Difference between revisions of "Pancreatic NET"
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− | + | <div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px"> | |
− | + | [[#top|Back to Top]] | |
− | + | </div> | |
− | + | {{#lst:Editorial board transclusions|giei}} | |
− | + | ''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> | |
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<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div> | <div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div> | ||
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{{TOC limit|limit=3}} | {{TOC limit|limit=3}} | ||
=Guidelines= | =Guidelines= | ||
− | ==[ | + | '''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.''' |
− | *''' | + | ==[https://www.asco.org/ ASCO]== |
+ | *'''2023:''' Del Rivero et al. [https://doi.org/10.1200/jco.23.01529 Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline] [https://pubmed.ncbi.nlm.nih.gov/37774329/ PubMed] | ||
+ | ==[https://www.esmo.org/ ESMO]== | ||
+ | *'''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] [https://pubmed.ncbi.nlm.nih.gov/32272208/ PubMed] | ||
+ | **'''2012:''' Öberg et al. [https://doi.org/10.1093/annonc/mds295 Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/22997445/ PubMed] | ||
+ | **'''2010:''' Öberg et al. [https://doi.org/10.1093/annonc/mdq192 Neuroendocrine gastroenteropancreatic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/20555086/ PubMed] | ||
+ | **'''2009:''' Öberg & Jelic. [https://doi.org/10.1093/annonc/mdp158 Neuroendocrine gastroenteropancreatic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454440/ PubMed] | ||
+ | **'''2008:''' Öberg & Jelic. [https://doi.org/10.1093/annonc/mdn117 Neuroendocrine gastroenteropancreatic tumors: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456741/ PubMed] | ||
− | ==[https://www. | + | ==NANETS== |
− | *[https://www.nccn.org/ | + | *'''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] [https://pubmed.ncbi.nlm.nih.gov/32675783/ PubMed] |
+ | *'''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://pubmed.ncbi.nlm.nih.gov/31856076/ PubMed] | ||
+ | ==NCCN== | ||
+ | *''NCCN does not currently have guidelines at this granular level; please see [https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448 NCCN Guidelines - Neuroendocrine and Adrenal Tumors]''. | ||
=All lines of therapy= | =All lines of therapy= | ||
==Capecitabine & Temozolomide {{#subobject:738284|Regimen=1}}== | ==Capecitabine & Temozolomide {{#subobject:738284|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:fc2dd9|Variant=1}}=== | ===Regimen {{#subobject:fc2dd9|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665634/ Strosberg et al. 2011] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665634/ Strosberg et al. 2011] | ||
− | |style="background-color:#ffffbe"|Retrospective | + | |2005-09 to 2009-01 |
+ | | style="background-color:#ffffbe" |Retrospective | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14 | *[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14 | ||
− | *[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day | + | *[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day on days 10 to 14, taken at bedtime |
− | |||
− | |||
− | |||
+ | ====Supportive therapy==== | ||
+ | *[[Ondansetron (Zofran)]] 8 mg (route not specified) once per day on days 1 to 14, prior to temozolomide | ||
'''28-day cycles''' | '''28-day cycles''' | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # '''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:// | + | # '''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] |
− | |||
==Doxorubicin & Streptozocin {{#subobject:5c625d|Regimen=1}}== | ==Doxorubicin & Streptozocin {{#subobject:5c625d|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:a9c7ed|Variant=1}}=== | ===Regimen {{#subobject:a9c7ed|Variant=1}}=== | ||
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !style="width: 20%"|Dates of enrollment |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |rowspan=2|[https:// | + | | rowspan="2" |[https://doi.org/10.1056/NEJM199202203260804 Moertel et al. 1992] |
− | |rowspan=2 style="background-color:#1a9851"|Phase | + | |rowspan=2|1978-1985 |
− | |1. Chlorozotocin | + | | rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic) |
− | |style="background-color:#1a9850"|Superior OS | + | |1. [[#Chlorozotocin_monotherapy_888|Chlorozotocin]] |
+ | | style="background-color:#1a9850" |Superior OS | ||
|- | |- | ||
− | |2. [[#Fluorouracil_. | + | |2. [[#Fluorouracil_.26_Streptozocin|5-FU & Streptozocin]] |
− | |style="background-color:#1a9850"|Superior OS | + | | style="background-color:#1a9850" |Superior OS |
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 22 | *[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 22 | ||
*[[Streptozocin (Zanosar)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5 | *[[Streptozocin (Zanosar)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
− | |||
'''42-day cycles''' | '''42-day cycles''' | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # 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:// | + | # 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] |
− | |||
==Everolimus monotherapy {{#subobject:78dff1|Regimen=1}}== | ==Everolimus monotherapy {{#subobject:78dff1|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:5ea369|Variant=1}}=== | ===Regimen {{#subobject:5ea369|Variant=1}}=== | ||
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !style="width: 20%"|Dates of enrollment |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ Yao et al. 2010] | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ Yao et al. 2010 (RADIANT-1)] |
− | |style="background-color:#91cf61"|Phase | + | |2006-2007 |
− | |style="background-color:#d3d3d3"| | + | | style="background-color:#91cf61" |Phase 2 |
− | |style="background-color:#d3d3d3"| | + | | style="background-color:#d3d3d3" | |
+ | | style="background-color:#d3d3d3" | | ||
|- | |- | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208619/ Yao et al. 2011 (RADIANT-3)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208619/ Yao et al. 2011 (RADIANT-3)] | ||
− | |style="background-color:#1a9851"|Phase | + | <!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26" |
− | |[[#Placebo|Placebo]] | + | |'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-149-1 <span style="color:white;">ESMO-MCBS (3)</span>]''' |
− | |style="background-color:#1a9850"|Superior PFS | + | |- |
+ | |} --> | ||
+ | |2007-2009 | ||
+ | | style="background-color:#1a9851" |Phase 3 (E-RT-esc) | ||
+ | |[[Pancreatic_NET_-_null_regimens#Placebo|Placebo]] | ||
+ | | style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 11 vs 4.6 mo<br>(HR 0.35, 95% CI 0.27-0.45)<br><br>Did not meet secondary endpoint of OS<sup>1</sup><br>Median OS: 44 vs 37.7 mo<br>(HR 0.94, 95% CI 0.73-1.20) | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | ''<sup>1</sup>Reported efficacy for OS is based on the 2016 update.'' |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Targeted therapy==== | ||
*[[Everolimus (Afinitor)]] 10 mg PO once per day | *[[Everolimus (Afinitor)]] 10 mg PO once per day | ||
− | + | '''Continued indefinitely''' | |
− | ''' | + | </div></div> |
− | |||
===References=== | ===References=== | ||
− | # 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. [ | + | # '''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] [https://clinicaltrials.gov/study/NCT00363051 NCT00363051] |
− | # '''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:// | + | # '''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] [https://clinicaltrials.gov/study/NCT00510068 NCT00510068] |
− | # '''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. [ | + | ## '''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. [https://doi.org/10.1158/0008-5472.can-12-3923 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23436795/ PubMed] | ||
+ | #'''COMPETE:''' [https://clinicaltrials.gov/study/NCT03049189 NCT03049189] | ||
+ | #'''COMPOSE:''' [https://clinicaltrials.gov/study/NCT04919226 NCT04919226] | ||
==Everolimus & Octreotide {{#subobject:d6b3eb|Regimen=1}}== | ==Everolimus & Octreotide {{#subobject:d6b3eb|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen variant #1 {{#subobject:b0f62f|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008] | |
− | + | |2005-2006 | |
− | + | | style="background-color:#91cf61" |Phase 2 | |
− | |||
− | |||
− | |||
− | |||
− | |[https://www.ncbi.nlm.nih.gov/pmc/articles/ | ||
− | |style="background-color:#91cf61"|Phase | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#b3e2cd"> | |
− | + | ====Targeted therapy==== | |
− | ==== | + | *[[Everolimus (Afinitor)]] 5 mg PO once per day on days 1 to 28 |
− | *[[Everolimus (Afinitor)]] | + | ====Endocrine therapy==== |
− | *[[Octreotide LAR (Sandostatin LAR)]] | + | *[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1 |
− | |||
'''28-day cycles''' | '''28-day cycles''' | ||
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: | + | ===Regimen variant #2 {{#subobject:f82bb5|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008] | ||
− | |style="background-color:#91cf61"|Phase | + | |2005-2006 |
+ | | style="background-color:#91cf61" |Phase 2 | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ Yao et al. 2010 (RADIANT-1)] | ||
+ | |2006-2007 | ||
+ | | style="background-color:#91cf61" |Phase 2 | ||
|- | |- | ||
|} | |} | ||
− | ''Note: | + | ''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"> |
− | *[[Everolimus (Afinitor)]] | + | ====Targeted therapy==== |
+ | *[[Everolimus (Afinitor)]] 10 mg PO once per day on days 1 to 28 | ||
+ | ====Endocrine therapy==== | ||
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1 | *[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1 | ||
− | + | '''28-day cycles''' | |
− | '''28-day | + | </div></div> |
− | |||
===References=== | ===References=== | ||
− | # 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. [ | + | # 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] |
− | # 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. [ | + | # '''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] [https://clinicaltrials.gov/study/NCT00363051 NCT00363051] |
− | |||
==FAS {{#subobject:66b05e|Regimen=1}}== | ==FAS {{#subobject:66b05e|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
FAS: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>S</u>'''treptozocin | FAS: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>S</u>'''treptozocin | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
===Regimen {{#subobject:de76a2|Variant=1}}=== | ===Regimen {{#subobject:de76a2|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2004.04.024 Kouvaraki et al. 2004] |
− | |style="background-color:#ffffbe"|Retrospective | + | |1992-01 to 2003-09 |
+ | | style="background-color:#ffffbe" |Retrospective | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5 | *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5 | ||
*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV bolus once on day 1 | *[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV bolus once on day 1 | ||
*[[Streptozocin (Zanosar)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5 | *[[Streptozocin (Zanosar)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5 | ||
− | + | '''28-day cycles''' | |
− | '''28-day cycles | + | </div></div> |
− | |||
===References=== | ===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. [ | + | # '''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}}== | ==Fluorouracil & Streptozocin {{#subobject:6f7b84|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
===Regimen {{#subobject:e45011|Variant=1}}=== | ===Regimen {{#subobject:e45011|Variant=1}}=== | ||
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !style="width: 20%"|Dates of enrollment |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1056/NEJM198011203032101 Moertel et al. 1980] |
− | |style="background-color:#1a9851"|Phase | + | |1972-1978 |
− | |Fluorouracil | + | | style="background-color:#1a9851" |Phase 3 (E-esc) |
+ | |[[#Fluorouracil_monotherapy_888|Fluorouracil]] | ||
| style="background-color:#d9ef8b" |Might have superior OS | | style="background-color:#d9ef8b" |Might have superior OS | ||
|- | |- | ||
− | |rowspan=2|[https:// | + | | rowspan="2" |[https://doi.org/10.1056/NEJM199202203260804 Moertel et al. 1992] |
− | |rowspan=2 style="background-color:#1a9851"|Phase | + | |rowspan=2|1978-1985 |
− | |1. Chlorozotocin | + | | rowspan="2" style="background-color:#1a9851" |Phase 3 (C) |
− | |style="background-color:#ffffbf"| | + | |1. [[#Chlorozotocin_monotherapy_888|Chlorozotocin]] |
+ | | style="background-color:#ffffbf" |Did not meet endpoint of OS | ||
|- | |- | ||
|2. [[#Doxorubicin_.26_Streptozocin|Doxorubicin & Streptozocin]] | |2. [[#Doxorubicin_.26_Streptozocin|Doxorubicin & Streptozocin]] | ||
− | |style="background-color:#d73027"|Inferior OS | + | | style="background-color:#d73027" |Inferior OS |
|- | |- | ||
|} | |} | ||
''Note: treatment details are from Moertel et al. 1992.'' | ''Note: treatment details are from Moertel et al. 1992.'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Streptozocin (Zanosar)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5 | *[[Streptozocin (Zanosar)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5 | *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5 | ||
− | |||
'''42-day cycles''' | '''42-day cycles''' | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # 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:// | + | # 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] |
− | # 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:// | + | # 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] |
− | |||
==Lanreotide Depot/Autogel monotherapy {{#subobject:8bca3a|Regimen=1}}== | ==Lanreotide Depot/Autogel monotherapy {{#subobject:8bca3a|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:a9ee08|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !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/10.1056/NEJMoa1316158 Caplin et al. 2014 (CLARINET)] |
− | + | <!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26" | |
− | + | |'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-148-1 <span style="color:white;">ESMO-MCBS (3)</span>]''' | |
− | |||
− | {| class="wikitable" style=" | ||
− | |||
− | |||
− | |||
− | |||
|- | |- | ||
− | | | + | |} --> |
− | |style="background-color:#1a9851"|Phase | + | |2006-2013 |
− | |[[#Placebo|Placebo]] | + | | style="background-color:#1a9851" |Phase 3 (E-RT-esc) |
− | |style="background-color:#1a9850"|Superior PFS | + | |[[Pancreatic_NET_-_null_regimens#Placebo|Placebo]] |
+ | | style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: NYR vs 18 mo<br>(HR 0.47, 95% CI 0.30-0.73) | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#b3e2cd"> |
+ | ====Endocrine therapy==== | ||
*[[Lanreotide (Somatuline) | Lanreotide (Somatuline) Depot/Autogel]] 120 mg SC once on day 1 | *[[Lanreotide (Somatuline) | Lanreotide (Somatuline) Depot/Autogel]] 120 mg SC once on day 1 | ||
− | + | '''28-day cycle for 96 weeks''' | |
− | '''28-day cycle for 96 weeks | + | </div></div> |
− | |||
− | |||
− | |||
===References=== | ===References=== | ||
− | # '''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:// | + | # '''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] [https://clinicaltrials.gov/study/NCT00353496 NCT00353496] |
− | |||
==Lanreotide & Interferon alfa-2b {{#subobject:9c5a59|Regimen=1}}== | ==Lanreotide & Interferon alfa-2b {{#subobject:9c5a59|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:652f4d|Variant=1}}=== | ===Regimen {{#subobject:652f4d|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1385/mo:19:1:35 Fjällskog et al. 2002] |
− | |style="background-color:#ffffbe"|Pilot, | + | |NR |
+ | | style="background-color:#ffffbe" |Pilot, fewer than 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.'' | + | ''Note: 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 | + | <div class="toccolours" style="background-color:#b3e2cd"> |
+ | ====Endocrine therapy==== | ||
*[[Lanreotide (Somatuline)]] 3 mg SC twice per day | *[[Lanreotide (Somatuline)]] 3 mg SC twice per day | ||
− | *[[Interferon alfa-2b (Intron-A)]] 3 to 5 | + | ====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=== | ===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. [ | + | # 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. [https://doi.org/10.1385/mo:19:1:35 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12025889/ PubMed] |
− | |||
==Octreotide monotherapy {{#subobject:665a8b|Regimen=1}}== | ==Octreotide monotherapy {{#subobject:665a8b|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
===Regimen {{#subobject:cd8cf6|Variant=1}}=== | ===Regimen {{#subobject:cd8cf6|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable" style="width: 40%; text-align:center;" |
− | !style="width: 50%"|Study | + | ! style="width: 50%" |Study |
− | !style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]] | + | ! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]] |
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1093/annonc/mdh216 Oberg et al. 2004] |
− | |style="background-color:#ffffbe"|Consensus guideline | + | | style="background-color:#ffffbe" |Consensus guideline |
|- | |- | ||
|} | |} | ||
− | ==== | + | ''Note: per the consensus guideline, a "reasonable starting dose" was 0.15 mg SC three times per day |
− | *[[Octreotide (Sandostatin)]] 0.1 to 0.5 mg SC given | + | <div class="toccolours" style="background-color:#b3e2cd"> |
− | + | ====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 | |
− | ''' | + | '''Continued indefinitely''' |
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # '''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. [ | + | # '''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] |
− | # '''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. [ | + | # '''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] |
==Octreotide LAR monotherapy {{#subobject:e356ea|Regimen=1}}== | ==Octreotide LAR monotherapy {{#subobject:e356ea|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen {{#subobject:f0bc1b|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | + | !style="width: 20%"|Study | |
− | + | !style="width: 20%"|Dates of enrollment | |
− | === | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | !style="width: 20%"|Comparator |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
− | !style="width: | ||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | !style="width: | ||
− | |||
− | !style="width: | ||
− | !style="width: | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2009.22.8510 Rinke et al. 2009 (PROMID)] |
− | |style="background-color:#1a9851"|Phase | + | |2001-2008 |
− | |[[#Placebo|Placebo]] | + | | style="background-color:#1a9851" |Phase 3 (E-esc) |
− | |style="background-color:#1a9850"|Superior TTP | + | |[[Pancreatic_NET_-_null_regimens#Placebo|Placebo]] |
+ | | style="background-color:#1a9850" |Superior TTP (primary endpoint)<br>Median TTP: 14.3 vs 6 mo<br>(HR 0.34, 95% CI 0.20-0.59) | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#b3e2cd"> |
+ | ====Endocrine therapy==== | ||
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1, with potentially higher doses if needed for symptom control | *[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1, with potentially higher doses if needed for symptom control | ||
− | |||
'''28-day cycles''' | '''28-day cycles''' | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # '''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. [ | + | # '''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] |
− | # '''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. [ | + | # '''PROMID:''' Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. [https://doi.org/10.1200/jco.2009.22.8510 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19704057/ PubMed] [https://clinicaltrials.gov/study/NCT00171873 NCT00171873] |
− | + | # '''NETTER-1:''' Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. [https://doi.org/10.1056/NEJMoa1607427 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28076709/ PubMed] [https://clinicaltrials.gov/study/NCT01578239 NCT01578239] | |
+ | ## '''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:''' [https://clinicaltrials.gov/study/NCT03972488 NCT03972488] | ||
==Octreotide & Interferon alfa {{#subobject:1cf4c5|Regimen=1}}== | ==Octreotide & Interferon alfa {{#subobject:1cf4c5|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:cbf5c4|Variant=1}}=== | ===Regimen {{#subobject:cbf5c4|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1385/mo:19:1:35 Fjällskog et al. 2002] |
− | |style="background-color:#ffffbe"|Pilot, | + | |NR |
+ | | style="background-color:#ffffbe" |Pilot, fewer than 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.'' | + | ''Note: 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 | + | <div class="toccolours" style="background-color:#b3e2cd"> |
− | *[[Octreotide (Sandostatin)]] 0.05 to 0.5 mg SC given | + | ====Endocrine therapy==== |
− | *[[Interferon alfa-2b (Intron-A)]] 3 to 5 | + | *[[Octreotide (Sandostatin)]] 0.05 to 0.5 mg SC given two to three times 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=== | ===References=== | ||
− | # 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:// | + | # 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] |
− | # 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. [ | + | # 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. [https://doi.org/10.1385/mo:19:1:35 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"> |
− | + | ===Regimen {{#subobject:33d0ef|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | + | !style="width: 17%"|Study | |
− | + | !style="width: 15%"|Dates of enrollment | |
− | + | !style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | ===Regimen=== | + | !style="width: 17%"|Comparator |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | !style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
− | !style="width: | + | !style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]] |
− | !style="width: | ||
− | !style="width: | ||
− | !style="width: | ||
− | !style="width: | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ Strosberg et al. 2017 (NETTER-1)] |
− | | | + | <!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26" |
− | + | |'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-152-1 <span style="color:white;">ESMO-MCBS (4)</span>]''' | |
− | |||
− | |style=" | ||
|- | |- | ||
− | | | + | |} --> |
− | | | + | |2012-2016 |
− | + | | style="background-color:#1a9851" |Phase 3 (E-RT-esc) | |
− | + | | [[#Octreotide_LAR_monotherapy|Octreotide LAR]]; high-dose | |
− | |style="background-color:#1a9850"| | + | | style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: NYR vs 8.4 mo<br>(HR 0.21, 95% CI 0.13-0.33)<br><br>Did not meet secondary endpoint of OS<sup>1</sup><br>Median OS: 48 vs 36.3 mo<br>(HR 0.84, 95% CI 0.60-1.17) |
− | + | | style="background-color:#d73027" |More cytopenias (neutropenia, thrombocytopenia and lymphopenia) | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |style="background-color:# | ||
− | |||
− | |||
− | |||
|- | |- | ||
|} | |} | ||
− | '' | + | ''<sup>1</sup>Reported efficacy for OS is based on the 2021 update.''<br> |
+ | ''Note: patients had well-differentiated (Ki67 less than 20%) midgut neuroendocrine tumors with somatostatin receptors present in all target lesions'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Endocrine therapy==== | ||
+ | * [[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''' | ||
+ | </div></div> | ||
===References=== | ===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] [https://clinicaltrials.gov/study/NCT01578239 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}}== | ==Sunitinib monotherapy {{#subobject:ee13d2|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:80d0ef|Variant=1}}=== | ===Regimen {{#subobject:80d0ef|Variant=1}}=== | ||
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 17%"|Study |
− | !style="width: | + | !style="width: 15%"|Dates of enrollment |
− | !style="width: | + | !style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !style="width: 17%"|Comparator |
− | !style="width: | + | !style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
+ | !style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]] | ||
|- | |- | ||
− | + | |[https://doi.org/10.1056/NEJMoa1003825 Raymond et al. 2011 (A6181111)] | |
− | | | + | <!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26" |
− | | | + | |'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-151-1 <span style="color:white;">ESMO-MCBS (3)</span>]''' |
− | |||
− | |||
|- | |- | ||
− | |style="background-color:# | + | |} --> |
+ | |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> (primary endpoint)<br>Median PFS: 12.6 vs 5.8 mo<br>(HR 0.32, 95% CI 0.18-0.55)<br><br>Did not meet secondary endpoint of OS<sup>1</sup><br>Median OS: 38.6 vs 29.1 mo<br>(HR 0.73, 95% CI 0.50-1.06) | ||
+ | | style="background-color:#d73027" |More diarrhea; seems to have worse insomnia | ||
|- | |- | ||
|} | |} | ||
− | '' | + | ''<sup>1</sup>Reported efficacy is based on the 2017 update.''<br> |
− | ==== | + | <div class="toccolours" style="background-color:#b3e2cd"> |
− | *[[Sunitinib (Sutent)]] 37.5 mg PO once per day | + | ====Targeted therapy==== |
− | + | *[[Sunitinib (Sutent)]] 37.5 mg PO once per day on days 1 to 42 | |
− | ''' | + | '''42-day cycles''' |
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # '''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:// | + | # '''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] [https://clinicaltrials.gov/study/NCT00428597 NCT00428597] |
− | ## '''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:// | + | ## '''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] |
− | ## '''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:// | + | ## '''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] |
+ | ## '''Update:''' Fazio N, Kulke M, Rosbrook B, Fernandez K, Raymond E. Updated Efficacy and Safety Outcomes for Patients with Well-Differentiated Pancreatic Neuroendocrine Tumors Treated with Sunitinib. Target Oncol. 2021 Jan;16(1):27-35. Epub 2021 Jan 7. [https://doi.org/10.1007/s11523-020-00784-0 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7810649/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33411058/ PubMed] | ||
==Temozolomide monotherapy {{#subobject:69ae1c|Regimen=1}}== | ==Temozolomide monotherapy {{#subobject:69ae1c|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:6aac4c|Variant=1}}=== | ===Regimen {{#subobject:6aac4c|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1158/1078-0432.ccr-06-2053 Ekeblad et al. 2007] |
− | |style="background-color:# | + | |1999-10 to 2006-01 |
+ | | style="background-color:#ffffbe" |Retrospective | ||
|- | |- | ||
|} | |} | ||
+ | ''Note: Temozolomide dose was increased only if the starting dose is tolerated.'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Temozolomide (Temodar)]] as follows: | *[[Temozolomide (Temodar)]] as follows: | ||
− | **Cycle 1: 100 | + | **Cycle 1: 100 to 150 mg/m<sup>2</sup> PO once per day on days 1 to 5 |
− | **Cycle 2 onwards: | + | **Cycle 2 onwards: 200 mg/m<sup>2</sup> PO once per day on days 1 to 5 |
− | + | ====Supportive therapy==== | |
− | ====Supportive | ||
*[[Tropisetron (Navoban)]] (dose/route/schedule not specified) routinely used as an antiemetic | *[[Tropisetron (Navoban)]] (dose/route/schedule not specified) routinely used as an antiemetic | ||
− | |||
'''28-day cycles''' | '''28-day cycles''' | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # 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. [ | + | # '''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. [https://doi.org/10.1158/1078-0432.ccr-06-2053 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17505000/ PubMed] |
==Temozolomide & Bevacizumab {{#subobject:ce7fe6|Regimen=1}}== | ==Temozolomide & Bevacizumab {{#subobject:ce7fe6|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:be3718|Variant=1}}=== | ===Regimen {{#subobject:be3718|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874232/ Chan et al. 2012] | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874232/ Chan et al. 2012 (DFCI 04-272)] |
− | |style="background-color:#91cf61"|Phase | + | |2004-2005 |
+ | | style="background-color:#91cf61" |Phase 2 | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Temozolomide (Temodar)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 7, 15 to 21 | *[[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 | *[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1 & 15 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *PCP prophylaxis: [[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO once every Monday, Wednesday, and Friday |
− | *[[Trimethoprim | + | **Allergic patients received alternate prophylaxis |
− | *[[Acyclovir (Zovirax)]] 400 mg PO three times per day | + | *VZV prophylaxis: [[Acyclovir (Zovirax)]] 400 mg PO three times per day |
− | |||
'''28-day cycles''' | '''28-day cycles''' | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # 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. [ | + | # '''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] [https://clinicaltrials.gov/study/NCT00137774 NCT00137774] |
− | |||
==Temozolomide & Thalidomide {{#subobject:16afb7|Regimen=1}}== | ==Temozolomide & Thalidomide {{#subobject:16afb7|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:ceca5a|Variant=1}}=== | ===Regimen {{#subobject:ceca5a|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2005.03.6046 Kulke et al. 2006] |
− | |style="background-color:#91cf61"|Phase | + | |NR |
+ | | style="background-color:#91cf61" |Phase 2 | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Temozolomide (Temodar)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 7, 15 to 21 | *[[Temozolomide (Temodar)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 7, 15 to 21 | ||
+ | ====Targeted therapy==== | ||
*[[Thalidomide (Thalomid)]] 200 mg PO once per day | *[[Thalidomide (Thalomid)]] 200 mg PO once per day | ||
− | |||
'''28-day cycles''' | '''28-day cycles''' | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # 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. [ | + | <!-- Presented in part at the 2003 Chemotherapy Foundation Symposium, New York, NY, November 12-15, 2003. --> |
− | + | # 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] | |
[[Category:Pancreatic NET regimens]] | [[Category:Pancreatic NET regimens]] | ||
[[Category:Disease-specific pages]] | [[Category:Disease-specific pages]] | ||
[[Category:Endocrine cancers]] | [[Category:Endocrine cancers]] | ||
[[Category:Gastrointestinal cancers]] | [[Category:Gastrointestinal cancers]] |
Revision as of 10:14, 2 July 2024
Section editor | |
---|---|
Eric I. Marks, MD Boston University Boston, MA, USA |
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.
16 regimens on this page
18 variants on this page
|
Guidelines
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
ASCO
- 2023: Del Rivero et al. Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline PubMed
ESMO
- 2020: Pavel et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2012: Öberg et al. Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2010: Öberg et al. Neuroendocrine gastroenteropancreatic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2009: Öberg & Jelic. Neuroendocrine gastroenteropancreatic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up PubMed
- 2008: Öberg & Jelic. Neuroendocrine gastroenteropancreatic tumors: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
NANETS
- 2020: Halfdanarson et al. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Pancreatic Neuroendocrine Tumors PubMed
- 2020: Howe et al. The North American Neuroendocrine Tumor Society Consensus Paper on the Surgical Management of Pancreatic Neuroendocrine Tumors PubMed
NCCN
- NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Neuroendocrine and Adrenal Tumors.
All lines of therapy
Capecitabine & Temozolomide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Strosberg et al. 2011 | 2005-09 to 2009-01 | Retrospective |
Chemotherapy
- Capecitabine (Xeloda) 750 mg/m2 PO twice per day on days 1 to 14
- Temozolomide (Temodar) 200 mg/m2 PO once per day on days 10 to 14, taken at bedtime
Supportive therapy
- Ondansetron (Zofran) 8 mg (route not specified) once per day on days 1 to 14, prior to temozolomide
28-day cycles
References
- 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 | Dates 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
- Doxorubicin (Adriamycin) 50 mg/m2 IV once per day on days 1 & 22
- Streptozocin (Zanosar) 500 mg/m2 IV once per day on days 1 to 5
42-day cycles
References
- 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 | Dates 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 (primary endpoint) Median PFS: 11 vs 4.6 mo (HR 0.35, 95% CI 0.27-0.45) Did not meet secondary endpoint of OS1 Median OS: 44 vs 37.7 mo (HR 0.94, 95% CI 0.73-1.20) |
1Reported efficacy for OS is based on the 2016 update.
References
- 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
- 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
- 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
- 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
- COMPETE: NCT03049189
- COMPOSE: NCT04919226
Everolimus & Octreotide
Regimen variant #1
Study | Dates of enrollment | Evidence |
---|---|---|
Yao et al. 2008 | 2005-2006 | Phase 2 |
Targeted therapy
- Everolimus (Afinitor) 5 mg PO once per day on days 1 to 28
Endocrine therapy
- Octreotide LAR (Sandostatin LAR) 30 mg IM once on day 1
28-day cycles
Regimen variant #2
Study | Dates 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
- Everolimus (Afinitor) 10 mg PO once per day on days 1 to 28
Endocrine therapy
- Octreotide LAR (Sandostatin LAR) 30 mg IM once on day 1
28-day cycles
References
- 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
- 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 | Dates of enrollment | Evidence |
---|---|---|
Kouvaraki et al. 2004 | 1992-01 to 2003-09 | Retrospective |
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 to 5
- Doxorubicin (Adriamycin) 40 mg/m2 IV bolus once on day 1
- Streptozocin (Zanosar) 400 mg/m2 IV bolus once per day on days 1 to 5
28-day cycles
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. link to original article contains dosing details in manuscript PubMed
Fluorouracil & Streptozocin
Regimen
Study | Dates 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
- Streptozocin (Zanosar) 500 mg/m2 IV once per day on days 1 to 5
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 to 5
42-day cycles
References
- 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
- 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 | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Caplin et al. 2014 (CLARINET) | 2006-2013 | Phase 3 (E-RT-esc) | Placebo | Superior PFS (primary endpoint) Median PFS: NYR vs 18 mo (HR 0.47, 95% CI 0.30-0.73) |
Endocrine therapy
- Lanreotide (Somatuline) Depot/Autogel 120 mg SC once on day 1
28-day cycle for 96 weeks
References
- 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
Lanreotide & Interferon alfa-2b
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Fjällskog et al. 2002 | NR | Pilot, fewer than 20 pts |
Note: 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)
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. link to original article PubMed
Octreotide monotherapy
Regimen
Study | Evidence |
---|---|
Oberg et al. 2004 | Consensus guideline |
Note: per the consensus guideline, a "reasonable starting dose" was 0.15 mg SC three times per day
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
Continued indefinitely
References
- 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
- 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 | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Rinke et al. 2009 (PROMID) | 2001-2008 | Phase 3 (E-esc) | Placebo | Superior TTP (primary endpoint) Median TTP: 14.3 vs 6 mo (HR 0.34, 95% CI 0.20-0.59) |
Endocrine therapy
- Octreotide LAR (Sandostatin LAR) 30 mg IM once on day 1, with potentially higher doses if needed for symptom control
28-day cycles
References
- 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
- 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
- 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
- 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
- NETTER-2: NCT03972488
Octreotide & Interferon alfa
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Fjällskog et al. 2002 | NR | Pilot, fewer than 20 pts |
Note: 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
- Octreotide (Sandostatin) 0.05 to 0.5 mg SC given two to three times 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)
References
- 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
- 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 | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Strosberg et al. 2017 (NETTER-1) | 2012-2016 | Phase 3 (E-RT-esc) | Octreotide LAR; high-dose | Superior PFS (primary endpoint) Median PFS: NYR vs 8.4 mo (HR 0.21, 95% CI 0.13-0.33) Did not meet secondary endpoint of OS1 Median OS: 48 vs 36.3 mo (HR 0.84, 95% CI 0.60-1.17) |
More cytopenias (neutropenia, thrombocytopenia and lymphopenia) |
1Reported efficacy for OS is based on the 2021 update.
Note: patients had well-differentiated (Ki67 less than 20%) midgut neuroendocrine tumors with somatostatin receptors present in all target lesions
Endocrine therapy
- 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. link to original article contains dosing details in manuscript link to PMC article 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. link to original article PubMed
Sunitinib monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Raymond et al. 2011 (A6181111) | 2007-2009 | Phase 3 (E-RT-esc) | Placebo | Superior PFS1 (primary endpoint) Median PFS: 12.6 vs 5.8 mo (HR 0.32, 95% CI 0.18-0.55) Did not meet secondary endpoint of OS1 Median OS: 38.6 vs 29.1 mo (HR 0.73, 95% CI 0.50-1.06) |
More diarrhea; seems to have worse insomnia |
1Reported efficacy is based on the 2017 update.
References
- 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
- 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
- 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
- Update: Fazio N, Kulke M, Rosbrook B, Fernandez K, Raymond E. Updated Efficacy and Safety Outcomes for Patients with Well-Differentiated Pancreatic Neuroendocrine Tumors Treated with Sunitinib. Target Oncol. 2021 Jan;16(1):27-35. Epub 2021 Jan 7. link to original article link to PMC article PubMed
Temozolomide monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Ekeblad et al. 2007 | 1999-10 to 2006-01 | Retrospective |
Note: Temozolomide dose was increased only if the starting dose is tolerated.
Chemotherapy
- Temozolomide (Temodar) as follows:
- Cycle 1: 100 to 150 mg/m2 PO once per day on days 1 to 5
- Cycle 2 onwards: 200 mg/m2 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
References
- 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 | Dates of enrollment | Evidence |
---|---|---|
Chan et al. 2012 (DFCI 04-272) | 2004-2005 | Phase 2 |
Chemotherapy
- Temozolomide (Temodar) 150 mg/m2 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
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. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00137774
Temozolomide & Thalidomide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Kulke et al. 2006 | NR | Phase 2 |
Chemotherapy
- Temozolomide (Temodar) 150 mg/m2 PO once per day on days 1 to 7, 15 to 21
Targeted therapy
- Thalidomide (Thalomid) 200 mg PO once per day
28-day cycles
References
- 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