Pancreatic NET

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Neeta K. Venepalli, MD, MBA
Chicago, IL
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Jeena M. Varghese, MBBS
Houston, TX

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15 regimens on this page
17 variants on this page

Contents


Guidelines

ESMO

NCCN

All lines of therapy

Capecitabine & Temozolomide

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Regimen

Study Evidence
Strosberg et al. 2011 Retrospective

Chemotherapy

Supportive medications

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) Chlorozotocin Superior OS
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 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

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

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

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

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. 1992 Phase III (C) Chlorozotocin Seems not superior
Doxorubicin & Streptozocin Inferior 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 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

Endocrine therapy

28-day cycle for 96 weeks (CLARINET), until progression of disease, or unacceptable toxicity

Patients in NET729 (unpublished) could be treated for up to 8 years.

References

  1. Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlácková 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. Lanreotide (Somatuline) package insert
  3. NIHR (National Institute for Health Research) Horizon Scanning Centre, School of Health & Population Sciences, University of Birmingham. Lanreotide for unresectable, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumours – first line
  4. ClinicalTrials.gov: Study of Lanreotide Autogel 120mg in Patients With Non-functioning Entero- Pancreatic Endocrine Tumour (NET729)

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

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

Endocrine therapy

  • 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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Variant #1

Study Evidence
Oberg et al. 2004 Consensus guideline

Endocrine therapy

  • Octreotide LAR (Sandostatin LAR) 20 to 30 mg IM once on day 1, with potentially higher doses if needed for symptom control
    • "As a general rule, if the total [octreotide] IR dose is 200 to 600 mcg/day, LAR 20 mg should be tried, and if total IR dose is 750 to 1500 mcg/day, LAR 30 mg should be tried."
  • Octreotide (Sandostatin) (dose not specified) SC as needed for additional symptom control

28-day cycles; treatment continued indefinitely unless patients have unmanageable side-effects or insufficient control of symptoms

Variant #2

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

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 verified protocol PubMed
  2. 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

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, Cwikla JB, Phan AT, Raderer M, Sedlácková 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

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

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

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

Supportive medications

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

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