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Treatment Strategies for Metastatic Neuroendocrine Tumors of the Gastrointestinal Tract

  • Lower Gastrointestinal Cancers (AB Benson, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

The therapeutic landscape of gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) has evolved significantly in recent years. Current and emerging treatment options include somatostatin analogs, radiolabeled somatostatin analogs, the mTOR inhibitor everolimus, and the tyrosine kinase inhibitor sunitinib. Although high-quality data from phase III trials are lacking, cytotoxic agents are commonly used for the treatment of poorly differentiated neuroendocrine carcinomas and well-differentiated NETs originating in the pancreas. Hepatic-directed therapies are recommended for patients with slow-growing, liver-predominant disease but have never been compared to systemic agents. Telotristat ethyl, a novel serotonin synthesis inhibitor, has recently demonstrated efficacy in palliating diarrhea in patients with poorly controlled carcinoid syndrome. In the absence of definite predictive biomarkers, therapeutic decisions in most cases rely on clinical and pathological criteria. However, navigating the current therapeutic algorithm may be challenging, and future trials need to address several important questions: what is the best sequence of treatment? Is there a role for combination therapies in GEP-NETs? Are neoadjuvant, adjuvant, or maintenance strategies safe and effective? Do all NET patients require active treatment? What new molecular targets can be clinically exploited? A tight integration between basic and clinical research is needed to further advance the field of NETs.

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References and Recommended Reading

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

  1. Cives M, Strosberg J. An update on gastroenteropancreatic neuroendocrine tumors. Oncology (Williston Park). 2014;28(9):749–56.

    Google Scholar 

  2. 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.

    Article  PubMed  Google Scholar 

  3. Fraenkel M, Kim M, Faggiano A, de Herder WW, Valk GD, Knowledge NETwork. Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature. Endocr Relat Cancer. 2014;21:R153–63.

    Article  CAS  PubMed  Google Scholar 

  4. Strosberg JR, Cheema A, Weber J, Han G, Coppola D, Kvols LK. Prognostic validity of a novel American Joint Committee on Cancer Staging Classification for pancreatic neuroendocrine tumors. J Clin Oncol. 2011;29:3044–9.

    Article  PubMed  Google Scholar 

  5. Strosberg JR, Weber JM, Feldman M, Coppola D, Meredith K, Kvols LK. Prognostic validity of the American Joint Committee on Cancer staging classification for midgut neuroendocrine tumors. J Clin Oncol. 2013;31:420–5.

    Article  PubMed  Google Scholar 

  6. Rindi G, Arnold R. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman F, Carneiro F, Hruban R, Theise N, editors. World Health Organization classification of tumors of the digestive system. Lyon: IARC Press; 2010. p. 13–4.

    Google Scholar 

  7. Kunz PL. Carcinoid and neuroendocrine tumors: building on success. J Clin Oncol. 2015;33:1855–63.

    Article  CAS  PubMed  Google Scholar 

  8. Modlin IM, Pavel M, Kidd M, Gustafsson BI. Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther. 2010;31:169–88.

    CAS  PubMed  Google Scholar 

  9. Cives M, Strosberg J. The expanding role of somatostatin analogs in gastroenteropancreatic and lung neuroendocrine tumors. Drugs. 2015;75:847–58.

    Article  CAS  PubMed  Google Scholar 

  10. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471–84.

    Article  CAS  PubMed  Google Scholar 

  11. Jiao Y, Shi C, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Qian ZR, Ter-Minassian M, Chan JA, Imamura Y, Hooshmand SM, Kuchiba A, et al. Prognostic significance of MTOR pathway component expression in neuroendocrine tumors. J Clin Oncol. 2013;31:3418–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. •• Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387:968–77. This is the first phase III trial to demonstrate that everolimus is active in gastrointestinal and lung NETs

    Article  CAS  PubMed  Google Scholar 

  14. Oberg K, Casanovas O, Castaño JP, Chung D, Delle Fave G, Denèfle P, et al. Molecular pathogenesis of neuroendocrine tumors: implications for current and future therapeutic approaches. Clin Cancer Res. 2013;19:2842–9.

    Article  CAS  PubMed  Google Scholar 

  15. Scoazec JY. Angiogenesis in neuroendocrine tumors: therapeutic applications. Neuroendocrinology. 2013;97:45–56.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. Katz SC, Donkor C, Glasgow K, Pillarisetty VG, Gönen M, Espat NJ, et al. T cell infiltrate and outcome following resection of intermediate-grade primary neuroendocrine tumours and liver metastases. HPB (Oxford). 2010;12:674–83.

    Article  Google Scholar 

  18. Vikman S, Sommaggio R, De La Torre M, Oberg K, Essand M, Giandomenico V, et al. Midgut carcinoid patients display increased numbers of regulatory T cells in peripheral blood with infiltration into tumor tissue. Acta Oncol. 2009;48:391–400.

    Article  CAS  PubMed  Google Scholar 

  19. Kim ST, Ha SY, Lee S, Ahn S, Lee J, Park SH, et al. The impact of PD-L1 expression in patients with metastatic GEP-NETs. J Cancer. 2016;7:484–9.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Da Silva A, Qian Z, Zhang S, Masugi Y, Rodig S, Brais L, et al. Immune checkpoint markers and immune response in well differentiated neuroendocrine tumors (NET) of the small intestine and pancreas. Abstract presented at NANETS 2016, Jackson Hole.

  21. •• Kulke MH, Hörsch D, Caplin ME, Anthony LB, Bergsland E, Öberg K, et al. Telotristat Ethyl, a Tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome. J Clin Oncol. 2017;35(1):14–23. This phase III study provides evidence that the new serotonin synthesis inhibitor telotristat ethyl is effective for diarrhea palliation in patients with poorly controlled carcinoid syndrome.

  22. Rubin J, Ajani J, Schirmer W, Venook AP, Bukowski R, Pommier R, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol. 1999;17:600–6.

    Article  CAS  PubMed  Google Scholar 

  23. O’Toole D, Ducreux M, Bommelaer G, Wemeau JL, Bouché O, Catus F, et al. Treatment of carcinoid syndrome: a prospective crossover evaluation of lanreotide versus octreotide in terms of efficacy, patient acceptability, and tolerance. Cancer. 2000;88:770–6.

    Article  PubMed  Google Scholar 

  24. Toumpanakis C, Garland J, Marelli L, Srirajaskanthan R, Soh J, Davies P, et al. Long-term results of patients with malignant carcinoid syndrome receiving octreotide LAR. Aliment Pharmacol Ther. 2009;30:733–40.

    Article  CAS  PubMed  Google Scholar 

  25. Khan MS, El-Khouly F, Davies P, Toumpanakis C, Caplin ME. Long-term results of treatment of malignant carcinoid syndrome with prolonged release Lanreotide (Somatuline Autogel). Aliment Pharmacol Ther. 2011;34:235–42.

    Article  CAS  PubMed  Google Scholar 

  26. Strosberg JR, Benson AB, Huynh L, Duh MS, Goldman J, Sahai V, et al. Clinical benefits of above-standard dose of octreotide LAR in patients with neuroendocrine tumors for control of carcinoid syndrome symptoms: a multicenter retrospective chart review study. Oncologist. 2014;19:930–6.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wolin EM, Jarzab B, Eriksson B, Walter T, Toumpanakis C, Morse MA, et al. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther. 2015;9:5075–86.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Pavel M, Gross D, Benavent M, Caplin M, Perros P, Srirajaskanthan R, et al. Efficacy and safety results of telotristat ethyl in patients with carcinoid syndrome during the double-blind treatment period of the TELECAST phase 3 clinical trial. Abstract presented at NANETS 2016, Jackson Hole, WY, USA.

  29. Saltz L, Trochanowski B, Buckley M, Heffernan B, Niedzwiecki D, Tao Y, Kelsen D. Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors. Cancer. 1993;72:244–8.

    Article  CAS  PubMed  Google Scholar 

  30. Aparicio T, Ducreux M, Baudin E, Sabourin JC, De Baere T, Mitry E, et al. Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours. Eur J Cancer. 2001;37:1014–9.

    Article  CAS  PubMed  Google Scholar 

  31. Arnold R, Neuhaus C, Benning R, Schwerk WB, Trautmann ME, Joseph K, Bruns C. Somatostatin analog sandostatin and inhibition of tumor growth in patients with metastatic endocrine gastroenteropancreatic tumors. World J Surg. 1993;17:511–9.

    Article  CAS  PubMed  Google Scholar 

  32. Ducreux M, Ruszniewski P, Chayvialle JA, Blumberg J, Cloarec D, Michel H, et al. The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors. Am J Gastroenterol. 2000;95:3276–81.

    Article  CAS  PubMed  Google Scholar 

  33. Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, 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.

    Article  CAS  PubMed  Google Scholar 

  34. Rinke A, Wittenberg M, Schade-Brittinger C, Aminossadati B, Ronicke E, Gress TM, 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 (PROMID): results of long-term survival. Neuroendocrinology. 2017;104:26–32.

    Article  CAS  PubMed  Google Scholar 

  35. •• Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371:224–33. This phase III study provides high-level evidence that lanreotide delays progression in patients with GEP-NETs

    Article  PubMed  Google Scholar 

  36. Valkema R, De Jong M, Bakker WH, Breeman WA, Kooij PP, Lugtenburg PJ, et al. Phase I study of peptide receptor radionuclide therapy with [In-DTPA]octreotide: the Rotterdam experience. Semin Nucl Med. 2002;32:110–22.

    Article  PubMed  Google Scholar 

  37. Anthony LB, Woltering EA, Espenan GD, Cronin MD, Maloney TJ, McCarthy KE. Indium-111-pentetreotide prolongs survival in gastroenteropancreatic malignancies. Semin Nucl Med. 2002;32:123–32.

    Article  PubMed  Google Scholar 

  38. Kwekkeboom DJ, Krenning EP. Peptide receptor radionuclide therapy in the treatment of neuroendocrine tumors. Hematol Oncol Clin North Am. 2016;30:179–91.

    Article  PubMed  Google Scholar 

  39. •• 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(2):125–35. This is the first phase III trial to demonstrate that PRRT is safe and effective in patients with progressive, somatostatin receptor positive midgut NETs

  40. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yao JC, Pavel M, Lombard-Bohas C, Van Cutsem E, Voi M, Brandt U, 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; ahead of print.

  42. Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011;378:2005–12.

    Article  CAS  PubMed  Google Scholar 

  43. Faivre S, Niccoli P, Castellano D, Valle JW, Hammel P, Raoul JL, et al. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol 2016; ahead of print.

  44. Phan AT, Halperin DM, Chan JA, Fogelman DR, Hess KR, Malinowski P, et al. Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study. Lancet Oncol. 2015;16:695–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yao JC, Phan A, Hoff PM, Chen HX, Charnsangavej C, Yeung SC, et al. Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol. 2008;26:1316–23.

    Article  CAS  PubMed  Google Scholar 

  46. •• Yao JC, Guthrie K, Moran C, Strosberg JR, Kulke MH, Chan JA, et al. SWOG S0518: phase III prospective randomized comparison of depot octreotide plus interferon alpha-2b versus depot octreotide plus bevacizumab (NSC #704865) in advanced, poor prognosis carcinoid patients (NCT00569127). J Clin Oncol. 2015;33:4004. This phase III study did not demonstrate superiority of bevacizumab over interferon alpha in a population of progressive or otherwise high risk NETs of the GI tract and lungs

    Article  Google Scholar 

  47. •• Hobday TJ, Qin R, Reidy-Lagunes D, Moore MJ, Strosberg J, Kaubisch A, et al. Multicenter phase II trial of temsirolimus and bevacizumab in pancreatic neuroendocrine tumors. J Clin Oncol. 2015;33:1551–6. This is the first trial showing that high response rates may be achieved in NETs by combining mTOR inhibition and angiogenesis suppression

    Article  CAS  PubMed  Google Scholar 

  48. Kulke M, Niedzwiecki D, Foster N, Fruth B, Kunz P, Kennecke H, et al. Randomized phase II study of everolimus (E) versus everolimus plus bevacizumab (E + B) in patients (Pts) with locally advanced or metastatic pancreatic neuroendocrine tumors (pNET), CALGB 80701 (Alliance). J Clin Oncol 2015:33 (Supplement) abstract 4005.

  49. Detjen KM, Welzel M, Farwig K, Brembeck FH, Kaiser A, Riecken EO, et al. Molecular mechanism of interferon alfa-mediated growth inhibition in human neuroendocrine tumor cells. Gastroenterology. 2000;118:735–48.

    Article  CAS  PubMed  Google Scholar 

  50. Oberg K, Funa K, Alm G. Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med. 1983;309:129–33.

    Article  CAS  PubMed  Google Scholar 

  51. Janson ET, Oberg K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32:225–9.

    Article  CAS  PubMed  Google Scholar 

  52. Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003;90:687–93.

    Article  PubMed  Google Scholar 

  53. Arnold R, Rinke A, Klose KJ, Müller HH, Wied M, Zamzow K, et al. Octreotide versus octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: a randomized trial. Clin Gastroenterol Hepatol. 2005;3:761–71.

    Article  CAS  PubMed  Google Scholar 

  54. Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, et al. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors—the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003;21:2689–96.

    Article  CAS  PubMed  Google Scholar 

  55. Bergsland E, Roy R, Elvin J, Graeme-Cook F, Bailey M, Stephens P, et al. Genomic profiling distinguishes gastroenteropancreatic poorly differentiated neuroendocrine carcinomas (GEP-NEC) from small cell lung carcinoma (SCLC). Abstract presented at NANETS 2016; Jackson Hole (WY, USA).

  56. Kulke MH, Hornick JL, Frauenhoffer C, Hooshmand S, Ryan DP, Enzinger PC, et al. O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res. 2009;15:338–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Strosberg JR, Choi J, Cantor AB, Kvols LK. Selective hepatic artery embolization for treatment of patients with metastatic carcinoid and pancreatic endocrine tumors. Cancer Control. 2006;13:72–8.

    PubMed  Google Scholar 

  58. Barbier CE, Garske-Roman U, Sandstrom M, Nyman R, Granberg D. Selective internal radiation therapy in patients with progressive neuroendocrine liver metastases. Eur J Nucl Med Mol Imaging. 2016;43:1425–31.

    Article  CAS  PubMed  Google Scholar 

  59. Gupta S, Johnson MM, Murthy R, Ahrar K, Wallace MJ, Madoff DC, et al. Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival. Cancer. 2005;104:1590–602.

    Article  PubMed  Google Scholar 

  60. Memon K, Lewandowski RJ, Riaz A, Salem R. Chemoembolization and radioembolization for metastatic disease to the liver: available data and future studies. Curr Treat Options in Oncol. 2012;13:403–15.

    Article  Google Scholar 

  61. Chen JX, Rose S, White SB, El-Haddad G, Fidelman N, Yarmohammadi H, et al. Embolotherapy for neuroendocrine tumor liver metastases: prognostic factors for hepatic progression-free survival and overall survival. Cardiovasc Intervent Radiol 2016; ahead of print.

  62. Paul D, Ostwal V, Bose S, Basu S, Gupta S. Personalized treatment approach to gastroenteropancreatic neuroendocrine tumors: a medical oncologist’s perspective. Eur J Gastroenterol Hepatol. 2016;28:985–90.

    Article  CAS  PubMed  Google Scholar 

  63. Shi C, Gonzalez RS, Zhao Z, Koyama T, Cornish TC, Hande KR, et al. Liver metastases of small intestine neuroendocrine tumors: Ki-67 heterogeneity and World Health Organization grade discordance with primary tumors. Am J Clin Pathol. 2015;143:398–404.

    Article  PubMed  PubMed Central  Google Scholar 

  64. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351:1463–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Naing A, Gelderblom H, Gainor JF, Forde PM, Butler M, Lin CC, et al. A first-in-human phase I/II study of the anti-PD-1 antibody PDR001 in patients with advanced solid tumors. J Clin Oncol 2016:34 (suppl; abstr 3060).

  66. Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, et al. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res. 2015;21:4286–93.

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA

    Mauro Cives MD & Jonathan Strosberg MD

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Jonathan Strosberg has performed consultation for Novartis, Pfizer, Genentech, and Ipsen within institutional conflict-of-interest payment guidelines.

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Cives, M., Strosberg, J. Treatment Strategies for Metastatic Neuroendocrine Tumors of the Gastrointestinal Tract. Curr. Treat. Options in Oncol. 18, 14 (2017). https://doi.org/10.1007/s11864-017-0461-5

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