab_2|FOLFIRI & Cetuximab]]<br />
| style="background-color:#d73027" |Inferior OS (*)<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.31552 Sanoff et al. 2018]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|FOLFIRI & Regorafenib<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|}<br />
''Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.''<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first, with leucovorin'''<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #3, 500/2000/80, 6 out of 7 weeks ("AIO regimen") {{#subobject:310a1a|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2005.05.546 Köhne et al. 2005 (EORTC 40986)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Fluorouracil_.26_Folinic_acid_3|5-FU & LV]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S0959804910009068 Fischer von Weikersthal et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|mIROX<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36<br />
*[[Irinotecan (Camptosar)]] 80 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36<br />
<br />
'''7-week cycles'''<br />
<br />
===Variant #4, 500/2300/80, weekly {{#subobject:355f88|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext Douillard et al. 2000]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Fluorouracil_.26_Folinic_acid_3|5-FU & LV]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/26/6/1201/161806 Passardi et al. 2015 (ITACa)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2300 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1<br />
*[[Irinotecan (Camptosar)]] 80 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''7-day cycles'''<br />
<br />
===References===<br />
<br />
#Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10744089 PubMed]<br />
#'''EORTC 40986:''' Köhne CH, van Cutsem E, Wils J, Bokemeyer C, El-Serafi M, Lutz MP, Lorenz M, Reichardt P, Rückle-Lanz H, Frickhofen N, Fuchs R, Mergenthaler HG, Langenbuch T, Vanhoefer U, Rougier P, Voigtmann R, Müller L, Genicot B, Anak O, Nordlinger B; European Organisation for Research and Treatment of Cancer Gastrointestinal Group. Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol. 2005 Aug 1;23(22):4856-65. Epub 2005 Jun 6. [https://ascopubs.org/doi/full/10.1200/JCO.2005.05.546 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15939923 PubMed]<br />
#Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, Kakolyris S, Tsousis S, Kouroussis Ch, Vamvakas L, Kalykaki A, Samonis G, Mavroudis D, Georgoulias V. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-805. [https://www.nature.com/articles/6603011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361370/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16508637 PubMed]<br />
<!-- Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006, and at the American Society of Clinical Oncology 2006 Gastrointestinal Cancers Symposium, San Francisco, CA, January 24-27, 2006. --><br />
#Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6. [http://jco.ascopubs.org/content/25/13/1670.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17470860 PubMed]<br />
<!-- Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA. --><br />
#'''BICC-C:''' Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. [http://jco.ascopubs.org/content/25/30/4779.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947725 PubMed]<br />
##'''Update:''' Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. [http://jco.ascopubs.org/content/26/4/689.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18235136 PubMed]<br />
#'''EORTC 40015:''' Köhne CH, De Greve J, Hartmann JT, Lang I, Vergauwe P, Becker K, Braumann D, Joosens E, Müller L, Janssens J, Bokemeyer C, Reimer P, Link H, Späth-Schwalbe E, Wilke HJ, Bleiberg H, Van Den Brande J, Debois M, Bethe U, Van Cutsem E. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer: EORTC study 40015. Ann Oncol. 2008 May;19(5):920-6. Epub 2007 Dec 6. [https://academic.oup.com/annonc/article/19/5/920/167346 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18065406 PubMed]<br />
#Glimelius B, Sørbye H, Balteskard L, Byström P, Pfeiffer P, Tveit K, Heikkilä R, Keldsen N, Albertsson M, Starkhammar H, Garmo H, Berglund A. A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer. Ann Oncol. 2008 May;19(5):909-14. Epub 2008 Jan 21. [https://academic.oup.com/annonc/article/19/5/909/168102 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18209013 PubMed]<br />
#Aranda E, Valladares M, Martinez-Villacampa M, Benavides M, Gomez A, Massutti B, Marcuello E, Constenla M, Cámara JC, Carrato A, Dueñas R, Reboredo M, Navarro M, Díaz-Rubio E. Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study. Ann Oncol. 2009 Feb;20(2):251-7. Epub 2008 Aug 20. [https://academic.oup.com/annonc/article/20/2/251/164564 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18718892 PubMed]<br />
#'''CRYSTAL:''' Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. [https://www.nejm.org/doi/full/10.1056/NEJMoa0805019 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19339720 PubMed]<br />
<!-- ## '''Update: Abstract:''' E. Van Cutsem, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D. Cunningham, I. Celik, C. Kohne. Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome. 2010 ASCO Annual Meeting abstract 3570. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=54429 link to abstract] --><br />
##'''Update:''' Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. [http://jco.ascopubs.org/content/29/15/2011.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21502544 PubMed]<br />
##'''Pooled Update:''' Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://www.ejcancer.com/article/S0959-8049(12)00209-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22446022 PubMed]<br />
##'''Biomarker analysis:''' Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. [https://ascopubs.org/doi/full/10.1200/JCO.2014.59.4812 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25605843 PubMed]<br />
#Fischer von Weikersthal L, Schalhorn A, Stauch M, Quietzsch D, Maubach PA, Lambertz H, Oruzio D, Schlag R, Weigang-Köhler K, Vehling-Kaiser U, Schulze M, Truckenbrodt J, Goebeler M, Mittermüller J, Bosse D, Szukics B, Grundeis M, Zwingers T, Giessen C, Heinemann V. Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer. Eur J Cancer. 2011 Jan;47(2):206-14. [https://www.sciencedirect.com/science/article/pii/S0959804910009068 link to SD article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20971632 PubMed]<br />
#'''ITACa:''' Passardi A, Nanni O, Tassinari D, Turci D, Cavanna L, Fontana A, Ruscelli S, Mucciarini C, Lorusso V, Ragazzini A, Frassineti GL, Amadori D. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015 Jun;26(6):1201-7. Epub 2015 Mar 3. [https://academic.oup.com/annonc/article/26/6/1201/161806 link to original article] '''refers to Douillard et al. 2000''' [https://www.ncbi.nlm.nih.gov/pubmed/25735317 PubMed]<br />
#Sanoff HK, Goldberg RM, Ivanova A, O'Reilly S, Kasbari SS, Kim RD, McDermott R, Moore DT, Zamboni W, Grogan W, Cohn AL, Bekaii-Saab TS, Leonard G, Ryan T, Olowokure OO, Fernando NH, McCaffrey J, El-Rayes BF, Horgan AM, Sherrill GB, Yacoub GH, O'Neil BH. Multicenter, randomized, double-blind phase 2 trial of FOLFIRI with regorafenib or placebo as second-line therapy for metastatic colorectal cancer. Cancer. 2018 Aug 1;124(15):3118-3126. Epub 2018 Jun 15. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.31552 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29905927 PubMed]<br />
<br />
==FOLFIRI (L-Leucovorin) {{#subobject:e98yb0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
===Variant #1, 200/2000/150 {{#subobject:ad9b82|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2005.07.113 Colucci et al. 2005 (GOIM 9901)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFOX4_3|FOLFOX4]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
''Note: this variant was intended for patients between 70 to 75 years old.''<br />
====Chemotherapy====<br />
<br />
*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given third''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, 200/2000/180 {{#subobject:87b4fe|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2005.07.113 Colucci et al. 2005 (GOIM 9901)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFOX4_3|FOLFOX4]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[https://academic.oup.com/annonc/article/22/5/1236/178870 Labianca et al. 2010]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Intermittent FOLFIRI<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given third''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #3, 200/2800/180 {{#subobject:a3c9bd|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0805019 Van Cutsem et al. 2009 (CRYSTAL)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Colon_cancer,_KRAS_wild-type#FOLFIRI_.26_Cetuximab_2|FOLFIRI & Cetuximab]]<br />
| style="background-color:#d73027" |Inferior OS (*)<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2012.45.1930 Carrato et al. 2013 (SUN 1122)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FOLFIRI & Sunitinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.''<br />
====Chemotherapy====<br />
<br />
*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1, '''given first, with levoleucovorin'''<br />
<br />
'''14-day cycles'''<br />
===References===<br />
<br />
#'''GOIM 9901:''' Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N, Cartenì G, Agostara B, Pezzella G, Manzione L, Borsellino N, Misino A, Romito S, Durini E, Cordio S, Di Seri M, Lopez M, Maiello E, Montemurro S, Cramarossa A, Lorusso V, Di Bisceglie M, Chiarenza M, Valerio MR, Guida T, Leonardi V, Pisconti S, Rosati G, Carrozza F, Nettis G, Valdesi M, Filippelli G, Fortunato S, Mancarella S, Brunetti C; Gruppo Oncologico Dell'Italia Meridionale. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol. 2005 Aug 1;23(22):4866-75. Epub 2005 Jun 6. [https://ascopubs.org/doi/full/10.1200/JCO.2005.07.113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15939922 PubMed]<br />
#'''CRYSTAL:''' Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. [https://www.nejm.org/doi/full/10.1056/NEJMoa0805019 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19339720 PubMed]<br />
<!-- ## '''Update: Abstract:''' E. Van Cutsem, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D. Cunningham, I. Celik, C. Kohne. Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome. 2010 ASCO Annual Meeting abstract 3570. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=54429 link to abstract] --><br />
##'''Update:''' Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. [http://jco.ascopubs.org/content/29/15/2011.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21502544 PubMed]<br />
##'''Pooled Update:''' Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://www.ejcancer.com/article/S0959-8049(12)00209-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22446022 PubMed]<br />
##'''Biomarker analysis:''' Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. [https://ascopubs.org/doi/full/10.1200/JCO.2014.59.4812 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25605843 PubMed]<br />
#Labianca R, Sobrero A, Isa L, Cortesi E, Barni S, Nicolella D, Aglietta M, Lonardi S, Corsi D, Turci D, Beretta GD, Fornarini G, Dapretto E, Floriani I, Zaniboni A; Italian Group for the Study of Gastrointestinal Cancer-GISCAD. Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised 'GISCAD' trial. Ann Oncol. 2011 May;22(5):1236-42. Epub 2010 Nov 15. [https://academic.oup.com/annonc/article/22/5/1236/178870 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21078826 PubMed]<br />
#'''SUN 1122:''' Carrato A, Swieboda-Sadlej A, Staszewska-Skurczynska M, Lim R, Roman L, Shparyk Y, Bondarenko I, Jonker DJ, Sun Y, De la Cruz JA, Williams JA, Korytowsky B, Christensen JG, Lin X, Tursi JM, Lechuga MJ, Van Cutsem E. Fluorouracil, leucovorin, and irinotecan plus either sunitinib or placebo in metastatic colorectal cancer: a randomized, phase III trial. J Clin Oncol. 2013 Apr 1;31(10):1341-7. Epub 2013 Jan 28. [https://ascopubs.org/doi/full/10.1200/JCO.2012.45.1930 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23358972 PubMed]<br />
<br />
==FOLFIRI & Bevacizumab {{#subobject:80d6b8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI & Bevacizumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Bevacizumab<br />
===Variant #1, indefinite {{#subobject:28b67a|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4779.long Fuchs et al. 2007 (BICC-C)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#IFL_.26_Bevacizumab|mIFL & Bevacizumab]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/27/8/1539/2237296 Yamazaki et al. 2016 (WJOG4407G)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#mFOLFOX6_.26_Bevacizumab|mFOLFOX6 & Bevacizumab]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first, with leucovorin'''<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given second'''<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, lower dose leucovorin {{#subobject:1bfcd9|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://academic.oup.com/annonc/article/24/9/2335/202863 Johnsson et al. 2013 (Nordic ACT)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 44 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 120 minutes once on day 1<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1<br />
<br />
'''14-day cycle for 9 cycles'''<br />
====Subsequent treatment====<br />
<br />
*Nordic ACT: [[#Bevacizumab_monotherapy|Bevacizumab]] versus Erlotinib & Bevacizumab maintenance<br />
<br />
===References===<br />
<!-- Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA. --><br />
<br />
#'''BICC-C:''' Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. [http://jco.ascopubs.org/content/25/30/4779.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947725 PubMed]<br />
##'''Update:''' Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. [http://jco.ascopubs.org/content/26/4/689.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18235136 PubMed]<br />
#'''Observational cohort:''' Bendell JC, Bekaii-Saab TS, Cohn AL, Hurwitz HI, Kozloff M, Tezcan H, Roach N, Mun Y, Fish S, Flick ED, Dalal D, Grothey A. Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-bevacizumab or FOLFIRI-bevacizumab: results from ARIES, a bevacizumab observational cohort study. Oncologist. 2012;17(12):1486-95. [http://theoncologist.alphamedpress.org/content/17/12/1486.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528380/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23015662 PubMed]<br />
#'''Nordic ACT:''' Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. [https://academic.oup.com/annonc/article/24/9/2335/202863 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23788755 PubMed]<br />
#'''WJOG4407G:''' Yamazaki K, Nagase M, Tamagawa H, Ueda S, Tamura T, Murata K, Eguchi Nakajima T, Baba E, Tsuda M, Moriwaki T, Esaki T, Tsuji Y, Muro K, Taira K, Denda T, Funai S, Shinozaki K, Yamashita H, Sugimoto N, Okuno T, Nishina T, Umeki M, Kurimoto T, Takayama T, Tsuji A, Yoshida M, Hosokawa A, Shibata Y, Suyama K, Okabe M, Suzuki K, Seki N, Kawakami K, Sato M, Fujikawa K, Hirashima T, Shimura T, Taku K, Otsuji T, Tamura F, Shinozaki E, Nakashima K, Hara H, Tsushima T, Ando M, Morita S, Boku N, Hyodo I. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol. 2016 Aug;27(8):1539-46. Epub 2016 May 13. [https://academic.oup.com/annonc/article/27/8/1539/2237296 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27177863 PubMed]<br />
<br />
==FOLFIRI & Bevacizumab (L-Leucovorin) {{#subobject:92d6b8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI & Bevacizumab: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Bevacizumab<br />
===Regimen {{#subobject:58ae38|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1403108 Loupakis et al. 2014 (TRIBE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX_.26_Bevacizumab|FOLFOXIRI & Bevacizumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: Loupakis et al. 2014 listed folinic acid 200 mg/m<sup>2</sup> in the body of the paper, whereas the protocol in the supplementary material stated that levoleucovorin 200 mg/m<sup>2</sup> was used. We have contacted NEJM regarding this suspected error.''<br />
====Chemotherapy====<br />
<br />
*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV over 30 minutes once on day 1<br />
<br />
'''14-day cycle for up to 12 cycles'''<br />
====Subsequent treatment====<br />
<br />
*Fluorouracil, leucovorin, bevacizumab maintenance<br />
<br />
===References===<br />
<!-- # Fotios Loupakis, Chiara Cremolini, Gianluca Masi, Sara Lonardi, Vittorina Zagonel, Patrizia Trenta, Gianluca Tomasello, Monica Ronzoni, Libero Ciuffreda, Alberto Zaniboni, Giuseppe Tonini, Angela Buonadonna, Chiara Valsuani, Silvana Chiara, Chiara Carlomagno, Corrado Boni, Lorenzo Marcucci, Luca Boni, Alfredo Falcone. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (MCRC): Results of the phase III randomized TRIBE trial. 2013 ASCO Gastrointestinal Cancers Symposium abstract 336. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=105744 link to abstract] [http://meetinglibrary.asco.org/presentationBySession/5250/1300 link to video presentation] --><br />
<br />
#'''TRIBE:''' Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014 Oct 23;371(17):1609-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1403108 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1403108/suppl_file/nejmoa1403108_protocol.pdf link to protocol in supplementary material] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25337750 PubMed]<br />
##'''Update:''' Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, Mezi S, Tomasello G, Ronzoni M, Zaniboni A, Tonini G, Carlomagno C, Allegrini G, Chiara S, D'Amico M, Granetto C, Cazzaniga M, Boni L, Fontanini G, Falcone A. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015 Oct;16(13):1306-15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00122-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26338525 PubMed]<br />
<br />
==FOLFIRINOX {{#subobject:7c3585|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
<br>FOLFOXIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>IRI</u>'''notecan<br />
===Regimen {{#subobject:4620e1|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361370/ Souglakos et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#FOLFIRI_2|FOLFIRI]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/13/1670.long Falcone et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#FOLFIRI_2|FOLFIRI]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: In contrast to Falcone et al. 2007, some guidelines list the dose of folinic acid as 400 mg/m<sup>2</sup> IV on day 1. No primary reference could be found for this.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 1600 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 3200 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, Kakolyris S, Tsousis S, Kouroussis Ch, Vamvakas L, Kalykaki A, Samonis G, Mavroudis D, Georgoulias V. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-805. [https://www.nature.com/articles/6603011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361370/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16508637 PubMed]<br />
<!-- Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006, and at the American Society of Clinical Oncology 2006 Gastrointestinal Cancers Symposium, San Francisco, CA, January 24-27, 2006. --><br />
#Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6. [http://jco.ascopubs.org/content/25/13/1670.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17470860 PubMed]<br />
<br />
==FOLFIRINOX & Bevacizumab (L-Leucovorin) {{#subobject:9bf7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX & Bevacizumab: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin, Bevacizumab<br />
<br>FOLFOXIRI & Bevacizumab: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>IRI</u>'''notecan, Bevacizumab<br />
===Regimen {{#subobject:19365|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1403108 Loupakis et al. 2014 (TRIBE)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: Loupakis et al. 2014 listed folinic acid 200 mg/m<sup>2</sup> in the body of the paper, whereas the protocol in the supplementary material stated that levoleucovorin 200 mg/m<sup>2</sup> was used. We have contacted NEJM regarding this suspected error. Some guidelines list either folinic acid 400 mg/m<sup>2</sup> IV once on day 1 or levoleucovorin 200 mg/m<sup>2</sup> IV once on day 1 as options.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 1600 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1, '''given fourth''' (total dose per cycle: 3200 mg/m<sup>2</sup>)<br />
*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given third, with oxaliplatin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given third, with levoleucovorin'''<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given second'''<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV over 30 minutes once on day 1, '''given first'''<br />
<br />
'''14-day cycle for up to 12 cycles'''<br />
====Subsequent treatment====<br />
<br />
*Fluorouracil, leucovorin, bevacizumab maintenance (specific details not provided)<br />
<br />
===References===<br />
<!-- # Fotios Loupakis, Chiara Cremolini, Gianluca Masi, Sara Lonardi, Vittorina Zagonel, Patrizia Trenta, Gianluca Tomasello, Monica Ronzoni, Libero Ciuffreda, Alberto Zaniboni, Giuseppe Tonini, Angela Buonadonna, Chiara Valsuani, Silvana Chiara, Chiara Carlomagno, Corrado Boni, Lorenzo Marcucci, Luca Boni, Alfredo Falcone. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (MCRC): Results of the phase III randomized TRIBE trial. 2013 ASCO Gastrointestinal Cancers Symposium abstract 336. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=105744 link to abstract] [http://meetinglibrary.asco.org/presentationBySession/5250/1300 link to video presentation] --><br />
<br />
#'''TRIBE:''' Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014 Oct 23;371(17):1609-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1403108 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1403108/suppl_file/nejmoa1403108_protocol.pdf link to protocol in supplementary material] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25337750 PubMed]<br />
##'''Update:''' Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, Mezi S, Tomasello G, Ronzoni M, Zaniboni A, Tonini G, Carlomagno C, Allegrini G, Chiara S, D'Amico M, Granetto C, Cazzaniga M, Boni L, Fontanini G, Falcone A. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015 Oct;16(13):1306-15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00122-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26338525 PubMed]<br />
<br />
==FOLFOX2 {{#subobject:429ff9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX2: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:d356da|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2006.06.1440 Giacchetti et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|chronoFLO4<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 600 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''<br />
*[[Fluorouracil (5-FU)]] 1500 mg/m<sup>2</sup> IV continuous infusion over 22 hours once per day, started on days 1 & 2, '''given second''' (total dose per cycle: 3000 mg/m<sup>2</sup>)<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#Giacchetti S, Bjarnason G, Garufi C, Genet D, Iacobelli S, Tampellini M, Smaaland R, Focan C, Coudert B, Humblet Y, Canon JL, Adenis A, Lo Re G, Carvalho C, Schueller J, Anciaux N, Lentz MA, Baron B, Gorlia T, Lévi F; European Organisation for Research and Treatment of Cancer Chronotherapy Group. Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group. J Clin Oncol. 2006 Aug 1;24(22):3562-9. [https://ascopubs.org/doi/full/10.1200/JCO.2006.06.1440 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16877722 PubMed]<br />
<br />
==FOLFOX4 {{#subobject:7239a0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:ab483a|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/18/16/2938.long de Gramont et al. 2000]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Fluorouracil_.26_Folinic_acid_3|5-FU & Folinic acid]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/JCO.2004.09.046 Goldberg et al. 2003 (NCCTG N9741)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#IFL|IFL]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. [[#IROX|IROX]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP<br />
|-<br />
|[http://jco.ascopubs.org/content/24/3/394.long Tournigand et al. 2006 (OPTIMOX1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFOX_7_.26_sLV5FU2|FOLFOX7/LV5FU2]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DDC<br />
|-<br />
| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 Cassidy et al. 2008 (NO16966)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#CapeOx_2|XELOX]]<br> 3. [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
| rowspan="2" |[http://jco.ascopubs.org/content/26/12/2013.long Saltz et al. 2008 (NO16966)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]<br> 2. [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|3. [[#CapeOx_2|XELOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2008.20.8397 Bokemeyer et al. 2008 (OPUS)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[Colon_cancer,_KRAS_wild-type#FOLFOX4_.26_Cetuximab|FOLFOX4 & Cetuximab]]<br />
| style="background-color:#d73027" |Inferior OS (*)<br />
|-<br />
|[http://jco.ascopubs.org/content/28/31/4697.long Douillard et al. 2010 (PRIME)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Colon_cancer,_KRAS_wild-type#FOLFOX4_.26_Panitumumab|FOLFOX4 & Panitumumab]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS (*)<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2010.29.4496 Hecht et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FOLFOX4 & Vatalanib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[http://jco.ascopubs.org/content/30/29/3596.long Hoff et al. 2012 (HORIZON II)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. CAPOX & Cediranib<br> 2. FOLFOX4 & Cediranib<br> 3. mFOLFOX6 & Cediranib<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://academic.oup.com/annonc/article/26/6/1201/161806 Passardi et al. 2015 (ITACa)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''Note: in PRIME, patients with KRAS wild-type tumors receiving this regimen seem to have inferior OS, based on the 2014 update. Conversely, in KRAS mutants, this regimen seems to have superior PFS. Reported efficacy for OPUS is based on the 2012 pooled update and is only for KRAS wild-type tumors.''<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. [http://jco.ascopubs.org/content/18/16/2938.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10944126 PubMed]<br />
#'''NCCTG N9741:''' Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. Epub 2003 Dec 9. [https://ascopubs.org/doi/full/10.1200/JCO.2004.09.046 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14665611 PubMed]<br />
#'''OPTIMOX1:''' Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, Mineur L, Carola E, Etienne PL, Rivera F, Chirivella I, Perez-Staub N, Louvet C, André T, Tabah-Fisch I, de Gramont A. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006 Jan 20;24(3):394-400. [http://jco.ascopubs.org/content/24/3/394.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16421419 PubMed]<br />
#'''Retrospective:''' Goldberg RM, Tabah-Fisch I, Bleiberg H, de Gramont A, Tournigand C, Andre T, Rothenberg ML, Green E, Sargent DJ. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol. 2006 Sep 1;24(25):4085-91. [http://jco.ascopubs.org/content/24/25/4085.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16943526 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
<!-- Presented in part at the 31st European Society of Medical Oncology Congress, Istanbul, Turkey, September 29- October 3, 2006; the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Orlando, FL, January 19-21, 2007; and the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007. --><br />
#'''NO16966:''' Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. [https://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18421053 PubMed]<br />
##'''Update:''' Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. [http://jco.ascopubs.org/content/26/12/2013.long link to original article] '''refers to de Gramont et al. 2000 for protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18421054 PubMed]<br />
##'''Update:''' Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64. Epub 2011 Jun 14. [https://www.nature.com/articles/bjc2011201 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137415/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21673685 PubMed]<br />
#'''OPUS:''' Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29. [https://ascopubs.org/doi/full/10.1200/JCO.2008.20.8397 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19114683 PubMed]<br />
##'''Update:''' Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011 Jul;22(7):1535-46. Epub 2011 Jan 12. [https://academic.oup.com/annonc/article/22/7/1535/187254 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21228335 PubMed]<br />
##'''Pooled Update:''' Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://www.ejcancer.com/article/S0959-8049(12)00209-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22446022 PubMed]<br />
#'''PRIME:''' Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010 Nov 1;28(31):4697-705. Epub 2010 Oct 4. [http://jco.ascopubs.org/content/28/31/4697.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20921465 PubMed]<br />
##'''Biomarker analysis:''' Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013 Sep 12;369(11):1023-34. [https://www.nejm.org/doi/full/10.1056/NEJMoa1305275 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24024839 PubMed]<br />
##'''Update:''' Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jul;25(7):1346-55. Epub 2014 Apr 8. [https://academic.oup.com/annonc/article/25/7/1346/2801199 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24718886 PubMed]<br />
#Hecht JR, Trarbach T, Hainsworth JD, Major P, Jäger E, Wolff RA, Lloyd-Salvant K, Bodoky G, Pendergrass K, Berg W, Chen BL, Jalava T, Meinhardt G, Laurent D, Lebwohl D, Kerr D. Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):1997-2003. Epub 2011 Apr 4. [https://ascopubs.org/doi/full/10.1200/JCO.2010.29.4496 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21464406 PubMed]<br />
#'''HORIZON II:''' Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. [http://jco.ascopubs.org/content/30/29/3596.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22965965 PubMed]<br />
#'''ITACa:''' Passardi A, Nanni O, Tassinari D, Turci D, Cavanna L, Fontana A, Ruscelli S, Mucciarini C, Lorusso V, Ragazzini A, Frassineti GL, Amadori D. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015 Jun;26(6):1201-7. Epub 2015 Mar 3. [https://academic.oup.com/annonc/article/26/6/1201/161806 link to original article] '''refers to de Gramont et al. 2000''' [https://www.ncbi.nlm.nih.gov/pubmed/25735317 PubMed]<br />
<br />
==FOLFOX4 (L-Leucovorin) {{#subobject:73uba0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX4: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:0af678|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2005.07.113 Colucci et al. 2005 (GOIM 9901)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRI_2|FOLFIRI]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2010.29.4496 Hecht et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FOLFOX4 & Vatalanib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://insights.ovid.com/pubmed?pmid=24316553 Correale et al. 2014 (GOLFIG-2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|GOLFIG<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with leucovorin'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''GOIM 9901:''' Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N, Cartenì G, Agostara B, Pezzella G, Manzione L, Borsellino N, Misino A, Romito S, Durini E, Cordio S, Di Seri M, Lopez M, Maiello E, Montemurro S, Cramarossa A, Lorusso V, Di Bisceglie M, Chiarenza M, Valerio MR, Guida T, Leonardi V, Pisconti S, Rosati G, Carrozza F, Nettis G, Valdesi M, Filippelli G, Fortunato S, Mancarella S, Brunetti C; Gruppo Oncologico Dell'Italia Meridionale. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol. 2005 Aug 1;23(22):4866-75. Epub 2005 Jun 6. [https://ascopubs.org/doi/full/10.1200/JCO.2005.07.113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15939922 PubMed]<br />
#Hecht JR, Trarbach T, Hainsworth JD, Major P, Jäger E, Wolff RA, Lloyd-Salvant K, Bodoky G, Pendergrass K, Berg W, Chen BL, Jalava T, Meinhardt G, Laurent D, Lebwohl D, Kerr D. Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):1997-2003. Epub 2011 Apr 4. [https://ascopubs.org/doi/full/10.1200/JCO.2010.29.4496 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21464406 PubMed]<br />
#'''GOLFIG-2:''' Correale P, Botta C, Rotundo MS, Guglielmo A, Conca R, Licchetta A, Pastina P, Bestoso E, Ciliberto D, Cusi MG, Fioravanti A, Guidelli GM, Bianco MT, Misso G, Martino E, Caraglia M, Tassone P, Mini E, Mantovani G, Ridolfi R, Pirtoli L, Tagliaferri P. Gemcitabine, oxaliplatin, levofolinate, 5-fluorouracil, granulocyte-macrophage colony-stimulating factor, and interleukin-2 (GOLFIG) versus FOLFOX chemotherapy in metastatic colorectal cancer patients: the GOLFIG-2 multicentric open-label randomized phase III trial. J Immunother. 2014 Jan;37(1):26-35. [https://insights.ovid.com/pubmed?pmid=24316553 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24316553 PubMed]<br />
<br />
==mFOLFOX6 {{#subobject:e4bda7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
<br>OxMdG: '''<u>Ox</u>'''aliplatin '''<u>M</u>'''odified '''<u>d</u>'''e '''<u>G</u>'''ramont<br />
<br />
===Example orders===<br />
<br />
*[[Example orders for mFOLFOX 6 in colon cancer]]<br />
<br />
===Variant #1, LCV 200 mg/m<sup>2</sup> {{#subobject:792d00|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2015.66.1181 van Hazel et al. 2016 (SIRFLOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|mFOLFOX6 plus SIRT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS (*)<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext Wasan et al. 2017 (FOXFIRE-Global)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|mFOLFOX6 plus SIRT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: Wasan et al. 2017, which is an update for SIRFLOX and the first publication for FOXFIRE-Global, describes the folinic acid as a flat 200 mg dose; van Hazel et al. 2016 reports 200 mg/m<sup>2</sup>; the authors were contacted for clarification.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, LCV 350 mg/m<sup>2</sup> {{#subobject:90f8fc|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376131/ Cheeseman et al. 2002]<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://ascopubs.org/doi/abs/10.1200/JCO.2007.15.4138 Hochster et al. 2008 (TREE-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. bFOL<br />
| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints<br />
|-<br />
|2. [[#CapeOx_2|CapeOx]]<br />
| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159415/ Maughan et al. 2011 (UK MRC COIN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|mFOLFOX6 & Cetuximab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext Wasan et al. 2017 (FOXFIRE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|OxMdG plus SIRT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: TREE-1 did not have any primary endpoints. Efficacy for UK MRC COIN is as reported for KRAS wild-type patients.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 350 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #3, LCV 400 mg/m<sup>2</sup> {{#subobject:db877a|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/30/29/3596.long Hoff et al. 2012 (HORIZON II)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. CAPOX & Cediranib<br> 2. FOLFOX4 & Cediranib<br> 3. mFOLFOX6 & Cediranib<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12;87(4):393-9. [https://www.nature.com/bjc/journal/v87/n4/full/6600467a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376131/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/12177775 PubMed]<br />
#'''TREE-1:''' Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. [https://ascopubs.org/doi/abs/10.1200/JCO.2007.15.4138 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18640933 PubMed]<br />
#'''UK MRC COIN:''' Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP; MRC COIN Trial Investigators. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011 Jun 18;377(9783):2103-14. Epub 2011 Jun 5. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60613-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159415/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21641636 PubMed]<br />
##'''Update:''' Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, Kenny SL, Kay E, Hodgkinson E, Pope M, Rogers P, Wasan H, Falk S, Gollins S, Hickish T, Bessell EM, Propper D, Kennedy MJ, Kaplan R, Maughan TS; MRC COIN Trial Investigators. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011 Jul;12(7):642-53. Epub 2011 Jun 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70102-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159416/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21641867 PubMed]<br />
#'''HORIZON II:''' Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. [http://jco.ascopubs.org/content/30/29/3596.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22965965 PubMed]<br />
#'''SIRFLOX:''' van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M, Perez D, Robinson BA, Strickland AH, Ferguson T, Rodríguez J, Kröning H, Wolf I, Ganju V, Walpole E, Boucher E, Tichler T, Shacham-Shmueli E, Powell A, Eliadis P, Isaacs R, Price D, Moeslein F, Taieb J, Bower G, Gebski V, Van Buskirk M, Cade DN, Thurston K, Gibbs P. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2016 May 20;34(15):1723-31. Epub 2016 Feb 22. [https://ascopubs.org/doi/full/10.1200/JCO.2015.66.1181 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26903575 PubMed]<br />
##'''Pooled update:''' Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A, van Hazel G, Sharma RA; FOXFIRE/SIRFLOX/FOXFIRE-Global trial investigators. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. Epub 2017 Aug 3. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28781171 PubMed]<br />
#'''FOXFIRE; FOXFIRE-Global:''' Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A, van Hazel G, Sharma RA; FOXFIRE/SIRFLOX/FOXFIRE-Global trial investigators. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. Epub 2017 Aug 3. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28781171 PubMed]<br />
<br />
==mFOLFOX6 (L-Leucovorin) {{#subobject:e46gn7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:8c4386|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159415/ Maughan et al. 2011 (UK MRC COIN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|mFOLFOX6 & Cetuximab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext Wasan et al. 2017 (FOXFIRE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|OxMdG plus SIRT<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: Efficacy for UK MRC COIN is as reported for KRAS wild-type patients.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Levoleucovorin (Fusilev)]] 175 mg IV over 2 hours once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''14-day cycles'''<br />
===References===<br />
<br />
#'''UK MRC COIN:''' Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP; MRC COIN Trial Investigators. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011 Jun 18;377(9783):2103-14. Epub 2011 Jun 5. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60613-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159415/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21641636 PubMed]<br />
##'''Update:''' Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, Kenny SL, Kay E, Hodgkinson E, Pope M, Rogers P, Wasan H, Falk S, Gollins S, Hickish T, Bessell EM, Propper D, Kennedy MJ, Kaplan R, Maughan TS; MRC COIN Trial Investigators. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011 Jul;12(7):642-53. Epub 2011 Jun 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70102-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159416/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21641867 PubMed]<br />
#'''FOXFIRE; FOXFIRE-Global:''' Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A, van Hazel G, Sharma RA; FOXFIRE/SIRFLOX/FOXFIRE-Global trial investigators. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. Epub 2017 Aug 3. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28781171 PubMed]<br />
<br />
==FOLFOX 7/sLV5FU2 {{#subobject:5513db|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX 7/sLV5FU2: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin alternating with '''<u>s</u>'''implified '''<u>L</u>'''euco'''<u>V</u>'''orin, '''<u>5-FU</u>''', '''<u>2</u>'''-weekly (every 2 weeks)<br />
<br />
===Regimen {{#subobject:b39a65|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/3/394.long Tournigand et al. 2006 (OPTIMOX1)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#FOLFOX4_2|FOLFOX4]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DDC<br />
|-<br />
|}<br />
''Note: this regimen has an unusual alternating schedule; see paper for more details.''<br />
====Chemotherapy, FOLFOX 7 portion====<br />
<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, started on day 1, '''given third'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
<br />
'''14-day cycle for up to 6 cycles, then proceed to sLV5FU2:'''<br />
<br />
====Chemotherapy, sLV5FU2 portion====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1500 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 3000 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycle for up to 12 cycles, then resume FOLFOX 7 for 6 additional cycles as described above'''<br />
<br />
===References===<br />
<br />
#'''OPTIMOX1:''' Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, Mineur L, Carola E, Etienne PL, Rivera F, Chirivella I, Perez-Staub N, Louvet C, André T, Tabah-Fisch I, de Gramont A. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006 Jan 20;24(3):394-400. [http://jco.ascopubs.org/content/24/3/394.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16421419 PubMed]<br />
<br />
==FOLFOX 7/sLV5FU2 (L-Leucovorin) {{#subobject:66b3db|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX 7/sLV5FU2: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin alternating with '''<u>s</u>'''implified L-'''<u>L</u>'''euco'''<u>V</u>'''orin, '''<u>5-FU</u>''', '''<u>2</u>'''-weekly (every 2 weeks)<br />
<br />
===Regimen {{#subobject:b39a65|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/3/394.long Tournigand et al. 2006 (OPTIMOX1)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#FOLFOX4_2|FOLFOX4]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of DDC<br />
|-<br />
|}<br />
''Note: this regimen has an unusual alternating schedule; see paper for more details.''<br />
====Chemotherapy, FOLFOX 7 portion====<br />
<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, started on day 1, '''given third'''<br />
*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
<br />
'''14-day cycle for up to 6 cycles, then proceed to sLV5FU2:'''<br />
<br />
====Chemotherapy, sLV5FU2 portion====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1500 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 3000 mg/m<sup>2</sup>)<br />
*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycle for up to 12 cycles, then resume FOLFOX 7 for 6 additional cycles as described above'''<br />
<br />
===References===<br />
<br />
#'''OPTIMOX1:''' Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, Mineur L, Carola E, Etienne PL, Rivera F, Chirivella I, Perez-Staub N, Louvet C, André T, Tabah-Fisch I, de Gramont A. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006 Jan 20;24(3):394-400. [http://jco.ascopubs.org/content/24/3/394.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16421419 PubMed]<br />
<br />
==mFOLFOX7 {{#subobject:7ff5f5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOX7: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:d39fe0|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://ascopubs.org/doi/full/10.1200/JCO.2009.23.4344 Chibaudel et al. 2009 (OPTIMOX2)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Chemotherapy, FOLFOX 7 portion====<br />
<br />
*[[Fluorouracil (5-FU)]] 3000 mg/m<sup>2</sup> IV continuous infusion over 46 hours, started on day 1, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with leucovorin'''<br />
<br />
'''14-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*sLV5FU2 versus no further treatment<br />
<br />
===References===<br />
<br />
#'''OPTIMOX2:''' Chibaudel B, Maindrault-Goebel F, Lledo G, Mineur L, André T, Bennamoun M, Mabro M, Artru P, Carola E, Flesch M, Dupuis O, Colin P, Larsen AK, Afchain P, Tournigand C, Louvet C, de Gramont A. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol. 2009 Dec 1;27(34):5727-33. Epub 2009 Sep 28. [https://ascopubs.org/doi/full/10.1200/JCO.2009.23.4344 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19786657 PubMed]<br />
<br />
==mFOLFOX7 (L-Leucovorin) {{#subobject:7f8nb5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOX7: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:d39g0k|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://ascopubs.org/doi/full/10.1200/JCO.2009.23.4344 Chibaudel et al. 2009 (OPTIMOX2)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Chemotherapy, FOLFOX 7 portion====<br />
<br />
*[[Fluorouracil (5-FU)]] 3000 mg/m<sup>2</sup> IV continuous infusion over 46 hours, started on day 1, '''given second'''<br />
*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with leucovorin'''<br />
<br />
'''14-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
<br />
*sLV5FU2 versus no further treatment<br />
<br />
===References===<br />
<br />
#'''OPTIMOX2:''' Chibaudel B, Maindrault-Goebel F, Lledo G, Mineur L, André T, Bennamoun M, Mabro M, Artru P, Carola E, Flesch M, Dupuis O, Colin P, Larsen AK, Afchain P, Tournigand C, Louvet C, de Gramont A. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol. 2009 Dec 1;27(34):5727-33. Epub 2009 Sep 28. [https://ascopubs.org/doi/full/10.1200/JCO.2009.23.4344 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19786657 PubMed]<br />
<br />
==FOLFOX4 & Bevacizumab {{#subobject:e93745|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX4 & Bevacizumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab<br />
<br>FOLFOX-B: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab<br />
===Regimen {{#subobject:c7030b|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894803/ Emmanouilides et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 Cassidy et al. 2008 (NO16966)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#FOLFOX4_3|FOLFOX4]]<br> 2. [[#CapeOx_2|XELOX]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|3. [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given first'''<br />
**Infusion times are 2 hours for cycle 1, 1 hour for cycle 2, then 30 minutes for cycles 3 and later<br />
<br />
'''14-day cycles'''<br />
===References===<br />
<br />
#Emmanouilides C, Sfakiotaki G, Androulakis N, Kalbakis K, Christophylakis C, Kalykaki A, Vamvakas L, Kotsakis A, Agelaki S, Diamandidou E, Touroutoglou N, Chatzidakis A, Georgoulias V, Mavroudis D, Souglakos J. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. BMC Cancer. 2007 May 30;7:91. [http://www.biomedcentral.com/1471-2407/7/91 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894803/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/17537235 PubMed]<br />
<!-- Presented in part at the 31st European Society of Medical Oncology Congress, Istanbul, Turkey, September 29- October 3, 2006; the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Orlando, FL, January 19-21, 2007; and the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007. --><br />
#'''NO16966:''' Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. [https://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18421053 PubMed]<br />
##'''Update:''' Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. [http://jco.ascopubs.org/content/26/12/2013.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18421054 PubMed]<br />
##'''Update:''' Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64. Epub 2011 Jun 14. [https://www.nature.com/articles/bjc2011201 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137415/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21673685 PubMed]<br />
<br />
==mFOLFOX6 & Bevacizumab {{#subobject:b74416|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOX6 & Bevacizumab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Bevacizumab<br />
<br>FOLFOX-B: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab<br />
===Example orders===<br />
<br />
*[[Example orders for mFOLFOX 6 & Bevacizumab (Avastin) in colon cancer]]<br />
<br />
===Variant #1 {{#subobject:eeb338|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#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
| rowspan="2" |[http://jco.ascopubs.org/content/26/21/3523.full Hochster et al. 2008 (TREE-2)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. bFOL & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints<br />
| style="background-color:#ffffbf" |Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment<br />
|-<br />
|2. [[#CapeOx_.26_Bevacizumab|CapeOx & Bevacizumab]]<br />
| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints<br />
| style="background-color:#ffffbf" |Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment<br />
|-<br />
|[https://ascopubs.org/doi/10.1200/JCO.2008.19.8135 Hecht et al. 2008 (PACCE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|mFOLFOX6 & Bevacizumab & Panitumumab<br />
| style="background-color:#1a9850" |Superior PFS<br />
|<br />
|-<br />
|[http://www.clinical-colorectal-cancer.com/article/S1533-0028(11)00063-6/fulltext Saltz et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FOLF-CB<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS12<br />
|<br />
|-<br />
|[http://jco.ascopubs.org/content/30/29/3588.long Schmoll et al. 2012 (HORIZON III)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|mFOLFOX6 & Cediranib<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS<br />
|<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70490-X/fulltext Yamada et al. 2013 (SOFT<sub>CRC</sub>)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#SOX_.26_Bevacizumab|SOX & Bevacizumab]]<br />
| style="background-color:#eeee01" |Seems to have non-inferior PFS<br />
|<br />
|-<br />
|[https://academic.oup.com/annonc/article/27/8/1539/2237296 Yamazaki et al. 2016 (WJOG4407G)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|<br />
|-<br />
|}<br />
''This was the most common oxaliplatin-based reigimen used in PACCE. There is another trial by the name of SOFT in breast cancer.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, lower dose leucovorin {{#subobject:3c348b|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://academic.oup.com/annonc/article/24/9/2335/202863 Johnsson et al. 2013 (Nordic ACT)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 44 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 120 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1<br />
<br />
'''14-day cycle for 9 cycles'''<br />
====Subsequent treatment====<br />
<br />
*Nordic ACT: [[#Bevacizumab_monotherapy|Bevacizumab]] versus Erlotinib & Bevacizumab maintenance<br />
<br />
===References===<br />
<br />
#'''TREE-2:''' Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. [http://jco.ascopubs.org/content/26/21/3523.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18640933 PubMed]<br />
#'''PACCE:''' Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, Marshall J, Cohn A, McCollum D, Stella P, Deeter R, Shahin S, Amado RG. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):672-80. Epub 2008 Dec 29. [https://ascopubs.org/doi/10.1200/JCO.2008.19.8135 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19114685 PubMed]<br />
#Saltz L, Badarinath S, Dakhil S, Bienvenu B, Harker WG, Birchfield G, Tokaz LK, Barrera D, Conkling PR, O'Rourke MA, Richards DA, Reidy D, Solit D, Vakiani E, Capanu M, Scales A, Zhan F, Boehm KA, Asmar L, Cohn A. Phase III trial of cetuximab, bevacizumab, and 5-fluorouracil/leucovorin vs FOLFOX-bevacizumab in colorectal cancer. Clin Colorectal Cancer. 2012 Jun;11(2):101-11. Epub 2011 Nov 4. [http://www.clinical-colorectal-cancer.com/article/S1533-0028(11)00063-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22055112 PubMed]<br />
#'''HORIZON III:''' Schmoll HJ, Cunningham D, Sobrero A, Karapetis CS, Rougier P, Koski SL, Kocakova I, Bondarenko I, Bodoky G, Mainwaring P, Salazar R, Barker P, Mookerjee B, Robertson J, Van Cutsem E. Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III). J Clin Oncol. 2012 Oct 10;30(29):3588-95. Epub 2012 Sep 10. [http://jco.ascopubs.org/content/30/29/3588.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22965961 PubMed]<br />
#'''Observational cohort:''' Bendell JC, Bekaii-Saab TS, Cohn AL, Hurwitz HI, Kozloff M, Tezcan H, Roach N, Mun Y, Fish S, Flick ED, Dalal D, Grothey A. Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-bevacizumab or FOLFIRI-bevacizumab: results from ARIES, a bevacizumab observational cohort study. Oncologist. 2012;17(12):1486-95. Epub 2012 Sep 26. [http://theoncologist.alphamedpress.org/content/17/12/1486.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528380/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23015662 PubMed]<br />
#'''Nordic ACT:''' Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. [https://academic.oup.com/annonc/article/24/9/2335/202863 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23788755 PubMed]<br />
#'''SOFT:''' Yamada Y, Takahari D, Matsumoto H, Baba H, Nakamura M, Yoshida K, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1278-86. Epub 2013 Nov 11. Erratum in: Lancet Oncol. 2014 Jan;15(1):e4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70490-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24225157 PubMed]<br />
##'''Update:''' Baba H, Yamada Y, Takahari D, Matsumoto H, Yoshida K, Nakamura M, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K. S-1 and oxaliplatin (SOX) plus bevacizumab versus mFOLFOX6 plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer: updated overall survival analyses of the open-label, non-inferiority, randomised phase III: SOFT study. ESMO Open. 2017 Mar 9;2(1):e000135. [https://esmoopen.bmj.com/content/2/1/e000135 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519807/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28761727 PubMed]<br />
#'''SIRFLOX:''' van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M, Perez D, Robinson BA, Strickland AH, Ferguson T, Rodríguez J, Kröning H, Wolf I, Ganju V, Walpole E, Boucher E, Tichler T, Shacham-Shmueli E, Powell A, Eliadis P, Isaacs R, Price D, Moeslein F, Taieb J, Bower G, Gebski V, Van Buskirk M, Cade DN, Thurston K, Gibbs P. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2016 May 20;34(15):1723-31. Epub 2016 Feb 22. [https://ascopubs.org/doi/full/10.1200/JCO.2015.66.1181 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26903575 PubMed]<br />
#'''WJOG4407G:''' Yamazaki K, Nagase M, Tamagawa H, Ueda S, Tamura T, Murata K, Eguchi Nakajima T, Baba E, Tsuda M, Moriwaki T, Esaki T, Tsuji Y, Muro K, Taira K, Denda T, Funai S, Shinozaki K, Yamashita H, Sugimoto N, Okuno T, Nishina T, Umeki M, Kurimoto T, Takayama T, Tsuji A, Yoshida M, Hosokawa A, Shibata Y, Suyama K, Okabe M, Suzuki K, Seki N, Kawakami K, Sato M, Fujikawa K, Hirashima T, Shimura T, Taku K, Otsuji T, Tamura F, Shinozaki E, Nakashima K, Hara H, Tsushima T, Ando M, Morita S, Boku N, Hyodo I. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol. 2016 Aug;27(8):1539-46. Epub 2016 May 13. [https://academic.oup.com/annonc/article/27/8/1539/2237296 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27177863 PubMed]<br />
<br />
==mFOLFOX6 & Bevacizumab (L-Leucovorin) {{#subobject:b7yy26|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
mFOLFOX6 & Bevacizumab: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Bevacizumab<br />
<br>FOLFOX-B: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab<br />
===Regimen {{#subobject:1d15de|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/29/3/624/4779925 Yamada et al. 2018 (TRICOLORE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#IRIS_.26_Bevacizumab|IRIS & Bevacizumab]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
===References===<br />
<br />
#'''TRICOLORE:''' Yamada Y, Denda T, Gamoh M, Iwanaga I, Yuki S, Shimodaira H, Nakamura M, Yamaguchi T, Ohori H, Kobayashi K, Tsuda M, Kobayashi Y, Miyamoto Y, Kotake M, Shimada K, Sato A, Morita S, Takahashi S, Komatsu Y, Ishioka C. S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized, open-label, phase III, noninferiority trial. Ann Oncol. 2018 Mar 1;29(3):624-631. [https://academic.oup.com/annonc/article/29/3/624/4779925 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29293874 PubMed]<br />
<br />
==FUIRI {{#subobject:e8ugac|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
FUIRI: 5-'''<u>FU</u>''' & '''<u>IRI</u>'''notecan<br />
<br />
===Regimen {{#subobject:08ucb7|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/20/2/251/164564 Aranda et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|[[#FOLFIRI_2|FOLFIRI]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR (*)<br />
|-<br />
|}<br />
''Note: Aranda et al. 2008 is described by the authors as a non-inferiority trial but the statistics used are superiority-based.''<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 1125 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1, '''given second''' (total dose per cycle: 2250 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 80 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given first'''<br />
<br />
'''7-day cycles'''<br />
<br />
===References===<br />
<br />
#Aranda E, Valladares M, Martinez-Villacampa M, Benavides M, Gomez A, Massutti B, Marcuello E, Constenla M, Cámara JC, Carrato A, Dueñas R, Reboredo M, Navarro M, Díaz-Rubio E. Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study. Ann Oncol. 2009 Feb;20(2):251-7. Epub 2008 Aug 20. [https://academic.oup.com/annonc/article/20/2/251/164564 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18718892 PubMed]<br />
<br />
==FUOX {{#subobject:b4j3b5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FUOX: 5-'''<u>FU</u>''' & '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:975a54|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/27/4224.long Díaz-Rubio et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CapeOx_2|CapeOx]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP<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 />
*[[Fluorouracil (5-FU)]] 1125 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on days 1 & 8 (total dose per cycle: 4500 mg/m<sup>2</sup>)<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''14-day cycle for 18 cycles'''<br />
<br />
===References===<br />
<!-- Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2005, Atlanta, GA; and the Annual Meeting of the European Society for Medical Oncology, Istanbul, Turkey, September 29-October 3, 2006. --><br />
<br />
#Díaz-Rubio E, Tabernero J, Gómez-España A, Massutí B, Sastre J, Chaves M, Abad A, Carrato A, Queralt B, Reina JJ, Maurel J, González-Flores E, Aparicio J, Rivera F, Losa F, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol. 2007 Sep 20;25(27):4224-30. Epub 2007 Jun 4. [http://jco.ascopubs.org/content/25/27/4224.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17548839 PubMed]<br />
<br />
==IFL {{#subobject:544878|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
IFL: '''<u>I</u>'''rinotecan, '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin (Folinic acid)<br />
<br>mIFL: '''<u>m</u>'''odified '''<u>I</u>'''rinotecan, '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin (Folinic acid)<br />
===Variant #1, q3wk {{#subobject:2354b5|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.karger.com/Article/FullText/320520 Stathopoulos et al. 2010]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#IFL_.26_Bevacizumab|IFL & Bevacizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS36<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 135 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2, 4 out of 6 weeks {{#subobject:1ec9e5|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 Saltz et al. 2000]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|1. [[#Fluorouracil_.26_Folinic_acid_3|FULV]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|2. [[#Irinotecan_monotherapy|Irinotecan]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/JCO.2004.09.046 Goldberg et al. 2003 (NCCTG N9741)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#FOLFOX4_3|FOLFOX4]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. [[#IROX|IROX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa032691 Hurwitz et al. 2004 (AVF2107g)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. FULV & Bevacizumab<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#IFL_.26_Bevacizumab|IFL & Bevacizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
| rowspan="2" |[http://jco.ascopubs.org/content/25/30/4779.long Fuchs et al. 2007 (BICC-C)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#CAPIRI|CapeIRI]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|2. [[#FOLFIRI_2|FOLFIRI]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012268/ Guan et al. 2011 (ARTIST<sub>CRC</sub>)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#IFL_.26_Bevacizumab|mIFL & Bevacizumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: 5-FU in ARTIST was given over 6 to 8 hours. ARTIST should not be confused for the trial with the same name in gastric cancer.''<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<br />
#Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. [https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11006366 PubMed]<br />
#'''NCCTG N9741:''' Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. Epub 2003 Dec 9. [https://ascopubs.org/doi/full/10.1200/JCO.2004.09.046 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14665611 PubMed]<br />
#'''AVF2107g:''' Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa032691 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15175435 PubMed]<br />
##'''Update:''' Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, Hambleton J, Novotny WF, Kabbinavar F. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol. 2005 May 20;23(15):3502-8. [https://ascopubs.org/doi/full/10.1200/JCO.2005.10.017 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15908660 PubMed]<br />
<!-- Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA. --><br />
#'''BICC-C:''' Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. [http://jco.ascopubs.org/content/25/30/4779.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947725 PubMed]<br />
##'''Update:''' Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. [http://jco.ascopubs.org/content/26/4/689.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18235136 PubMed]<br />
#Stathopoulos GP, Batziou C, Trafalis D, Koutantos J, Batzios S, Stathopoulos J, Legakis J, Armakolas A. Treatment of colorectal cancer with and without bevacizumab: a phase III study. Oncology. 2010;78(5-6):376-81. Epub 2010 Aug 27. [https://www.karger.com/Article/FullText/320520 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20798560 PubMed]<br />
#'''ARTIST:''' Guan ZZ, Xu JM, Luo RC, Feng FY, Wang LW, Shen L, Yu SY, Ba Y, Liang J, Wang D, Qin SK, Wang JJ, He J, Qi C, Xu RH. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer. 2011 Oct;30(10):682-9. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012268/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21959045 PubMed]<br />
<br />
==IFL & Bevacizumab {{#subobject:1d3c2e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
IFL & Bevacizumab: '''<u>I</u>'''rinotecan, '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin (Folinic acid), Bevacizumab<br />
<br>mIFL & Bevacizumab: '''<u>m</u>'''odified '''<u>I</u>'''rinotecan, '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin (Folinic acid), Bevacizumab<br />
===Variant #1, IFL {{#subobject:772ed7|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa032691 Hurwitz et al. 2004 (AVF2107g)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|1. FL & Bevacizumab<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. [[#IFL|IFL]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4779.long Fuchs et al. 2007 (BICC-C)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI+Bev]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 8<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8<br />
*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2, mIFL {{#subobject:e336a6|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012268/ Guan et al. 2011 (ARTIST<sub>CRC</sub>)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#IFL|mIFL]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: this trial should not be confused for the trial with the same name in gastric cancer.''<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV over 6 to 8 hours once per day on days 1, 8, 15, 22<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1, 15, 29<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<br />
#'''AVF2107g:''' Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa032691 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15175435 PubMed]<br />
<!-- Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA. --><br />
#'''BICC-C:''' Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. [http://jco.ascopubs.org/content/25/30/4779.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947725 PubMed]<br />
##'''Update:''' Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. [http://jco.ascopubs.org/content/26/4/689.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18235136 PubMed]<br />
#'''ARTIST:''' Guan ZZ, Xu JM, Luo RC, Feng FY, Wang LW, Shen L, Yu SY, Ba Y, Liang J, Wang D, Qin SK, Wang JJ, He J, Qi C, Xu RH. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer. 2011 Oct;30(10):682-9. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012268/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21959045 PubMed]<br />
<br />
==Irinotecan monotherapy {{#subobject:e5bfc5|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 Irinotecan (Camptosar) in colon cancer]]<br />
<br />
===Regimen {{#subobject:7e0a89|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 Saltz et al. 2000]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|1. [[#Fluorouracil_.26_Folinic_acid_3|5-FU & LV]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|2. [[#IFL|IFL]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<br />
#Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. [https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11006366 PubMed]<br />
<br />
==IRIS & Bevacizumab {{#subobject:923b54|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
IRIS & Bevacizumab: '''<u>IRI</u>'''notecan, '''<u>S</u>'''-1, Bevacizumab<br />
===Variant #1, q3wk {{#subobject:e8b674|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/29/3/624/4779925 Yamada et al. 2018 (TRICOLORE)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#CapeOx_.26_Bevacizumab|CapeOx & Bevacizumab]]<br> 2. [[#mFOLFOX6_.26_Bevacizumab_2|mFOLFOX6 & Bevacizumab]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV once on day 1, '''given second'''<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 15, beginning in the evening (28 doses per cycle)<br />
*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1, '''given first'''<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2, q4wk {{#subobject:081d47|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/29/3/624/4779925 Yamada et al. 2018 (TRICOLORE)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|1. [[#CapeOx_.26_Bevacizumab|CapeOx & Bevacizumab]]<br> 2. [[#mFOLFOX6_.26_Bevacizumab_2|mFOLFOX6 & Bevacizumab]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 15, '''given second'''<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 15, beginning in the evening (28 doses per cycle)<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1 & 15, '''given first'''<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''TRICOLORE:''' Yamada Y, Denda T, Gamoh M, Iwanaga I, Yuki S, Shimodaira H, Nakamura M, Yamaguchi T, Ohori H, Kobayashi K, Tsuda M, Kobayashi Y, Miyamoto Y, Kotake M, Shimada K, Sato A, Morita S, Takahashi S, Komatsu Y, Ishioka C. S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized, open-label, phase III, noninferiority trial. Ann Oncol. 2018 Mar 1;29(3):624-631. [https://academic.oup.com/annonc/article/29/3/624/4779925 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29293874 PubMed]<br />
<br />
==IROX {{#subobject:e2032d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
IROX: '''<u>IR</u>'''inotecan & '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e75779|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/JCO.2004.09.046 Goldberg et al. 2003 (NCCTG N9741)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|1. [[#FOLFOX4_3|FOLFOX4]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP<br />
|-<br />
|2. [[#IFL|IFL]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''NCCTG N9741:''' Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. Epub 2003 Dec 9. [https://ascopubs.org/doi/full/10.1200/JCO.2004.09.046 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14665611 PubMed]<br />
<br />
==Nordic FLOX {{#subobject:68f8a9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FLOX: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>OX</u>'''aliplatin<br />
<br />
===Example orders===<br />
<br />
*[[Example orders for FLOX in colon cancer]]<br />
<br />
===Regimen {{#subobject:8220b4|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2004.05.188 Sørbye et al. 2004]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2011.38.0915 Tveit et al. 2012 (NORDIC-VII)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Nordic FLOX & Cetuximab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of 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 />
<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 60 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, '''given third, 30 minutes after 5-FU'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first'''<br />
<br />
'''14-day cycle for 8 cycles (NORDIC-VII) or indefinitely (Sørbye et al. 2004)'''<br />
<br />
===References===<br />
<br />
#Sørbye H, Glimelius B, Berglund A, Fokstuen T, Tveit KM, Braendengen M, Øgreid D, Dahl O. Multicenter phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):31-8. [https://ascopubs.org/doi/full/10.1200/JCO.2004.05.188 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14701765 PubMed]<br />
#'''NORDIC-VII:''' Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, Sigurdsson F, Kure E, Ikdahl T, Skovlund E, Fokstuen T, Hansen F, Hofsli E, Birkemeyer E, Johnsson A, Starkhammar H, Yilmaz MK, Keldsen N, Erdal AB, Dajani O, Dahl O, Christoffersen T. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012 May 20;30(15):1755-62. Epub 2012 Apr 2. [https://ascopubs.org/doi/full/10.1200/JCO.2011.38.0915 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22473155 PubMed]<br />
##'''Update:''' Guren TK, Thomsen M, Kure EH, Sorbye H, Glimelius B, Pfeiffer P, Österlund P, Sigurdsson F, Lothe IMB, Dalsgaard AM, Skovlund E, Christoffersen T, Tveit KM. Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study. Br J Cancer. 2017 May 9;116(10):1271-1278. Epub 2017 Apr 11. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482736/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28399112 PubMed]<br />
<br />
==OXAFAFU {{#subobject:a38b7e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OXAFAFU: '''<u>OXA</u>'''liplatin, '''<u>F</u>'''olinic '''<u>A</u>'''cid (Leucovorin), 5-'''<u>FU</u>''' (Fluorouracil)<br />
===Regimen {{#subobject:3dcd8b|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/16/6/878/193940 Comella et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|IRIFAFU<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
*[[Folinic acid (Leucovorin)]] 250 mg/m<sup>2</sup> IV once on day 2<br />
*[[Fluorouracil (5-FU)]] 850 mg/m<sup>2</sup> IV once on day 2<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#Comella P, Massidda B, Filippelli G, Palmeri S, Natale D, Farris A, De Vita F, Buzzi F, Tafuto S, Maiorino L, Mancarella S, Leo S, Lorusso V, De Lucia L, Roselli M. Oxaliplatin plus high-dose folinic acid and 5-fluorouracil IV bolus (OXAFAFU) versus irinotecan plus high-dose folinic acid and 5-fluorouracil IV bolus (IRIFAFU) in patients with metastatic colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase III trial. Ann Oncol. 2005 Jun;16(6):878-86. Epub 2005 Apr 18. [https://academic.oup.com/annonc/article/16/6/878/193940 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15837702 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:32c8c6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b1642a|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#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://academic.oup.com/annonc/article-abstract/28/6/1288/3102942 Kwakman et al. 2017 (SALTO)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Capecitabine_monotherapy_2|Capecitabine]]<br />
| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints (*)<br />
| style="background-color:#1a9850" |Lower incidence of hand-foot syndrome<br />
|-<br />
|}<br />
''Note: this trial had a primary toxicity endpoint; reported efficacy is based on the 2019 update.'' <br />
====Chemotherapy====<br />
<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] 30 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles''' <br />
===References===<br />
<br />
#'''SALTO:''' Kwakman JJM, Simkens LHJ, van Rooijen JM, van de Wouw AJ, Ten Tije AJ, Creemers GJM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, van Werkhoven E, Punt CJA. Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group. Ann Oncol. 2017 Jun 1;28(6):1288-1293. [https://academic.oup.com/annonc/article-abstract/28/6/1288/3102942 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28383633 PubMed]<br />
##'''Update:''' Kwakman JJM, van Werkhoven E, Simkens LHJ, van Rooijen JM, van de Wouw YAJ, Tije AJT, Creemers GM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, Punt CJA. Updated Survival Analysis of the Randomized Phase III Trial of S-1 Versus Capecitabine in the First-Line Treatment of Metastatic Colorectal Cancer by the Dutch Colorectal Cancer Group. Clin Colorectal Cancer. 2019 Jun;18(2):e229-e230. Epub 2019 Jan 29. [https://www.clinical-colorectal-cancer.com/article/S1533-0028(18)30531-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30782413 PubMed]<br />
<br />
==SOX {{#subobject:693823|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
SOX: '''<u>S</u>'''-1 & '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:c54d08|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext Hong et al. 2012 (SMC 2008-03-012)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#CapeOx_2|CapeOX]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycle for up to 9 cycles''' <br />
====Subsequent treatment====<br />
<br />
*Patients were allowed to continue [[#S-1_monotherapy_2|S-1 maintenance]]<br />
<br />
===References===<br />
<br />
#'''SMC 2008-03-012:''' Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23062232 PubMed]<br />
##'''Update:''' Kim ST, Hong YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Lee JW, Jo SJ, Park YS. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: updated results from a phase 3 trial. BMC Cancer. 2014 Nov 26;14:883. [https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-14-883 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289339/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25424120 PubMed]<br />
<br />
==SOX & Bevacizumab {{#subobject:6c92b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
SOX & Bevacizumab: '''<u>S</u>'''-1, '''<u>OX</u>'''aliplatin, Bevacizumab<br />
===Regimen {{#subobject:cjcn88|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70490-X/fulltext Yamada et al. 2013 (SOFT<sub>CRC</sub>)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#mFOLFOX6_.26_Bevacizumab|mFOLFOX6 & Bevacizumab]]<br />
| style="background-color:#eeee01" |Seems to have non-inferior PFS<br />
|-<br />
|}<br />
<br />
''Note: S-1 is given starting on the evening of day 1, completing after breakfast on day 15.''<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 14 (see note)<br />
**BSA between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14 (see note)<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 14 (see note)<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1, '''given second'''<br />
*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1, '''given first'''<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''SOFT:''' Yamada Y, Takahari D, Matsumoto H, Baba H, Nakamura M, Yoshida K, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1278-86. Epub 2013 Nov 11. Erratum in: Lancet Oncol. 2014 Jan;15(1):e4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70490-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24225157 PubMed]<br />
##'''Update:''' Baba H, Yamada Y, Takahari D, Matsumoto H, Yoshida K, Nakamura M, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K. S-1 and oxaliplatin (SOX) plus bevacizumab versus mFOLFOX6 plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer: updated overall survival analyses of the open-label, non-inferiority, randomised phase III: SOFT study. ESMO Open. 2017 Mar 9;2(1):e000135. [https://esmoopen.bmj.com/content/2/1/e000135 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519807/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28761727 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Bevacizumab monotherapy {{#subobject:caff58|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:ab34c1|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/24/9/2335/202863 Johnsson et al. 2013 (Nordic ACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Erlotinib & Bevacizumab<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|[https://academic.oup.com/annonc/article/26/4/709/204652 Koeberle et al. 2015 (SAKK 41/06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Observation_3|No further treatment]]<br />
| style="background-color:#ffffbf" |Inconclusive whether non-inferior TTP<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00042-X/fulltext Hegewisch-Becker et al. 2015 (AIO KRK 0207)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)<br />
|1. [[#Observation_3|No further treatment]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|2. Fluoropyrimidine & Bevacizumab<br />
| style="background-color:#eeee01" |Non-inferior TTF<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00216-8/fulltext Tournigand et al. 2015 (OPTIMOX3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Erlotinib & Bevacizumab<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2017.75.2931 Aparicio et al. 2018 (PRODIGE 9)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation_3|No further treatment]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TCD<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Nordic ACT: [[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]] x 9 or [[#mFOLFOX6_.26_Bevacizumab|mFOLFOX6 & Bevacizumab]] x 9 or [[#CAPIRI-Bev|XELIRI & Bevacizumab]] x 6 or [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]] x 6<br />
*AIO KRK 0207 & OPTIMOX3: Bevacizumab-containing chemotherapy<br />
<br />
====Chemotherapy====<br />
<br />
*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Nordic ACT:''' Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. [https://academic.oup.com/annonc/article/24/9/2335/202863 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23788755 PubMed]<br />
#'''SAKK 41/06:''' Koeberle D, Betticher DC, von Moos R, Dietrich D, Brauchli P, Baertschi D, Matter K, Winterhalder R, Borner M, Anchisi S, Moosmann P, Kollar A, Saletti P, Roth A, Frueh M, Kueng M, Popescu RA, Schacher S, Hess V, Herrmann R. Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06). Ann Oncol. 2015 Apr;26(4):709-14. Epub 2015 Jan 20. [https://academic.oup.com/annonc/article/26/4/709/204652 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25605741 PubMed]<br />
#'''AIO KRK 0207:''' Hegewisch-Becker S, Graeven U, Lerchenmüller CA, Killing B, Depenbusch R, Steffens CC, Al-Batran SE, Lange T, Dietrich G, Stoehlmacher J, Tannapfel A, Reinacher-Schick A, Quidde J, Trarbach T, Hinke A, Schmoll HJ, Arnold D. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1355-69. Epub 2015 Sep 8. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00042-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26361971 PubMed]<br />
#'''OPTIMOX3:''' Tournigand C, Chibaudel B, Samson B, Scheithauer W, Vernerey D, Mésange P, Lledo G, Viret F, Ramée JF, Tubiana-Mathieu N, Dauba J, Dupuis O, Rinaldi Y, Mabro M, Aucoin N, Latreille J, Bonnetain F, Louvet C, Larsen AK, André T, de Gramont A. Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1493-1505. Epub 2015 Oct 22. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00216-8/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26474518 PubMed]<br />
#'''PRODIGE 9:''' Aparicio T, Ghiringhelli F, Boige V, Le Malicot K, Taieb J, Bouché O, Phelip JM, François E, Borel C, Faroux R, Dahan L, Jacquot S, Genet D, Khemissa F, Suc E, Desseigne F, Texereau P, Lepage C, Bennouna J; PRODIGE 9 Investigators. Bevacizumab maintenance versus no maintenance during chemotherapy-free intervals in metastatic colorectal cancer: a randomized phase III trial (PRODIGE 9). J Clin Oncol. 2018 Mar 1;36(7):674-681. Epub 2018 Jan 18. [https://ascopubs.org/doi/full/10.1200/JCO.2017.75.2931 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29346040 PubMed]<br />
<br />
==Capecitabine monotherapy {{#subobject:66ad1e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:796f2e|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext Hong et al. 2012]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://academic.oup.com/annonc/article/27/6/1074/1741605 Luo et al. 2016]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation_3|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*Hong et al. 2012: [[#CapeOx_2|CapeOX]] x 9<br />
*Luo et al. 2016: [[#mFOLFOX6_3|FOLFOX]] or [[#CapeOx_2|XELOX]]<br />
<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23062232 PubMed]<br />
#Luo HY, Li YH, Wang W, Wang ZQ, Yuan X, Ma D, Wang FH, Zhang DS, Lin DR, Lin YC, Jia J, Hu XH, Peng JW, Xu RH. Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety. Ann Oncol. 2016 Jun;27(6):1074-81. Epub 2016 Mar 2. [https://academic.oup.com/annonc/article/27/6/1074/1741605 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26940686 PubMed]<br />
<br />
==Capecitabine & Bevacizumab {{#subobject:083f75|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CAP-B: '''<u>CAP</u>'''ecitabine & '''<u>B</u>'''evacizumab<br />
===Regimen {{#subobject:49256d|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.karger.com/Article/FullText/355914 Yalcin et al. 2013 (Stop and Go)]<br />
| style="background-color:#1a9851" |Phase III (E-de-esc)<br />
|Continued XELOX-B<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62004-3/fulltext Simkens et al. 2015 (CAIRO3)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Observation_3|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS-2<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#CapeOx_.26_Bevacizumab|CAPOX-B]] x 6<br />
<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day<br />
*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''Stop and Go:''' Yalcin S, Uslu R, Dane F, Yilmaz U, Zengin N, Buyukunal E, Buyukberber S, Camci C, Sencan O, Kilickap S, Ozdener F, Cevik D. Bevacizumab + capecitabine as maintenance therapy after initial bevacizumab + XELOX treatment in previously untreated patients with metastatic colorectal cancer: phase III 'Stop and Go' study results--a Turkish Oncology Group Trial. Oncology. 2013;85(6):328-35. Epub 2013 Nov 12. [https://www.karger.com/Article/FullText/355914 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24247559 PubMed]<br />
#'''CAIRO3:''' Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoeven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, Honkoop AH, Mol L, Punt CJ, Koopman M. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015 May 9;385(9980):1843-52. Epub 2015 Apr 7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62004-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25862517 PubMed]<br />
##'''Update:''' Goey KKH, Elias SG, van Tinteren H, Laclé MM, Willems SM, Offerhaus GJA, de Leng WWJ, Strengman E, Ten Tije AJ, Creemers GM, van der Velden A, de Jongh FE, Erdkamp FLG, Tanis BC, Punt CJA, Koopman M. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann Oncol. 2017 Sep 1;28(9):2128-2134. [https://academic.oup.com/annonc/article/28/9/2128/3884600 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28911067 PubMed]<br />
<br />
==Observation==<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62004-3/fulltext Simkens et al. 2015 (CAIRO3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Bevacizumab_2|CAP-B]]<br />
| style="background-color:#d73027" |Inferior PFS2<br />
|-<br />
|[https://academic.oup.com/annonc/article/27/6/1074/1741605 Luo et al. 2016]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_monotherapy|Capecitabine]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2017.75.2931 Aparicio et al. 2018 (PRODIGE 9)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Bevacizumab_monotherapy|Bevacizumab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of TCD<br />
|-<br />
|}<br />
''No further treatment after first-line induction.''<br />
====Preceding treatment====<br />
<br />
*CAIRO3: [[#CapeOx_.26_Bevacizumab|CAPOX-B]] x 6<br />
*Luo et al. 2016: [[#mFOLFOX6_3|FOLFOX]] or [[#CapeOx_2|XELOX]]<br />
<br />
===References===<br />
<br />
#'''CAIRO3:''' Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoeven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, Honkoop AH, Mol L, Punt CJ, Koopman M. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015 May 9;385(9980):1843-52. Epub 2015 Apr 7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62004-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25862517 PubMed]<br />
##'''Update:''' Goey KKH, Elias SG, van Tinteren H, Laclé MM, Willems SM, Offerhaus GJA, de Leng WWJ, Strengman E, Ten Tije AJ, Creemers GM, van der Velden A, de Jongh FE, Erdkamp FLG, Tanis BC, Punt CJA, Koopman M. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann Oncol. 2017 Sep 1;28(9):2128-2134. [https://academic.oup.com/annonc/article/28/9/2128/3884600 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28911067 PubMed]<br />
#Luo HY, Li YH, Wang W, Wang ZQ, Yuan X, Ma D, Wang FH, Zhang DS, Lin DR, Lin YC, Jia J, Hu XH, Peng JW, Xu RH. Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety. Ann Oncol. 2016 Jun;27(6):1074-81. Epub 2016 Mar 2. [https://academic.oup.com/annonc/article/27/6/1074/1741605 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26940686 PubMed]<br />
#'''PRODIGE 9:''' Aparicio T, Ghiringhelli F, Boige V, Le Malicot K, Taieb J, Bouché O, Phelip JM, François E, Borel C, Faroux R, Dahan L, Jacquot S, Genet D, Khemissa F, Suc E, Desseigne F, Texereau P, Lepage C, Bennouna J; PRODIGE 9 Investigators. Bevacizumab maintenance versus no maintenance during chemotherapy-free intervals in metastatic colorectal cancer: a randomized phase III trial (PRODIGE 9). J Clin Oncol. 2018 Mar 1;36(7):674-681. Epub 2018 Jan 18. [https://ascopubs.org/doi/full/10.1200/JCO.2017.75.2931 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29346040 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:b5a1dd|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:608e8f|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(12)70363-7/fulltext Hong et al. 2012]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#SOX_2|SOX]] x 9<br />
<br />
====Chemotherapy====<br />
<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles''' <br />
===References===<br />
<br />
#Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23062232 PubMed]<br />
<br />
=Advanced or metastatic disease, second-line therapy=<br />
==CapeOx {{#subobject:6b5972|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda, '''<u>OX</u>'''aliplatin<br />
===Example orders===<br />
<br />
*[[Example orders for CapeOx (XELOX) in colon cancer]]<br />
<br />
===Regimen {{#subobject:df3e12|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext Koopman et al. 2007 (CAIRO)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[Complex_multipart_regimens#CAIRO|See link]]<br />
| style="background-color:#ffffbf" |[[Complex_multipart_regimens#CAIRO|See link]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/19/10/1720/240463 Rothenberg et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#FOLFOX4_4|FOLFOX4]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*CAIRO: [[#CAPIRI|CAPIRI]], with progression<br />
<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles''' <br />
<br />
===References===<br />
<br />
#'''CAIRO:''' Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. [https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17630036 PubMed]<br />
#Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, Gollins S, Siu LL, Laguerre S, Cunningham D. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008 Oct;19(10):1720-6. Epub 2008 Jun 10. [https://academic.oup.com/annonc/article/19/10/1720/240463 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18550577 PubMed]<br />
<br />
==CAPIRI {{#subobject:26c557|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeIRI: '''<u>Cape</u>'''citabine and '''<u>IRI</u>'''notecan<br />
<br>CAPIRI: '''<u>CAP</u>'''ecitabine and '''<u>IRI</u>'''notecan<br />
<br>XELIRI: '''<u>XEL</u>'''ox (Capecitabine) and '''<u>IRI</u>'''notecan<br />
<br>mXELIRI: '''<u>m</u>'''odified '''<u>XEL</u>'''ox (Capecitabine) and '''<u>IRI</u>'''notecan<br />
===Variant #1, "standard" {{#subobject:f1b041|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815882/ Lim et al. 2015 (SMC 2009-11-017)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|XELIRI & Simvastatin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #2, "modified" {{#subobject:b3be15|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#FOLFIRI_3|FOLFIRI]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''SMC 2009-11-017:''' Lim SH, Kim TW, Hong YS, Han SW, Lee KH, Kang HJ, Hwang IG, Lee JY, Kim HS, Kim ST, Lee J, Park JO, Park SH, Park YS, Lim HY, Jung SH, Kang WK. A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer. Br J Cancer. 2015 Nov 17;113(10):1421-6. Epub 2015 Oct 27. [https://www.nature.com/bjc/journal/v113/n10/full/bjc2015371a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815882/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26505681 PubMed]<br />
#'''AXEPT:''' Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29555258 PubMed]<br />
<br />
==CAPIRI-Bev {{#subobject:7c6914|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CAPIRI-Bev: '''<u>CAP</u>'''ecitabine, '''<u>IRI</u>'''notecan, '''<u>Bev</u>'''acizumab<br />
<br>mXELIRI & Bevacizumab: '''<u>m</u>'''odified '''<u>XEL</u>'''ox (Capecitabine), '''<u>IRI</u>'''notecan, Bevacizumab<br />
===Regimen {{#subobject:b94028|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#FOLFIRI_.26_Bevacizumab_2|FOLFIRI & Bevacizumab]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV over 30 to 90 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''AXEPT:''' Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29555258 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:8ff0ed|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a2b84b|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext Rougier et al. 1998 (V302)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Irinotecan_monotherapy_2|Irinotecan]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: this was one of three control regimens; see paper for details.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 250 to 300 mg/m<sup>2</sup>/day IV continuous infusion<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<br />
#'''V302:''' Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Awad L, Herait P, Jacques C. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1407-12. Erratum in: Lancet 1998 Nov 14;352(9140):1634. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9807986 PubMed]<br />
<br />
==FOLFIRI {{#subobject:7325e5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
===Example orders===<br />
<br />
*[[Example orders for FOLFIRI in colon cancer]]<br />
<br />
===Variant #1, lower-dose leucovorin {{#subobject:b1e6e2|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815882/ Lim et al. 2015 (SMC 2009-11-017)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FOLFIRI & Simvastatin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, higher-dose leucovorin {{#subobject:3cf53b|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2004.05.113 Tournigand et al. 2003]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#mFOLFOX6_3|mFOLFOX6]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS15<br />
|-<br />
|[http://jco.ascopubs.org/content/28/31/4706.long Peeters et al. 2010 (20050181)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Colon_cancer,_KRAS_wild-type#FOLFIRI_.26_Panitumumab|FOLFIRI & Panitumumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS (*)<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2012.42.8201 Van Cutsem et al. 2012 (VELOUR)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRI_.26_Ziv-aflibercept|FOLFIRI & Ziv-aflibercept]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/26/4/724/204710 Masi et al. 2015 (BEBYP)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRI_.26_Bevacizumab_2|FOLFIRI & Bevacizumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2815%2970127-0/fulltext Tabernero et al. 2015 (RAISE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRI_.26_Ramucirumab|FOLFIRI & Ramucirumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CAPIRI_2|CAPIRI]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
''Note: BEBYP does not provide dosing details; this is the most commonly used variant of FOLFIRI. Reported efficacy for 20050181 is for wild-type KRAS, only, and is based on the 2014 update.''<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
**In Tournigand et al. 2003, if no toxicity greater than grade 1 in cycles 1 & 2, increased to: 400 mg/m<sup>2</sup> IV bolus once on day 1, then 3000 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 3400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first, with leucovorin'''<br />
<br />
'''14-day cycles'''<br />
====Subsequent treatment====<br />
<br />
*Tournigand et al. 2003, upon progression: [[#mFOLFOX6_4|mFOLFOX6]]<br />
<br />
===References===<br />
<br />
#Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15;22(2):229-37. Epub 2003 Dec 2. [https://ascopubs.org/doi/full/10.1200/JCO.2004.05.113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14657227 PubMed]<br />
#'''20050181:''' Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010 Nov 1;28(31):4706-13. Epub 2010 Oct 4. [http://jco.ascopubs.org/content/28/31/4706.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20921462 PubMed]<br />
##'''Update:''' Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tian Y, Sidhu R. Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jan;25(1):107-16. Erratum in: Ann Oncol. 2014 Mar;25(3):757. [https://academic.oup.com/annonc/article/25/1/107/166332 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24356622 PubMed]<br />
#'''FFCD 2000-05:''' Ducreux M, Malka D, Mendiboure J, Etienne PL, Texereau P, Auby D, Rougier P, Gasmi M, Castaing M, Abbas M, Michel P, Gargot D, Azzedine A, Lombard-Bohas C, Geoffroy P, Denis B, Pignon JP, Bedenne L, Bouché O; Fédération Francophone de Cancérologie Digestive (FFCD) 2000–05 Collaborative Group. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol. 2011 Oct;12(11):1032-44. Epub 2011 Sep 6. [https://www.thelancet.com/journals/lancetonc/article/PIIS1470204511701991/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21903473 PubMed]<br />
<!-- Presented in part at the European Society for Medical Oncology 13th World Congress on Gastrointestinal Cancer, June 22-25, 2011, Barcelona, Spain; and the 2011 European Multidisciplinary Cancer Congress, September 24-27, 2011, Stockholm, Sweden. --><br />
#'''VELOUR:''' Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012 Oct 1;30(28):3499-506. [https://ascopubs.org/doi/full/10.1200/JCO.2012.42.8201 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22949147 PubMed]<br />
##'''Subgroup analysis:''' Tabernero J, Van Cutsem E, Lakomý R, Prausová J, Ruff P, van Hazel GA, Moiseyenko VM, Ferry DR, McKendrick JJ, Soussan-Lazard K, Chevalier S, Allegra CJ. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014 Jan;50(2):320-31. [https://www.ejcancer.com/article/S0959-8049%2813%2900853-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24140268 PubMed]<br />
##'''Subgroup analysis:''' Ruff P, Van Cutsem E, Lakomy R, Prausova J, van Hazel GA, Moiseyenko VM, Soussan-Lazard K, Dochy E, Magherini E, Macarulla T, Papamichael D. Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: An age-based analysis from the randomized placebo-controlled phase III VELOUR trial. J Geriatr Oncol. 2018 Jan;9(1):32-39. Epub 2017 Aug 12. [https://www.geriatriconcology.net/article/S1879-4068(17)30140-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28807738 PubMed]<br />
#'''BEBYP:''' Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-30. Epub 2015 Jan 18. [https://academic.oup.com/annonc/article/26/4/724/204710 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25600568 PubMed]<br />
#'''RAISE:''' Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F; RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 May;16(5):499-508. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2815%2970127-0/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25877855 PubMed]<br />
##'''Subgroup analysis:''' Obermannová R, Van Cutsem E, Yoshino T, Bodoky G, Prausová J, Garcia-Carbonero R, Ciuleanu T, Garcia Alfonso P, Portnoy D, Cohn A, Yamazaki K, Clingan P, Lonardi S, Kim TW, Yang L, Nasroulah F, Tabernero J. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016 Nov;27(11):2082-2090. Epub 2016 Aug 29. [https://academic.oup.com/annonc/article/27/11/2082/2467255 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091322/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27573561 PubMed]<br />
#'''SMC 2009-11-017:''' Lim SH, Kim TW, Hong YS, Han SW, Lee KH, Kang HJ, Hwang IG, Lee JY, Kim HS, Kim ST, Lee J, Park JO, Park SH, Park YS, Lim HY, Jung SH, Kang WK. A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer. Br J Cancer. 2015 Nov 17;113(10):1421-6. Epub 2015 Oct 27. [https://www.nature.com/bjc/journal/v113/n10/full/bjc2015371a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815882/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26505681 PubMed]<br />
#'''AXEPT:''' Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29555258 PubMed]<br />
<br />
==FOLFIRI (L-Leucovorin) {{#subobject:7477e5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
===Regimen {{#subobject:db9c30|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2004.05.113 Tournigand et al. 2003]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#mFOLFOX6_3|mFOLFOX6]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS15<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CAPIRI_2|CAPIRI]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
**In Tournigand et al. 2003, if no toxicity greater than grade 1 in cycles 1 & 2, increased to: 400 mg/m<sup>2</sup> IV bolus once on day 1, then 3000 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 3400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given first, with levoleucovorin'''<br />
<br />
'''14-day cycles'''<br />
====Subsequent treatment====<br />
<br />
*Tournigand et al. 2003, upon progression: [[#mFOLFOX6_4|mFOLFOX6]]<br />
<br />
===References===<br />
<br />
#Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15;22(2):229-37. Epub 2003 Dec 2. [https://ascopubs.org/doi/full/10.1200/JCO.2004.05.113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14657227 PubMed]<br />
#'''AXEPT:''' Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29555258 PubMed]<br />
<br />
==FOLFIRI & Bevacizumab {{#subobject:bcdb7d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI & Bevacizumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Bevacizumab<br />
<br />
===Regimen {{#subobject:548cd8a|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70477-1/fulltext Bennouna et al. 2012 (ML18147)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#FOLFIRI_3|FOLFIRI]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/26/4/724/204710 Masi et al. 2015 (BEBYP)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#FOLFIRI_3|FOLFIRI]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CAPIRI-Bev_2|mXELIRI & Bevacizumab]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
''Note: the abstract of ML18147 does not specify the exact type of chemotherapy; patients had to be previously bevacizumab-exposed. BEBYP does not provide dosing details; this is the most commonly used variant of FOLFIRI.''<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given first, with leucovorin'''<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given second'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ML18147:''' Bennouna J, Sastre J, Arnold D, Österlund P, Greil R, Van Cutsem E, von Moos R, Viéitez JM, Bouché O, Borg C, Steffens CC, Alonso-Orduña V, Schlichting C, Reyes-Rivera I, Bendahmane B, André T, Kubicka S; ML18147 Study Investigators. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013 Jan;14(1):29-37. Epub 2012 Nov 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70477-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23168366 PubMed]<br />
#'''BEBYP:''' Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-30. Epub 2015 Jan 18. [https://academic.oup.com/annonc/article/26/4/724/204710 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25600568 PubMed]<br />
#'''AXEPT:''' Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29555258 PubMed]<br />
<br />
==FOLFIRI & Bevacizumab (L-Leucovorin) {{#subobject:bedg7d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI & Bevacizumab: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Bevacizumab<br />
===Variant #1, 200/2800/150/5 {{#subobject:5b2542|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478977/ Iwamoto et al. 2015 (EAGLE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRI_.26_Bevacizumab_.28L-Leucovorin.29_2|FOLFIRI & Bevacizumab]]; lower-dose bevacizumab (10 mg/kg)<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, with irinotecan'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given second, with levoleucovorin'''<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV over 30 minutes once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, 200/2800/180/5 {{#subobject:2c0ba3|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#CAPIRI-Bev_2|mXELIRI & Bevacizumab]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given first, with levoleucovorin'''<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given second'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''EAGLE:''' Iwamoto S, Takahashi T, Tamagawa H, Nakamura M, Munemoto Y, Kato T, Hata T, Denda T, Morita Y, Inukai M, Kunieda K, Nagata N, Kurachi K, Ina K, Ooshiro M, Shimoyama T, Baba H, Oba K, Sakamoto J, Mishima H. FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study. Ann Oncol. 2015 Jul;26(7):1427-33. Epub 2015 Apr 23. [https://academic.oup.com/annonc/article/26/7/1427/165485 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478977/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25908603 PubMed]<br />
#'''AXEPT:''' Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29555258 PubMed]<br />
<br />
==FOLFIRI & Ramucirumab {{#subobject:pyr1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI & Ramucirumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan & Ramucirumab<br />
<br />
===Regimen {{#subobject:pyv1|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%" |[[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.thelancet.com/journals/lanonc/article/PIIS1470-2045%2815%2970127-0/fulltext Tabernero et al. 2015 (RAISE)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#FOLFIRI_3|FOLFIRI]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''either given third or concurrently with irinotecan'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given second'''<br />
*[[Ramucirumab (Cyramza)]] 8 mg/kg IV over 60 minutes once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''RAISE:''' Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F; RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 May;16(5):499-508. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2815%2970127-0/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25877855 PubMed]<br />
##'''Subgroup analysis:''' Obermannová R, Van Cutsem E, Yoshino T, Bodoky G, Prausová J, Garcia-Carbonero R, Ciuleanu T, Garcia Alfonso P, Portnoy D, Cohn A, Yamazaki K, Clingan P, Lonardi S, Kim TW, Yang L, Nasroulah F, Tabernero J. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016 Nov;27(11):2082-2090. Epub 2016 Aug 29. [https://academic.oup.com/annonc/article/27/11/2082/2467255 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091322/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27573561 PubMed]<br />
<br />
==FOLFIRI & Ziv-aflibercept {{#subobject:615d3f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI & Ziv-aflibercept: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Ziv-aflibercept<br />
===Regimen {{#subobject:29895|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2012.42.8201 Van Cutsem et al. 2012 (VELOUR)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#FOLFIRI_3|FOLFIRI]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.futuremedicine.com/doi/10.2217/fon-2017-0669 Li et al. 2018 (AFLAME)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#FOLFIRI_3|FOLFIRI]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given second'''<br />
*[[Ziv-aflibercept (Zaltrap)]] 4 mg/kg IV over 60 minutes once on day 1, '''given first'''<br />
<br />
====Supportive medications====<br />
<br />
*"Premedication with [[Atropine (Atropen)]] and [[:Category:Emesis_prevention|anti-emetics]] was permitted. [[:Category:Granulocyte_colony-stimulating_factors|Granulocyte-colony stimulating factor (G-CSF)]] was used according to the [http://jop.ascopubs.org/content/2/4/196.full American Society of Clinical Oncology guidelines (2006)]."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<!-- Presented in part at the European Society for Medical Oncology 13th World Congress on Gastrointestinal Cancer, June 22-25, 2011, Barcelona, Spain; and the 2011 European Multidisciplinary Cancer Congress, September 24-27, 2011, Stockholm, Sweden. --><br />
<br />
#'''VELOUR:''' Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012 Oct 1;30(28):3499-506. [https://ascopubs.org/doi/full/10.1200/JCO.2012.42.8201 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22949147 PubMed]<br />
##'''Subgroup analysis:''' Tabernero J, Van Cutsem E, Lakomý R, Prausová J, Ruff P, van Hazel GA, Moiseyenko VM, Ferry DR, McKendrick JJ, Soussan-Lazard K, Chevalier S, Allegra CJ. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014 Jan;50(2):320-31. [https://www.ejcancer.com/article/S0959-8049%2813%2900853-8/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24140268 PubMed]<br />
##'''Subgroup analysis:''' Ruff P, Van Cutsem E, Lakomy R, Prausova J, van Hazel GA, Moiseyenko VM, Soussan-Lazard K, Dochy E, Magherini E, Macarulla T, Papamichael D. Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: An age-based analysis from the randomized placebo-controlled phase III VELOUR trial. J Geriatr Oncol. 2018 Jan;9(1):32-39. Epub 2017 Aug 12. [https://www.geriatriconcology.net/article/S1879-4068(17)30140-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28807738 PubMed]<br />
#'''AFLAME:''' Li J, Xu R, Qin S, Liu T, Pan H, Xu J, Bi F, Lim R, Zhang S, Ba Y, Bai Y, Fan N, Tsuji A, Yeh KH, Ma B, Wei V, Shi D, Magherini E, Shen L. Aflibercept plus FOLFIRI in Asian patients with pretreated metastatic colorectal cancer: a randomized Phase III study. Future Oncol. 2018 Aug;14(20):2031-2044. Epub 2018 Aug 17. Erratum in: Future Oncol. 2019 Feb;15(4):451. [https://www.futuremedicine.com/doi/10.2217/fon-2017-0669 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30117334 PubMed]<br />
<br />
==FOLFOX4 {{#subobject:9034b5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:78b107|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2003.11.126 Rothenberg et al. 2003]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|1. LV5FU2<br> 2. Oxaliplatin<br />
| style="background-color:#1a9850" |Superior TTP<br />
|-<br />
|[https://academic.oup.com/annonc/article/19/10/1720/240463 Rothenberg et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#CapeOx_3|XELOX]]<br />
| style="background-color:#eeee01" |Non-inferior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, Hart LL, Gupta S, Garay CA, Burger BG, Le Bail N, Haller DG. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol. 2003 Jun 1;21(11):2059-69. [https://ascopubs.org/doi/full/10.1200/JCO.2003.11.126 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12775730 PubMed]<br />
#Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, Gollins S, Siu LL, Laguerre S, Cunningham D. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008 Oct;19(10):1720-6. Epub 2008 Jun 10. [https://academic.oup.com/annonc/article/19/10/1720/240463 link to original article] '''refers to de Gramont et al. 2000 protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18550577 PubMed]<br />
<br />
==mFOLFOX6 {{#subobject:9a3dc9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Example orders===<br />
<br />
*[[Example orders for mFOLFOX 6 in colon cancer]]<br />
<br />
===Regimen {{#subobject:f71fa5|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/26/4/724/204710 Masi et al. 2015 (BEBYP)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#mFOLFOX6_.26_Bevacizumab_2|mFOLFOX6 & Bevacizumab]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: BEBYP does not provide dosing details; this is the most commonly used variant of mFOLFOX6.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''BEBYP:''' Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-30. Epub 2015 Jan 18. [https://academic.oup.com/annonc/article/26/4/724/204710 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25600568 PubMed]<br />
<br />
==mFOLFOX6 & Bevacizumab {{#subobject:46965e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFOX6 & Bevacizumab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Bevacizumab<br />
===Regimen {{#subobject:61186f|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://academic.oup.com/annonc/article/26/4/724/204710 Masi et al. 2015 (BEBYP)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#mFOLFOX6_3|mFOLFOX6]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: BEBYP does not provide dosing details; this is the most commonly used variant of mFOLFOX6.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''BEBYP:''' Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-30. Epub 2015 Jan 18. [https://academic.oup.com/annonc/article/26/4/724/204710 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25600568 PubMed]<br />
<br />
==Irinotecan monotherapy {{#subobject:d4d4f9|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 Irinotecan (Camptosar) in colon cancer]]<br />
<br />
===Variant #1, 100 mg/m<sup>2</sup>, 4 weeks out of 6 {{#subobject:77bz17|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/full/10.1002/%28SICI%291097-0142%2819990215%2985%3A4%3C786%3A%3AAID-CNCR5%3E3.0.CO%3B2-9 Rothenberg et al. 1999]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
''Note: this was a mid-protocol dose amendment for excess toxicity.''<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
'''42-day cycles'''<br />
<br />
===Variant #2, 125 mg/m<sup>2</sup>, 4 weeks out of 6 {{#subobject:73a017|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.4.1128 Rothenberg et al. 1996]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.8.2910 Pitot et al. 1997]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://jco.ascopubs.org/content/21/5/807.long Fuchs et al. 2003]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Irinotecan_monotherapy_2|Irinotecan]]; every 3 weeks<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS12<br />
|-<br />
|}<br />
''Note: In contrast to what is described here, some guidelines list irinotecan as being given on days 1 & 8 of a 21-day cycle. No primary reference could be found for this.''<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22<br />
<br />
'''42-day cycles'''<br />
<br />
===Variant #3, 250 mg/m<sup>2</sup> q3wk {{#subobject:7c1d8f|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/26/28/4544.long Haller et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#IROX_2|IROX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''This starting dose was intended for patients who were at least 65 years old, had prior abdomen/pelvic radiation, or had elevated bilirubin. Dose escalations in the absence of grade 2 or higher toxicities were allowed.''<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, 300 mg/m<sup>2</sup> q3wk {{#subobject:190e25|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext Rougier et al. 1998 (V302)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Fluorouracil_monotherapy_2|CI 5-FU]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/21/5/807.long Fuchs et al. 2003]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Irinotecan_monotherapy_2|Irinotecan]]; 4 weeks out of 6<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS12<br />
|-<br />
|[http://jco.ascopubs.org/content/26/14/2311.long Sobrero et al. 2008 (EPIC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Colon_cancer,_KRAS_wild-type#Irinotecan_.26_Cetuximab|Irinotecan & Cetuximab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698019/ Kim et al. 2009 (N9841)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFOX4_4|FOLFOX4]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
''Note: This was the lower bound of the dosing range described by Rougier et al. 1998. In some trials, this starting dose was intended for patients who were at least 70 years old, had [[Performance status|ECOG performance status]] 2 or more, or had prior pelvic radiation. Patients in N9841 had not previously received irinotecan or oxaliplatin.''<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 300 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #5, 350 mg/m<sup>2</sup> q3wk {{#subobject:627110|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.1.251 Rougier et al. 1997]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext Rougier et al. 1998 (V302)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)<br />
|[[#Fluorouracil_monotherapy_2|CI 5-FU]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/21/5/807.long Fuchs et al. 2003]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#Irinotecan_monotherapy_2|Irinotecan]]; 4 weeks out of 6<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS12<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2004.01.005 Lal et al. 2004]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Irinotecan_monotherapy_2|Irinotecan]] x 8<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of FFS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext Koopman et al. 2007 (CAIRO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#CAIRO|See link]]<br />
| style="background-color:#ffffbf" |[[Complex_multipart_regimens#CAIRO|See link]]<br />
|-<br />
|[http://jco.ascopubs.org/content/26/14/2311.long Sobrero et al. 2008 (EPIC)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Irinotecan_.26_Cetuximab|Irinotecan & Cetuximab]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[http://jco.ascopubs.org/content/26/28/4544.long Haller et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#IROX_2|IROX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698019/ Kim et al. 2009 (N9841)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFOX4_4|FOLFOX4]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|}<br />
''Note: This was the upper bound of the dosing range described by Rougier et al. 1998. Patients in N9841 had not previously received irinotecan or oxaliplatin.''<br />
====Preceding treatment====<br />
<br />
*CAIRO: [[#Capecitabine_monotherapy_2|Capecitabine]], with progression<br />
<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 350 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*(varied depending on reference):<br />
*"Standard regimens of [[:Category:Emesis_prevention|antiemetics]], [[Atropine (Atropen)]], and intensive [[Loperamide (Imodium)]]," but no prophylactic [[Atropine (Atropen)]] allowed on cycle 1 day 1<br />
<br />
'''21-day cycles'''<br />
====Subsequent treatment====<br />
<br />
*CAIRO, with progression: [[#CapeOx_4|CapeOx]]<br />
<br />
===References===<br />
<br />
#Rothenberg ML, Eckardt JR, Kuhn JG, Burris HA 3rd, Nelson J, Hilsenbeck SG, Rodriguez GI, Thurman AM, Smith LS, Eckhardt SG, Weiss GR, Elfring GL, Rinaldi DA, Schaaf LJ, Von Hoff DD. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol. 1996 Apr;14(4):1128-35. [https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.4.1128 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8648367 PubMed]<br />
#Rougier P, Bugat R, Douillard JY, Culine S, Suc E, Brunet P, Becouarn Y, Ychou M, Marty M, Extra JM, Bonneterre J, Adenis A, Seitz JF, Ganem G, Namer M, Conroy T, Negrier S, Merrouche Y, Burki F, Mousseau M, Herait P, Mahjoubi M. Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol. 1997 Jan;15(1):251-60. [https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.1.251 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8996150 PubMed]<br />
#Pitot HC, Wender DB, O'Connell MJ, Schroeder G, Goldberg RM, Rubin J, Mailliard JA, Knost JA, Ghosh C, Kirschling RJ, Levitt R, Windschitl HE. Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol. 1997 Aug;15(8):2910-9. [https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.8.2910 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9256135 PubMed]<br />
#Rothenberg ML, Cox JV, DeVore RF, Hainsworth JD, Pazdur R, Rivkin SE, Macdonald JS, Geyer CE Jr, Sandbach J, Wolf DL, Mohrland JS, Elfring GL, Miller LL, Von Hoff DD. A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer. 1999 Feb 15;85(4):786-95. [https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819990215%2985%3A4%3C786%3A%3AAID-CNCR5%3E3.0.CO%3B2-9 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10091755 PubMed]<br />
#'''V302:''' Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Awad L, Herait P, Jacques C. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1407-12. Erratum in: Lancet 1998 Nov 14;352(9140):1634. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9807986 PubMed]<br />
#Fuchs CS, Moore MR, Harker G, Villa L, Rinaldi D, Hecht JR. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003 Mar 1;21(5):807-14. [http://jco.ascopubs.org/content/21/5/807.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12610178 PubMed]<br />
#Lal R, Dickson J, Cunningham D, Chau I, Norman AR, Ross PJ, Topham C, Middleton G, Hill M, Oates J. A randomized trial comparing defined-duration with continuous irinotecan until disease progression in fluoropyrimidine and thymidylate synthase inhibitor-resistant advanced colorectal cancer. J Clin Oncol. 2004 Aug 1;22(15):3023-31. [https://ascopubs.org/doi/full/10.1200/JCO.2004.01.005 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15284252 PubMed]<br />
#'''CAIRO:''' Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. [https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17630036 PubMed]<br />
<!-- Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, June 2005; the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2006; safety and efficacy results from this study were presented at the Annual Meeting of the American Association for Cancer Research, April 14-18, 2007, Los Angeles, CA; and the quality of life results from this study were presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 2007. --><br />
#'''EPIC:''' Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kröning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008 May 10;26(14):2311-9. Epub 2008 Apr 7. [http://jco.ascopubs.org/content/26/14/2311.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18390971 PubMed]<br />
#Haller DG, Rothenberg ML, Wong AO, Koralewski PM, Miller WH Jr, Bodoky G, Habboubi N, Garay C, Olivatto LO. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008 Oct 1;26(28):4544-50. [http://jco.ascopubs.org/content/26/28/4544.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18824706 PubMed]<br />
#'''N9841:''' Kim GP, Sargent DJ, Mahoney MR, Rowland KM Jr, Philip PA, Mitchell E, Mathews AP, Fitch TR, Goldberg RM, Alberts SR, Pitot HC. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol. 2009 Jun 10;27(17):2848-54. Epub 2009 Apr 20. [https://ascopubs.org/doi/full/10.1200/JCO.2008.20.4552 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698019/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19380443 PubMed]<br />
<br />
==IRIS {{#subobject:7f7223|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
IRIS: '''<u>IRI</u>'''notecan & '''<u>S</u>'''-1<br />
===Regimen {{#subobject:dd01b1|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.sciencedirect.com/science/article/pii/S1470204510701819 Muro et al. 2010 (FIRIS)]<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#FOLFIRI_3|FOLFIRI]]<br />
| style="background-color:#eeee01" |Non-inferior OS (*)<br />
|-<br />
|}<br />
''Note: reported efficacy is based on the 2014 update.''<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV once per day on days 1 & 15<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 14<br />
**BSA between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14<br />
**BSA at least 1.5 m<sup>2</sup>: 60 mg PO twice per day on days 1 to 14<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''FIRIS:''' Muro K, Boku N, Shimada Y, Tsuji A, Sameshima S, Baba H, Satoh T, Denda T, Ina K, Nishina T, Yamaguchi K, Takiuchi H, Esaki T, Tokunaga S, Kuwano H, Komatsu Y, Watanabe M, Hyodo I, Morita S, Sugihara K. Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study). Lancet Oncol. 2010 Sep;11(9):853-60. Epub 2010 Aug 12. [https://www.sciencedirect.com/science/article/pii/S1470204510701819 link to SD article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20708966 PubMed]<br />
##'''Update:''' Yasui H, Muro K, Shimada Y, Tsuji A, Sameshima S, Baba H, Satoh T, Denda T, Ina K, Nishina T, Yamaguchi K, Esaki T, Tokunaga S, Kuwano H, Boku N, Komatsu Y, Watanabe M, Hyodo I, Morita S, Sugihara K. A phase 3 non-inferiority study of 5-FU/l-leucovorin/irinotecan (FOLFIRI) versus irinotecan/S-1 (IRIS) as second-line chemotherapy for metastatic colorectal cancer: updated results of the FIRIS study. J Cancer Res Clin Oncol. 2015 Jan;141(1):153-60. Epub 2014 Aug 9. [https://link.springer.com/article/10.1007%2Fs00432-014-1783-3 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25106731 PubMed]<br />
<br />
==IROX {{#subobject:2c150d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
IROX: '''<u>IR</u>'''inotecan & '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:78e355|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/26/28/4544.long Haller et al. 2008]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Irinotecan_monotherapy_2|Irinotecan]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given second'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Haller DG, Rothenberg ML, Wong AO, Koralewski PM, Miller WH Jr, Bodoky G, Habboubi N, Garay C, Olivatto LO. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008 Oct 1;26(28):4544-50. [http://jco.ascopubs.org/content/26/28/4544.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18824706 PubMed]<br />
<br />
=Advanced or metastatic disease, third-line therapy=<br />
==CapeOx {{#subobject:fed770|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
===Example orders===<br />
<br />
*[[Example orders for CapeOx (XELOX) in colon cancer]]<br />
<br />
===Regimen {{#subobject:09dff5|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext Koopman et al. 2007 (CAIRO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#CAIRO|See link]]<br />
| style="background-color:#ffffbf" |[[Complex_multipart_regimens#CAIRO|See link]]<br />
|-<br />
|}<br />
====Preceding treatment====<br />
<br />
*[[#Irinotecan_monotherapy_2|Irinotecan]], with progression<br />
<br />
====Chemotherapy====<br />
<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles''' <br />
<br />
===References===<br />
<br />
#'''CAIRO:''' Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. [https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17630036 PubMed]<br />
<br />
==FOLFIRI {{#subobject:f7001b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
===Example orders===<br />
<br />
*[[Example orders for FOLFIRI in colon cancer]]<br />
<br />
===Regimen {{#subobject:31fcbe|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.ejcancer.com/article/S0959-8049(99)00150-1/fulltext André et al. 1999]<br />
| style="background-color:#91cf61" |Non-randomized<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
**In André et al. 1999, the continuous infusion dose could be increased from 1200 mg/m<sup>2</sup>/day to 1500 mg/m<sup>2</sup>/day if there were no toxicities higher than grade 1<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first, with leucovorin'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#André T, Louvet C, Maindrault-Goebel F, Couteau C, Mabro M, Lotz JP, Gilles-Amar V, Krulik M, Carola E, Izrael V, de Gramont A. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer; GERCOR. Eur J Cancer. 1999 Sep;35(9):1343-7. [https://www.ejcancer.com/article/S0959-8049(99)00150-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10658525 PubMed]<br />
<br />
==Regorafenib monotherapy {{#subobject:b6f523|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:7ab205|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30027-0/fulltext Eng et al. 2019 (IMblaze370)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Atezolizumab<br> 2. Atezolizumab & Cobimetinib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#'''IMblaze370:''' Eng C, Kim TW, Bendell J, Argilés G, Tebbutt NC, Di Bartolomeo M, Falcone A, Fakih M, Kozloff M, Segal NH, Sobrero A, Yan Y, Chang I, Uyei A, Roberts L, Ciardiello F; IMblaze370 Investigators. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2019 Jun;20(6):849-861. Epub 2019 Apr 16. Erratum in: Lancet Oncol. 2019 Jun;20(6):e293. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30027-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31003911 PubMed]<br />
<br />
=Advanced or metastatic disease, subsequent lines of therapy=<br />
''Note: these are trials that are for lines other than first-line; trials that specify an inclusion criteria restricted to second-line or third-line therapy are to be found in the sections above.''<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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2898%2902309-5/fulltext Cunningham et al. 1998 (V301)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Irinotecan_monotherapy_3|Irinotecan]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/13/1658.long Van Cutsem et al. 2007 (20020408)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Colon_cancer,_KRAS_wild-type#Panitumumab_monotherapy|Panitumumab]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa071834 Jonker et al. 2007 (NCIC CTG CO.17)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Colon_cancer,_KRAS_wild-type#Cetuximab_monotherapy_2|Cetuximab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''No treatment except for supportive care.''<br />
<br />
===References===<br />
<br />
#'''V301:''' Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1413-8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2898%2902309-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9807987 PubMed]<br />
<!-- Presented at the 97th Annual Meeting of the American Association for Cancer Research, April 1-5, 2006, Washington, DC; 2nd Annual Conference of the Hematology/Oncology Pharmacy Association, June 15-18, 2006, Orlando, FL; 8th Annual Conference of the World Congress on Gastrointestinal Cancer, June 28-July 1, 2006, Barcelona, Spain; and at the 31st European Society of Medical Oncology Congress, September 29-October 3, 2006, Istanbul, Turkey. --><br />
#'''20020408:''' Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1;25(13):1658-64. [http://jco.ascopubs.org/content/25/13/1658.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17470858 PubMed]<br />
<!-- # Bristol-Myers Squibb and ImClone. A Phase III Randomized Study of Cetuximab (Erbitux, C225) and Best Supportive Care Versus Best Supportive Care in Patients with Pretreated Metastatic Epidermal Growth Factor Receptor (EGFR)-Positive Colorectal Carcinoma. Final Clinical Study Report for CA225025. 2007 Mar 5. [http://ctr.bms.com/pdf//CA225025.pdf link to original report] '''contains verified protocol''' --><br />
#'''NCIC CTG CO.17:''' Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007 Nov 15;357(20):2040-8. [https://www.nejm.org/doi/full/10.1056/NEJMoa071834 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18003960 PubMed]<br />
##'''Subgroup analysis:''' Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008 Oct 23;359(17):1757-65. [https://www.nejm.org/doi/10.1056/NEJMoa0804385 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18946061 PubMed]<br />
##'''Subgroup analysis:''' Asmis TR, Powell E, Karapetis CS, Jonker DJ, Tu D, Jeffery M, Pavlakis N, Gibbs P, Zhu L, Dueck DA, Whittom R, Langer C, O'Callaghan CJ. Comorbidity, age and overall survival in cetuximab-treated patients with advanced colorectal cancer (ACRC)--results from NCIC CTG CO.17: a phase III trial of cetuximab versus best supportive care. Ann Oncol. 2011 Jan;22(1):118-26. Epub 2010 Jul 5. [http://annonc.oxfordjournals.org/content/22/1/118.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20603436 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:8bb0ed|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c0f84b|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2010.28.5643 Hendlisz et al. 2010]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & Radioembolization<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion over 14 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#Hendlisz A, Van den Eynde M, Peeters M, Maleux G, Lambert B, Vannoote J, De Keukeleire K, Verslype C, Defreyne L, Van Cutsem E, Delatte P, Delaunoit T, Personeni N, Paesmans M, Van Laethem JL, Flamen P. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol. 2010 Aug 10;28(23):3687-94. Epub 2010 Jun 21. [https://ascopubs.org/doi/full/10.1200/JCO.2010.28.5643 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20567019 PubMed]<br />
<br />
==FOLFOX4 {{#subobject:be6f3b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:ecdc32|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/JCO.2006.09.6305 Giantonio et al. 2007 (ECOG E3200)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Bevacizumab<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698019/ Kim et al. 2009 (N9841)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Irinotecan_monotherapy_2|Irinotecan]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2010.29.5436 Van Cutsem et al. 2011 (CONFIRM 2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FOLFOX4 & Vatalanib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: patients in N9841 had not previously received irinotecan or oxaliplatin; patients in CONFIRM 2 had not previously received oxaliplatin.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''ECOG E3200:''' Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd; Eastern Cooperative Oncology Group Study E3200. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007 Apr 20;25(12):1539-44. [https://ascopubs.org/doi/full/10.1200/JCO.2006.09.6305 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17442997 PubMed]<br />
#'''N9841:''' Kim GP, Sargent DJ, Mahoney MR, Rowland KM Jr, Philip PA, Mitchell E, Mathews AP, Fitch TR, Goldberg RM, Alberts SR, Pitot HC. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol. 2009 Jun 10;27(17):2848-54. Epub 2009 Apr 20. [https://ascopubs.org/doi/full/10.1200/JCO.2008.20.4552 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698019/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19380443 PubMed]<br />
#'''CONFIRM 2:''' Van Cutsem E, Bajetta E, Valle J, Köhne CH, Hecht JR, Moore M, Germond C, Berg W, Chen BL, Jalava T, Lebwohl D, Meinhardt G, Laurent D, Lin E. Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):2004-10. Epub 2011 Apr 4. [https://ascopubs.org/doi/full/10.1200/JCO.2010.29.5436 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21464401 PubMed]<br />
<br />
==FOLFOX4 (L-Leucovorin) {{#subobject:be17hb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX4: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:16c59a|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2010.29.5436 Van Cutsem et al. 2011 (CONFIRM 2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|FOLFOX4 & Vatalanib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''Note: these patients had not previously received oxaliplatin.''<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''CONFIRM 2:''' Van Cutsem E, Bajetta E, Valle J, Köhne CH, Hecht JR, Moore M, Germond C, Berg W, Chen BL, Jalava T, Lebwohl D, Meinhardt G, Laurent D, Lin E. Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):2004-10. Epub 2011 Apr 4. [https://ascopubs.org/doi/full/10.1200/JCO.2010.29.5436 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21464401 PubMed]<br />
<br />
==FOLFOX4 & Bevacizumab {{#subobject:8228ca|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX4 & Bevacizumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab<br />
===Regimen {{#subobject:2d2be1|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/JCO.2006.09.6305 Giantonio et al. 2007 (ECOG E3200)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|1. [[#FOLFOX4_5|FOLFOX4]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Bevacizumab<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
*[[Bevacizumab (Avastin)]] 10 mg/kg IV over 30 to 90 minutes once on day 1<br />
<br />
'''14-day cycles'''<br />
===References===<br />
<br />
#'''ECOG E3200:''' Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd; Eastern Cooperative Oncology Group Study E3200. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007 Apr 20;25(12):1539-44. [https://ascopubs.org/doi/full/10.1200/JCO.2006.09.6305 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17442997 PubMed]<br />
<br />
==FULV & Bevacizumab {{#subobject:83ygca|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FULV & Bevacizumab: 5-'''<u>FU</u>''', '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid), Bevacizumab<br />
===Regimen {{#subobject:2d7yqg|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.2005.05.1573 Chen et al. 2006 (TRC-301)]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Fluorouracil (5-FU)]]<br />
*[[Folinic acid (Leucovorin)]]<br />
*[[Bevacizumab (Avastin)]]<br />
<br />
===References===<br />
<br />
#'''TRC-301:''' Chen HX, Mooney M, Boron M, Vena D, Mosby K, Grochow L, Jaffe C, Rubinstein L, Zwiebel J, Kaplan RS. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. J Clin Oncol. 2006 Jul 20;24(21):3354-60. [https://ascopubs.org/doi/full/10.1200/JCO.2005.05.1573 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16849749 PubMed]<br />
<br />
==Irinotecan monotherapy {{#subobject:ea8bb0|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 Irinotecan (Camptosar) in colon cancer]]<br />
<br />
===Regimen {{#subobject:37d8df|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2898%2902309-5/fulltext Cunningham et al. 1998 (V301)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Best_supportive_care|Supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Irinotecan (Camptosar)]] 350 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
<br />
====Supportive medications====<br />
<br />
*(varied depending on reference):<br />
*"Standard regimens of [[:Category:Emesis_prevention|antiemetics]], [[Atropine (Atropen)]], and intensive [[Loperamide (Imodium)]]," but no prophylactic [[Atropine (Atropen)]] allowed on cycle 1 day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
<br />
#'''V301:''' Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1413-8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2898%2902309-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9807987 PubMed]<br />
<br />
==Nivolumab monotherapy {{#subobject:ac98g4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:91abt2|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/PMC6207072/ Overman et al. 2017 (CheckMate 142)]<br />
| style="background-color:#91cf61" |Phase II (RT)<br />
|-<br />
|}<br />
'''Biomarker eligibility criteria'''<br />
<br />
dMMR or MSI-H colorectal cancer.<br />
====Immunotherapy====<br />
<br />
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1<br />
*<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<br />
#'''CheckMate 142:''' Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, Desai J, Hill A, Axelson M, Moss RA, Goldberg MV, Cao ZA, Ledeine JM, Maglinte GA, Kopetz S, André T. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017 Sep;18(9):1182-1191. Epub 2017 Jul 19. Erratum in: Lancet Oncol. 2017 Sep;18(9):e510. [https://www.sciencedirect.com/science/article/pii/S1470204517304229 link to SD article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207072/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28734759 PubMed]<br />
<br />
==Pembrolizumab monotherapy {{#subobject:ac2c94|Regimen=1}}==<br />
{{#subobject:fe5344|Variant=1}}<br />
{{#subobject:B34AD4|Variant=1}}<br />
{{:Pembrolizumab (Keytruda) for unresectable or metastatic colon cancer}}<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" 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://ascopubs.org/doi/full/10.1200/JCO.2004.10.037 Rao et al. 2004]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Tipifarnib<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70345-5/fulltext Yoshino et al. 2012]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Trifluridine_and_tipiracil_monotherapy|Trifluridine and tipiracil]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961900-X/fulltext Grothey et al. 2013 (CORRECT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Regorafenib_monotherapy_2|Regorafenib]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70156-7/fulltext Li et al. 2015 (CONCUR)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Regorafenib_monotherapy_2|Regorafenib]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1414325 Mayer et al. 2015 (RECOURSE)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Trifluridine_and_tipiracil_monotherapy|Trifluridine and tipiracil]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30006-2/fulltext Hickish et al. 2017 (2014-PT026)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|MABp1<br />
| style="background-color:#d73027" |Inferior primary endpoint<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2017.74.3245 Xu et al. 2017 (TERRA)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Trifluridine_and_tipiracil_monotherapy|Trifluridine and tipiracil]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/langas/article/PIIS2468-1253(18)30009-8/fulltext Jonker et al. 2018 (NCIC CTG CO.23)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Napabucasin<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/2685988 Li et al. 2018 (FRESCO)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Fruquintinib<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158765/ Van Cutsem et al. 2018 (LUME-Colon 1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Nintedanib<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|}<br />
''No active antineoplastic treatment.''<br />
===References===<br />
<br />
#Rao S, Cunningham D, de Gramont A, Scheithauer W, Smakal M, Humblet Y, Kourteva G, Iveson T, Andre T, Dostalova J, Illes A, Belly R, Perez-Ruixo JJ, Park YC, Palmer PA. Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. J Clin Oncol. 2004 Oct 1;22(19):3950-7. [https://ascopubs.org/doi/full/10.1200/JCO.2004.10.037 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15459217 PubMed]<br />
#Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, Tsuji A, Yamaguchi K, Muro K, Sugimoto N, Tsuji Y, Moriwaki T, Esaki T, Hamada C, Tanase T, Ohtsu A. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2012 Oct;13(10):993-1001. Epub 2012 Aug 28. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70345-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22951287 PubMed]<br />
<!-- # '''Abstract:''' Axel Grothey, Alberto F. Sobrero, Salvatore Siena, Alfredo Falcone, Marc Ychou, Heinz-Josef Lenz, Takayuki Yoshino, Frank Cihon, Andrea Wagner, Eric Van Cutsem, on behalf of the CORRECT Study Team. Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. 2012 ASCO Gastrointestinal Cancers Symposium abstract LBA385 [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=115&abstractID=87795 link to abstract] '''contains verified protocol''' --><br />
#'''CORRECT:''' Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961900-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23177514 PubMed]<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/273 Project Data Sphere]<br />
#'''CONCUR:''' Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L, Yeh KH, Bi F, Cheng Y, Le AT, Lin JK, Liu T, Ma D, Kappeler C, Kalmus J, Kim TW; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):619-29. Epub 2015 May 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70156-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25981818 PubMed]<br />
#'''RECOURSE:''' Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14;372(20):1909-19. [https://www.nejm.org/doi/full/10.1056/NEJMoa1414325 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25970050 PubMed]<br />
##'''Subgroup analysis:''' Van Cutsem E, Mayer RJ, Laurent S, Winkler R, Grávalos C, Benavides M, Longo-Munoz F, Portales F, Ciardiello F, Siena S, Yamaguchi K, Muro K, Denda T, Tsuji Y, Makris L, Loehrer P, Lenz HJ, Ohtsu A; RECOURSE Study Group. The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer. Eur J Cancer. 2018 Feb;90:63-72. Epub 2017 Dec 21. [https://www.sciencedirect.com/science/article/pii/S0959804917313497 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/29274618 PubMed]<br />
#'''2014-PT026:''' Hickish T, Andre T, Wyrwicz L, Saunders M, Sarosiek T, Kocsis J, Nemecek R, Rogowski W, Lesniewski-Kmak K, Petruzelka L, Apte RN, Mohanty P, Stecher M, Simard J, de Gramont A. MABp1 as a novel antibody treatment for advanced colorectal cancer: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2017 Feb;18(2):192-201. Epub 2017 Jan 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30006-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28094194 PubMed]<br />
#'''TERRA:''' Xu J, Kim TW, Shen L, Sriuranpong V, Pan H, Xu R, Guo W, Han SW, Liu T, Park YS, Shi C, Bai Y, Bi F, Ahn JB, Qin S, Li Q, Wu C, Ma D, Lin D, Li J. Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: The TERRA study. J Clin Oncol. 2018 Feb 1;36(4):350-358. Epub 2017 Dec 7. [https://ascopubs.org/doi/full/10.1200/JCO.2017.74.3245 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29215955 PubMed]<br />
#'''NCIC CTC CO.23:''' Jonker DJ, Nott L, Yoshino T, Gill S, Shapiro J, Ohtsu A, Zalcberg J, Vickers MM, Wei AC, Gao Y, Tebbutt NC, Markman B, Price T, Esaki T, Koski S, Hitron M, Li W, Li Y, Magoski NM, Li CJ, Simes J, Tu D, O'Callaghan CJ. Napabucasin versus placebo in refractory advanced colorectal cancer: a randomised phase 3 trial. Lancet Gastroenterol Hepatol. 2018 Apr;3(4):263-270. Epub 2018 Feb 1. [https://www.thelancet.com/journals/langas/article/PIIS2468-1253(18)30009-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29397354 PubMed]<br />
#'''FRESCO:''' Li J, Qin S, Xu RH, Shen L, Xu J, Bai Y, Yang L, Deng Y, Chen ZD, Zhong H, Pan H, Guo W, Shu Y, Yuan Y, Zhou J, Xu N, Liu T, Ma D, Wu C, Cheng Y, Chen D, Li W, Sun S, Yu Z, Cao P, Chen H, Wang J, Wang S, Wang H, Fan S, Hua Y, Su W. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018 Jun 26;319(24):2486-2496. [https://jamanetwork.com/journals/jama/fullarticle/2685988 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29946728 PubMed]<br />
#'''LUME-Colon 1:''' Van Cutsem E, Yoshino T, Lenz HJ, Lonardi S, Falcone A, Limón ML, Saunders M, Sobrero A, Park YS, Ferreiro R, Hong YS, Tomasek J, Taniguchi H, Ciardiello F, Stoehr J, Oum'Hamed Z, Vlassak S, Studeny M, Argiles G. Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study. Ann Oncol. 2018 Sep 1;29(9):1955-1963. [https://academic.oup.com/annonc/article/29/9/1955/5053583 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158765/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30010751 PubMed]<br />
<br />
==Regorafenib monotherapy {{#subobject:b6f696|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, Standard Dosing {{#subobject:77bz17|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961900-X/fulltext Grothey et al. 2013 (CORRECT)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Placebo_2|Placebo]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70156-7/fulltext Li et al. 2015 (CONCUR)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Placebo_2|Placebo]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21<br />
**Taken with a low-fat (less than 30% fat) breakfast<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, Dose-escalation {{#subobject:55bz17|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#Comparative_efficacy|Comparative Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30272-4/fulltext Bekaii-Saab et al. 2019 (ReDOS)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Regorafenib_monotherapy_2|Regorafenib]]; standard dosing<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
| style="background-color:#1a9850" |Superior rate of patients proceeding to cycle 3<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
<br />
**[[Regorafenib (Stivarga)]] as follows:<br />
**Cycle 1: 80 mg PO once per day on days 1 to 7, then 120 mg PO once per day on days 8 to 15, then 160 mg PO once per day on days 16 to 21<br />
**Cycle 2 onwards: 160 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
<br />
*Patients received 0.05% [[Clobetasol]] cream twice daily applied to palms and soles starting cycle 1 day 1 or applied when when hand-foot skin reaction developed (no difference in adverse events was found between the two clobetasol strategy groups)<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Axel Grothey, Alberto F. Sobrero, Salvatore Siena, Alfredo Falcone, Marc Ychou, Heinz-Josef Lenz, Takayuki Yoshino, Frank Cihon, Andrea Wagner, Eric Van Cutsem, on behalf of the CORRECT Study Team. Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. 2012 ASCO Gastrointestinal Cancers Symposium abstract LBA385 [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=115&abstractID=87795 link to abstract] '''contains verified protocol''' --><br />
<br />
#'''CORRECT:''' Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961900-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23177514 PubMed]<br />
##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/273 Project Data Sphere]<br />
#'''CONCUR:''' Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L, Yeh KH, Bi F, Cheng Y, Le AT, Lin JK, Liu T, Ma D, Kappeler C, Kalmus J, Kim TW; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):619-29. Epub 2015 May 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70156-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25981818 PubMed]<br />
#'''ReDOS:''' Bekaii-Saab TS, Ou FS, Ahn DH, Boland PM, Ciombor KK, Heying EN, Dockter TJ, Jacobs NL, Pasche BC, Cleary JM, Meyers JP, Desnoyers RJ, McCune JS, Pedersen K, Barzi A, Chiorean EG, Sloan J, Lacouture ME, Lenz HJ, Grothey A. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019 Aug;20(8):1070-1082. Epub 2019 Jun 28. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30272-4/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25981818 PubMed]<br />
<br />
==Trifluridine and tipiracil monotherapy {{#subobject:pyr2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:pyv2|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#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70345-5/fulltext Yoshino et al. 2012]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#Placebo_2|Placebo]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1414325 Mayer et al. 2015 (RECOURSE)]<br />
| style="background-color:#1a9851" |Phase III (E-RT-esc)<br />
|[[#Placebo_2|Placebo]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.2017.74.3245 Xu et al. 2017 (TERRA)]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Placebo_2|Placebo]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
<br />
*[[Trifluridine and tipiracil (Lonsurf)]] 35 mg/m<sup>2</sup> PO twice per day, used within 1 hour after the morning and evening meals on days 1 to 5, 8 to 12<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
<br />
#Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, Tsuji A, Yamaguchi K, Muro K, Sugimoto N, Tsuji Y, Moriwaki T, Esaki T, Hamada C, Tanase T, Ohtsu A. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2012 Oct;13(10):993-1001. Epub 2012 Aug 28. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70345-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22951287 PubMed]<br />
#'''RECOURSE:''' Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14;372(20):1909-19. [https://www.nejm.org/doi/full/10.1056/NEJMoa1414325 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25970050 PubMed]<br />
##'''Subgroup analysis:''' Van Cutsem E, Mayer RJ, Laurent S, Winkler R, Grávalos C, Benavides M, Longo-Munoz F, Portales F, Ciardiello F, Siena S, Yamaguchi K, Muro K, Denda T, Tsuji Y, Makris L, Loehrer P, Lenz HJ, Ohtsu A; RECOURSE Study Group. The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer. Eur J Cancer. 2018 Feb;90:63-72. Epub 2017 Dec 21. [https://www.sciencedirect.com/science/article/pii/S0959804917313497 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/29274618 PubMed]<br />
#'''TERRA:''' Xu J, Kim TW, Shen L, Sriuranpong V, Pan H, Xu R, Guo W, Han SW, Liu T, Park YS, Shi C, Bai Y, Bi F, Ahn JB, Qin S, Li Q, Wu C, Ma D, Lin D, Li J. Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: The TERRA study. J Clin Oncol. 2018 Feb 1;36(4):350-358. Epub 2017 Dec 7. [https://ascopubs.org/doi/full/10.1200/JCO.2017.74.3245 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29215955 PubMed]<br />
<br />
[[Category:Colon cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Colorectal cancers]]</div>Dweeraratne