Neuroendocrine tumor

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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.
Last updated on 2024-07-23:14 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 EuroPMC
==ESMO==
*2024: Hadoux et al. Neuroendocrine neoplasms of head and neck, genitourinary and gynaecological systems, unknown primaries, parathyroid carcinomas and intrathyroid thymic neoplasms: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up EuroPMC
*2021: Baudin et al. Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2012: Öberg et al. Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2010: Oberg et al. Neuroendocrine bronchial and thymic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2009: Oberg & Jelic. Neuroendocrine bronchial and thymic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up EuroPMC
**2008: Oberg & Jelic. Neuroendocrine bronchial and thymic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up EuroPMC
*2012: Öberg et al. Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. EuroPMC
==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) EuroPMC
==NANETS==
*2017: Strosberg et al. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Midgut Neuroendocrine Tumors EuroPMC
*2013: Kunz et al. Consensus Guidelines for the Management and Treatment of Neuroendocrine Tumors EuroPMC
==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. EuroPMC
**2012: Kulke et al. Neuroendocrine tumors. EuroPMC
**2009: Clark et al. NCCN Clinical Practice Guidelines in Oncology: neuroendocrine tumors. EuroPMC
**2006: Clark et al. Neuroendocrine tumors. EuroPMC
==SEOM-GETNE==
*2023: Castillón et al. SEOM-GETNE clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2022) EuroPMC
=All lines of therapy=
==Cabozantinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Chan et al. 2024 (CABINET extrapancreatic)	2018-10 to 2023-08 	Phase 3 (E-esc)	Placebo 	Longer PFS (primary endpoint)Median PFS: 8.4 vs 3.9 mo(HR 0.38, 95% CI 0.25-0.59)
====Targeted therapy====
*Cabozantinib (Cometriq) 60 mg PO once per day
Continued indefinitely
===References===
#CABINET extrapancreatic: Chan JA, Geyer S, Zemla T, Knopp MV, Behr S, Pulsipher S, Ou FS, Dueck AC, Acoba J, Shergill A, Wolin EM, Halfdanarson TR, Konda B, Trikalinos NA, Tawfik B, Raj N, Shaheen S, Vijayvergia N, Dasari A, Strosberg JR, Kohn EC, Kulke MH, O'Reilly EM, Meyerhardt JA. Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors. N Engl J Med. 2025 Feb;392(7):653-665. Epub 2024 Sep 18. link to original article dosing details in manuscript have been reviewed by our editors link to EuroPMC NCT03375320
==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 EuroPMC NCT03079440
==Doxorubicin & Fluorouracil==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Sun et al. 2005 (ECOG E1281)	1981-1990 	Phase 2/3 (C)	Fluorouracil & Streptozocin	Seems to have shorter OS (secondary endpoint)Median OS: 15.7 vs 24.3 mo(HR not reported, p=0.0267)
====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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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 	Longer PFS (primary endpoint)Median PFS: 11 vs 3.9 mo(HR 0.48, 95% CI 0.35-0.67)Might have longer OS (secondary endpoint)Median OS: NYR vs NYR(HR 0.64, 95% CI 0.40-1.05)	Equivalent HRQoL
====Targeted therapy====
*Everolimus (Afinitor) 10 mg PO once per day
Continued indefinitely
===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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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 EuroPMC
==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 longer 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 EuroPMC
==Fluorouracil & Streptozocin==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Engstrom et al. 1984 (ECOG E5275)	1976-1981 	Phase 2/3 (E-esc) 	Doxorubicin 	Did not meet co-primary endpoints of ORR/OS
Sun et al. 2005 (ECOG E1281) 	1981-1990 	Phase 2/3 (E-switch-ic)	Doxorubicin & Fluorouracil	Seems to have longer OS (secondary endpoint)Median OS: 24.3 vs 15.7 mo(HR not reported, p=0.0267)
====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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Interferon alfa-2b monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Oberg et al. 1983	Not reported 	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
Faiss et al. 2003	1995-1998 	Phase 3 (E-de-esc) 	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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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
Faiss et al. 2003	1995-1998 	Phase 3 (E-de-esc)	2. Lanreotide & Interferon alfa-2b	Did not meet primary endpoint of ORR at 12 mo
====Endocrine therapy====
*Lanreotide (Somatuline) 1 mg SC three times per day
Continued indefinitely 
====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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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 dosing details in manuscript have been reviewed by our editors EuroPMC 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
Faiss et al. 2003	1995-1998 	Phase 3 (E-esc)	2. Lanreotide 	Did not meet primary endpoint of ORR at 12 mo
====Endocrine therapy====
*Lanreotide (Somatuline) 1 mg SC three times per day on days 1 to 7
====Immunotherapy====
*Interferon alfa-2b (Intron-A) 5,000,000 units SC once per day on days 1, 3, 5
7-day cycles
===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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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	Longer 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 OS1Median OS: 48 vs 36.3 mo(HR 0.84, 95% CI 0.60-1.17)
1Reported efficacy for NETTER-1 is based on the 2021 update.
====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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01578239
##HRQoL analysis: Strosberg J, Wolin E, Chasen B, Kulke M, Bushnell D, Caplin M, Baum RP, Kunz P, Hobday T, Hendifar A, Oberg K, Sierra ML, Thevenet T, Margalet I, Ruszniewski P, Krenning E; NETTER-1 Study Group. Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With 177Lu-Dotatate in the Phase III NETTER-1 Trial. J Clin Oncol. 2018 Sep;36(25):2578-2584. link to original article link to EuroPMC
## 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 EuroPMC
# 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 EuroPMC
==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 	Dates of enrollment	Evidence
Kvols et al. 1986	Not reported 	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	Shorter TTP(HR 3.57, 95% CI 2.22-6.25)
====Endocrine therapy====
*Octreotide (Sandostatin) 0.1 mg SC twice per day
Continued indefinitely
====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 	Dates of enrollment	Evidence
Janson & Oberg 1993	Not reported 	Non-randomized
====Endocrine therapy====
*Octreotide (Sandostatin) 0.05 mg SC twice per day
Continued indefinitely
===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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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 	Longer 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 OS1Median 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 shorter PFSMedian PFS: 11.3 vs 16.4 mo(HR 1.30, 95% CI 1.00-1.69)
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
====Endocrine therapy====
*Octreotide LAR (Sandostatin LAR) 40 mg IM once on day 1
28-day cycles
===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	Shorter PFS (primary endpoint)Median PFS: 8.4 vs NYR mo(HR 4.76, 95% CI 3.03-7.69)Did not meet secondary endpoint of OS1Median OS: 36.3 vs 48 mo(HR 1.19, 95% CI 0.85-1.67)
1Reported efficacy is based on the 2021 update.
====Endocrine therapy====
*Octreotide LAR (Sandostatin LAR) 60 mg IM once on day 1
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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 EuroPMC
##HRQoL analysis: Rinke A, Neary MP, Eriksson J, Hunger M, Doan T, Karli D, Arnold R. Health-Related Quality of Life for Long-Acting Octreotide versus Placebo in Patients with Metastatic Midgut Neuroendocrine Tumors in the Phase 3 PROMID Trial. Neuroendocrinology. 2019;109(2):141-151. Epub 2019 Mar 11. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01578239
##HRQoL analysis: Strosberg J, Wolin E, Chasen B, Kulke M, Bushnell D, Caplin M, Baum RP, Kunz P, Hobday T, Hendifar A, Oberg K, Sierra ML, Thevenet T, Margalet I, Ruszniewski P, Krenning E; NETTER-1 Study Group. Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With 177Lu-Dotatate in the Phase III NETTER-1 Trial. J Clin Oncol. 2018 Sep;36(25):2578-2584. link to original article link to EuroPMC
## 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 EuroPMC
==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 	Longer TTP(HR 0.28, 95% CI 0.16-0.45)
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 on days 1 to 7
====Immunotherapy====
*Interferon alfa-2b (Intron-A) 3,000,000 units (route not specified) once per day on days 1, 3, 5 (3 times per week)
7-day cycles
====Dose and schedule modifications====
*Patients with persistent carcinoid symptoms could receive increased doses of octreotide up to 0.2 mg SC three times per day
*Interferon alfa-2b 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC NCT00569127
==Temozolomide monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Ekeblad et al. 2007	1999-10 to 2006-01 	Retrospective
Note: Temozolomide dose was 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 dosing details in manuscript have been reviewed by our editors EuroPMC
Category:Neuroendocrine tumor regimens
Category:Disease-specific pages
Category:Endocrine cancers