Difference between revisions of "Neuroendocrine tumor"
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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.''' | ||
==CommNETS/NANETS== | ==CommNETS/NANETS== | ||
*'''2020:''' Singh et al. [https://doi.org/10.1016/j.jtho.2020.06.021 Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society Guidelines for the Diagnosis and Management of Patients With Lung Neuroendocrine Tumors: An International Collaborative Endorsement and Update of the 2015 European Neuroendocrine Tumor Society Expert Consensus Guidelines] [https://www.ncbi.nlm.nih.gov/pubmed/32663527 PubMed] | *'''2020:''' Singh et al. [https://doi.org/10.1016/j.jtho.2020.06.021 Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society Guidelines for the Diagnosis and Management of Patients With Lung Neuroendocrine Tumors: An International Collaborative Endorsement and Update of the 2015 European Neuroendocrine Tumor Society Expert Consensus Guidelines] [https://www.ncbi.nlm.nih.gov/pubmed/32663527 PubMed] | ||
− | ==[ | + | ==[https://www.esmo.org/ ESMO]== |
*'''2021:''' Baudin et al. [https://doi.org/10.1016/j.annonc.2021.01.003 Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/33482246/ PubMed] | *'''2021:''' Baudin et al. [https://doi.org/10.1016/j.annonc.2021.01.003 Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/33482246/ PubMed] | ||
**'''2012:''' Öberg et al. [https://doi.org/10.1093/annonc/mds267 Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/22997444/ PubMed] | **'''2012:''' Öberg et al. [https://doi.org/10.1093/annonc/mds267 Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/22997444/ PubMed] | ||
+ | **'''2010:''' Oberg et al. [https://doi.org/10.1093/annonc/mdq191 Neuroendocrine bronchial and thymic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/20555085/ PubMed] | ||
**'''2009:''' Oberg & Jelic. [https://doi.org/10.1093/annonc/mdp157 Neuroendocrine bronchial and thymic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454438/ PubMed] | **'''2009:''' Oberg & Jelic. [https://doi.org/10.1093/annonc/mdp157 Neuroendocrine bronchial and thymic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454438/ PubMed] | ||
**'''2008:''' Oberg & Jelic. [https://doi.org/10.1093/annonc/mdn116 Neuroendocrine bronchial and thymic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456740/ PubMed] | **'''2008:''' Oberg & Jelic. [https://doi.org/10.1093/annonc/mdn116 Neuroendocrine bronchial and thymic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456740/ PubMed] | ||
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==NANETS== | ==NANETS== | ||
− | *'''2017:''' Strosberg et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5642985/ The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Midgut Neuroendocrine Tumors] | + | *'''2017:''' Strosberg et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5642985/ The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Midgut Neuroendocrine Tumors] [https://www.ncbi.nlm.nih.gov/pubmed/28609356 PubMed] |
− | + | ||
− | *'''2013:''' Kunz et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4304762/ Consensus Guidelines for the Management and Treatment of Neuroendocrine Tumors] | + | *'''2013:''' Kunz et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4304762/ Consensus Guidelines for the Management and Treatment of Neuroendocrine Tumors] [https://www.ncbi.nlm.nih.gov/pubmed/23591432 PubMed] |
− | + | ||
− | *''NCCN does not have guidelines at this granular level; please see [https://www.nccn.org/ | + | ==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]''. | |
− | *'''2015:''' Kulke et al. [https://doi.org/10.6004/ | + | **'''2015:''' Kulke et al. [https://doi.org/10.6004/Jnccn.2015.0011 Neuroendocrine tumors, version 1.2015.] [https://pubmed.ncbi.nlm.nih.gov/25583772/ PubMed] |
+ | **'''2012:''' Kulke et al. [https://doi.org/10.6004/Jnccn.2012.0075 Neuroendocrine tumors.] [https://pubmed.ncbi.nlm.nih.gov/22679117/ PubMed] | ||
+ | **'''2009:''' Clark et al. [https://doi.org/10.6004/Jnccn.2009.0050 NCCN Clinical Practice Guidelines in Oncology: neuroendocrine tumors.] [https://pubmed.ncbi.nlm.nih.gov/19635226/ PubMed] | ||
+ | **'''2006:''' Clark et al. [https://doi.org/10.6004/Jnccn.2006.0013 Neuroendocrine tumors.] [https://pubmed.ncbi.nlm.nih.gov/16451769/ PubMed] | ||
=All lines of therapy= | =All lines of therapy= | ||
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===References=== | ===References=== | ||
# '''Asan-ONCHBP-2017-002:''' Jeong H, Shin J, Jeong JH, Kim KP, Hong SM, Kim YI, Ryu JS, Ryoo BY, Yoo C. Capecitabine plus temozolomide in patients with grade 3 unresectable or metastatic gastroenteropancreatic neuroendocrine neoplasms with Ki-67 index <55%: single-arm phase II study. ESMO Open. 2021 Jun;6(3):100119. [https://doi.org/10.1016/j.esmoop.2021.100119 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099746/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33901869/ PubMed] [https://clinicaltrials.gov/study/NCT03079440 NCT03079440] | # '''Asan-ONCHBP-2017-002:''' Jeong H, Shin J, Jeong JH, Kim KP, Hong SM, Kim YI, Ryu JS, Ryoo BY, Yoo C. Capecitabine plus temozolomide in patients with grade 3 unresectable or metastatic gastroenteropancreatic neuroendocrine neoplasms with Ki-67 index <55%: single-arm phase II study. ESMO Open. 2021 Jun;6(3):100119. [https://doi.org/10.1016/j.esmoop.2021.100119 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099746/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33901869/ PubMed] [https://clinicaltrials.gov/study/NCT03079440 NCT03079440] | ||
+ | |||
+ | ==Doxorubicin & Fluorouracil {{#subobject:bd83do|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:d3fu72|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/10.1200/JCO.2005.03.616 Sun et al. 2005] | ||
+ | |1981-1990 | ||
+ | |style="background-color:#1a9851"|Phase 2/3 (C) | ||
+ | |[[#Fluorouracil_.26_Streptozocin|Fluorouracil & Streptozocin]] | ||
+ | | style="background-color:#fc8d59" |Seems to have inferior OS | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Chemotherapy==== | ||
+ | *[[Doxorubicin (Adriamycin)]] by the following symptom-based criteria: | ||
+ | **No jaundice: 40 mg/m<sup>2</sup> IV push once on day 1 | ||
+ | **Jaundiced: 25 mg/m<sup>2</sup> IV push once on day 1 | ||
+ | *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV push once per day on days 1 to 5 | ||
+ | '''35-day cycles''' | ||
+ | </div></div> | ||
+ | |||
+ | ===References=== | ||
+ | # '''ECOG E1281:''' Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG; [[Study_Groups#ECOG|ECOG]]. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005 Aug 1;23(22):4897-904. [https://doi.org/10.1200/JCO.2005.03.616 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16051944/ PubMed] | ||
==Everolimus monotherapy {{#subobject:99989f|Regimen=1}}== | ==Everolimus monotherapy {{#subobject:99989f|Regimen=1}}== | ||
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|- | |- | ||
|} --> | |} --> | ||
− | |2012-2013 | + | |2012-04 to 2013-08 |
|style="background-color:#1a9851"|Phase 3 (E-RT-esc) | |style="background-color:#1a9851"|Phase 3 (E-RT-esc) | ||
|[[Neuroendocrine_tumor_-_null_regimens#Placebo|Placebo]] | |[[Neuroendocrine_tumor_-_null_regimens#Placebo|Placebo]] | ||
Line 86: | Line 120: | ||
'''Continued indefinitely''' | '''Continued indefinitely''' | ||
</div></div> | </div></div> | ||
+ | |||
===References=== | ===References=== | ||
# '''RADIANT-4:''' Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H, Voi M, Pacaud LB, Rouyrre N, Sachs C, Valle JW, Fave GD, Van Cutsem E, Tesselaar M, Shimada Y, Oh DY, Strosberg J, Kulke MH, Pavel ME; RAD001 in Advanced Neuroendocrine Tumours Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016 Mar 5;387(10022):968-977. Epub 2015 Dec 17. [https://doi.org/10.1016/S0140-6736(15)00817-X link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063317/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26703889/ PubMed] [https://clinicaltrials.gov/study/NCT01524783 NCT01524783] | # '''RADIANT-4:''' Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H, Voi M, Pacaud LB, Rouyrre N, Sachs C, Valle JW, Fave GD, Van Cutsem E, Tesselaar M, Shimada Y, Oh DY, Strosberg J, Kulke MH, Pavel ME; RAD001 in Advanced Neuroendocrine Tumours Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016 Mar 5;387(10022):968-977. Epub 2015 Dec 17. [https://doi.org/10.1016/S0140-6736(15)00817-X link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063317/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26703889/ PubMed] [https://clinicaltrials.gov/study/NCT01524783 NCT01524783] | ||
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<div class="toccolours" style="background-color:#b3e2cd"> | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Targeted therapy==== | ====Targeted therapy==== | ||
− | *[[Everolimus (Afinitor)]] 5 mg PO once per day | + | *[[Everolimus (Afinitor)]] 5 mg PO once per day on days 1 to 28 |
====Endocrine therapy==== | ====Endocrine therapy==== | ||
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1 | *[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1 | ||
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<div class="toccolours" style="background-color:#b3e2cd"> | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Targeted therapy==== | ====Targeted therapy==== | ||
− | *[[Everolimus (Afinitor)]] 10 mg PO once per day | + | *[[Everolimus (Afinitor)]] 10 mg PO once per day on days 1 to 28 |
====Endocrine therapy==== | ====Endocrine therapy==== | ||
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1 | *[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1 | ||
Line 162: | Line 197: | ||
|[https://doi.org/10.1200/JCO.2005.03.616 Sun et al. 2005] | |[https://doi.org/10.1200/JCO.2005.03.616 Sun et al. 2005] | ||
|1981-1990 | |1981-1990 | ||
− | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) | + | |style="background-color:#1a9851"|Phase 2/3 (E-switch-ic) |
− | |[[#Doxorubicin_. | + | |[[#Doxorubicin_.26_Fluorouracil|Doxorubicin & Fluorouracil]] |
| style="background-color:#91cf60" |Seems to have superior OS | | style="background-color:#91cf60" |Seems to have superior OS | ||
|- | |- | ||
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<div class="toccolours" style="background-color:#b3e2cd"> | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Fluorouracil (5-FU)]] | + | *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV push once per day on days 1 to 5, 36 to 40 |
− | *[[Streptozocin (Zanosar)]] | + | *[[Streptozocin (Zanosar)]] 500 mg/m<sup>2</sup> IV push once per day on days 1 to 5 |
+ | '''10-week cycles''' | ||
</div></div> | </div></div> | ||
+ | |||
===References=== | ===References=== | ||
− | # '''ECOG E5275:''' Engstrom PF, Lavin PT, Moertel CG, Folsch E, Douglass HO Jr. Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol. 1984 Nov;2(11):1255-9. [https://doi.org/10.1200/JCO.1984.2.11.1255 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6238136/ PubMed] | + | # '''ECOG E5275:''' Engstrom PF, Lavin PT, Moertel CG, Folsch E, Douglass HO Jr. Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol. 1984 Nov;2(11):1255-9. [https://doi.org/10.1200/JCO.1984.2.11.1255 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/6238136/ PubMed] |
− | # '''ECOG E1281:''' Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG; [[Study_Groups#ECOG|ECOG]]. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005 Aug 1;23(22):4897-904. [https://doi.org/10.1200/JCO.2005.03.616 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16051944/ PubMed] | + | # '''ECOG E1281:''' Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG; [[Study_Groups#ECOG|ECOG]]. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005 Aug 1;23(22):4897-904. [https://doi.org/10.1200/JCO.2005.03.616 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16051944/ PubMed] |
+ | |||
==Interferon alfa-2b monotherapy {{#subobject:557a2f|Regimen=1}}== | ==Interferon alfa-2b monotherapy {{#subobject:557a2f|Regimen=1}}== | ||
<div class="toccolours" style="background-color:#eeeeee"> | <div class="toccolours" style="background-color:#eeeeee"> | ||
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<div class="toccolours" style="background-color:#b3e2cd"> | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Immunotherapy==== | ====Immunotherapy==== | ||
− | *[[Interferon alfa-2b (Intron-A)]] 5,000,000 units SC once per day, 3 times per week | + | *[[Interferon alfa-2b (Intron-A)]] 5,000,000 units SC once per day on days 1, 3, 5 (3 times per week) |
− | ''' | + | '''7-day cycles''' |
</div> | </div> | ||
<div class="toccolours" style="background-color:#cbd5e7"> | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *Patients who progressed on monotherapy | + | *Patients who progressed on monotherapy: Second-line [[#Lanreotide_.26_Interferon_alfa-2b|lanreotide & interferon alfa]] |
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
# Oberg K, Funa K, Alm G. Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med. 1983 Jul 21;309(3):129-33. [https://doi.org/10.1056/NEJM198307213090301 linkt to original article] [https://pubmed.ncbi.nlm.nih.gov/6191217/ PubMed] | # Oberg K, Funa K, Alm G. Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med. 1983 Jul 21;309(3):129-33. [https://doi.org/10.1056/NEJM198307213090301 linkt to original article] [https://pubmed.ncbi.nlm.nih.gov/6191217/ PubMed] | ||
# Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. [https://doi.org/10.1200/jco.2003.12.142 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12860945/ PubMed] | # Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. [https://doi.org/10.1200/jco.2003.12.142 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12860945/ PubMed] | ||
+ | |||
==Lanreotide monotherapy {{#subobject:c44a4e|Regimen=1}}== | ==Lanreotide monotherapy {{#subobject:c44a4e|Regimen=1}}== | ||
<div class="toccolours" style="background-color:#eeeeee"> | <div class="toccolours" style="background-color:#eeeeee"> | ||
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<div class="toccolours" style="background-color:#cbd5e7"> | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *Faiss et al. 2003, patients who progressed on monotherapy: [[#Lanreotide_.26_Interferon_alfa-2b|Lanreotide & interferon alfa]] | + | *Faiss et al. 2003, patients who progressed on monotherapy: Second-line [[#Lanreotide_.26_Interferon_alfa-2b|Lanreotide & interferon alfa]] |
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
Line 256: | Line 295: | ||
|- | |- | ||
|[https://doi.org/10.4158/ep151172.or Vinik et al. 2016 (ELECT)] | |[https://doi.org/10.4158/ep151172.or Vinik et al. 2016 (ELECT)] | ||
− | | | + | |2009-05 to 2013-05 |
| style="background-color:#1a9851"|Phase 3 (E-esc) | | style="background-color:#1a9851"|Phase 3 (E-esc) | ||
|[[#Placebo_888|Placebo]] | |[[#Placebo_888|Placebo]] | ||
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</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | # '''ELECT:''' Vinik AI, Wolin EM, Liyanage N, Gomez-Panzani E, Fisher GA; ELECT Study Group. Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment (ELECT): A Randomized, Double-Blind, Placebo-Controlled Trial. Endocr Pract. 2016 Sep;22(9):1068-80. Epub 2016 May 23. [https://doi.org/10.4158/ep151172.or link to original article] [https://pubmed.ncbi.nlm.nih.gov/27214300/ PubMed] [https://clinicaltrials.gov/study/NCT00774930 NCT00774930] | + | # '''ELECT:''' Vinik AI, Wolin EM, Liyanage N, Gomez-Panzani E, Fisher GA; ELECT Study Group. Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment (ELECT): A Randomized, Double-Blind, Placebo-Controlled Trial. Endocr Pract. 2016 Sep;22(9):1068-80. Epub 2016 May 23. [https://doi.org/10.4158/ep151172.or link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27214300/ PubMed] [https://clinicaltrials.gov/study/NCT00774930 NCT00774930] |
+ | |||
==Lanreotide & Interferon alfa-2b {{#subobject:ce8ef2|Regimen=1}}== | ==Lanreotide & Interferon alfa-2b {{#subobject:ce8ef2|Regimen=1}}== | ||
<div class="toccolours" style="background-color:#eeeeee"> | <div class="toccolours" style="background-color:#eeeeee"> | ||
Line 319: | Line 359: | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ Strosberg et al. 2017 (NETTER-1)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ Strosberg et al. 2017 (NETTER-1)] | ||
|2012-2016 | |2012-2016 | ||
− | |style="background-color:#1a9851"|Phase 3 (E-RT- | + | |style="background-color:#1a9851"|Phase 3 (E-RT-esc) |
− | |[[#Octreotide_LAR_monotherapy|Octreotide LAR]] | + | |[[#Octreotide_LAR_monotherapy|Octreotide LAR]]; high-dose |
|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) | |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) | ||
|- | |- | ||
Line 334: | Line 374: | ||
'''8-week cycle for 4 cycles, then monthly cycles''' | '''8-week cycle for 4 cycles, then monthly cycles''' | ||
</div></div> | </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] | # '''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] | ## '''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] | ||
# '''ERASMUS:''' Brabander T, van der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA, de Herder WW, van Eijck CHJ, Franssen GJH, Krenning EP, Kwekkeboom DJ. Long-Term Efficacy, Survival, and Safety of [177Lu-DOTA0,Tyr3]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors. Clin Cancer Res. 2017 Aug 15;23(16):4617-4624. Epub 2017 Apr 20. [https://doi.org/10.1158/1078-0432.ccr-16-2743 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28428192/ PubMed] | # '''ERASMUS:''' Brabander T, van der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA, de Herder WW, van Eijck CHJ, Franssen GJH, Krenning EP, Kwekkeboom DJ. Long-Term Efficacy, Survival, and Safety of [177Lu-DOTA0,Tyr3]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors. Clin Cancer Res. 2017 Aug 15;23(16):4617-4624. Epub 2017 Apr 20. [https://doi.org/10.1158/1078-0432.ccr-16-2743 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28428192/ PubMed] | ||
+ | |||
==Octreotide monotherapy {{#subobject:1b6b74|Regimen=1}}== | ==Octreotide monotherapy {{#subobject:1b6b74|Regimen=1}}== | ||
<div class="toccolours" style="background-color:#eeeeee"> | <div class="toccolours" style="background-color:#eeeeee"> | ||
Line 345: | Line 387: | ||
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | !style="width: 25%"|[[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.'' | ||
<div class="toccolours" style="background-color:#b3e2cd"> | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Endocrine therapy==== | ====Endocrine therapy==== | ||
*[[Octreotide (Sandostatin)]] 0.1 to 0.5 mg SC given 2 to four times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms | *[[Octreotide (Sandostatin)]] 0.1 to 0.5 mg SC given 2 to four times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms | ||
− | |||
'''Continued indefinitely''' | '''Continued indefinitely''' | ||
</div></div><br> | </div></div><br> | ||
Line 389: | Line 431: | ||
====Endocrine therapy==== | ====Endocrine therapy==== | ||
*[[Octreotide (Sandostatin)]] 0.1 mg SC twice per day | *[[Octreotide (Sandostatin)]] 0.1 mg SC twice per day | ||
− | |||
'''Continued indefinitely''' | '''Continued indefinitely''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#fff2ae"> | ||
+ | ====Dose and schedule modifications==== | ||
+ | *Patients with persistent carcinoid symptoms could receive increased doses up to 0.2 mg SC three times per day | ||
</div></div><br> | </div></div><br> | ||
<div class="toccolours" style="background-color:#eeeeee"> | <div class="toccolours" style="background-color:#eeeeee"> | ||
Line 412: | Line 457: | ||
# Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003 Jun;90(6):687-93. [https://doi.org/10.1002/bjs.4149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12808615/ PubMed] | # Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003 Jun;90(6):687-93. [https://doi.org/10.1002/bjs.4149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12808615/ PubMed] | ||
# '''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] | # '''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:3fde03|Regimen=1}}== | ==Octreotide LAR monotherapy {{#subobject:3fde03|Regimen=1}}== | ||
<div class="toccolours" style="background-color:#eeeeee"> | <div class="toccolours" style="background-color:#eeeeee"> | ||
Line 458: | Line 504: | ||
|2008-2012 | |2008-2012 | ||
|style="background-color:#1a9851"|Phase 3 (C) | |style="background-color:#1a9851"|Phase 3 (C) | ||
− | |[[# | + | |[[#Pasireotide_LAR_999|Pasireotide LAR]] |
| style="background-color:#ffffbf" |Did not meet primary endpoint of symptom control | | style="background-color:#ffffbf" |Did not meet primary endpoint of symptom control | ||
|- | |- | ||
Line 494: | Line 540: | ||
# '''RADIANT-2:''' Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011 Dec 10;378(9808):2005-12. Epub 2011 Nov 25. [https://doi.org/10.1016/S0140-6736(11)61742-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22119496/ PubMed] [https://clinicaltrials.gov/study/NCT00412061 NCT00412061] | # '''RADIANT-2:''' Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011 Dec 10;378(9808):2005-12. Epub 2011 Nov 25. [https://doi.org/10.1016/S0140-6736(11)61742-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22119496/ PubMed] [https://clinicaltrials.gov/study/NCT00412061 NCT00412061] | ||
## '''Update:''' Pavel ME, Baudin E, Öberg KE, Hainsworth JD, Voi M, Rouyrre N, Peeters M, Gross DJ, Yao JC. Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. 2017 Jul 1;28(7):1569-1575. [https://doi.org/10.1093/annonc/mdx193 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7360141/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28444114/ PubMed] | ## '''Update:''' Pavel ME, Baudin E, Öberg KE, Hainsworth JD, Voi M, Rouyrre N, Peeters M, Gross DJ, Yao JC. Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. 2017 Jul 1;28(7):1569-1575. [https://doi.org/10.1093/annonc/mdx193 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7360141/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28444114/ PubMed] | ||
− | # '''CSOM230C2303:''' Wolin EM, Jarzab B, Eriksson B, Walter T, Toumpanakis C, Morse MA, Tomassetti P, Weber MM, Fogelman DR, Ramage J, Poon D, Gadbaw B, Li J, Pasieka JL, Mahamat A, Swahn F, Newell-Price J, Mansoor W, Öberg K. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin | + | # '''CSOM230C2303:''' Wolin EM, Jarzab B, Eriksson B, Walter T, Toumpanakis C, Morse MA, Tomassetti P, Weber MM, Fogelman DR, Ramage J, Poon D, Gadbaw B, Li J, Pasieka JL, Mahamat A, Swahn F, Newell-Price J, Mansoor W, Öberg K. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther. 2015 Sep 3;9:5075-86. [https://doi.org/10.2147/DDDT.S84177 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562767/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26366058/ PubMed] [https://clinicaltrials.gov/study/NCT00690430 NCT00690430] |
# '''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] | # '''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] | ## '''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] | ||
Line 541: | Line 587: | ||
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1158/1078-0432.ccr-06-2053 Ekeblad et al. 2007] |
| style="background-color:#ffffbe" |Retrospective | | style="background-color:#ffffbe" |Retrospective | ||
|- | |- | ||
|} | |} | ||
+ | ''Note: Temozolomide dose is only increased if tolerated at the prior dose.'' | ||
<div class="toccolours" style="background-color:#b3e2cd"> | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Temozolomide (Temodar)]] as follows: | *[[Temozolomide (Temodar)]] as follows: | ||
**Cycle 1: 100 to 150 mg/m<sup>2</sup> PO once per day on days 1 to 5 | **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 therapy==== | ||
*[[Tropisetron (Navoban)]] (dose/route/schedule not specified) routinely used as an antiemetic | *[[Tropisetron (Navoban)]] (dose/route/schedule not specified) routinely used as an antiemetic | ||
Line 555: | Line 602: | ||
</div></div> | </div></div> | ||
===References=== | ===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. [ | + | # '''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] |
[[Category:Neuroendocrine tumor regimens]] | [[Category:Neuroendocrine tumor regimens]] | ||
[[Category:Disease-specific pages]] | [[Category:Disease-specific pages]] | ||
[[Category:Endocrine cancers]] | [[Category:Endocrine cancers]] |
Revision as of 23:51, 30 June 2024
Section editor | |
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Unfilled If you are interested in this role, please contact us at [email protected]. |
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: This page is now exclusively focused on those tumors commonly called carcinoids, which may or may not be associated with the carcinoid syndrome; there are now separate pages for pancreatic NET and other endocrine cancers. Neuroendocrine tumors of unknown primary and poorly differentiated (high-grade) neuroendocrine carcinomas are usually treated with a small cell lung cancer regimen; see this page for histology-specific options.
14 regimens on this page
20 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.
CommNETS/NANETS
- 2020: Singh et al. Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society Guidelines for the Diagnosis and Management of Patients With Lung Neuroendocrine Tumors: An International Collaborative Endorsement and Update of the 2015 European Neuroendocrine Tumor Society Expert Consensus Guidelines PubMed
ESMO
- 2021: Baudin et al. Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2012: Öberg et al. Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2010: Oberg et al. Neuroendocrine bronchial and thymic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2009: Oberg & Jelic. Neuroendocrine bronchial and thymic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up PubMed
- 2008: Oberg & Jelic. Neuroendocrine bronchial and thymic tumors: ESMO clinical recommendation 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
French Intergroup
- 2020: de Mestier et al. Digestive Neuroendocrine Neoplasms (NEN): French Intergroup clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, GTE, RENATEN, TENPATH, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR) PubMed
NANETS
- 2017: Strosberg et al. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Midgut Neuroendocrine Tumors PubMed
- 2013: Kunz et al. Consensus Guidelines for the Management and Treatment of Neuroendocrine Tumors PubMed
NCCN
- NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Neuroendocrine and Adrenal Tumors.
- 2015: Kulke et al. Neuroendocrine tumors, version 1.2015. PubMed
- 2012: Kulke et al. Neuroendocrine tumors. PubMed
- 2009: Clark et al. NCCN Clinical Practice Guidelines in Oncology: neuroendocrine tumors. PubMed
- 2006: Clark et al. Neuroendocrine tumors. PubMed
All lines of therapy
Capecitabine & Temozolomide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Jeong et al. 2021 (Asan-ONCHBP-2017-002) | 2017-2021 | Phase 2 |
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
28-day cycles
References
- Asan-ONCHBP-2017-002: Jeong H, Shin J, Jeong JH, Kim KP, Hong SM, Kim YI, Ryu JS, Ryoo BY, Yoo C. Capecitabine plus temozolomide in patients with grade 3 unresectable or metastatic gastroenteropancreatic neuroendocrine neoplasms with Ki-67 index <55%: single-arm phase II study. ESMO Open. 2021 Jun;6(3):100119. link to original article link to PMC article PubMed NCT03079440
Doxorubicin & Fluorouracil
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sun et al. 2005 | 1981-1990 | Phase 2/3 (C) | Fluorouracil & Streptozocin | Seems to have inferior OS |
Chemotherapy
- Doxorubicin (Adriamycin) by the following symptom-based criteria:
- No jaundice: 40 mg/m2 IV push once on day 1
- Jaundiced: 25 mg/m2 IV push once on day 1
- Fluorouracil (5-FU) 400 mg/m2 IV push once per day on days 1 to 5
35-day cycles
References
- ECOG E1281: Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG; ECOG. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005 Aug 1;23(22):4897-904. link to original article contains dosing details in manuscript PubMed
Everolimus monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Yao et al. 2015 (RADIANT-4) | 2012-04 to 2013-08 | Phase 3 (E-RT-esc) | Placebo | Superior PFS (primary endpoint) Median PFS: 11 vs 3.9 mo (HR 0.48, 95% CI 0.35-0.67) Might have superior OS (secondary endpoint) Median OS: NYR vs NYR (HR 0.64, 95% CI 0.40-1.05) |
Equivalent HRQoL |
References
- RADIANT-4: Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H, Voi M, Pacaud LB, Rouyrre N, Sachs C, Valle JW, Fave GD, Van Cutsem E, Tesselaar M, Shimada Y, Oh DY, Strosberg J, Kulke MH, Pavel ME; RAD001 in Advanced Neuroendocrine Tumours Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016 Mar 5;387(10022):968-977. Epub 2015 Dec 17. link to original article contains dosing details in abstract link to PMC article PubMed NCT01524783
- HRQoL analysis: Pavel ME, Singh S, Strosberg JR, Bubuteishvili-Pacaud L, Degtyarev E, Neary MP, Carnaghi C, Tomasek J, Wolin E, Raderer M, Lahner H, Valle JW, Pommier R, Van Cutsem E, Tesselaar MET, Fave GD, Buzzoni R, Hunger M, Eriksson J, Cella D, Ricci JF, Fazio N, Kulke MH, Yao JC. Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1411-1422. Epub 2017 Aug 30. link to original article PubMed
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 | Comparator | Comparative Efficacy |
---|---|---|---|---|
Yao et al. 2008 | 2005-2006 | Phase 2 | ||
Pavel et al. 2011 (RADIANT-2) | 2007-2010 | Phase 3 (E-esc) | Octreotide LAR | Seems to have superior PFS (primary endpoint) Median PFS: 16.4 vs 11.3 mo (HR 0.77, 95% CI 0.59-1.00) |
Note: RADIANT-2 did not meet its primary endpoint, based on a pre-specified p-value cutoff of 0.0246.
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-2: Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011 Dec 10;378(9808):2005-12. Epub 2011 Nov 25. link to original article contains dosing details in manuscript PubMed NCT00412061
- Update: Pavel ME, Baudin E, Öberg KE, Hainsworth JD, Voi M, Rouyrre N, Peeters M, Gross DJ, Yao JC. Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. 2017 Jul 1;28(7):1569-1575. link to original article link to PMC article PubMed
Fluorouracil & Streptozocin
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Engstrom et al. 1984 (ECOG E5275) | 1976-1981 | Phase 3 (E-esc) | Doxorubicin | Did not meet co-primary endpoints of ORR/OS |
Sun et al. 2005 | 1981-1990 | Phase 2/3 (E-switch-ic) | Doxorubicin & Fluorouracil | Seems to have superior OS |
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV push once per day on days 1 to 5, 36 to 40
- Streptozocin (Zanosar) 500 mg/m2 IV push once per day on days 1 to 5
10-week cycles
References
- ECOG E5275: Engstrom PF, Lavin PT, Moertel CG, Folsch E, Douglass HO Jr. Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol. 1984 Nov;2(11):1255-9. link to original article contains dosing details in manuscript PubMed
- ECOG E1281: Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG; ECOG. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005 Aug 1;23(22):4897-904. link to original article contains dosing details in manuscript PubMed
Interferon alfa-2b monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Oberg et al. 1983 | NR | Non-randomized, fewer than 20 pts | ||
Faiss et al. 2003 | 1995-1998 | Phase 3 (E-de-esc) | 1. Lanreotide | Did not meet primary endpoint of ORR at 12 mo |
2. Lanreotide & Interferon alfa-2b | Did not meet primary endpoint of ORR at 12 mo |
Note: Treatment details are from Faiss et al. 2003.
Immunotherapy
- Interferon alfa-2b (Intron-A) 5,000,000 units SC once per day on days 1, 3, 5 (3 times per week)
7-day cycles
Subsequent treatment
- Patients who progressed on monotherapy: Second-line lanreotide & interferon alfa
References
- Oberg K, Funa K, Alm G. Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med. 1983 Jul 21;309(3):129-33. linkt to original article PubMed
- Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. link to original article contains dosing details in manuscript PubMed
Lanreotide monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Faiss et al. 2003 | 1995-1998 | Phase 3 (E-de-esc) | 1. Interferon alfa-2b | Did not meet primary endpoint of ORR at 12 mo |
2. Lanreotide & Interferon alfa-2b | Did not meet primary endpoint of ORR at 12 mo |
Subsequent treatment
- Faiss et al. 2003, patients who progressed on monotherapy: Second-line Lanreotide & interferon alfa
References
- Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. link to original article contains dosing details in manuscript PubMed
Lanreotide LAR monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Vinik et al. 2016 (ELECT) | 2009-05 to 2013-05 | Phase 3 (E-esc) | Placebo | Decreased need for short-acting octreotide rescue (primary endpoint) |
Endocrine therapy
- Lanreotide LAR (Somatuline Depot) 120 mg IM once on day 1
28-day cycle for 4 cycles
References
- ELECT: Vinik AI, Wolin EM, Liyanage N, Gomez-Panzani E, Fisher GA; ELECT Study Group. Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment (ELECT): A Randomized, Double-Blind, Placebo-Controlled Trial. Endocr Pract. 2016 Sep;22(9):1068-80. Epub 2016 May 23. link to original article contains dosing details in manuscript PubMed NCT00774930
Lanreotide & Interferon alfa-2b
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Faiss et al. 2003 | 1995-1998 | Phase 3 (E-esc) | 1. Interferon alfa-2b | Did not meet primary endpoint of ORR at 12 mo |
2. Lanreotide | Did not meet primary endpoint of ORR at 12 mo |
Endocrine therapy
- Lanreotide (Somatuline) 1 mg SC three times per day
Immunotherapy
- Interferon alfa-2b (Intron-A) 5,000,000 units SC once per day, 3 times per week
References
- Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. link to original article contains dosing details in manuscript PubMed
Lutetium Lu 177 dotatate & Octreotide LAR
FDA-recommended dose |
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brabander et al. 2017 (ERASMUS) | 2000-2015 | Case series (RT) | ||
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) |
Radioconjugate therapy
- Lutetium Lu 177 dotatate (Lutathera) 7.4 GBq (200 mCi) IV over 30 minutes once on day 1
8-week cycle for 4 cycles
Endocrine therapy
- Octreotide LAR (Sandostatin LAR) as follows:
- Cycles 1 to 4: 30 mg IM once on day 2, given approximately 24 hours after lutetium Lu 177 dotatate
- Cycle 5 onwards: 30 mg IM once on day 1
8-week cycle for 4 cycles, then monthly 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
- ERASMUS: Brabander T, van der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA, de Herder WW, van Eijck CHJ, Franssen GJH, Krenning EP, Kwekkeboom DJ. Long-Term Efficacy, Survival, and Safety of [177Lu-DOTA0,Tyr3]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors. Clin Cancer Res. 2017 Aug 15;23(16):4617-4624. Epub 2017 Apr 20. link to original article PubMed
Octreotide monotherapy
Regimen variant #1
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 2 to four times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms
Continued indefinitely
Regimen variant #2
Study | Evidence |
---|---|
Kvols et al. 1986 | Phase 2 |
Endocrine therapy
- Octreotide (Sandostatin) 0.15 mg SC twice per day on days 1 & 2, then 0.15 mg SC three times per day from day 3 onward
Continued indefinitely
Regimen variant #3
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kölby et al. 2003 | 1991-1998 | Randomized Phase 2 (C) | Octreotide & Interferon alfa | Inferior TTP |
Dose and schedule modifications
- Patients with persistent carcinoid symptoms could receive increased doses up to 0.2 mg SC three times per day
Regimen variant #4, low-dose
Study | Evidence |
---|---|
Janson & Oberg 1993 | Non-randomized |
References
- Kvols LK, Moertel CG, O'Connell MJ, Schutt AJ, Rubin J, Hahn RG. Treatment of the malignant carcinoid syndrome: evaluation of a long-acting somatostatin analogue. N Engl J Med. 1986 Sep 11;315(11):663-6. link to original article contains dosing details in manuscript PubMed
- 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 contains dosing details in abstract PubMed
- Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003 Jun;90(6):687-93. link to original article contains dosing details in manuscript 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 variant #1, 30 mg
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) Did not meet secondary endpoint of OS1 Median OS: 84.7 vs 83.7 mo (HR 0.83, 95% CI 0.47-1.46) |
Pavel et al. 2011 (RADIANT-2) | 2007-2010 | Phase 3 (C) | Octreotide LAR & Everolimus | Seems to have inferior PFS |
1Reported efficacy for OS in PROMID is based on the 2016 update.
Note: RADIANT-2 did not meet its primary endpoint, based on a pre-specified p-value cutoff of 0.0246.
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
Regimen variant #2, 40 mg
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wolin et al. 2015 (CSOM230C2303) | 2008-2012 | Phase 3 (C) | Pasireotide LAR | Did not meet primary endpoint of symptom control |
Regimen variant #3, 60 mg
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Strosberg et al. 2017 (NETTER-1) | 2012-2016 | Phase 3 (C) | Lutetium Lu 177 dotatate & Octreotide LAR | Inferior PFS |
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
- Update: Rinke A, Wittenberg M, Schade-Brittinger C, Aminossadati B, Ronicke E, Gress TM, Müller HH, Arnold R; PROMID Study Group. Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors (PROMID): Results of Long-Term Survival. Neuroendocrinology. 2017;104(1):26-32. Epub 2016 Jan 6. link to original article PubMed
- RADIANT-2: Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011 Dec 10;378(9808):2005-12. Epub 2011 Nov 25. link to original article contains dosing details in manuscript PubMed NCT00412061
- Update: Pavel ME, Baudin E, Öberg KE, Hainsworth JD, Voi M, Rouyrre N, Peeters M, Gross DJ, Yao JC. Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. 2017 Jul 1;28(7):1569-1575. link to original article link to PMC article PubMed
- CSOM230C2303: Wolin EM, Jarzab B, Eriksson B, Walter T, Toumpanakis C, Morse MA, Tomassetti P, Weber MM, Fogelman DR, Ramage J, Poon D, Gadbaw B, Li J, Pasieka JL, Mahamat A, Swahn F, Newell-Price J, Mansoor W, Öberg K. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther. 2015 Sep 3;9:5075-86. link to original article link to PMC article contains dosing details in abstract PubMed NCT00690430
- 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
Octreotide & Interferon alfa
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kölby et al. 2003 | 1991-1998 | Randomized Phase 2 (E-esc) | Octreotide LAR | Superior TTP |
Yao et al. 2017 (SWOG S0518) | 2007-2012 | Phase 3 (C) | Octreotide & Bevacizumab | Did not meet primary endpoint of PFS |
Note: Kölby et al. 2003 did not specifically say whether Interferon alfa-2b (Intron-A) or Interferon alfa-2a (Roferon-A) was used.
Endocrine therapy
- Octreotide (Sandostatin) 0.1 mg SC twice per day
- Patients with persistent carcinoid symptoms could receive increased doses up to 0.2 mg SC three times per day
Immunotherapy
- Interferon alfa-2b (Intron-A) 3,000,000 units (route not specified) once per day, 3 days per week
- Increased as needed based on symptoms up to 5,000,000 units (route not specified) once per day, 5 days 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
- Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003 Jun;90(6):687-93. link to original article contains dosing details in manuscript PubMed
- SWOG S0518: Yao JC, Guthrie KA, Moran C, Strosberg JR, Kulke MH, Chan JA, LoConte N, McWilliams RR, Wolin EM, Mattar B, McDonough S, Chen H, Blanke CD, Hochster HS. Phase III Prospective Randomized Comparison Trial of Depot Octreotide Plus Interferon Alfa-2b Versus Depot Octreotide Plus Bevacizumab in Patients With Advanced Carcinoid Tumors: SWOG S0518. J Clin Oncol. 2017 May 20;35(15):1695-1703. Epub 2017 Apr 6. link to original article link to PMC article PubMed NCT00569127
Temozolomide monotherapy
Regimen
Study | Evidence |
---|---|
Ekeblad et al. 2007 | Retrospective |
Note: Temozolomide dose is only increased if tolerated at the prior dose.
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