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Note: for more general neuroendocrine regimens, please visit the neuroendocrine tumors page.
Last updated on 2024-09-06:16 regimens on this page
18 variants on this page
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==ASCO==
*2023: Del Rivero et al. Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline EuroPMC
==ESMO==
*2020: Pavel et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2012: Öberg et al. Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2010: Öberg et al. Neuroendocrine gastroenteropancreatic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2009: Öberg & Jelic. Neuroendocrine gastroenteropancreatic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up EuroPMC
**2008: Öberg & Jelic. Neuroendocrine gastroenteropancreatic tumors: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
==NANETS==
*2020: Halfdanarson et al. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Pancreatic Neuroendocrine Tumors EuroPMC
*2020: Howe et al. The North American Neuroendocrine Tumor Society Consensus Paper on the Surgical Management of Pancreatic Neuroendocrine Tumors EuroPMC
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Neuroendocrine and Adrenal Tumors.
=All lines of therapy=
==Cabozantinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Chan et al. 2024 (CABINET pancreatic)	2018-10 to 2023-08 	Phase 3 (E-esc)	Placebo 	Longer PFS (primary endpoint)Median PFS: 13.8 vs 4.4 mo(HR 0.23, 95% CI 0.12-0.42)
====Targeted therapy====
*Cabozantinib (Cometriq) 60 mg PO once per day
Continued indefinitely
===References===
#CABINET pancreatic: Chan JA, Geyer S, Zemla T, Knopp MV, Behr S, Pulsipher S, Ou FS, Dueck AC, Acoba J, Shergill A, Wolin EM, Halfdanarson TR, Konda B, Trikalinos NA, Tawfik B, Raj N, Shaheen S, Vijayvergia N, Dasari A, Strosberg JR, Kohn EC, Kulke MH, O'Reilly EM, Meyerhardt JA. Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors. N Engl J Med. 2025 Feb;392(7):653-665. Epub 2024 Sep 18. link to original article dosing details in manuscript have been reviewed by our editors link to EuroPMC NCT03375320
==Capecitabine & Temozolomide==
===Regimen===
Study 	Dates of enrollment	Evidence
Strosberg et al. 2011	2005-09 to 2009-01 	Retrospective
====Chemotherapy====
*Capecitabine (Xeloda) 750 mg/m2 PO twice per day on days 1 to 14
*Temozolomide (Temodar) 200 mg/m2 PO once per day on days 10 to 14, taken at bedtime
====Supportive therapy====
*Ondansetron (Zofran) 8 mg (route not specified) once per day on days 1 to 14, prior to temozolomide
28-day cycles
===References===
# Retrospective: Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, Helm J, Kvols L. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011 Jan 15;117(2):268-75. Epub 2010 Sep 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Doxorubicin & Streptozocin==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Moertel et al. 1992	1978-1985 	Phase 3 (E-switch-ic)	1. Chlorozotocin 	Longer OS
Moertel et al. 1992	1978-1985 	Phase 3 (E-switch-ic)	2. 5-FU & Streptozocin	Longer OS
====Chemotherapy====
*Doxorubicin (Adriamycin) 50 mg/m2 IV once per day on days 1 & 22
*Streptozocin (Zanosar) 500 mg/m2 IV once per day on days 1 to 5
42-day cycles
===References===
# Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Everolimus monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Yao et al. 2010 (RADIANT-1)	2006-2007 	Phase 2 	 	
Yao et al. 2011 (RADIANT-3)	2007-2009 	Phase 3 (E-RT-esc)	Placebo 	Longer PFS (primary endpoint)Median PFS: 11 vs 4.6 mo(HR 0.35, 95% CI 0.27-0.45)Did not meet secondary endpoint of OS1Median OS: 44 vs 37.7 mo(HR 0.94, 95% CI 0.73-1.20)
1Reported efficacy for OS is based on the 2016 update.
====Targeted therapy====
*Everolimus (Afinitor) 10 mg PO once per day
Continued indefinitely
===References===
# RADIANT-1: Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. Epub 2009 Nov 23. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00363051
# RADIANT-3: Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Öberg K; RAD001 in Advanced Neuroendocrine Tumors Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00510068
## Update: Yao JC, Pavel M, Lombard-Bohas C, Van Cutsem E, Voi M, Brandt U, He W, Chen D, Capdevila J, de Vries EGE, Tomassetti P, Hobday T, Pommier R, Öberg K. Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: overall survival and circulating biomarkers from the randomized, phase III RADIANT-3 study. J Clin Oncol. 2016 Nov 10;34(32):3906-3913. Epub 2016 Sep 30. link to original article link to PMC article EuroPMC
# Review: Yao JC, Phan AT, Jehl V, Shah G, Meric-Bernstam F. Everolimus in advanced pancreatic neuroendocrine tumors: the clinical experience. Cancer Res. 2013 Mar 1;73(5):1449-53. Epub 2013 Feb 22. link to original article EuroPMC
#COMPETE: NCT03049189
#COMPOSE: NCT04919226
==Everolimus & Octreotide==
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Yao et al. 2008	2005-2006 	Phase 2
====Targeted therapy====
*Everolimus (Afinitor) 5 mg PO once per day on days 1 to 28
====Endocrine therapy====
*Octreotide LAR (Sandostatin LAR) 30 mg IM once on day 1
28-day cycles
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Yao et al. 2008 	2005-2006 	Phase 2
Yao et al. 2010 (RADIANT-1)	2006-2007 	Phase 2
Note: In Yao et al. 2008, everolimus "dose of 10 mg was associated with superior PFS...however, the study was not prospectively powered for these comparisons. These analyses should be considered exploratory." Patients in RADIANT-1 who received this regimen had already been receiving octreotide LAR for at least 3 months before participating in the study; they were continued on their prestudy dose up to 30 mg.
====Targeted therapy====
*Everolimus (Afinitor) 10 mg PO once per day on days 1 to 28
====Endocrine therapy====
*Octreotide LAR (Sandostatin LAR) 30 mg IM once on day 1
28-day cycles
===References===
# Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008 Sep 10;26(26):4311-8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# RADIANT-1: Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. Epub 2009 Nov 23. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00363051
==FAS==
FAS: Fluorouracil, Adriamycin (Doxorubicin), Streptozocin
===Regimen===
Study 	Dates of enrollment	Evidence
Kouvaraki et al. 2004	1992-01 to 2003-09 	Retrospective
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 to 5
*Doxorubicin (Adriamycin) 40 mg/m2 IV bolus once on day 1
*Streptozocin (Zanosar) 400 mg/m2 IV bolus once per day on days 1 to 5
28-day cycles
===References===
# Retrospective: Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, Yao JC. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004 Dec 1;22(23):4762-71. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Fluorouracil & Streptozocin==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Moertel et al. 1980	1972-1978 	Phase 3 (E-esc)	Fluorouracil 	Might have longer OS
Moertel et al. 1992	1978-1985 	Phase 3 (C) 	1. Chlorozotocin 	Did not meet endpoint of OS
Moertel et al. 1992	1978-1985 	Phase 3 (C) 	2. Doxorubicin & Streptozocin	Shorter OS
Note: treatment details are from Moertel et al. 1992.
====Chemotherapy====
*Streptozocin (Zanosar) 500 mg/m2 IV once per day on days 1 to 5
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 to 5
42-day cycles
===References===
# Moertel CG, Hanley JA, Johnson LA. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1980 Nov 20;303(21):1189-94. link to original article EuroPMC
# Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Lanreotide Depot/Autogel monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Caplin et al. 2014 (CLARINET)	2006-2013 	Phase 3 (E-RT-esc)	Placebo 	Longer PFS (primary endpoint)Median PFS: NYR vs 18 mo(HR 0.47, 95% CI 0.30-0.73)
====Endocrine therapy====
* Lanreotide (Somatuline) Depot/Autogel 120 mg SC once on day 1
28-day cycle for 96 weeks
===References===
# CLARINET: Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00353496
==Lanreotide & Interferon alfa-2b==
===Regimen===
Study 	Dates of enrollment	Evidence
Fjällskog et al. 2002	Not reported 	Pilot, fewer than 20 pts
Note: Fjällskog et al. 2002 contained case reports of several patients treated with lanreotide & interferon alfa. Each patient received individualized therapy rather than a standard regimen.
====Endocrine therapy====
*Lanreotide (Somatuline) 3 mg SC twice per day
====Immunotherapy====
*Interferon alfa-2b (Intron-A) 3,000,000 to 5,000,000 units SC once per day, 3 to 7 days per week (total of 9,000,000 to 25,000,000 units per week)
Continued indefinitely
===References===
# Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. link to original article EuroPMC
==Octreotide monotherapy==
===Regimen===
Study 	Evidence
Oberg et al. 2004	Consensus guideline
Note: per the consensus guideline, a "reasonable starting dose" was 0.15 mg SC three times per day
====Endocrine therapy====
*Octreotide (Sandostatin) 0.1 to 0.5 mg SC given two to four times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms
Continued indefinitely
===References===
# Review: Brentjens R, Saltz L. Islet cell tumors of the pancreas: the medical oncologist's perspective. Surg Clin North Am. 2001 Jun;81(3):527-42. link to original article EuroPMC
# Review: Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Octreotide LAR monotherapy==
===Regimen variant #1, standard-dose===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Rinke et al. 2009 (PROMID)	2001-2008 	Phase 3 (E-esc)	Placebo 	Longer TTP (primary endpoint)Median TTP: 14.3 vs 6 mo(HR 0.34, 95% CI 0.20-0.59)
====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, high-dose===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Strosberg et al. 2017 (NETTER-1)	2012-2016 	Phase 3 (C)	Lutetium dotatate & Octreotide	Shorter PFS (primary endpoint)Median PFS: 8.4 vs NYR mo(HR 4.76, 95% CI 3.03-7.69)Did not meet secondary endpoint of OS1Median OS: 36.3 vs 48 mo(HR 1.19, 95% CI 0.85-1.67)
Singh et al. 2024 (NETTER-2) 	2020-01-22 to 2022-10-13	Phase 3 (C)	Lutetium dotatate & Octreotide	Shorter PFS (primary endpoint)Median PFS: 8.5 vs 22.8 mo(HR 3.57, 95% CI 2.38-5.56)
1Reported efficacy for NETTER-1 is based on the 2021 update.
====Endocrine therapy====
*Octreotide LAR (Sandostatin LAR) 60 mg IM once on day 1
28-day cycles
===References===
# Review: Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# PROMID: Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00171873
##Update: Rinke A, Wittenberg M, Schade-Brittinger C, Aminossadati B, Ronicke E, Gress TM, Müller HH, Arnold R; PROMID Study Group. Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors (PROMID): Results of Long-Term Survival. Neuroendocrinology. 2017;104(1):26-32. Epub 2016 Jan 6. link to original article EuroPMC
##HRQoL analysis: Rinke A, Neary MP, Eriksson J, Hunger M, Doan T, Karli D, Arnold R. Health-Related Quality of Life for Long-Acting Octreotide versus Placebo in Patients with Metastatic Midgut Neuroendocrine Tumors in the Phase 3 PROMID Trial. Neuroendocrinology. 2019;109(2):141-151. Epub 2019 Mar 11. link to original article EuroPMC
# NETTER-1: Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01578239
##HRQoL analysis: Strosberg J, Wolin E, Chasen B, Kulke M, Bushnell D, Caplin M, Baum RP, Kunz P, Hobday T, Hendifar A, Oberg K, Sierra ML, Thevenet T, Margalet I, Ruszniewski P, Krenning E; NETTER-1 Study Group. Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With 177Lu-Dotatate in the Phase III NETTER-1 Trial. J Clin Oncol. 2018 Sep;36(25):2578-2584. link to original article link to EuroPMC
## Update: Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. link to original article EuroPMC
#NETTER-2: Singh S, Halperin D, Myrehaug S, Herrmann K, Pavel M, Kunz PL, Chasen B, Tafuto S, Lastoria S, Capdevila J, García-Burillo A, Oh DY, Yoo C, Halfdanarson TR, Falk S, Folitar I, Zhang Y, Aimone P, de Herder WW, Ferone D; all the NETTER-2 Trial Investigators. [177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high‑dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet. 2024 Jun 29;403(10446):2807-2817. Epub 2024 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03972488
==Octreotide & Interferon alfa==
===Regimen===
Study 	Dates of enrollment	Evidence
Fjällskog et al. 2002	Not reported 	Pilot, fewer than 20 pts
Note: Fjällskog et al. 2002 contained case reports of several patients treated with octreotide & interferon alfa. Each patient received individualized therapy rather than a standard regimen.
====Endocrine therapy====
*Octreotide (Sandostatin) 0.05 to 0.5 mg SC given two to three times per day
====Immunotherapy====
*Interferon alfa-2b (Intron-A) 3,000,000 to 5,000,000 units SC once per day, 3 to 7 days per week (total of 9,000,000 to 25,000,000 units per week)
7-day cycles
===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 does not contain dosing details in manuscript EuroPMC
# Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. link to original article EuroPMC
==Lutetium Lu 177 dotatate & Octreotide LAR ==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Strosberg et al. 2017 (NETTER-1)	2012-2016 	Phase 3 (E-RT-esc)	Octreotide LAR; high-dose	Longer PFS (primary endpoint)Median PFS: NYR vs 8.4 mo(HR 0.21, 95% CI 0.13-0.33)Did not meet secondary endpoint of OS1Median OS: 48 vs 36.3 mo(HR 0.84, 95% CI 0.60-1.17)	More cytopenias (neutropenia, thrombocytopenia and lymphopenia)
Singh et al. 2024 (NETTER-2) 	2020-01-22 to 2022-10-13	Phase 3 (E-esc) 	Octreotide LAR; high-dose	Longer PFS (primary endpoint)Median PFS: 22.8 vs 8.5 mo(HR 0.28, 95% CI 0.18-0.42) 	More grade 3 to 5 AEs: 35% vs 27%
1Reported efficacy for NETTER-1 is based on the 2021 update.
Note: patients had well-differentiated (Ki67 less than 20%) midgut neuroendocrine tumors with somatostatin receptors present in all target lesions
====Endocrine therapy====
* Octreotide LAR (Sandostatin LAR) as follows:
**Cycles 1 to 4: 30 mg SC once per day on on days 1 & 29, given 2 hours after each lutetium Lu 177 dotatate infusion
**Cycle 5 onwards: 30 mg SC once on day 1
====Radioconjugate therapy====
* Lutetium Lu 177 dotatate (Lutathera) as follows:
**Cycles 1 to 4: 7.4 GBq (200 mCi) IV once on day 1
====Supportive therapy====
* For renal protection, an IV amino acid solution was administered concomitantly for at least 4 hours, starting 30 minutes prior to lutetium Lu 177 dotatate infusion
8-week cycle for 4 cycles, then 4-week cycles
===References===
# NETTER-1: Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01578239
##HRQoL analysis: Strosberg J, Wolin E, Chasen B, Kulke M, Bushnell D, Caplin M, Baum RP, Kunz P, Hobday T, Hendifar A, Oberg K, Sierra ML, Thevenet T, Margalet I, Ruszniewski P, Krenning E; NETTER-1 Study Group. Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With 177Lu-Dotatate in the Phase III NETTER-1 Trial. J Clin Oncol. 2018 Sep;36(25):2578-2584. link to original article link to EuroPMC
## Update: Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. link to original article EuroPMC
#NETTER-2: Singh S, Halperin D, Myrehaug S, Herrmann K, Pavel M, Kunz PL, Chasen B, Tafuto S, Lastoria S, Capdevila J, García-Burillo A, Oh DY, Yoo C, Halfdanarson TR, Falk S, Folitar I, Zhang Y, Aimone P, de Herder WW, Ferone D; all the NETTER-2 Trial Investigators. [177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high‑dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet. 2024 Jun 29;403(10446):2807-2817. Epub 2024 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03972488
==Sunitinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Raymond et al. 2011 (A6181111)	2007-2009 	Phase 3 (E-RT-esc)	Placebo 	Longer PFS1 (primary endpoint)Median PFS: 12.6 vs 5.8 mo(HR 0.32, 95% CI 0.18-0.55)Did not meet secondary endpoint of OS1Median OS: 38.6 vs 29.1 mo(HR 0.73, 95% CI 0.50-1.06)	More diarrhea; seems to have worse insomnia
1Reported efficacy is based on the 2017 update.
====Targeted therapy====
*Sunitinib (Sutent) 37.5 mg PO once per day on days 1 to 42
42-day cycles
===References===
# A6181111: Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):501-13. Erratum in: N Engl J Med. 2011 Mar 17;364(11):1082. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00428597
## HRQoL analysis: Vinik A, Bottomley A, Korytowsky B, Bang YJ, Raoul JL, Valle JW, Metrakos P, Hörsch D, Mundayat R, Reisman A, Wang Z, Chao RC, Raymond E. Patient-reported outcomes and quality of life with sunitinib versus placebo for pancreatic neuroendocrine tumors: results from an international phase III trial. Target Oncol. 2016 Dec;11(6):815-824. link to original article EuroPMC
## Update: Faivre S, Niccoli P, Castellano D, Valle JW, Hammel P, Raoul JL, Vinik A, Van Cutsem E, Bang YJ, Lee SH, Borbath I, Lombard-Bohas C, Metrakos P, Smith D, Chen JS, Ruszniewski P, Seitz JF, Patyna S, Lu DR, Ishak KJ, Raymond E. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol. 2017 Feb 1;28(2):339-343. link to original article EuroPMC
## Update: Fazio N, Kulke M, Rosbrook B, Fernandez K, Raymond E. Updated Efficacy and Safety Outcomes for Patients with Well-Differentiated Pancreatic Neuroendocrine Tumors Treated with Sunitinib. Target Oncol. 2021 Jan;16(1):27-35. Epub 2021 Jan 7. link to original article link to PMC article EuroPMC
==Temozolomide monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Ekeblad et al. 2007	1999-10 to 2006-01 	Retrospective
Note: Temozolomide dose was increased only if the starting dose is tolerated.
====Chemotherapy====
*Temozolomide (Temodar) as follows:
**Cycle 1: 100 to 150 mg/m2 PO once per day on days 1 to 5
**Cycle 2 onwards: 200 mg/m2 PO once per day on days 1 to 5
====Supportive therapy====
*Tropisetron (Navoban) (dose/route/schedule not specified) routinely used as an antiemetic
28-day cycles
===References===
# Retrospective: Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007 May 15;13(10):2986-91. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Temozolomide & Bevacizumab==
===Regimen===
Study 	Dates of enrollment	Evidence
Chan et al. 2012 (DFCI 04-272)	2004-2005 	Phase 2
====Chemotherapy====
*Temozolomide (Temodar) 150 mg/m2 PO once per day on days 1 to 7, 15 to 21
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once per day on days 1 & 15
====Supportive therapy====
*PCP prophylaxis: Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO once every Monday, Wednesday, and Friday
**Allergic patients received alternate prophylaxis
*VZV prophylaxis: Acyclovir (Zovirax) 400 mg PO three times per day
28-day cycles
===References===
# DFCI 04-272: Chan JA, Stuart K, Earle CC, Clark JW, Bhargava P, Miksad R, Blaszkowsky L, Enzinger PC, Meyerhardt JA, Zheng H, Fuchs CS, Kulke MH. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol. 2012 Aug 20;30(24):2963-8. Epub 2012 Jul 9. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00137774
==Temozolomide & Thalidomide==
===Regimen===
Study 	Dates of enrollment	Evidence
Kulke et al. 2006	Not reported 	Phase 2
====Chemotherapy====
*Temozolomide (Temodar) 150 mg/m2 PO once per day on days 1 to 7, 15 to 21
====Targeted therapy====
*Thalidomide (Thalomid) 200 mg PO once per day
28-day cycles
===References===
# Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, Vincitore M, Michelini A, Fuchs CS. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006 Jan 20;24(3):401-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
Category:Pancreatic NET regimens
Category:Disease-specific pages
Category:Endocrine cancers
Category:Gastrointestinal cancers