Neuroendocrine tumor

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Note: This page is now exclusively focused on those tumors commonly called carcinoids, which may or may not be associated with the carcinoid syndrome; there are now separate pages for pancreatic NET and other endocrine cancers. Neuroendocrine tumors of unknown primary and poorly differentiated (high-grade) neuroendocrine tumors are usually treated with a small cell lung cancer regimen.

12 regimens on this page
18 variants on this page


Guidelines

CommNETS/NANETS

ESMO

Older

NANETS

Older

NCCN

All lines of therapy

Everolimus monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Yao et al. 2015 (RADIANT-4) 2012-2013 Phase 3 (E-RT-esc) Placebo Might have superior OS
Median OS: NYR vs NYR
(HR 0.64, 95% CI 0.40-1.05)
Equivalent HRQoL

Targeted therapy

Continued indefinitely

References

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

Targeted therapy

Endocrine therapy

28-day cycles

Regimen variant #2

Study Years of enrollment Evidence 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
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

Endocrine therapy

28-day cycles

References

  1. Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008 Sep 10;26(26):4311-8. link to original article contains dosing details in manuscript link to PMC article PubMed
  2. RADIANT-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 PubMed

Fluorouracil & Streptozocin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Engstrom et al. 1984 (ECOG E5275) 1976-1981 Phase 3 (E-esc) Doxorubicin Did not meet primary endpoints of ORR/OS
Sun et al. 2005 1981-1990 Phase 3 (E-switch-ic) Doxorubicin & Fluorouracil Seems to have superior OS

Chemotherapy

References

  1. 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 PubMed
  2. 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 PubMed

Interferon alfa-2b monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Oberg et al. 1983 NR Non-randomized, <20 pts
Faiss et al. 2003 1995-1998 Phase 3 (E-de-esc) 1. Lanreotide Did not meet primary endpoint of ORR at 12 mo
2. Lanreotide & Interferon alfa-2b Did not meet primary endpoint of ORR at 12 mo

Treatment details are from Faiss et al. 2003.

Immunotherapy

Continued indefinitely

Subsequent treatment

References

  1. 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
  2. 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 Years of enrollment Evidence Comparator Comparative Efficacy
Faiss et al. 2003 1995-1998 Phase 3 (E-de-esc) 1. Interferon alfa-2b Did not meet primary endpoint of ORR at 12 mo
2. Lanreotide & Interferon alfa-2b Did not meet primary endpoint of ORR at 12 mo

Endocrine therapy

Continued indefinitely

Subsequent treatment

References

  1. 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 Years of enrollment Evidence Comparator Comparative Efficacy
Vinik et al. 2016 (ELECT) NR in abstract Phase 3 (E-esc) Placebo Decreased need for short-acting octreotide rescue

Endocrine therapy

28-day cycle for 4 cycles

References

  1. 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 PubMed NCT00774930

Lanreotide & Interferon alfa-2b

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Faiss et al. 2003 1995-1998 Phase 3 (E-esc) 1. Interferon alfa-2b Did not meet primary endpoint of ORR at 12 mo
2. Lanreotide Did not meet primary endpoint of ORR at 12 mo

Endocrine therapy

Immunotherapy

References

  1. 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 Years 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-switch-ooc) Octreotide LAR Superior PFS
Median PFS: NYR vs 8.4 mo
(HR 0.21, 95% CI 0.13-0.33)

This is the FDA-recommended dose.

Radioconjugate therapy

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

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

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

Regimen variant #2

Study Evidence
Kvols et al. 1986 Phase 2

Endocrine therapy

Continued indefinitely

Regimen variant #3

Study Years 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
    • Patients with persistent carcinoid symptoms could receive increased doses up to 0.2 mg SC three times per day

Continued indefinitely

Regimen variant #4, low-dose

Study Evidence
Janson & Oberg 1993 Non-randomized

Endocrine therapy

Continued indefinitely

References

  1. 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
  2. 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
  3. 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
  4. 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 Years of enrollment Evidence Comparator Comparative Efficacy
Rinke et al. 2009 (PROMID) 2001-2008 Phase 3 (E-esc) Placebo Superior TTP
Median TTP: 14.3 vs 6 mo
(HR 0.34, 95% CI 0.20-0.59)
Pavel et al. 2011 (RADIANT-2) 2007-2010 Phase 3 (C) Octreotide LAR & Everolimus Seems to have inferior PFS

Note: RADIANT-2 did not meet its primary endpoint, based on a pre-specified p-value cutoff of 0.0246.

Endocrine therapy

28-day cycles

Regimen variant #2, 40 mg

Study Years 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

28-day cycles

Regimen variant #3, 60 mg

Study Years 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

28-day cycles

References

  1. Review: Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. link to original article contains dosing details in manuscript PubMed
  2. PROMID: Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. link to original article contains dosing details in manuscript PubMed NCT00171873
  3. 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 PubMed
  4. 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
  5. 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 Years 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

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

  1. Janson ET, Oberg K. Long-term management of the carcinoid syndrome: treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. link to original article PubMed
  2. 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
  3. 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

Chemotherapy

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

Supportive medications

28-day cycles

References

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