Pancreatic NET

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Section editor
Eric Marks Headshot.jpg
 Eric I. Marks, MD
Boston University
Boston, MA, USA

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: for more general neuroendocrine regimens, please visit the neuroendocrine tumors page.

16 regimens on this page
17 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

ESMO

NANETS

NCCN

All lines of therapy

Capecitabine & Temozolomide

Regimen

Study Evidence
Strosberg et al. 2011 Retrospective

Chemotherapy

Supportive therapy

28-day cycles

References

  1. 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 contains dosing details in manuscript link to PMC article PubMed

Doxorubicin & Streptozocin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Moertel et al. 1992 1978-1985 Phase 3 (E-switch-ic) 1. Chlorozotocin Superior OS
2. 5-FU & Streptozocin Superior OS

Chemotherapy

42-day cycles

References

  1. 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 contains dosing details in manuscript PubMed

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 Superior 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 OS1
Median 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

Continued indefinitely

References

  1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00363051
  2. 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 contains dosing details in manuscript link to PMC article PubMed NCT00510068
    1. 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 PubMed
  3. 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 PubMed
  4. COMPETE: NCT03049189
  5. COMPOSE: NCT04919226

Everolimus & Octreotide

Regimen variant #1

Study Dates of enrollment Evidence
Yao et al. 2008 2005-2006 Phase 2

Targeted therapy

Endocrine therapy

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

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-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 contains dosing details in manuscript link to PMC article PubMed NCT00363051

FAS

FAS: Fluorouracil, Adriamycin (Doxorubicin), Streptozocin

Regimen

Study Evidence
Kouvaraki et al. 2004 Retrospective

Chemotherapy

28-day cycles

References

  1. 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 contains dosing details in manuscript PubMed

Fluorouracil & Streptozocin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Moertel et al. 1980 1972-1978 Phase 3 (E-esc) Fluorouracil Might have superior OS
Moertel et al. 1992 1978-1985 Phase 3 (C) 1. Chlorozotocin Did not meet endpoint of OS
2. Doxorubicin & Streptozocin Inferior OS

Note: treatment details are from Moertel et al. 1992.

Chemotherapy

42-day cycles

References

  1. 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 PubMed
  2. 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 contains dosing details in manuscript PubMed

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 Superior PFS (primary endpoint)
Median PFS: NYR vs 18 mo
(HR 0.47, 95% CI 0.30-0.73)

Endocrine therapy

28-day cycle for 96 weeks

References

  1. 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 contains dosing details in manuscript PubMed NCT00353496

Lanreotide & Interferon alfa-2b

Regimen

Study Evidence
Fjällskog et al. 2002 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

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)

References

  1. 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 PubMed

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

  1. 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 PubMed
  2. 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

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)

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. 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
  4. NETTER-2: NCT03972488

Octreotide & Interferon alfa

Regimen

Study Evidence
Fjällskog et al. 2002 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

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)

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. 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 PubMed

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 Superior 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 OS1
Median OS: 48 vs 36.3 mo
(HR 0.84, 95% CI 0.60-1.17) 		More cytopenias (neutropenia, thrombocytopenia and lymphopenia)

1Reported efficacy for OS 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

4-week cycles

Radioconjugate therapy

Supportive therapy

  • For renal protection, an IV amino acid solution was administered concomitantly for at least 4 hours, starting 30 minutes prior to drug infusion.

8-week cycle for 4 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

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 Superior 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 OS1
Median 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

42-day cycles

References

  1. 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 contains dosing details in manuscript PubMed NCT00428597
    1. 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 PubMed
    2. 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 PubMed
    3. 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 PubMed

Temozolomide monotherapy

Regimen

Study Evidence
Ekeblad et al. 2007 Retrospective

Note: Temozolomide dose is 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

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

Temozolomide & Bevacizumab

Regimen

Study Dates of enrollment Evidence
Chan et al. 2012 (DFCI 04-272) 2004-2005 Phase 2

Chemotherapy

Targeted therapy

Supportive therapy

28-day cycles

References

  1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00137774

Temozolomide & Thalidomide

Regimen

Study Evidence
Kulke et al. 2006 Phase 2

Chemotherapy

Targeted therapy

28-day cycles

References

  1. 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 contains dosing details in manuscript PubMed
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