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Systemic Therapies for Metastatic Pancreatic Neuroendocrine Tumors

  • Neuroendocrine Cancers (JR Strosberg, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Over the years, there have been significant advances in systemic treatments for metastatic pancreatic neuroendocrine tumors (panNETs). Despite these advancements, uncertainty remains regarding how to best sequence available therapies. For well-differentiated and metastatic panNETs that are somatostatin receptor (SSTR) avid on functional imaging, first-line therapy typically consists of somatostatin analogs (SSAs), given their favorable toxicity profile and overall low burden for patients. When progression of disease is observed on an SSA, multiple treatment options are available, including the targeted agents everolimus and sunitinib, peptide receptor radionuclide therapy (PRRT), as well as chemotherapy, with the latter often preferred for those panNETs of heavy tumor burden, higher grade, and/or more aggressive behavior clinically and/or radiographically. Here, we review panNET classification, currently available systemic treatments, therapy sequencing, and areas of active investigation to further our treatments for the disease.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Kunz PL, Reidy-Lagunes D, Anthony LB, Bertino EM, Brendtro K, Chan JA, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013;42:557–77.

    PubMed  PubMed Central  Google Scholar 

  2. Dumlu EG, Karakoc D, Ozdemir A. Nonfunctional pancreatic neuroendocrine tumors: advances in diagnosis, management, and controversies. Int Surg. 2015;100:1089–97.

    PubMed  PubMed Central  Google Scholar 

  3. Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology. 2008;135:1469–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063–72.

    PubMed  Google Scholar 

  5. Halfdanarson TR, Rabe KG, Rubin J, Petersen GM. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol. 2008;19:1727–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. Jama Oncol. 2017;3:1335–42.

    PubMed  PubMed Central  Google Scholar 

  7. Lloyd RV, Osamura RY, Klöppel G, et al. WHO classification of tumours of endocrine organs. International Agency for Research on Cancer, 2017. The WHO pathologic classification remains the most significant prognostic tool. The 2017 classification of pancreatic neuroendocrine neoplasms (NENs) remains consistent with the previous 2010 WHO classification by stratifying by both differentiation and grade but offers important updates recognizing the heterogeneity of grade 3 pancreatic NENs.

  8. Inzani F, Petrone G, Rindi G. The new World Health Organization classification for pancreatic neuroendocrine neoplasia. Endocrinol Metab Clin N Am. 2018;47:463−+.

    Google Scholar 

  9. Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol. 2013;24:152–60.

    CAS  PubMed  Google Scholar 

  10. Raj N, Valentino E, Capanu M, Tang LH, Basturk O, Untch BR, et al. Treatment response and outcomes of grade 3 pancreatic neuroendocrine neoplasms based on morphology well differentiated versus poorly differentiated. Pancreas. 2017;46:296–301.

    PubMed  PubMed Central  Google Scholar 

  11. Basturk O, Yang ZH, Tang LH, Hruban RH, Adsay V, McCall C, et al. The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogeneous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol. 2015;39:683–90.

    PubMed  PubMed Central  Google Scholar 

  12. Tang LH, Untch BR, Reidy DL, et al. Well-differentiated neuroendocrine tumors with a morphologically apparent high-grade component: a pathway distinct from poorly differentiated neuroendocrine carcinomas (vol 22, pg 1011, 2016). Clin Cancer Res. 2016;22:4273–3.

  13. Crippa S, Partelli S, Bassi C, Berardi R, Capelli P, Scarpa A, et al. Long-term outcomes and prognostic factors in neuroendocrine carcinomas of the pancreas: morphology matters. Surgery. 2016;159:862–71.

    PubMed  Google Scholar 

  14. Jensen RI, Berna MJ, Bingham DB, et al. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer. 2008;113:1807–43.

    PubMed  PubMed Central  Google Scholar 

  15. Jiao YC, Shi CJ, Edil BH, de Wilde RF, Klimstra DS, Maitra A, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199–203.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. • Scarpa A, Chang DK, Nones K, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543:65 A comprehensive molecular analysis of 102 clinically sporadic panNETs to describe the mutational landscape and the mutational signatures that underlie pathogenesis. Importantly, this study identified a larger than anticipated germline contribution including previously unreported germline mutations in DNA repair genes.

    CAS  PubMed  Google Scholar 

  17. Raj N, Shah R, Stadler Z, et al. Real-time genomic characterization of metastatic pancreatic neuroendocrine tumors has prognostic implications and identifies potential germline actionability. JCO Precis Oncol. 2018;2018:1–18.

    Google Scholar 

  18. Rinke A, Muller HH, Schade-Brittinger C, et al. 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;27:4656–63.

    CAS  PubMed  Google Scholar 

  19. Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371:224–33.

    PubMed  Google Scholar 

  20. Clark OH, Benson AB 3rd, Berlin JD, et al. NCCN clinical practice guidelines in oncology: neuroendocrine tumors. J Natl Compr Cancer Netw. 2009;7:712–47.

    CAS  Google Scholar 

  21. Raj N, Reidy-Lagunes D. Systemic therapies for advanced pancreatic neuroendocrine tumors. Hematol Oncol Clin North Am. 2016;30:119–33.

    PubMed  Google Scholar 

  22. Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501–13.

    CAS  PubMed  Google Scholar 

  23. Raymond E, Niccoli P, Castellano D, et al. Sunitinib (SU) in patients with advanced, progressive pancreatic neuroendocrine tumors (pNET): final overall survival (OS) results from a phase III randomized study including adjustment for crossover. Proc Am Soc Clin Oncol. 2016; The 5 year follow up results to a pivotal randomized, multinational, phase III study that led to the FDA approval of sunitinib in panNETs.

  24. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. • Yao JC, Pavel M, Lombard-Bohas C, et al. 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;34:3906–13 The final overall survival data from the RADIANT-3 study that led to the FDA approval of everolimus in panNETs.

    PubMed  PubMed Central  Google Scholar 

  26. Murray-Lyon IM, Eddleston AL, Williams R, Brown M, Hogbin BM, Bennett A, et al. Treatment of multiple-hormone-producing malignant islet-cell tumour with streptozotocin. Lancet. 1968;2:895–8.

    CAS  PubMed  Google Scholar 

  27. Moertel CG, Lefkopoulo M, Lipsitz S, et al. Streptozocin–doxorubicin, streptozocin–fluorouracil, or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992;326:519–23.

    CAS  PubMed  Google Scholar 

  28. Cheng PN, Saltz LB. Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma. Cancer. 1999;86:944–8.

    CAS  PubMed  Google Scholar 

  29. Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004;22:4762–71.

    CAS  PubMed  Google Scholar 

  30. Altimari AF, Badrinath K, Reisel HJ, Prinz RA. DTIC therapy in patients with malignant intra-abdominal neuroendocrine tumors. Surgery. 1987;102:1009–17.

    CAS  PubMed  Google Scholar 

  31. Kessinger A, Foley J, Lemon H. Use of DTIC in the malignant carcinoid syndrome. Cancer Treat Rep. 1977;61:101.

    CAS  PubMed  Google Scholar 

  32. Ramanathan RK, Cnaan A, Hahn RG, Carbone PP, Haller DG. Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the eastern cooperative oncology group-E6282. Ann Oncol. 2001;12:1139–43.

    CAS  PubMed  Google Scholar 

  33. Stevens MF, Hickman JA, Langdon SP, Chubb D, Vickers L, Stone R, et al. Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res. 1987;47:5846–52.

    CAS  PubMed  Google Scholar 

  34. Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006;24:401–6.

    CAS  PubMed  Google Scholar 

  35. Varker KA, Campbell J, Shah MH. Phase II study of thalidomide in patients with metastatic carcinoid and islet cell tumors. Cancer Chemother Pharmacol. 2008;61:661–8.

    CAS  PubMed  Google Scholar 

  36. Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007;13:2986–91.

    CAS  PubMed  Google Scholar 

  37. Fine RL, Gulati AP, Krantz BA, Moss RA, Schreibman S, Tsushima DA, et al. Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: the pancreas Center at Columbia University experience. Cancer Chemother Pharmacol. 2013;71:663–70.

    CAS  PubMed  Google Scholar 

  38. Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011;117:268–75.

    CAS  PubMed  Google Scholar 

  39. Kunz PL, Catalano PJ, Nimeiri H, et al: A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: a trial of the ECOG-ACRIN Cancer research group (E2211). Am Soc Clin Oncol. 2018. The first prospective randomized trial to evaluate the benefit of single agent temozolomide versus combination temozolomide plus capecitabine in advanced panNETs.

  40. Moertel CG, Kvols LK, Oconnell MJ, et al. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer. 1991;68:227–32.

    CAS  PubMed  Google Scholar 

  41. Turner NC, Strauss SJ, Sarker D, Gillmore R, Kirkwood A, Hackshaw A, et al. Chemotherapy with 5-fluorouracil, cisplatin and streptozocin for neuroendocrine tumours. Br J Cancer. 2010;102:1106–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kunz PL, Balise RR, Fehrenbacher L, Pan M, Venook AP, Fisher GA, et al. Oxaliplatin-fluoropyrimidine chemotherapy plus bevacizumab in advanced neuroendocrine tumors: an analysis of 2 phase II trials. Pancreas. 2016;45:1394–400.

    CAS  PubMed  Google Scholar 

  43. Cives M, Strosberg J. Radionuclide therapy for neuroendocrine tumors. Curr Oncol Rep. 2017;19:9.

    PubMed  Google Scholar 

  44. Waldherr C, Pless M, Maecke HR, et al. Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq 90Y-DOTATOC. J Nucl Med. 2002;43:610–6.

    CAS  PubMed  Google Scholar 

  45. Kwekkeboom DJ, Kam BL, van Essen M, Teunissen JJ, van Eijck C, Valkema R, et al. Somatostatin-receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors. Endocr Relat Cancer. 2010;17:R53–73.

    CAS  PubMed  Google Scholar 

  46. Stefanova M, Kratochwil C, Mavriopoulou E, et al. SUV of 68Ga-DOTATOC PET/CT predicts response probability of PRRT in neuroendocrine tumors. J Nucl Med. 2014;55:1446–6.

  47. Capello A, Krenning EP, Breeman WA, et al. Peptide receptor radionuclide therapy in vitro using [111In-DTPA0] octreotide. J Nucl Med. 2003;44:98–104.

    CAS  PubMed  Google Scholar 

  48. Van Der Zwan WA, Bodei L, Mueller-Brand J, et al. GEP–NETs UPDATE: radionuclide therapy in neuroendocrine tumors. Eur J Endocrinol. 2015;172:R1–8.

    PubMed  Google Scholar 

  49. Ramage J, Naraev BG, Halfdanarson TR. Peptide receptor radionuclide therapy for patients with advanced pancreatic neuroendocrine tumors, Seminars in oncology, Elsevier, 2018.

  50. Khan S, Krenning EP, van Essen M, Kam BL, Teunissen JJ, Kwekkeboom DJ. Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumors treated with [177Lu-DOTA0,Tyr3]octreotate. J Nucl Med. 2011;52:1361–8.

    CAS  PubMed  Google Scholar 

  51. Kwekkeboom DJ, de Herder WW, Kam BL, et al: Treatment with the radiolabeled somatostatin analog [^ 1^ 7^ 7Lu-DOTA^ 0, Tyr^ 3] octreotate: toxicity, efficacy, and survival. 26:2124–2130, 2008.

  52. Brabander T, Van der Zwan WA, Teunissen JJ, et al. Long-term efficacy, survival, and safety of [177Lu-DOTA0, Tyr3] octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res. 2017;23:4617–24.

    CAS  PubMed  Google Scholar 

  53. •• Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of (177)Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376:125–35 The phase III NETTER-1 randomized prospective trial led to FDA approval of 177Lu-DOTATATE for the treatment of advanced gastroenteropancreatic NETs.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Yao J, Strosberg J, Fazio N, et al. 1308O Activity & safety of spartalizumab (PDR001) in patients (pts) with advanced neuroendocrine tumors (NET) of pancreatic (Pan), gastrointestinal (GI), or thoracic (T) origin, & gastroenteropancreatic neuroendocrine carcinoma (GEP NEC) who have progressed on prior treatment (Tx). 29:mdy293. 001, 2018.

  55. Mehnert J, Rugo H, O'neil B, et al. 427O Pembrolizumab for patients with PD-L1–positive advanced carcinoid or pancreatic neuroendocrine tumors: results from the KEYNOTE-028 study. 28, 2017.

  56. Strosberg JR, Mizuno N, Doi T, et al. Pembrolizumab treatment of advanced neuroendocrine tumors: results from the phase II KEYNOTE-158 study. American Society of Clinical Oncology, 2019.

  57. Chan JA, Faris JE, Murphy JE, et al. Phase II trial of cabozantinib in patients with carcinoid and pancreatic neuroendocrine tumors (pNET). American Society of Clinical Oncology, 2017.

  58. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10:2298–308.

    CAS  PubMed  Google Scholar 

  59. Reubi JC, Waser B, Macke H, et al. Highly increased 125I-JR11 antagonist binding in vitro reveals novel indications for sst2 targeting in human cancers. J Nucl Med. 2017;58:300–6.

    CAS  PubMed  Google Scholar 

  60. SINGH A, Zhang J, Kulkarni H, et al. Intra-arterial PRRT of SSTR-expressing tumors in patients with hepatic only versus extrahepatic tumor: efficacy and safety evaluation. J Nucl Med. 2019;60:625–5.

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Authors and Affiliations

  1. Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E66th Street, New York, NY, 10065, USA

    Haley Hauser BA & Nitya Raj MD

  2. ABC Medical Center, Sur 136 # 116, Colonia Las Américas, Delegación Álvaro Obregón, 01120, Ciudad de México, Mexico

    Daniela Shveid Gerson MD

  3. Chief of Clinical Operations, Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E66th Street, New York, NY, 10065, USA

    Diane Reidy-Lagunes MD

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Correspondence to Nitya Raj MD.

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Hauser, H., Gerson, D.S., Reidy-Lagunes, D. et al. Systemic Therapies for Metastatic Pancreatic Neuroendocrine Tumors. Curr. Treat. Options in Oncol. 20, 87 (2019). https://doi.org/10.1007/s11864-019-0690-x

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