Pancreatic NET

Page editor		Section editor
	Rozina Chowdhery, MD University of Illinois at Chicago Chicago, IL		Jeena M. Varghese, MBBS MD Anderson Cancer Center Houston, TX LinkedIn

16 regimens on this page 17 variants on this page

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

Guidelines

ESMO

• 2012: Öberg et al. Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

NCCN

• NCCN Guidelines - Neuroendocrine Tumors

All lines of therapy

Capecitabine & Temozolomide

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Regimen

Study	Evidence
Strosberg et al. 2011	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 at bedtime on days 10 to 14

Supportive medications

• Ondansetron (Zofran) 8 mg (route not specified) prior to each dose of Temozolomide (Temodar)

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 verified protocol link to PMC article PubMed

Doxorubicin & Streptozocin

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Regimen

Study	Evidence	Comparator	Efficacy
Moertel et al. 1992	Phase III (E)	1. Chlorozotocin	Superior OS
		2. 5-FU & Streptozocin	Superior 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

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 verified protocol PubMed

Everolimus monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Yao et al. 2010	Phase II
Yao et al. 2011 (RADIANT-3)	Phase III (E)	Placebo	Superior PFS

Chemotherapy

• Everolimus (Afinitor) 10 mg PO once per day

Given until progression of disease, unacceptable toxicity, drug interruption of 3 weeks or longer, or withdrawal of consent

References

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 verified protocol link to PMC article PubMed
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 verified protocol 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

Everolimus & Octreotide

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Variant #1

Study	Evidence
Yao et al. 2010	Phase II

Patients in Yao et al. 2010 who received this regimen had already been receiving octreotide LAR for at least 3 months before participating in the study.

Endocrine & Chemotherapy

• Everolimus (Afinitor) 10 mg PO once per day
• Octreotide LAR (Sandostatin LAR) up to 30 mg (whatever their prestudy dose was) IM once on day 1

28-day cycles

Variant #2

Study	Evidence
Yao et al. 2008	Phase II

Note: 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."

Endocrine & Chemotherapy

• Everolimus (Afinitor) 5 or 10 mg PO once per day on days 1 to 28
• Octreotide LAR (Sandostatin LAR) 30 mg IM once on day 1

28-day cycle for up to 12 cycles or until progression of disease, though treatment could be continued beyond this period if thought by the treating physician to be beneficial

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 verified protocol link to PMC article PubMed
2. 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 verified protocol link to PMC article PubMed

FAS

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FAS: Fluorouracil, Adriamycin (Doxorubicin), Streptozocin

Regimen

Study	Evidence
Kouvaraki et al. 2004	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, given until progression of disease, unacceptable toxicity, or patient intolerance

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 verified protocol PubMed

Fluorouracil & Streptozocin

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Regimen

Study	Evidence	Comparator	Efficacy
Moertel et al. 1980	Phase III (E)	Fluorouracil	Might have superior OS
Moertel et al. 1992	Phase III (C)	1. Chlorozotocin	Seems not superior
		2. Doxorubicin & Streptozocin	Inferior 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

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 verified protocol PubMed

Lanreotide Depot/Autogel monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Caplin et al. 2014 (CLARINET)	Phase III (E)	Placebo	Superior PFS
Caplin et al. 2016 (CLARINET extension)	Non-randomized

Hormonotherapy

• Lanreotide (Somatuline) Depot/Autogel 120 mg SC once on day 1

28-day cycle for 96 weeks (CLARINET) or up to 8 years (CLARINET extension)

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 verified protocol PubMed
2. CLARINET Extension: 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, Gomez-Panzani E, Ruszniewski P; CLARINET Investigators. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. Endocr Relat Cancer. 2016 Mar;23(3):191-9. Epub 2016 Jan 7. link to PMC article PubMed

Lanreotide & Interferon alfa-2b

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Regimen

Study	Evidence
Fjällskog et al. 2002	Pilot, <20 pts

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 & Immunotherapy

• Lanreotide (Somatuline) 3 mg SC twice per day
• Interferon alfa-2b (Intron-A) 3 to 5 million units SC given once per day, 3 to 7 days per week (total of 9 to 25 million 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

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Regimen

Study	Evidence
Oberg et al. 2004	Consensus guideline

Hormonotherapy

• Octreotide (Sandostatin) 0.1 to 0.5 mg SC given 2 to 4 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 TID

Treatment continued indefinitely unless patients have unmanageable side-effects or insufficient control of symptoms

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 SD 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 verified protocol PubMed

Octreotide LAR monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Rinke et al. 2009 (PROMID)	Phase III (E)	Placebo	Superior TTP

Hormonotherapy

• Octreotide LAR (Sandostatin LAR) 30 mg IM once on day 1, with potentially higher doses if needed for symptom control

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 verified protocol 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 verified protocol PubMed

Octreotide & Interferon alfa

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Regimen

Study	Evidence
Fjällskog et al. 2002	Pilot, <20 pts

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 & Immunotherapy

• Octreotide (Sandostatin) 0.05 to 0.5 mg SC given 2 to 3 times per day
• Interferon alfa-2b (Intron-A) 3 to 5 million units SC given once per day, 3 to 7 days per week (total of 9 to 25 million 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

Placebo

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Regimen

Study	Evidence	Comparator	Efficacy	Toxicity
Rinke et al. 2009 (PROMID)	Phase III (C)	Octreotide LAR	Inferior TTP
Raymond et al. 2011 (A6181111)	Phase III (C)	Sunitinib	Inferior PFS	Less diarrhea
				Seems to have better insomnia
Yao et al. 2011 (RADIANT-3)	Phase III (C)	Everolimus	Inferior PFS
Caplin et al. 2014 (CLARINET)	Phase III (C)	Lanreotide	Inferior PFS

No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only. Note: while the initial A6181111 publication seemed to have a significant survival disadvantage for this arm (p=0.02), this finding was no longer significant at the final update (p=0.094). The primary endpoint (PFS) remains significant.

References

1. 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 verified protocol PubMed
2. 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 verified protocol PubMed
   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. 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 verified protocol link to PMC article PubMed
4. 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 verified protocol PubMed

PRRT with ¹⁷⁷Lu-dotatate

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Regimen

Study	Evidence	Comparator	Efficacy	Toxicity
Strosberg et al. 2018 NETTER-1	Phase III (E)	High-dose Octreotide LAR	Superior PFS	More cytopenias (neutropenia, thrombocytopenia and lymphopenia)

Note: patients had well-differentiated (Ki67 ≤ 20%) midgut neuroendocrine tumors with somatostatin receptors present in all target lesions

Chemotherapy 

• 177Lu-Dotatate 7.4 GB1 (200 mCi) IV Q8 weeks x 4 cycles*
• Octreotide LAR 30mg SC Q4 weeks

Octreotide was given 2 hours after each infusion and then continued monthly 

*For renal protection, protection an IV amino acid solution was administered concomitantly for at least 4 hours, starting 30 minutes before drug infusion

References

1. NETTER-1: Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. (2017) 376:125–35. 10.1056/NEJMoa1607427.  Link to original article: https://www.nejm.org/doi/full/10.1056/NEJMoa1607427 contains verified protocol Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/28076709

Sunitinib monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy	Toxicity
Raymond et al. 2011 (A6181111)	Phase III (E)	Placebo	Superior PFS	More diarrhea
				Seems to have worse insomnia

Note: while the initial publication seemed to have a significant survival advantage for this arm (p=0.02), this finding was no longer significant at the final update (p=0.094). The primary endpoint (PFS) remains significant.

Chemotherapy

• Sunitinib (Sutent) 37.5 mg PO once per day

Given indefinitely

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 verified protocol PubMed
   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

Temozolomide monotherapy

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Regimen

Study	Evidence
Ekeblad et al. 2007	Phase II

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

• Tropisetron (Navoban) (dose/route/schedule not specified) routinely used as an antiemetic

28-day cycles

References

1. 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 verified protocol PubMed

Temozolomide & Bevacizumab

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Regimen

Study	Evidence
Chan et al. 2012	Phase II

Chemotherapy

• Temozolomide (Temodar) 150 mg/m² PO once per day on days 1 to 7, 15 to 21
• Bevacizumab (Avastin) 5 mg/kg IV once per day on days 1 & 15

Supportive medications

• Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO once every Monday, Wednesday, and Friday; allergic patients received alternate Pneumocystis carinii (PCP) prophylaxis
• Acyclovir (Zovirax) 400 mg PO three times per day as prophylaxis against varicella zoster

28-day cycles

References

1. 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 verified protocol link to PMC article PubMed

Temozolomide & Thalidomide

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Regimen

Study	Evidence
Kulke et al. 2006	Phase II

Chemotherapy

• Temozolomide (Temodar) 150 mg/m² PO once per day on days 1 to 7, 15 to 21
• Thalidomide (Thalomid) 200 mg PO once per day

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 verified protocol PubMed