Difference between revisions of "Staging page"

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[[#top|Back to Top]]
 
[[#top|Back to Top]]
 
</div>
 
</div>
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{{#lst:Section editor transclusions|breast}}
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{{#lst:Section editor transclusions|giei}}
−
<big>'''Note: these are regimens tested in patients with hormone receptor-positive, HER2-positive breast cancer. Please see the [[breast cancer|main breast cancer page]], [[Breast cancer, ER-positive|ER+ breast cancer page]], and [[Breast cancer, HER2-positive|HER2+ breast cancer page]] for other regimens.'''</big>
+
''Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit [[Pancreatic NET - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''<br>
 +
<big>Note: for more general neuroendocrine regimens, please visit the '''[[neuroendocrine tumors]]''' page.</big>
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
|-
 
|-
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|}
 
|}
 
{{TOC limit|limit=3}}
 
{{TOC limit|limit=3}}
−
=Neoadjuvant chemotherapy=
+
=Guidelines=
−
==Trastuzumab emtansine monotherapy {{#subobject:ef98f0|Regimen=1}}==
+
==[http://www.esmo.org/ ESMO]==
−
T-DM1: '''<u>T</u>'''rastuzumab-'''<u>DM1</u>''' (Trastuzumab emtansine)
+
*'''2020:''' Pavel et al. [https://doi.org/10.1016/j.annonc.2020.03.304 Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
 +
===Older===
 +
*'''2012:''' Öberg et al. [https://www.esmo.org/Guidelines/Endocrine-and-Neuroendocrine-Cancers/Neuroendocrine-Gastroenteropancreatic-Tumours Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
 +
==NANETS==
 +
*'''2020:''' Halfdanarson et al. [https://doi.org/10.1097/mpa.0000000000001597 The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Pancreatic Neuroendocrine Tumors]
 +
*'''2020:''' Howe et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7029300/ The North American Neuroendocrine Tumor Society Consensus Paper on the Surgical Management of Pancreatic Neuroendocrine Tumors]
 +
==[https://www.nccn.org/ NCCN]==
 +
*[https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf NCCN Guidelines - Neuroendocrine Tumors]
 +
=All lines of therapy=
 +
==Capecitabine & Temozolomide {{#subobject:738284|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:91b517|Variant=1}}===
+
===Regimen {{#subobject:fc2dd9|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 50%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|rowspan=2|[https://doi.org/10.1200/JCO.2016.71.9815 Harbeck et al. 2017 (WGSG ADAPT)]
 
−
|rowspan=2|2012-2015
 
−
|rowspan=2 style="background-color:#1a9851"|Randomized Phase 2 (E-switch-ic)
 
−
|1. [[#T-DM1_.26_ET|T-DM1 & ET]]
 
−
|style="background-color:#d0d0d0"|Not reported
 
 
|-
 
|-
−
|2. [[#Trastuzumab_.26_ET|Trastuzumab & ET]]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665634/ Strosberg et al. 2011]
−
|style="background-color:#1a9850"|Superior pCR rate
+
| style="background-color:#ffffbe" |Retrospective
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Antibody-drug conjugate therapy====
+
====Chemotherapy====
−
*[[Trastuzumab emtansine (Kadcyla)]] 3.6 mg/kg IV once on day 1
+
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14
−
'''21-day cycle for 4 cycles'''
+
*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day at bedtime on days 10 to 14
−
</div>
+
====Supportive therapy====
−
<div class="toccolours" style="background-color:#cbd5e7">
+
*[[Ondansetron (Zofran)]] 8 mg (route not specified) once per day on days 1 to 14, prior to [[Temozolomide (Temodar)]]
−
====Subsequent treatment====
+
'''28-day cycles'''
−
*[[Surgery#Breast_cancer_surgery|Surgery]] was performed within 3 weeks of the end of therapy. Adjuvant therapy consisted of [[Breast_cancer#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]], then [[#Paclitaxel_.26_Trastuzumab_.28TH.29_2|TH (Paclitaxel)]], unless the patient had pCR in which case adjuvant therapy was optional
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''WGSG ADAPT:''' Harbeck N, Gluz O, Christgen M, Kates RE, Braun M, Küemmel S, Schumacher C, Potenberg J, Kraemer S, Kleine-Tebbe A, Augustin D, Aktas B, Forstbauer H, Tio J, von Schumann R, Liedtke C, Grischke EM, Schumacher J, Wuerstlein R, Kreipe HH, Nitz UA; West German Study Group. De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): Final analysis of the West German Study Group Adjuvant Dynamic marker-Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor-positive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab plus ET. J Clin Oncol. 2017 Sep 10;35(26):3046-3054. Epub 2017 Jul 6. [https://doi.org/10.1200/JCO.2016.71.9815 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28682681 PubMed] NCT01817452
+
# '''Retrospective:''' Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, Helm J, Kvols L. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011 Jan 15;117(2):268-75. Epub 2010 Sep 7. [https://doi.org/10.1002/cncr.25425 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665634/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20824724 PubMed]
−
==T-DM1 & ET {{#subobject:207386|Regimen=1}}==
+
==Doxorubicin & Streptozocin {{#subobject:5c625d|Regimen=1}}==
−
T-DM1 & ET: '''<u>T</u>'''rastuzumab-DM1 (Trastuzumab emtansine) & '''<u>E</u>'''ndocrine '''<u>T</u>'''herapy
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:b28ce1|Variant=1}}===
+
===Regimen {{#subobject:a9c7ed|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 55: Line 54:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|rowspan=2|[https://doi.org/10.1200/JCO.2016.71.9815 Harbeck et al. 2017 (WGSG ADAPT)]
+
| rowspan="2" |[https://doi.org/10.1056/NEJM199202203260804 Moertel et al. 1992]
−
|rowspan=2|2012-2015
+
|rowspan=2|1978-1985
−
|rowspan=2 style="background-color:#1a9851"|Randomized Phase 2 (E-esc)
+
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
−
|1. [[#Trastuzumab_emtansine_monotherapy|T-DM1]]
+
|1. [[#Chlorozotocin_monotherapy_88|Chlorozotocin]]
−
|style="background-color:#d0d0d0"|Not reported
+
| style="background-color:#1a9850" |Superior OS
 
|-
 
|-
−
|2. [[#Trastuzumab_.26_ET|Trastuzumab & ET]]
+
|2. [[#Fluorouracil_.26_Streptozocin|5-FU & Streptozocin]]
−
|style="background-color:#1a9850"|Superior pCR rate
+
| style="background-color:#1a9850" |Superior OS
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Antibody-drug conjugate therapy====
+
====Chemotherapy====
−
*[[Trastuzumab emtansine (Kadcyla)]] 3.6 mg/kg IV once on day 1
+
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 22
−
====Endocrine therapy====
+
*[[Streptozocin (Zanosar)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5
−
*One of the following:
+
'''42-day cycles'''
−
**Premenopausal women: [[Tamoxifen (Nolvadex)]] recommended
 
−
**[[:Category:GnRH_agonists|GnRH analogs]] were also allowed
 
−
**Postmenopausal women: [[:Category:Aromatase inhibitors|Aromatase inhibitor]] recommended
 
−
'''21-day cycle for 4 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Breast_cancer_surgery|Surgery]] was performed within 3 weeks of the end of therapy. Adjuvant therapy consisted of [[Breast_cancer#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]], then [[#Paclitaxel_.26_Trastuzumab_.28TH.29_2|TH (Paclitaxel)]], unless the patient had pCR in which case adjuvant therapy was optional
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''WGSG ADAPT:''' Harbeck N, Gluz O, Christgen M, Kates RE, Braun M, Küemmel S, Schumacher C, Potenberg J, Kraemer S, Kleine-Tebbe A, Augustin D, Aktas B, Forstbauer H, Tio J, von Schumann R, Liedtke C, Grischke EM, Schumacher J, Wuerstlein R, Kreipe HH, Nitz UA; West German Study Group. De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): Final analysis of the West German Study Group Adjuvant Dynamic marker-Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor-positive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab plus ET. J Clin Oncol. 2017 Sep 10;35(26):3046-3054. Epub 2017 Jul 6. [https://doi.org/10.1200/JCO.2016.71.9815 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28682681 PubMed] NCT01817452
+
# Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. [https://doi.org/10.1056/NEJM199202203260804 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1310159 PubMed]
−
==Trastuzumab & ET {{#subobject:b9d62c|Regimen=1}}==
+
==Everolimus monotherapy {{#subobject:78dff1|Regimen=1}}==
−
Trastuzumab & ET: Trastuzumab & '''<u>E</u>'''ndocrine '''<u>T</u>'''herapy
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:d0233|Variant=1}}===
+
===Regimen {{#subobject:5ea369|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 92: Line 82:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2016.71.9815 Harbeck et al. 2017 (WGSG ADAPT)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ Yao et al. 2010 (RADIANT-1)]
−
|2012-2015
+
|2006-2007
−
|style="background-color:#1a9851"|Randomized Phase 2 (C)
+
| style="background-color:#91cf61" |Phase 2
−
|1. [[#Trastuzumab_emtansine_monotherapy|T-DM1]]<br> 2. [[#T-DM1_.26_ET|T-DM1 & ET]]
+
| style="background-color:#d3d3d3" |
−
|style="background-color:#d73027"|Inferior pCR rate
+
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208619/ Yao et al. 2011 (RADIANT-3)]
 +
|2007-2009
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[Pancreatic_NET_-_null_regimens#Placebo|Placebo]]
 +
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: 11 vs 4.6 mo<br>(HR 0.35, 95% CI 0.27-0.45)
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Trastuzumab (Herceptin)]] as follows:
+
*[[Everolimus (Afinitor)]] 10 mg PO once per day
−
**Cycle 1: 8 mg/kg IV once on day 1
+
'''Continued indefinitely'''
−
**Cycles 2 to 4: 6 mg/kg IV once on day 1
 
−
====Endocrine therapy====
 
−
*Endocrine therapy by the following criteria:
 
−
**Premenopausal women: [[Tamoxifen (Nolvadex)]] recommended
 
−
***[[:Category:GnRH_agonists|GnRH analogs]] were also allowed
 
−
**Postmenopausal women: [[:Category:Aromatase inhibitors|Aromatase inhibitor]] recommended
 
−
'''21-day cycle for 4 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Breast_cancer_surgery|Surgery]] was performed within 3 weeks of the end of therapy. Adjuvant therapy consisted of [[Breast_cancer#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]], then [[#Paclitaxel_.26_Trastuzumab_.28TH.29_2|TH (Paclitaxel)]], unless the patient had pCR in which case adjuvant therapy was optional
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''WGSG ADAPT:''' Harbeck N, Gluz O, Christgen M, Kates RE, Braun M, Küemmel S, Schumacher C, Potenberg J, Kraemer S, Kleine-Tebbe A, Augustin D, Aktas B, Forstbauer H, Tio J, von Schumann R, Liedtke C, Grischke EM, Schumacher J, Wuerstlein R, Kreipe HH, Nitz UA; West German Study Group. De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): Final analysis of the West German Study Group Adjuvant Dynamic marker-Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor-positive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab plus ET. J Clin Oncol. 2017 Sep 10;35(26):3046-3054. Epub 2017 Jul 6. [https://doi.org/10.1200/JCO.2016.71.9815 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28682681 PubMed] NCT01817452
+
# '''RADIANT-1:''' Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. Epub 2009 Nov 23. [https://doi.org/10.1200/jco.2009.24.2669 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19933912 PubMed] NCT00363051
−
=Adjuvant therapy=
+
# '''RADIANT-3:''' Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Öberg K; RAD001 in Advanced Neuroendocrine Tumors Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. [https://doi.org/10.1056/NEJMoa1009290 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208619/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21306238 PubMed] NCT00510068
−
==Anastrozole monotherapy {{#subobject:79h35|Regimen=1}}==
+
## '''Update:''' Yao JC, Pavel M, Lombard-Bohas C, Van Cutsem E, Voi M, Brandt U, He W, Chen D, Capdevila J, de Vries EGE, Tomassetti P, Hobday T, Pommier R, Öberg K. Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: overall survival and circulating biomarkers from the randomized, phase III RADIANT-3 study. J Clin Oncol. 2016 Nov 10;34(32):3906-3913. Epub 2016 Sep 30. [https://doi.org/10.1200/JCO.2016.68.0702 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791842/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27621394 PubMed]
 +
# '''Review:''' Yao JC, Phan AT, Jehl V, Shah G, Meric-Bernstam F. Everolimus in advanced pancreatic neuroendocrine tumors: the clinical experience. Cancer Res. 2013 Mar 1;73(5):1449-53. Epub 2013 Feb 22. [http://cancerres.aacrjournals.org/content/73/5/1449.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/23436795 PubMed]
 +
#'''COMPETE:''' NCT03049189
 +
#'''COMPOSE:''' NCT04919226
 +
==Everolimus & Octreotide {{#subobject:d6b3eb|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:gav33c|Variant=1}}===
+
===Regimen variant #1 {{#subobject:b0f62f|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
!style="width: 20%"|Study
+
!style="width: 33%"|Study
−
!style="width: 20%"|Years of enrollment
+
!style="width: 33%"|Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|Awaiting publication (eMonarcHER)
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008]
−
|2021-ongoing
+
|2005-2006
−
|style="background-color:#1a9851"|Phase 3 (C)
+
| style="background-color:#91cf61" |Phase 2
−
|[[#ET_.26_Abemaciclib_88|ET & Abemaciclib]]
 
−
| style="background-color:#d3d3d3" |In progress
 
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[Regimen_classes#Anti-HER2-based_regimen|HER2-targeted therapy]]
 
−
</div>
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Everolimus (Afinitor)]] 5 mg PO once per day
 
====Endocrine therapy====
 
====Endocrine therapy====
−
*[[Anastrozole (Arimidex)]] 1 mg PO once per day
+
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1
−
'''Continued for up to 10 years'''
+
'''28-day cycles'''
−
</div></div>
+
</div></div><br>
−
===References===
 
−
#'''eMonarcHER:''' NCT04752332
 
−
=Metastatic disease, first-line therapy=
 
−
==Anastrozole monotherapy {{#subobject:796bb|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:bd033c|Variant=1}}===
+
===Regimen variant #2 {{#subobject:f82bb5|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
!style="width: 20%"|Study
+
!style="width: 33%"|Study
−
!style="width: 20%"|Years of enrollment
+
!style="width: 33%"|Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
+
|-
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008]
 +
|2005-2006
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2008.20.6847 Kaufman et al. 2009 (TAnDEM)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ Yao et al. 2010 (RADIANT-1)]
−
|2001-2004
+
|2006-2007
−
|style="background-color:#1a9851"|Phase 3 (C)
+
| style="background-color:#91cf61" |Phase 2
−
|[[#Anastrozole_.26_Trastuzumab|Anastrozole & Trastuzumab]]
 
−
| style="background-color:#d73027" |Inferior PFS
 
 
|-
 
|-
 
|}
 
|}
 +
''Note: In Yao et al. 2008, everolimus "dose of 10 mg was associated with superior PFS...however, the study was not prospectively powered for these comparisons. These analyses should be considered exploratory." Patients in RADIANT-1 who received this regimen had already been receiving octreotide LAR for at least 3 months before participating in the study; they were continued on their prestudy dose up to 30 mg.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Everolimus (Afinitor)]] 10 mg PO once per day
 
====Endocrine therapy====
 
====Endocrine therapy====
−
*[[Anastrozole (Arimidex)]] 1 mg PO once per day
+
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1
 
'''28-day cycles'''
 
'''28-day cycles'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''TAnDEM:''' Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A, Révil C, Jones A. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009 Nov 20;27(33):5529-37. Epub 2009 Sep 28. [https://doi.org/10.1200/JCO.2008.20.6847 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19786670 PubMed] NCT00022672
+
# Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008 Sep 10;26(26):4311-8. [https://doi.org/10.1200/jco.2008.16.7858 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18779618 PubMed]
−
==Anastrozole & Trastuzumab {{#subobject:8077ad|Regimen=1}}==
+
# '''RADIANT-1:''' Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. Epub 2009 Nov 23. [https://doi.org/10.1200/jco.2009.24.2669 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19933912 PubMed] NCT00363051
 +
==FAS {{#subobject:66b05e|Regimen=1}}==
 +
FAS: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>S</u>'''treptozocin
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, weekly trastuzumab {{#subobject:e6f8f0|Variant=1}}===
+
===Regimen {{#subobject:de76a2|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 50%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2008.20.6847 Kaufman et al. 2009 (TAnDEM)]
+
|[https://doi.org/10.1200/jco.2004.04.024 Kouvaraki et al. 2004]
−
|2001-2004
+
| style="background-color:#ffffbe" |Retrospective
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
 
−
|[[#Anastrozole_monotherapy_2|Anastrozole]]
 
−
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: 4.8 vs 2.4 mo<br>(HR 0.63, 95% CI 0.47-0.84)
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Endocrine therapy====
+
====Chemotherapy====
−
*[[Anastrozole (Arimidex)]] 1 mg PO once per day
+
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
−
====Targeted therapy====
+
*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV bolus once on day 1
−
*[[Trastuzumab (Herceptin)]] as follows:
+
*[[Streptozocin (Zanosar)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
−
**Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
 
−
**Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22
 
 
'''28-day cycles'''
 
'''28-day cycles'''
−
</div></div><br>
+
</div></div>
 +
===References===
 +
# '''Retrospective:''' Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, Yao JC. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004 Dec 1;22(23):4762-71. [https://doi.org/10.1200/jco.2004.04.024 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15570077 PubMed]
 +
==Fluorouracil & Streptozocin {{#subobject:6f7b84|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, q3wk trastuzumab {{#subobject:ugibx4|Variant=1}}===
+
===Regimen {{#subobject:e45011|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 206: Line 185:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|rowspan=2|[https://doi.org/10.1200/jco.20.01894 Johnston et al. 2020 (ALTERNATIVE)]
+
|[https://doi.org/10.1056/NEJM198011203032101 Moertel et al. 1980]
−
|rowspan=2|2011-2016
+
|1972-1978
−
|rowspan=2 style="background-color:#1a9851"|Phase 3 (C)
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
|1. [[#Anastrozole_.26_Lapatinib_99|Anastrozole & Lapatinib]]<br> 2. [[#Exemestane_.26_Lapatinib_99|Exemestane & Lapatinib]]<br> 3. [[#Lapatinib_.26_Letrozole|Lapatinib & Letrozole]]
+
|[[#Fluorouracil_monotherapy_88|Fluorouracil]]
−
| style="background-color:#ffffbf" |Did not meet secondary endpoint of PFS
+
| style="background-color:#d9ef8b" |Might have superior OS
 
|-
 
|-
−
|4. [[#Anastrozole.2C_Lapatinib.2C_Trastuzumab|Anastrozole, Lapatinib, Trastuzumab]]<br> 5. [[#Exemestane.2C_Lapatinib.2C_Trastuzumab|Exemestane, Lapatinib, Trastuzumab]]<br> 6. [[#Lapatinib.2C_Letrozole.2C_Trastuzumab|Lapatinib, Letrozole, Trastuzumab]]
+
| rowspan="2" |[https://doi.org/10.1056/NEJM199202203260804 Moertel et al. 1992]
−
| style="background-color:#d73027" |Inferior PFS
+
|rowspan=2|1978-1985
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Chlorozotocin_monotherapy_88|Chlorozotocin]]
 +
| style="background-color:#ffffbf" |Did not meet endpoint of OS
 
|-
 
|-
−
|[https://doi.org/10.1158/1078-0432.ccr-21-3435 Hua et al. 2022 (SYSUCC-002)]
+
|2. [[#Doxorubicin_.26_Streptozocin|Doxorubicin & Streptozocin]]
−
|2013-2019
+
| style="background-color:#d73027" |Inferior OS
−
|style="background-color:#1a9851"|Phase 3 (E-switch-ooc)
 
−
|1. [[#Paclitaxel_.26_Trastuzumab_.28TH.29_88|TH (Paclitaxel)]]<br>2. [[#Docetaxel_.26_Trastuzumab_.28TH.29|TH (Docetaxel)]]<br>3. [[#Vinorelbine_.26_Trastuzumab_.28VH.29_88|VH]]; IV<br>4. [[#Vinorelbine_.26_Trastuzumab_.28VH.29_88|VH]]; PO<br>5. [[#Capecitabine_.26_Trastuzumab_.28XH.29|XH]]
 
−
| style="background-color:#eeee01" |Non-Inferior PFS<br>Median PFS: 19.2 vs 14.8 mo<br>(HR 0.88, 95% CI 0.71-1.09)
 
 
|-
 
|-
 
|}
 
|}
−
''Note: the original ALTERNATIVE article published in 2018 was retracted due to numeric errors in the analysis, and an update has been published. Hua et al. 2022 does not contain dosing instructions for anastrozole.''
+
''Note: treatment details are from Moertel et al. 1992.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Chemotherapy====
−
*[[Trastuzumab (Herceptin)]] as follows:
+
*[[Streptozocin (Zanosar)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5
−
**Cycle 1: 8 mg/kg IV once on day 1
+
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
−
**Cycle 2 onwards: 6 mg/kg IV once on day 1
+
'''42-day cycles'''
−
====Endocrine therapy====
 
−
*[[Anastrozole (Arimidex)]] 1 mg PO once per day
 
−
'''21-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''TAnDEM:''' Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A, Révil C, Jones A. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009 Nov 20;27(33):5529-37. Epub 2009 Sep 28. [https://doi.org/10.1200/JCO.2008.20.6847 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19786670 PubMed] NCT00022672
+
# Moertel CG, Hanley JA, Johnson LA. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1980 Nov 20;303(21):1189-94. [https://doi.org/10.1056/NEJM198011203032101 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6252466 PubMed]
−
<!--- # '''RETRACTED:''' Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: ALTERNATIVE. J Clin Oncol. 2018 Mar 10;36(8):741-748. Epub 2017 Dec 15. [https://doi.org/10.1200/JCO.2017.74.7824 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29244528 PubMed] -->
+
# Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. [https://doi.org/10.1056/NEJM199202203260804 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1310159 PubMed]
−
# '''ALTERNATIVE:''' Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. J Clin Oncol. 2021 Jan 1;39(1):79-89. Epub 2020 Aug 21. [https://doi.org/10.1200/jco.20.01894 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32822287 PubMed] NCT01160211
+
==Lanreotide Depot/Autogel monotherapy {{#subobject:8bca3a|Regimen=1}}==
−
# '''SYSUCC-002:''' Hua X, Bi XW, Zhao JL, Shi YX, Lin Y, Wu ZY, Zhang YQ, Zhang LH, Zhang AQ, Huang H, Liu XM, Xu F, Guo Y, Xia W, Hong RX, Jiang KK, Xue C, An X, Zhong YY, Wang SS, Huang JJ, Yuan ZY. Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002). Clin Cancer Res. 2022 Feb 15;28(4):637-645. [https://doi.org/10.1158/1078-0432.ccr-21-3435 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/34810217/ PubMed] NCT01950182
 
−
==Anastrozole, Lapatinib, Trastuzumab {{#subobject:gg0dbc|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:ug8a84|Variant=1}}===
+
===Regimen {{#subobject:a9ee08|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 247: Line 221:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|rowspan=2|[https://doi.org/10.1200/jco.20.01894 Johnston et al. 2020 (ALTERNATIVE)]
+
|[https://doi.org/10.1056/NEJMoa1316158 Caplin et al. 2014 (CLARINET)]
−
|rowspan=2|2011-2016
+
|2006-2013
−
|rowspan=2 style="background-color:#1a9851"|Phase 3 (E-esc)
+
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
−
|1. [[#Anastrozole_.26_Lapatinib_99|Anastrozole & Lapatinib]]<br> 2. [[#Exemestane_.26_Lapatinib_99|Exemestane & Lapatinib]]<br>3. [[#Lapatinib_.26_Letrozole|Lapatinib & Letrozole]]
+
|[[Pancreatic_NET_-_null_regimens#Placebo|Placebo]]
−
| style="background-color:#d3d3d3" |Not reported
+
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: NYR vs 18 mo<br>(HR 0.47, 95% CI 0.30-0.73)
 
|-
 
|-
−
|4. [[#Anastrozole_.26_Trastuzumab|Anastrozole & Trastuzumab]]<br> 5. [[#Exemestane_.26.Trastuzumab|Exemestane & Trastuzumab]]<br> 6. [[#Letrozole_.26_Trastuzumab|Letrozole & Trastuzumab]]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740728/ Caplin et al. 2016 (CLARINET OLE)]
−
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: 11 vs 5.6 mo<br>(HR 0.62, 95% CI 0.45-0.88)
+
|2009-NR
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 
|-
 
|-
 
|}
 
|}
−
''Note: the original article published in 2018 was retracted due to numeric errors in the analysis, and an update has been published.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
 
−
*[[Lapatinib (Tykerb)]] 1000 mg PO once per day
 
−
*[[Trastuzumab (Herceptin)]] as follows:
 
−
**Cycle 1: 8 mg/kg IV once on day 1
 
−
**Cycle 2 onwards: 6 mg/kg IV once on day 1
 
 
====Endocrine therapy====
 
====Endocrine therapy====
−
*[[Anastrozole (Arimidex)]] 1 mg PO once per day
+
*[[Lanreotide (Somatuline) | Lanreotide (Somatuline) Depot/Autogel]] 120 mg SC once on day 1
−
'''21-day cycles'''
+
'''28-day cycle for 96 weeks (CLARINET) or up to 8 years (CLARINET OLE)'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
<!--- # '''RETRACTED:''' Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: ALTERNATIVE. J Clin Oncol. 2018 Mar 10;36(8):741-748. Epub 2017 Dec 15. [https://doi.org/10.1200/JCO.2017.74.7824 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29244528 PubMed] -->
+
# '''CLARINET:''' Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33. [https://doi.org/10.1056/NEJMoa1316158 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25014687 PubMed] NCT00353496
−
# '''ALTERNATIVE:''' Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. J Clin Oncol. 2021 Jan 1;39(1):79-89. Epub 2020 Aug 21. [https://doi.org/10.1200/jco.20.01894 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32822287 PubMed] NCT01160211
+
# '''CLARINET OLE:''' Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Gomez-Panzani E, Ruszniewski P; CLARINET Investigators. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. Endocr Relat Cancer. 2016 Mar;23(3):191-9. Epub 2016 Jan 7. [https://doi.org/10.1530/erc-15-0490 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740728/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26743120 PubMed] NCT00842348
−
==Exemestane & Trastuzumab {{#subobject:ugjxbc|Regimen=1}}==
+
==Lanreotide & Interferon alfa-2b {{#subobject:9c5a59|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:1yga84|Variant=1}}===
+
===Regimen {{#subobject:652f4d|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 50%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|rowspan=2|[https://doi.org/10.1200/jco.20.01894 Johnston et al. 2020 (ALTERNATIVE)]
+
|[http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 Fjällskog et al. 2002]
−
|rowspan=2|2011-2016
+
| style="background-color:#ffffbe" |Pilot, <20 pts
−
|rowspan=2 style="background-color:#1a9851"|Phase 3 (C)
 
−
|1. [[#Anastrozole_.26_Lapatinib_99|Anastrozole & Lapatinib]]<br> 2. [[#Exemestane_.26_Lapatinib_99|Exemestane & Lapatinib]]<br>3. [[#Lapatinib_.26_Letrozole|Lapatinib & Letrozole]]
 
−
| style="background-color:#ffffbf" |Did not meet secondary endpoint of PFS
 
 
|-
 
|-
−
|4. [[#Anastrozole.2C_Lapatinib.2C_Trastuzumab|Anastrozole, Lapatinib, Trastuzumab]]<br> 5. [[#Exemestane.2C_Lapatinib.2C_Trastuzumab|Exemestane, Lapatinib, Trastuzumab]]<br> 6. [[#Lapatinib.2C_Letrozole.2C_Trastuzumab|Lapatinib, Letrozole, Trastuzumab]]
+
|}
−
| style="background-color:#d73027" |Inferior PFS
+
''Fjällskog et al. 2002 contained case reports of several patients treated with lanreotide & interferon alfa. Each patient received individualized therapy rather than a standard regimen.''
 +
====Endocrine therapy====
 +
*[[Lanreotide (Somatuline)]] 3 mg SC twice per day
 +
====Immunotherapy====
 +
*[[Interferon alfa-2b (Intron-A)]] 3,000,000 to 5,000,000 units SC once per day, 3 to 7 days per week (total of 9,000,000 to 25,000,000 units per week)
 +
</div></div>
 +
===References===
 +
# Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. [http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12025889 PubMed]
 +
==Octreotide monotherapy {{#subobject:665a8b|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:cd8cf6|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 50%" |Study
 +
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1158/1078-0432.ccr-21-3435 Hua et al. 2022 (SYSUCC-002)]
+
|[https://doi.org/10.1093/annonc/mdh216 Oberg et al. 2004]
−
|2013-2019
+
| style="background-color:#ffffbe" |Consensus guideline
−
|style="background-color:#1a9851"|Phase 3 (E-switch-ooc)
 
−
|1. [[#Paclitaxel_.26_Trastuzumab_.28TH.29_88|TH (Paclitaxel)]]<br>2. [[#Docetaxel_.26_Trastuzumab_.28TH.29|TH (Docetaxel)]]<br>3. [[#Vinorelbine_.26_Trastuzumab_.28VH.29_88|VH]]; IV<br>4. [[#Vinorelbine_.26_Trastuzumab_.28VH.29_88|VH]]; PO<br>5. [[#Capecitabine_.26_Trastuzumab_.28XH.29|XH]]
 
−
| style="background-color:#eeee01" |Non-Inferior PFS<br>Median PFS: 19.2 vs 14.8 mo<br>(HR 0.88, 95% CI 0.71-1.09)
 
 
|-
 
|-
 
|}
 
|}
−
''Note: the original ALTERNATIVE article published in 2018 was retracted due to numeric errors in the analysis, and an update has been published. Hua et al. 2022 does not contain dosing instructions for exemestane.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
 
−
*[[Trastuzumab (Herceptin)]] as follows:
 
−
**Cycle 1: 8 mg/kg IV once on day 1
 
−
**Cycle 2 onwards: 6 mg/kg IV once on day 1
 
 
====Endocrine therapy====
 
====Endocrine therapy====
−
*[[Exemestane (Aromasin)]] 1 mg PO once per day
+
*[[Octreotide (Sandostatin)]] 0.1 to 0.5 mg SC given two to four times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms
−
'''21-day cycles'''
+
**"A reasonable starting dose is" 0.15 mg SC three times per day
 +
'''Continued indefinitely'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
<!--- # '''RETRACTED:''' Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: ALTERNATIVE. J Clin Oncol. 2018 Mar 10;36(8):741-748. Epub 2017 Dec 15. [https://doi.org/10.1200/JCO.2017.74.7824 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29244528 PubMed] -->
+
# '''Review:''' Brentjens R, Saltz L. Islet cell tumors of the pancreas: the medical oncologist's perspective. Surg Clin North Am. 2001 Jun;81(3):527-42. [https://doi.org/10.1016/s0039-6109(05)70141-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11459269 PubMed]
−
# '''ALTERNATIVE:''' Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. J Clin Oncol. 2021 Jan 1;39(1):79-89. Epub 2020 Aug 21. [https://doi.org/10.1200/jco.20.01894 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32822287 PubMed] NCT01160211
+
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [https://doi.org/10.1093/annonc/mdh216 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15151956 PubMed]
−
# '''SYSUCC-002:''' Hua X, Bi XW, Zhao JL, Shi YX, Lin Y, Wu ZY, Zhang YQ, Zhang LH, Zhang AQ, Huang H, Liu XM, Xu F, Guo Y, Xia W, Hong RX, Jiang KK, Xue C, An X, Zhong YY, Wang SS, Huang JJ, Yuan ZY. Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002). Clin Cancer Res. 2022 Feb 15;28(4):637-645. [https://doi.org/10.1158/1078-0432.ccr-21-3435 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/34810217/ PubMed] NCT01950182
+
==Octreotide LAR monotherapy {{#subobject:e356ea|Regimen=1}}==
−
==Exemestane, Lapatinib, Trastuzumab {{#subobject:hh0dbc|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:258gja|Variant=1}}===
+
===Regimen {{#subobject:f0bc1b|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 321: Line 291:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|rowspan=2|[https://doi.org/10.1200/jco.20.01894 Johnston et al. 2020 (ALTERNATIVE)]
+
|[https://doi.org/10.1200/jco.2009.22.8510 Rinke et al. 2009 (PROMID)]
−
|rowspan=2|2011-2016
+
|2001-2008
−
|rowspan=2 style="background-color:#1a9851"|Phase 3 (E-esc)
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
|1. [[#Anastrozole_.26_Lapatinib_99|Anastrozole & Lapatinib]]<br> 2. [[#Exemestane_.26_Lapatinib_99|Exemestane & Lapatinib]]<br>3. [[#Lapatinib_.26_Letrozole|Lapatinib & Letrozole]]
+
|[[Pancreatic_NET_-_null_regimens#Placebo|Placebo]]
−
| style="background-color:#d3d3d3" |Not reported
+
| style="background-color:#1a9850" |Superior TTP<br>Median TTP: 14.3 vs 6 mo<br>(HR 0.34, 95% CI 0.20-0.59)
−
|-
 
−
|4. [[#Anastrozole_.26_Trastuzumab|Anastrozole & Trastuzumab]]<br> 5. [[#Exemestane_.26.Trastuzumab|Exemestane & Trastuzumab]]<br> 6. [[#Letrozole_.26_Trastuzumab|Letrozole & Trastuzumab]]
 
−
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: 11 vs 5.6 mo<br>(HR 0.62, 95% CI 0.45-0.88)
 
 
|-
 
|-
 
|}
 
|}
−
''Note: the original article published in 2018 was retracted due to numeric errors in the analysis, and an update has been published.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
 
−
*[[Lapatinib (Tykerb)]] 1000 mg PO once per day
 
−
*[[Trastuzumab (Herceptin)]] as follows:
 
−
**Cycle 1: 8 mg/kg IV once on day 1
 
−
**Cycle 2 onwards: 6 mg/kg IV once on day 1
 
 
====Endocrine therapy====
 
====Endocrine therapy====
−
*[[Exemestane (Aromasin)]] 25 mg PO once per day
+
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1, with potentially higher doses if needed for symptom control
−
'''21-day cycles'''
+
'''28-day cycles'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
<!--- # '''RETRACTED:''' Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: ALTERNATIVE. J Clin Oncol. 2018 Mar 10;36(8):741-748. Epub 2017 Dec 15. [https://doi.org/10.1200/JCO.2017.74.7824 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29244528 PubMed] -->
+
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [https://doi.org/10.1093/annonc/mdh216 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15151956 PubMed]
−
# '''ALTERNATIVE:''' Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. J Clin Oncol. 2021 Jan 1;39(1):79-89. Epub 2020 Aug 21. [https://doi.org/10.1200/jco.20.01894 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32822287 PubMed] NCT01160211
+
# '''PROMID:''' Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. [https://doi.org/10.1200/jco.2009.22.8510 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19704057 PubMed] NCT00171873
−
==Lapatinib & Letrozole {{#subobject:5fba83|Regimen=1}}==
+
# '''NETTER-1:''' Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. [https://doi.org/10.1056/NEJMoa1607427 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28076709 PubMed] NCT01578239
 +
## '''Update:''' Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. [https://doi.org/10.1016/s1470-2045(21)00572-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34793718/ PubMed]
 +
#'''NETTER-2:''' NCT03972488
 +
==Octreotide & Interferon alfa {{#subobject:1cf4c5|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:879969|Variant=1}}===
+
===Regimen {{#subobject:cbf5c4|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 50%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2009.23.3734 Johnston et al. 2009 (EGF30008)]
+
|[http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 Fjällskog et al. 2002]
−
|2003-2006
+
| style="background-color:#ffffbe" |Pilot, <20 pts
−
|style="background-color:#1a9851"|Phase 3 (E-RT-esc)
 
−
|[[#Letrozole_monotherapy_3|Letrozole]]
 
−
| style="background-color:#91cf60" |Seems to have superior PFS<br>Median PFS: 8.2 vs 3 mo<br>(HR 0.71, 95% CI 0.53-0.96)
 
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
''Fjällskog et al. 2002 contained case reports of several patients treated with octreotide & interferon alfa. Each patient received individualized therapy rather than a standard regimen.''
−
====Targeted therapy====
 
−
*[[Lapatinib (Tykerb)]] 1500 mg PO once per day
 
 
====Endocrine therapy====
 
====Endocrine therapy====
−
*[[Letrozole (Femara)]] 2.5 mg PO once per day
+
*[[Octreotide (Sandostatin)]] 0.05 to 0.5 mg SC given two to three times per day
−
'''Continued indefinitely'''
+
====Immunotherapy====
 +
*[[Interferon alfa-2b (Intron-A)]] 3,000,000 to 5,000,000 units SC once per day, 3 to 7 days per week (total of 9,000,000 to 25,000,000 units per week)
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''EGF30008:''' Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009 Nov 20;27(33):5538-46. Epub 2009 Sep 28. [https://doi.org/10.1200/JCO.2009.23.3734 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19786658 PubMed] NCT00073528
+
# Janson ET, Oberg K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. [https://doi.org/10.3109/02841869309083916 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7686765 PubMed]
−
==Lapatinib, Letrozole, Trastuzumab {{#subobject:ee0dbc|Regimen=1}}==
+
# Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. [http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12025889 PubMed]
 +
==Lutetium Lu 177 dotatate & Octreotide LAR {{#subobject:ee13c4|Regimen=1}} ==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:251384|Variant=1}}===
+
===Regimen {{#subobject:33d0ef|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
!style="width: 17%"|Study
−
!style="width: 20%"|Years of enrollment
+
!style="width: 15%"|Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
+
!style="width: 17%"|Comparator
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ Strosberg et al. 2017 (NETTER-1)]
 +
|2012-2016
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 +
| [[#Octreotide_LAR_monotherapy|Octreotide LAR]]; high-dose
 +
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: NYR vs 8.4 mo<br>(HR 0.21, 95% CI 0.13-0.33)
 +
| style="background-color:#d73027" |More cytopenias (neutropenia, thrombocytopenia and lymphopenia)
 
|-
 
|-
−
|rowspan=2|[https://doi.org/10.1200/jco.20.01894 Johnston et al. 2020 (ALTERNATIVE)]
+
|}
−
|rowspan=2|2011-2016
+
''Note: patients had well-differentiated (Ki67 less than 20%) midgut neuroendocrine tumors with somatostatin receptors present in all target lesions''
−
|rowspan=2 style="background-color:#1a9851"|Phase 3 (E-esc)
+
<div class="toccolours" style="background-color:#b3e2cd">
−
|1. [[#Anastrozole_.26_Lapatinib_99|Anastrozole & Lapatinib]]<br> 2. [[#Exemestane_.26_Lapatinib_99|Exemestane & Lapatinib]]<br>3. [[#Lapatinib_.26_Letrozole|Lapatinib & Letrozole]]
+
====Endocrine therapy====
−
| style="background-color:#d3d3d3" |Not reported
+
* [[Octreotide LAR (Sandostatin LAR)]] 30 mg SC once on day 1, '''given 2 hours after each lutetium Lu 177 dotatate infusion'''
 +
'''4-week cycles'''
 +
====Radioconjugate therapy====
 +
* [[Lutetium Lu 177 dotatate (Lutathera)]] 7.4 GBq (200 mCi) IV once on day 1
 +
====Supportive therapy====
 +
* For renal protection, an IV amino acid solution was administered concomitantly for at least 4 hours, starting 30 minutes prior to drug infusion.
 +
'''8-week cycle for 4 cycles'''
 +
=== References ===
 +
# '''NETTER-1:''' Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. [https://doi.org/10.1056/NEJMoa1607427 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28076709 PubMed] NCT01578239
 +
## '''Update:''' Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. [https://doi.org/10.1016/s1470-2045(21)00572-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34793718/ PubMed]
 +
==Sunitinib monotherapy {{#subobject:ee13d2|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:80d0ef|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Years of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
|-
 
|-
−
|4. [[#Anastrozole_.26_Trastuzumab|Anastrozole & Trastuzumab]]<br> 5. [[#Exemestane_.26.Trastuzumab|Exemestane & Trastuzumab]]<br> 6. [[#Letrozole_.26_Trastuzumab|Letrozole & Trastuzumab]]
+
|[https://doi.org/10.1056/NEJMoa1003825 Raymond et al. 2011 (A6181111)]
−
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: 11 vs 5.6 mo<br>(HR 0.62, 95% CI 0.45-0.88)
+
|2007-2009
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[Pancreatic_NET_-_null_regimens#Placebo|Placebo]]
 +
| style="background-color:#1a9850" |Superior PFS<sup>1</sup><br>Median PFS: 12.6 vs 5.8 mo<br>(HR 0.32, 95% CI 0.18-0.55)
 +
| style="background-color:#d73027" |More diarrhea; seems to have worse insomnia
 
|-
 
|-
 
|}
 
|}
−
''Note: the original article published in 2018 was retracted due to numeric errors in the analysis, and an update has been published.''
+
''<sup>1</sup>Reported efficacy is based on the 2017 update.''<br>
 +
''Note: while the initial publication seemed to have a significant survival advantage for this arm (p=0.02), this finding was no longer significant at the final update (p=0.094). The primary endpoint (PFS) remains significant.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Lapatinib (Tykerb)]] 1000 mg PO once per day
+
*[[Sunitinib (Sutent)]] 37.5 mg PO once per day
−
*[[Trastuzumab (Herceptin)]] as follows:
+
'''Continued indefinitely'''
−
**Cycle 1: 8 mg/kg IV once on day 1
 
−
**Cycle 2 onwards: 6 mg/kg IV once on day 1
 
−
====Endocrine therapy====
 
−
*[[Letrozole (Femara)]] 2.5 mg PO once per day
 
−
'''21-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
<!--- # '''RETRACTED:''' Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: ALTERNATIVE. J Clin Oncol. 2018 Mar 10;36(8):741-748. Epub 2017 Dec 15. [https://doi.org/10.1200/JCO.2017.74.7824 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29244528 PubMed] -->
+
# '''A6181111:''' Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):501-13. Erratum in: N Engl J Med. 2011 Mar 17;364(11):1082. [https://doi.org/10.1056/NEJMoa1003825 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21306237 PubMed] NCT00428597
−
# '''ALTERNATIVE:''' Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. J Clin Oncol. 2021 Jan 1;39(1):79-89. Epub 2020 Aug 21. [https://doi.org/10.1200/jco.20.01894 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32822287 PubMed] NCT01160211
+
## '''HRQoL analysis:''' Vinik A, Bottomley A, Korytowsky B, Bang YJ, Raoul JL, Valle JW, Metrakos P, Hörsch D, Mundayat R, Reisman A, Wang Z, Chao RC, Raymond E. Patient-reported outcomes and quality of life with sunitinib versus placebo for pancreatic neuroendocrine tumors: results from an international phase III trial. Target Oncol. 2016 Dec;11(6):815-824. [https://doi.org/10.1007/s11523-016-0462-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27924459 PubMed]
−
==Letrozole monotherapy {{#subobject:75d541|Regimen=1}}==
+
## '''Update:''' Faivre S, Niccoli P, Castellano D, Valle JW, Hammel P, Raoul JL, Vinik A, Van Cutsem E, Bang YJ, Lee SH, Borbath I, Lombard-Bohas C, Metrakos P, Smith D, Chen JS, Ruszniewski P, Seitz JF, Patyna S, Lu DR, Ishak KJ, Raymond E. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol. 2017 Feb 1;28(2):339-343. [https://doi.org/10.1093/annonc/mdw561 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27836885 PubMed]
 +
==Temozolomide monotherapy {{#subobject:69ae1c|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:d7ef99|Variant=1}}===
+
===Regimen {{#subobject:6aac4c|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 50%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2009.23.3734 Johnston et al. 2009 (EGF30008)]
+
|[http://clincancerres.aacrjournals.org/content/13/10/2986.long Ekeblad et al. 2007]
−
|2003-2006
+
| style="background-color:#ffffbe" |Retrospective
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Lapatinib_.26_Letrozole|Lapatinib & Letrozole]]
 
−
| style="background-color:#fc8d59" |Seems to have inferior PFS
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Endocrine therapy====
+
====Chemotherapy====
−
*[[Letrozole (Femara)]] 2.5 mg PO once per day
+
*[[Temozolomide (Temodar)]] as follows:
 +
**Cycle 1: 100 or 150 mg/m<sup>2</sup> PO once per day on days 1 to 5
 +
**Cycle 2 onwards: increased as tolerated up to 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
 +
====Supportive therapy====
 +
*[[Tropisetron (Navoban)]] (dose/route/schedule not specified) routinely used as an antiemetic
 
'''28-day cycles'''
 
'''28-day cycles'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''EGF30008:''' Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009 Nov 20;27(33):5538-46. Epub 2009 Sep 28. [https://doi.org/10.1200/JCO.2009.23.3734 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19786658 PubMed] NCT00073528
+
# '''Retrospective:''' Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007 May 15;13(10):2986-91. [http://clincancerres.aacrjournals.org/content/13/10/2986.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17505000 PubMed]
−
==Letrozole & Trastuzumab {{#subobject:8ugz41|Regimen=1}}==
+
==Temozolomide & Bevacizumab {{#subobject:ce7fe6|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:6cq284|Variant=1}}===
+
===Regimen {{#subobject:be3718|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
!style="width: 20%"|Study
+
!style="width: 33%"|Study
−
!style="width: 20%"|Years of enrollment
+
!style="width: 33%"|Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|rowspan=2|[https://doi.org/10.1200/jco.20.01894 Johnston et al. 2020 (ALTERNATIVE)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874232/ Chan et al. 2012 (DFCI 04-272)]
−
|rowspan=2|2011-2016
+
|2004-2005
−
|rowspan=2 style="background-color:#1a9851"|Phase 3 (C)
+
| style="background-color:#91cf61" |Phase 2
−
|1. [[#Anastrozole_.26_Lapatinib_99|Anastrozole & Lapatinib]]<br> 2. [[#Exemestane_.26_Lapatinib_99|Exemestane & Lapatinib]]<br>3. [[#Lapatinib_.26_Letrozole|Lapatinib & Letrozole]]
 
−
| style="background-color:#ffffbf" |Did not meet secondary endpoint of PFS
 
 
|-
 
|-
−
|4. [[#Anastrozole.2C_Lapatinib.2C_Trastuzumab|Anastrozole, Lapatinib, Trastuzumab]]<br> 5. [[#Exemestane.2C_Lapatinib.2C_Trastuzumab|Exemestane, Lapatinib, Trastuzumab]]<br> 6. [[#Lapatinib.2C_Letrozole.2C_Trastuzumab|Lapatinib, Letrozole, Trastuzumab]]
+
|}
−
| style="background-color:#d73027" |Inferior PFS
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Temozolomide (Temodar)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 7, 15 to 21
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1 & 15
 +
====Supportive therapy====
 +
*PCP prophylaxis: [[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO once every Monday, Wednesday, and Friday
 +
**Allergic patients received alternate prophylaxis
 +
*VZV prophylaxis: [[Acyclovir (Zovirax)]] 400 mg PO three times per day
 +
'''28-day cycles'''
 +
</div></div>
 +
===References===
 +
# '''DFCI 04-272:''' Chan JA, Stuart K, Earle CC, Clark JW, Bhargava P, Miksad R, Blaszkowsky L, Enzinger PC, Meyerhardt JA, Zheng H, Fuchs CS, Kulke MH. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol. 2012 Aug 20;30(24):2963-8. Epub 2012 Jul 9. [https://doi.org/10.1200/jco.2011.40.3147 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874232/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22778320 PubMed] NCT00137774
 +
==Temozolomide & Thalidomide {{#subobject:16afb7|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:ceca5a|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 50%" |Study
 +
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1158/1078-0432.ccr-21-3435 Hua et al. 2022 (SYSUCC-002)]
+
|[https://doi.org/10.1200/jco.2005.03.6046 Kulke et al. 2006]
−
|2013-2019
+
| style="background-color:#91cf61" |Phase 2
−
|style="background-color:#1a9851"|Phase 3 (E-switch-ooc)
 
−
|1. [[#Paclitaxel_.26_Trastuzumab_.28TH.29_88|TH (Paclitaxel)]]<br>2. [[#Docetaxel_.26_Trastuzumab_.28TH.29|TH (Docetaxel)]]<br>3. [[#Vinorelbine_.26_Trastuzumab_.28VH.29_88|VH]]; IV<br>4. [[#Vinorelbine_.26_Trastuzumab_.28VH.29_88|VH]]; PO<br>5. [[#Capecitabine_.26_Trastuzumab_.28XH.29|XH]]
 
−
| style="background-color:#eeee01" |Non-Inferior PFS<br>Median PFS: 19.2 vs 14.8 mo<br>(HR 0.88, 95% CI 0.71-1.09)
 
 
|-
 
|-
 
|}
 
|}
−
''Note: the original ALTERNATIVE article published in 2018 was retracted due to numeric errors in the analysis, and an update has been published. Hua et al. does not contain dosing instructions for letrozole.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Temozolomide (Temodar)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 7, 15 to 21
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Trastuzumab (Herceptin)]] as follows:
+
*[[Thalidomide (Thalomid)]] 200 mg PO once per day
−
**Cycle 1: 8 mg/kg IV once on day 1
+
'''28-day cycles'''
−
**Cycle 2 onwards: 6 mg/kg IV once on day 1
 
−
====Endocrine therapy====
 
−
*[[Letrozole (Femara)]] 2.5 mg PO once per day
 
−
'''21-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
<!--- # '''RETRACTED:''' Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: ALTERNATIVE. J Clin Oncol. 2018 Mar 10;36(8):741-748. Epub 2017 Dec 15. [https://doi.org/10.1200/JCO.2017.74.7824 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29244528 PubMed] -->
+
# Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, Vincitore M, Michelini A, Fuchs CS. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006 Jan 20;24(3):401-6. [https://doi.org/10.1200/jco.2005.03.6046 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16421420 PubMed]
−
# '''ALTERNATIVE:''' Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. J Clin Oncol. 2021 Jan 1;39(1):79-89. Epub 2020 Aug 21. [https://doi.org/10.1200/jco.20.01894 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32822287 PubMed] NCT01160211
+
[[Category:Pancreatic NET regimens]]
−
# '''SYSUCC-002:''' Hua X, Bi XW, Zhao JL, Shi YX, Lin Y, Wu ZY, Zhang YQ, Zhang LH, Zhang AQ, Huang H, Liu XM, Xu F, Guo Y, Xia W, Hong RX, Jiang KK, Xue C, An X, Zhong YY, Wang SS, Huang JJ, Yuan ZY. Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002). Clin Cancer Res. 2022 Feb 15;28(4):637-645. [https://doi.org/10.1158/1078-0432.ccr-21-3435 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/34810217/ PubMed] NCT01950182
+
[[Category:Disease-specific pages]]
−
[[Category:Breast cancer regimens]]
+
[[Category:Endocrine cancers]]
−
[[Category:Biomarker-specific pages]]
+
[[Category:Gastrointestinal cancers]]
−
[[Category:Malignant breast neoplasm]]
 

Revision as of 16:58, 15 October 2022

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Section editor transclusions Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: for more general neuroendocrine regimens, please visit the neuroendocrine tumors page.

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Guidelines

ESMO

Older

NANETS

NCCN

All lines of therapy

Capecitabine & Temozolomide

Regimen

Study Evidence
Strosberg et al. 2011 Retrospective

Chemotherapy

Supportive therapy

28-day cycles

References

  1. Retrospective: Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, Helm J, Kvols L. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011 Jan 15;117(2):268-75. Epub 2010 Sep 7. link to original article contains dosing details in manuscript link to PMC article PubMed

Doxorubicin & Streptozocin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Moertel et al. 1992 1978-1985 Phase 3 (E-switch-ic) 1. Chlorozotocin Superior OS
2. 5-FU & Streptozocin Superior OS

Chemotherapy

42-day cycles

References

  1. Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. link to original article contains dosing details in manuscript PubMed

Everolimus monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Yao et al. 2010 (RADIANT-1) 2006-2007 Phase 2
Yao et al. 2011 (RADIANT-3) 2007-2009 Phase 3 (E-RT-esc) Placebo Superior PFS
Median PFS: 11 vs 4.6 mo
(HR 0.35, 95% CI 0.27-0.45)

Targeted therapy

Continued indefinitely

References

  1. RADIANT-1: Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. Epub 2009 Nov 23. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00363051
  2. RADIANT-3: Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Öberg K; RAD001 in Advanced Neuroendocrine Tumors Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00510068
    1. Update: Yao JC, Pavel M, Lombard-Bohas C, Van Cutsem E, Voi M, Brandt U, He W, Chen D, Capdevila J, de Vries EGE, Tomassetti P, Hobday T, Pommier R, Öberg K. Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: overall survival and circulating biomarkers from the randomized, phase III RADIANT-3 study. J Clin Oncol. 2016 Nov 10;34(32):3906-3913. Epub 2016 Sep 30. link to original article link to PMC article PubMed
  3. Review: Yao JC, Phan AT, Jehl V, Shah G, Meric-Bernstam F. Everolimus in advanced pancreatic neuroendocrine tumors: the clinical experience. Cancer Res. 2013 Mar 1;73(5):1449-53. Epub 2013 Feb 22. link to original article PubMed
  4. COMPETE: NCT03049189
  5. COMPOSE: NCT04919226

Everolimus & Octreotide

Regimen variant #1

Study Years of enrollment Evidence
Yao et al. 2008 2005-2006 Phase 2

Targeted therapy

Endocrine therapy

28-day cycles


Regimen variant #2

Study Years of enrollment Evidence
Yao et al. 2008 2005-2006 Phase 2
Yao et al. 2010 (RADIANT-1) 2006-2007 Phase 2

Note: In Yao et al. 2008, everolimus "dose of 10 mg was associated with superior PFS...however, the study was not prospectively powered for these comparisons. These analyses should be considered exploratory." Patients in RADIANT-1 who received this regimen had already been receiving octreotide LAR for at least 3 months before participating in the study; they were continued on their prestudy dose up to 30 mg.

Targeted therapy

Endocrine therapy

28-day cycles

References

  1. Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008 Sep 10;26(26):4311-8. link to original article contains dosing details in manuscript link to PMC article PubMed
  2. RADIANT-1: Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. Epub 2009 Nov 23. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00363051

FAS

FAS: Fluorouracil, Adriamycin (Doxorubicin), Streptozocin

Regimen

Study Evidence
Kouvaraki et al. 2004 Retrospective

Chemotherapy

28-day cycles

References

  1. Retrospective: Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, Yao JC. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004 Dec 1;22(23):4762-71. link to original article contains dosing details in manuscript PubMed

Fluorouracil & Streptozocin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Moertel et al. 1980 1972-1978 Phase 3 (E-esc) Fluorouracil Might have superior OS
Moertel et al. 1992 1978-1985 Phase 3 (C) 1. Chlorozotocin Did not meet endpoint of OS
2. Doxorubicin & Streptozocin Inferior OS

Note: treatment details are from Moertel et al. 1992.

Chemotherapy

42-day cycles

References

  1. Moertel CG, Hanley JA, Johnson LA. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1980 Nov 20;303(21):1189-94. link to original article PubMed
  2. Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. link to original article contains dosing details in manuscript PubMed

Lanreotide Depot/Autogel monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Caplin et al. 2014 (CLARINET) 2006-2013 Phase 3 (E-RT-esc) Placebo Superior PFS
Median PFS: NYR vs 18 mo
(HR 0.47, 95% CI 0.30-0.73)
Caplin et al. 2016 (CLARINET OLE) 2009-NR Non-randomized

Endocrine therapy

28-day cycle for 96 weeks (CLARINET) or up to 8 years (CLARINET OLE)

References

  1. CLARINET: Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33. link to original article contains dosing details in manuscript PubMed NCT00353496
  2. CLARINET OLE: Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Gomez-Panzani E, Ruszniewski P; CLARINET Investigators. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. Endocr Relat Cancer. 2016 Mar;23(3):191-9. Epub 2016 Jan 7. link to original article link to PMC article PubMed NCT00842348

Lanreotide & Interferon alfa-2b

Regimen

Study Evidence
Fjällskog et al. 2002 Pilot, <20 pts

Fjällskog et al. 2002 contained case reports of several patients treated with lanreotide & interferon alfa. Each patient received individualized therapy rather than a standard regimen.

Endocrine therapy

Immunotherapy

  • Interferon alfa-2b (Intron-A) 3,000,000 to 5,000,000 units SC once per day, 3 to 7 days per week (total of 9,000,000 to 25,000,000 units per week)

References

  1. Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. link to original article PubMed

Octreotide monotherapy

Regimen

Study Evidence
Oberg et al. 2004 Consensus guideline

Endocrine therapy

  • Octreotide (Sandostatin) 0.1 to 0.5 mg SC given two to four times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms
    • "A reasonable starting dose is" 0.15 mg SC three times per day

Continued indefinitely

References

  1. Review: Brentjens R, Saltz L. Islet cell tumors of the pancreas: the medical oncologist's perspective. Surg Clin North Am. 2001 Jun;81(3):527-42. link to original article PubMed
  2. Review: Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. link to original article contains dosing details in manuscript PubMed

Octreotide LAR monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rinke et al. 2009 (PROMID) 2001-2008 Phase 3 (E-esc) Placebo Superior TTP
Median TTP: 14.3 vs 6 mo
(HR 0.34, 95% CI 0.20-0.59)

Endocrine therapy

28-day cycles

References

  1. Review: Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. link to original article contains dosing details in manuscript PubMed
  2. PROMID: Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. link to original article contains dosing details in manuscript PubMed NCT00171873
  3. NETTER-1: Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01578239
    1. Update: Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. link to original article PubMed
  4. NETTER-2: NCT03972488

Octreotide & Interferon alfa

Regimen

Study Evidence
Fjällskog et al. 2002 Pilot, <20 pts

Fjällskog et al. 2002 contained case reports of several patients treated with octreotide & interferon alfa. Each patient received individualized therapy rather than a standard regimen.

Endocrine therapy

Immunotherapy

  • Interferon alfa-2b (Intron-A) 3,000,000 to 5,000,000 units SC once per day, 3 to 7 days per week (total of 9,000,000 to 25,000,000 units per week)

References

  1. Janson ET, Oberg K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. link to original article PubMed
  2. Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. link to original article PubMed

Lutetium Lu 177 dotatate & Octreotide LAR

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Strosberg et al. 2017 (NETTER-1) 2012-2016 Phase 3 (E-switch-ooc) Octreotide LAR; high-dose Superior PFS
Median PFS: NYR vs 8.4 mo
(HR 0.21, 95% CI 0.13-0.33) 		More cytopenias (neutropenia, thrombocytopenia and lymphopenia)

Note: patients had well-differentiated (Ki67 less than 20%) midgut neuroendocrine tumors with somatostatin receptors present in all target lesions

Endocrine therapy

4-week cycles

Radioconjugate therapy

Supportive therapy

  • For renal protection, an IV amino acid solution was administered concomitantly for at least 4 hours, starting 30 minutes prior to drug infusion.

8-week cycle for 4 cycles

References

  1. NETTER-1: Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01578239
    1. Update: Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. link to original article PubMed

Sunitinib monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Raymond et al. 2011 (A6181111) 2007-2009 Phase 3 (E-RT-esc) Placebo Superior PFS1
Median PFS: 12.6 vs 5.8 mo
(HR 0.32, 95% CI 0.18-0.55) 		More diarrhea; seems to have worse insomnia

1Reported efficacy is based on the 2017 update.
Note: while the initial publication seemed to have a significant survival advantage for this arm (p=0.02), this finding was no longer significant at the final update (p=0.094). The primary endpoint (PFS) remains significant.

Targeted therapy

Continued indefinitely

References

  1. A6181111: Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):501-13. Erratum in: N Engl J Med. 2011 Mar 17;364(11):1082. link to original article contains dosing details in manuscript PubMed NCT00428597
    1. HRQoL analysis: Vinik A, Bottomley A, Korytowsky B, Bang YJ, Raoul JL, Valle JW, Metrakos P, Hörsch D, Mundayat R, Reisman A, Wang Z, Chao RC, Raymond E. Patient-reported outcomes and quality of life with sunitinib versus placebo for pancreatic neuroendocrine tumors: results from an international phase III trial. Target Oncol. 2016 Dec;11(6):815-824. link to original article PubMed
    2. Update: Faivre S, Niccoli P, Castellano D, Valle JW, Hammel P, Raoul JL, Vinik A, Van Cutsem E, Bang YJ, Lee SH, Borbath I, Lombard-Bohas C, Metrakos P, Smith D, Chen JS, Ruszniewski P, Seitz JF, Patyna S, Lu DR, Ishak KJ, Raymond E. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol. 2017 Feb 1;28(2):339-343. link to original article PubMed

Temozolomide monotherapy

Regimen

Study Evidence
Ekeblad et al. 2007 Retrospective

Chemotherapy

  • Temozolomide (Temodar) as follows:
    • Cycle 1: 100 or 150 mg/m2 PO once per day on days 1 to 5
    • Cycle 2 onwards: increased as tolerated up to 200 mg/m2 PO once per day on days 1 to 5

Supportive therapy

28-day cycles

References

  1. Retrospective: Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007 May 15;13(10):2986-91. link to original article contains dosing details in manuscript PubMed

Temozolomide & Bevacizumab

Regimen

Study Years of enrollment Evidence
Chan et al. 2012 (DFCI 04-272) 2004-2005 Phase 2

Chemotherapy

Targeted therapy

Supportive therapy

28-day cycles

References

  1. DFCI 04-272: Chan JA, Stuart K, Earle CC, Clark JW, Bhargava P, Miksad R, Blaszkowsky L, Enzinger PC, Meyerhardt JA, Zheng H, Fuchs CS, Kulke MH. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol. 2012 Aug 20;30(24):2963-8. Epub 2012 Jul 9. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00137774

Temozolomide & Thalidomide

Regimen

Study Evidence
Kulke et al. 2006 Phase 2

Chemotherapy

Targeted therapy

28-day cycles

References

  1. Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, Vincitore M, Michelini A, Fuchs CS. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006 Jan 20;24(3):401-6. link to original article contains dosing details in manuscript PubMed
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