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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

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 contains dosing details in abstract link to PMC article PubMed NCT01524783
1. 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
1. 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
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 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
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 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
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

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
1. Update: Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. link to original article PubMed
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

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	Evidence
Janson & Oberg 1993	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 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

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	Inferior PFS

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 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
1. 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
1. 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
1. Update: Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. link to original article PubMed

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

@@ Line 3: / Line 3: @@
 [[#top|Back to Top]]
 </div>
+{{#lst:Editorial board transclusions|endo}}
 ''Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit [[Neuroendocrine tumor - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''<br>
-<big>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 tumors are usually treated with a '''[[small cell lung cancer]]''' regimen.</big>
+<big>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 [[Neuroendocrine carcinoma|this page]] for histology-specific options.</big>
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
@@ Line 13: / Line 13: @@
 {{TOC limit|limit=3}}
 =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. [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]
+*'''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]
-==[http://www.esmo.org/ ESMO]==
+==[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]
+*'''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]
-===Older===
+**'''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://www.esmo.org/Guidelines/Endocrine-and-Neuroendocrine-Cancers/Neuroendocrine-Bronchial-and-Thymic-Tumours Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.]
+**'''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]
-*'''2012:''' Öberg et al. [http://annonc.oxfordjournals.org/content/23/suppl_7/vii124.full.pdf+html Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.] [https://pubmed.ncbi.nlm.nih.gov/22997445 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]
+*'''2012:''' Öberg et al. [https://doi.org/10.1093/annonc/mds295 Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.] [https://pubmed.ncbi.nlm.nih.gov/22997445/ PubMed]
+==French Intergroup==
+*'''2020:''' de Mestier et al. [https://doi.org/10.1016/j.dld.2020.02.011 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)] [https://pubmed.ncbi.nlm.nih.gov/32234416/ PubMed]
 ==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]
-===Older===
-*'''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]
-==[https://www.nccn.org/ NCCN]==
+==NCCN==
-*[https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf NCCN Guidelines - Neuroendocrine Tumors]
+*''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/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=
+==Capecitabine & Temozolomide {{#subobject:d67u17|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:9a3c15|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099746/ Jeong et al. 2021 (Asan-ONCHBP-2017-002)]
+|2017-2021
+| style="background-color:#91cf61" |Phase 2
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day on days 10 to 14
+'''28-day cycles'''
+</div></div>
+===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]
+==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}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:4ef82e|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 17%"|Study
-!style="width: 15%"|Years of enrollment
+!style="width: 15%"|Dates of enrollment
 !style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 17%"|Comparator
@@ Line 44: / Line 104: @@
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063317/ Yao et al. 2015 (RADIANT-4)]
-|2012-2013
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-93-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
+|-
+|} -->
+|2012-04 to 2013-08
 |style="background-color:#1a9851"|Phase 3 (E-RT-esc)
 |[[Neuroendocrine_tumor_-_null_regimens#Placebo|Placebo]]
-| style="background-color:#d9ef8b" |Might have superior OS<br>Median OS: NYR vs NYR<br>(HR 0.64, 95% CI 0.40-1.05)
+| style="background-color:#d9ef8b" |Superior PFS (primary endpoint)<br>Median PFS: 11 vs 3.9 mo<br>(HR 0.48, 95% CI 0.35-0.67)<br><br>Might have superior OS (secondary endpoint)<br>Median OS: NYR vs NYR<br>(HR 0.64, 95% CI 0.40-1.05)
 |style="background-color:#eeee01"|Equivalent HRQoL
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
 *[[Everolimus (Afinitor)]] 10 mg PO once per day
 '''Continued indefinitely'''
+</div></div>
 ===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://www.thelancet.com/journals/lancet/article/PIIS0140-6736(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] 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]
-## '''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30471-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28838862 PubMed]
+## '''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. [https://doi.org/10.1016/S1470-2045(17)30471-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28838862/ PubMed]
 ==Everolimus & Octreotide {{#subobject:d69a17|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #1 {{#subobject:9dd15|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 33%"|Dates of enrollment
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
@@ Line 73: / Line 138: @@
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====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====
 *[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1
 '''28-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2 {{#subobject:867317|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 94: / Line 160: @@
 | style="background-color:#d3d3d3" |
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61742-X Pavel et al. 2011 (RADIANT-2)]
+|[https://doi.org/10.1016/S0140-6736(11)61742-X Pavel et al. 2011 (RADIANT-2)]
 |2007-2010
 |style="background-color:#1a9851"|Phase 3 (E-esc)
 |[[#Octreotide_LAR_monotherapy|Octreotide LAR]]
-|style="background-color:#91cf60"|Seems to have superior PFS<br>Median PFS: 16.4 vs 11.3 mo<br>(HR 0.77, 95% CI 0.59-1.00)
+|style="background-color:#91cf60"|Seems to have superior PFS (primary endpoint)<br>Median PFS: 16.4 vs 11.3 mo<br>(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.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
-*[[Everolimus (Afinitor)]] 10 mg PO once per day
+*[[Everolimus (Afinitor)]] 10 mg PO once per day on days 1 to 28
 ====Endocrine therapy====
 *[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1
 '''28-day cycles'''
+</div></div>
 ===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. [https://doi.org/10.1200/jco.2008.16.7858 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18779618 PubMed]
+# Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008 Sep 10;26(26):4311-8. [https://doi.org/10.1200/jco.2008.16.7858 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18779618/ PubMed]
-# '''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://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61742-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22119496 PubMed] 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://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]
 ==Fluorouracil & Streptozocin {{#subobject:bd8397|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:d34072|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 127: / Line 192: @@
 |1976-1981
 |style="background-color:#1a9851"|Phase 3 (E-esc)
-|[[#Doxorubicin_monotherapy_88|Doxorubicin]]
+|[[#Doxorubicin_monotherapy_888|Doxorubicin]]
-| style="background-color:#ffffbf" |Did not meet primary endpoints of ORR/OS
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of ORR/OS
 |-
 |[https://doi.org/10.1200/JCO.2005.03.616 Sun et al. 2005]
 |1981-1990
-|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
+|style="background-color:#1a9851"|Phase 2/3 (E-switch-ic)
-|[[#Doxorubicin_.26_Fluorouracil_88|Doxorubicin & Fluorouracil]]
+|[[#Doxorubicin_.26_Fluorouracil|Doxorubicin & Fluorouracil]]
 | style="background-color:#91cf60" |Seems to have superior OS
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====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>
 ===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}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:a0cb2f|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 158: / Line 225: @@
 |[https://doi.org/10.1056/NEJM198307213090301 Oberg et al. 1983]
 |NR
-| style="background-color:#ffffbe" |Non-randomized, <20 pts
+| style="background-color:#ffffbe" |Non-randomized, fewer than 20 pts
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
@@ Line 172: / Line 239: @@
 |-
 |}
-''Treatment details are from Faiss et al. 2003.''
+''Note: Treatment details are from Faiss et al. 2003.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====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'''
-'''Continued indefinitely'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*Patients who progressed on monotherapy then received [[#Lanreotide_.26_Interferon_alfa-2b|lanreotide & interferon alfa]]
+*Patients who progressed on monotherapy: Second-line [[#Lanreotide_.26_Interferon_alfa-2b|lanreotide & interferon alfa]]
+</div></div>
 ===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}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:171ae2|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 205: / Line 273: @@
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Endocrine therapy====
 *[[Lanreotide (Somatuline)]] 1 mg SC three times per day
 '''Continued indefinitely'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====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>
 ===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. [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 LAR monotherapy {{#subobject:c4ugjc|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:741ae2|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 227: / Line 295: @@
 |-
 |[https://doi.org/10.4158/ep151172.or Vinik et al. 2016 (ELECT)]
-|NR in abstract
+|2009-05 to 2013-05
 | style="background-color:#1a9851"|Phase 3 (E-esc)
-|[[#Placebo_88|Placebo]]
+|[[#Placebo_888|Placebo]]
-| style="background-color:#1a9850" |Decreased need for short-acting octreotide rescue
+| style="background-color:#1a9850" |Decreased need for short-acting octreotide rescue (primary endpoint)
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Endocrine therapy====
 *[[Lanreotide LAR (Somatuline Depot)]] 120 mg IM once on day 1
 '''28-day cycle for 4 cycles'''
+</div></div>
 ===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] 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}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:87b3d6|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 262: / Line 329: @@
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====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
+</div></div>
 ===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. [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]
 ==Lutetium Lu 177 dotatate & Octreotide LAR {{#subobject:eca71b|Regimen=1}}==
 {| class="wikitable" style="color:white; background-color:#404040"
 |<small>'''FDA-recommended dose'''</small>
 |-
 |}
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:9df044|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 292: / Line 359: @@
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ Strosberg et al. 2017 (NETTER-1)]
 |2012-2016
-|style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc)
+|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<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)
 |-
 |}
-''This is the FDA-recommended dose.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====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'''
+</div></div>
 ===References===
-# '''NETTER-1:''' Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. [https://doi.org/10.1056/NEJMoa1607427 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28076709 PubMed] NCT01578239
+# '''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]
 ==Octreotide monotherapy {{#subobject:1b6b74|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #1 {{#subobject:eb529b|Variant=1}}===
 {| class="wikitable" style="width: 40%; text-align:center;"
@@ Line 327: / Line 391: @@
 |-
 |}
+''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">
 ====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
-**"A reasonable starting dose is" 0.15 mg SC three times per day
 '''Continued indefinitely'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2 {{#subobject:29f57|Variant=1}}===
 {| class="wikitable" style="width: 40%; text-align:center;"
@@ Line 342: / Line 407: @@
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====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'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #3 {{#subobject:a531c2|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!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://onlinelibrary.wiley.com/doi/10.1002/bjs.4149 Kölby et al. 2003]
+|[https://doi.org/10.1002/bjs.4149 Kölby et al. 2003]
 |1991-1998
 |style="background-color:#1a9851"|Randomized Phase 2 (C)
@@ Line 362: / Line 428: @@
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====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
 '''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 class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #4, low-dose {{#subobject:512195|Variant=1}}===
 {| class="wikitable" style="width: 40%; text-align:center;"
@@ Line 373: / Line 443: @@
 !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.tandfonline.com/doi/full/10.3109/02841869309083916 Janson & Oberg 1993]
+|[https://doi.org/10.3109/02841869309083916 Janson & Oberg 1993]
 |style="background-color:#91cf61"|Non-randomized
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Endocrine therapy====
 *[[Octreotide (Sandostatin)]] 0.05 mg SC twice per day
 '''Continued indefinitely'''
+</div></div>
 ===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. [https://doi.org/10.1056/NEJM198609113151102 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2427948 PubMed]
+# 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. [https://doi.org/10.1056/NEJM198609113151102 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2427948/ 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. [https://www.tandfonline.com/doi/full/10.3109/02841869309083916 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7686765 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. [https://doi.org/10.3109/02841869309083916 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7686765/ 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://onlinelibrary.wiley.com/doi/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}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #1, 30 mg {{#subobject:38d708|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 400: / Line 469: @@
 |-
 |[https://doi.org/10.1200/jco.2009.22.8510 Rinke et al. 2009 (PROMID)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-150-1 <span style="color:white;">ESMO-MCBS (2)</span>]'''
+|-
+|} -->
 |2001-2008
 |style="background-color:#1a9851"|Phase 3 (E-esc)
 |[[Neuroendocrine_tumor_-_null_regimens#Placebo|Placebo]]
-|style="background-color:#1a9850"|Superior TTP<br>Median TTP: 14.3 vs 6 mo<br>(HR 0.34, 95% CI 0.20-0.59)
+|style="background-color:#1a9850"|Superior TTP (primary endpoint)<br>Median TTP: 14.3 vs 6 mo<br>(HR 0.34, 95% CI 0.20-0.59)<br><br>Did not meet secondary endpoint of OS<sup>1</sup><br>Median OS: 84.7 vs 83.7 mo<br>(HR 0.83, 95% CI 0.47-1.46)
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61742-X Pavel et al. 2011 (RADIANT-2)]
+|[https://doi.org/10.1016/S0140-6736(11)61742-X Pavel et al. 2011 (RADIANT-2)]
 |2007-2010
 |style="background-color:#1a9851"|Phase 3 (C)
@@ Line 412: / Line 485: @@
 |-
 |}
+''<sup>1</sup>Reported efficacy for OS in PROMID is based on the 2016 update.''<br>
 ''Note: RADIANT-2 did not meet its primary endpoint, based on a pre-specified p-value cutoff of 0.0246.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Endocrine therapy====
 *[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1, with potentially higher doses if needed for symptom control
 '''28-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2, 40 mg {{#subobject:7c7215a|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 429: / Line 504: @@
 |2008-2012
 |style="background-color:#1a9851"|Phase 3 (C)
-|[[#Pasireotide_LAR_77|Pasireotide LAR]]
+|[[#Pasireotide_LAR_999|Pasireotide LAR]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of symptom control
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Endocrine therapy====
 *[[Octreotide LAR (Sandostatin LAR)]] 40 mg IM once on day 1
 '''28-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #3, 60 mg {{#subobject:7c826a|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 453: / Line 529: @@
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Endocrine therapy====
 *[[Octreotide LAR (Sandostatin LAR)]] 60 mg IM once on day 1
 '''28-day cycles'''
+</div></div>
 ===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. [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]
-# '''PROMID:''' Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. [https://doi.org/10.1200/jco.2009.22.8510 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19704057 PubMed] NCT00171873
+# '''PROMID:''' Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. [https://doi.org/10.1200/jco.2009.22.8510 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19704057/ PubMed] [https://clinicaltrials.gov/study/NCT00171873 NCT00171873]
-# '''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://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61742-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22119496 PubMed] NCT00412061
+##'''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. [https://doi.org/10.1159/000443612 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26731483/ 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://pubmed.ncbi.nlm.nih.gov/28444114 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. [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]
-# '''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://www.dovepress.com/phase-iii-study-of-pasireotide-long-acting-release-in-patients-with-me-peer-reviewed-article-DDDT 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] NCT00690430
+## '''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]
-# '''NETTER-1:''' Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. [https://doi.org/10.1056/NEJMoa1607427 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28076709 PubMed] NCT01578239
+# '''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]
-## '''Update:''' Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. [https://doi.org/10.1016/s1470-2045(21)00572-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34793718/ PubMed]
+# '''NETTER-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]
 ==Octreotide & Interferon alfa {{#subobject:dea906|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:b5051e|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!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://onlinelibrary.wiley.com/doi/10.1002/bjs.4149 Kölby et al. 2003]
+|[https://doi.org/10.1002/bjs.4149 Kölby et al. 2003]
 |1991-1998
 |style="background-color:#1a9851"|Randomized Phase 2 (E-esc)
@@ Line 487: / Line 563: @@
 |2007-2012
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Octreotide_.26_Bevacizumab_99|Octreotide & Bevacizumab]]
+|[[#Octreotide_.26_Bevacizumab_999|Octreotide & Bevacizumab]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |}
-''Kölby et al. 2003 did not specifically say whether [[Interferon alfa-2b (Intron-A)]] or [[Interferon alfa-2a (Roferon-A)]] was used.''
+''Note: Kölby et al. 2003 did not specifically say whether [[Interferon alfa-2b (Intron-A)]] or [[Interferon alfa-2a (Roferon-A)]] was used.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Endocrine therapy====
 *[[Octreotide (Sandostatin)]] 0.1 mg SC twice per day
@@ Line 498: / Line 575: @@
 *[[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
+</div></div>
 ===References===
-# Janson ET, Oberg K. Long-term management of the carcinoid syndrome: treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. [https://www.tandfonline.com/doi/full/10.3109/02841869309083916 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7686765 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. [https://doi.org/10.3109/02841869309083916 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7686765/ 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://onlinelibrary.wiley.com/doi/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]
-# '''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. [https://doi.org/10.1200/JCO.2016.70.4072 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455764/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28384065 PubMed] NCT00569127
+# '''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. [https://doi.org/10.1200/JCO.2016.70.4072 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455764/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28384065/ PubMed] [https://clinicaltrials.gov/study/NCT00569127 NCT00569127]
 ==Temozolomide monotherapy {{#subobject:5db4de|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:7e3904|Variant=1}}===
 {| class="wikitable" style="width: 40%; text-align:center;"
@@ Line 516: / Line 591: @@
 |-
 |}
+''Note: Temozolomide dose is only increased if tolerated at the prior dose.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Temozolomide (Temodar)]] as follows:
-**Cycle 1: 100 or 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: increased as tolerated up to 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
+**Cycle 2 onwards: 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
+====Supportive therapy====
-====Supportive medications====
 *[[Tropisetron (Navoban)]] (dose/route/schedule not specified) routinely used as an antiemetic
 '''28-day cycles'''
+</div></div>
 ===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. [http://clincancerres.aacrjournals.org/content/13/10/2986.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17505000 PubMed]
+# '''Retrospective:''' Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007 May 15;13(10):2986-91. [http://clincancerres.aacrjournals.org/content/13/10/2986.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17505000/ PubMed]
 [[Category:Neuroendocrine tumor regimens]]
 [[Category:Disease-specific pages]]
 [[Category:Endocrine cancers]]

Difference between revisions of "Neuroendocrine tumor"

Revision as of 17:47, 23 June 2024

Guidelines

CommNETS/NANETS

ESMO

French Intergroup

NANETS

NCCN

All lines of therapy

Capecitabine & Temozolomide

Regimen

Chemotherapy

References

Doxorubicin & Fluorouracil

Regimen

Chemotherapy

References

Everolimus monotherapy

Regimen

Targeted therapy

References

Everolimus & Octreotide

Regimen variant #1

Targeted therapy

Endocrine therapy

Regimen variant #2

Targeted therapy

Endocrine therapy

References

Fluorouracil & Streptozocin

Regimen

Chemotherapy

References

Interferon alfa-2b monotherapy

Regimen

Immunotherapy

Subsequent treatment

References

Lanreotide monotherapy

Regimen

Endocrine therapy

Subsequent treatment

References

Lanreotide LAR monotherapy

Regimen

Endocrine therapy

References

Lanreotide & Interferon alfa-2b

Regimen

Endocrine therapy

Immunotherapy

References

Lutetium Lu 177 dotatate & Octreotide LAR

Regimen

Radioconjugate therapy

Endocrine therapy

References

Octreotide monotherapy

Regimen variant #1

Endocrine therapy

Regimen variant #2

Endocrine therapy

Regimen variant #3

Endocrine therapy

Dose and schedule modifications

Regimen variant #4, low-dose

Endocrine therapy

References

Octreotide LAR monotherapy

Regimen variant #1, 30 mg

Endocrine therapy

Regimen variant #2, 40 mg

Endocrine therapy

Regimen variant #3, 60 mg

Endocrine therapy

References

Octreotide & Interferon alfa

Regimen

Endocrine therapy

Immunotherapy