New Treatment Options for Patients with Advanced Neuroendocrine Tumors

  • Jennifer A. Chan
  • Matthew H. Kulke
Gastrointestinal Malignancies

Opinion statement

Well- to moderately differentiated neuroendocrine tumors (NET) are a heterogeneous group of malignancies for which a range of therapeutic options have been employed. For patients with localized NET, surgical resection remains the mainstay of treatment. Surgical resection of hepatic metastases or hepatic artery embolization may also be beneficial in patients with hepatic-predominant metastatic disease. Symptoms of hormonal excess, such as carcinoid syndrome and syndromes associated with functional pancreatic NET, can be effectively treated with somatostatin analogs. Systemic treatment options for patients with advanced NET have been limited. Treatment with the somatostatin analog octreotide has been shown to improve progression-free survival in patients with advanced midgut carcinoid tumors, and the potential antiproliferative effect of somatostatin analogs in patients with other NET subtypes is currently under investigation. Patients with advanced pancreatic NET may also respond to treatment with streptozocin or temozolomide-based therapy. In patients with advanced pancreatic NET, randomized, placebo-controlled studies have recently demonstrated that treatment with the tyrosine kinase inhibitor sunitinib or with the mTOR inhibitor everolimus is associated with improved progression-free survival. Based on these studies, sunitinib or everolimus should now be considered as therapeutic options in patients with advanced pancreatic NET. Initial phase II studies have also suggested activity associated with VEGF pathway and mTOR inhibitors in patients with advanced carcinoid tumors. Future studies will likely further define the role of these agents in the advanced carcinoid patient population.


Sunitinib Octreotide Neuroendocrine Tumor Everolimus Carcinoid Tumor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



J. Chan: consulted for Bayer/Onyx; received grants or has grants pending from Novartis, Bayer/Onyx, Merck for clinical trial support; and received payment from Novartis for educational presentations; M. Kulke: consulted for Pfizer, Novartis, Lexicon, and Ipsen.

References and Recommended Reading

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

  1. 1.
    Yao JC, Hassan M, Phan A, 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(18):3063–72.PubMedCrossRefGoogle Scholar
  2. 2.
    Sarmiento JM, Que FG. Hepatic surgery for metastases from neuroendocrine tumors. Surg Oncol Clin N Am. 2003;12(1):231–42.PubMedCrossRefGoogle Scholar
  3. 3.
    Osborne DA, Zervos EE, Strosberg J, et al. Improved outcome with cytoreduction versus embolization for symptomatic hepatic metastases of carcinoid and neuroendocrine tumors. Ann Surg Oncol. 2006;13(4):572–81.PubMedCrossRefGoogle Scholar
  4. 4.
    Touzios JG, Kiely JM, Pitt SC, et al. Neuroendocrine hepatic metastases: does aggressive management improve survival? Ann Surg. 2005;241(5):776–83. discussion 783–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Givi B, Pommier SJ, Thompson AK, et al. Operative resection of primary carcinoid neoplasms in patients with liver metastases yields significantly better survival. Surgery. 2006;140(6):891–7. discussion 897–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Lang H, Oldhafer K, Weimann A, et al. Liver transplantation for metastatic neuroendocrine tumors. Ann Surg. 1997;225:347–54.PubMedCrossRefGoogle Scholar
  7. 7.
    Le Treut YP, Delpero JR, Dousset B, et al. Results of liver transplantation in the treatment of metastatic neuroendocrine tumors. A 31-case French multicentric report. Ann Surg. 1997;225(4):355–64.PubMedCrossRefGoogle Scholar
  8. 8.
    Gupta S, Yao J, Ahrar K, et al. Hepatic artery embolization and chemoembolization for treatment of patients with metastatic carcinoid tumors: the MD Anderson experience. Cancer J. 2003;9:261–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Loewe C, Schindl M, Cejna M, et al. Permanent transarterial embolization of neuroendocrine metastases of the liver using cyanoacrylate and lipiodol: assessment of mid- and long-term results. AJR Am J Roentgenol. 2003;180(5):1379–84.PubMedGoogle Scholar
  10. 10.
    Moertel C, Johnson C, McKusick M, et al. The management of patients with advanced carcinoid tumors and islet cell carcinoma. Ann Int Med. 1994;120:302–9.PubMedGoogle Scholar
  11. 11.
    Kennedy AS, Dezarn WA, McNeillie P, et al. Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in 148 patients. Am J Clin Oncol. 2008;31(3):271–9.PubMedCrossRefGoogle Scholar
  12. 12.
    King J, Quinn R, Glenn DM, et al. Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases. Cancer. 2008;113(5):921–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Krenning EP, Kwekkeboom DJ, Valkema R, et al. Peptide receptor radionuclide therapy. Ann NY Acad Sci. 2004;1014:234–45.PubMedCrossRefGoogle Scholar
  14. 14.
    Breeman WA, de Jong M, Kwekkeboom DJ, et al. Somatostatin receptor-mediated imaging and therapy: basic science, current knowledge, limitations and future perspectives. Eur J Nucl Med. 2001;28(9):1421–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Teunissen JJ, Kwekkeboom DJ, de Jong M, et al. Endocrine tumours of the gastrointestinal tract. Peptide receptor radionuclide therapy. Best Pract Res Clin Gastroenterol. 2005;19(4):595–616.PubMedCrossRefGoogle Scholar
  16. 16.
    Bushnell Jr DL, O’Dorisio TM, O’Dorisio MS, et al. 90Y-edotreotide for metastatic carcinoid refractory to octreotide. J Clin Oncol. 2010;28(10):1652–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0, Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26(13):2124–30.PubMedCrossRefGoogle Scholar
  18. 18.
    Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol. 1999;17:600–6.PubMedGoogle Scholar
  19. 19.
    Kvols L, Moertel C, O’Connell M, et al. Treatment of the malignant carcinoid syndrome: evaluation of a long-acting somatostatin analog. N Engl J Med. 1986;315:663–66.PubMedCrossRefGoogle Scholar
  20. 20.
    O’Toole D, Ducreux M, Bommelaer G, 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).Google Scholar
  21. 21.
    Schmid HA, Schoeffter P. Functional activity of the multiligand analog SOM230 at human recombinant somatostatin receptor subtypes supports its usefulness in neuroendocrine tumors. Neuroendocrinology. 2004;80 Suppl 1:47–50.PubMedCrossRefGoogle Scholar
  22. 22.
    Kvols L, Wiedenmann B, Oberg K, et al. Safety and efficacy of pasireotide (SOM230) in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR: Results of a phase II study. JCO, 2006. ASCO Annual Meeting(4082).Google Scholar
  23. 23.••
    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(28):4656–63.PubMedCrossRefGoogle Scholar
  24. 24.
    Frank M, Klose K, Wied M et al. Combination therapy with octreotide and alpha-interferon: Effect on tumor growth in metastatic endocrine gastroenteropancreatic tumors. Am J Gastroenterol. 1999;94(1381).Google Scholar
  25. 25.
    Janson E, 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.PubMedCrossRefGoogle Scholar
  26. 26.
    Oberg K, Eriksson B. The role of interferons in the management of carcinoid tumors. Acta Oncol. 1991;30:519–22.PubMedCrossRefGoogle Scholar
  27. 27.
    Sun W, Lipsitz S, Catalano P, et al. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005;23(22):4897–904.PubMedCrossRefGoogle Scholar
  28. 28.
    Moertel C, Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin, stretpozocin-fluorouracil, or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992;326:519–23.PubMedCrossRefGoogle Scholar
  29. 29.
    Kouvaraki M, Ajani J, Hoff P, 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.PubMedCrossRefGoogle Scholar
  30. 30.
    Stevens MF, Hickman JA, Langdon SP, 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(22):5846–52.PubMedGoogle Scholar
  31. 31.
    Ekeblad S, Sundin A, Janson ET, et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007;13(10):2986–91.PubMedCrossRefGoogle Scholar
  32. 32.
    Kulke M, Blaszkowsky L, Zhu A et al. Phase I/II study of everolimus (RAD001) in combination with temozolomide (TMZ) in patients (pts) with advanced pancreatic neuroendocrine tumors (NET). 2010 Gastrointestinal Cancers Symposium, 2010: p. Abstract 127.Google Scholar
  33. 33.
    Kulke M, Stuart K, Earle C et al. A phase II study of temozolomide and bevacizumab in patients with advanced neuroendocrine tumors. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings 2006;24(18S):Abstract 4044.Google Scholar
  34. 34.
    Kulke MH, Hornick JL, Frauenhoffer C, et al. O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res. 2009;15(1):338–45.PubMedCrossRefGoogle Scholar
  35. 35.
    Kulke MH, Stuart K, Enzinger PC, et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006;24(3):401–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Strosberg JR, Fine RL, Choi J et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 2010 [Epub ahead of print].Google Scholar
  37. 37.
    Yao JC, Phan A, Hoff PM, 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(8):1316–23.PubMedCrossRefGoogle Scholar
  38. 38.
    Hobday TJ, Rubin J, Holen K et al. MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I, 2007;25(18S):Abstract 4504.Google Scholar
  39. 39.
    Phan A, Yao J, Fogelman D et al. A prospective, multi-institutional phase II study of GW786034 (pazopanib) and depot octreotide (sandostatin LAR) in advanced low-grade neuroendocrine carcinoma (LGNEC). Journal of Clinical Oncology, 2010 ASCO Annual Meeting Proceedings 2010;28(15S):Abstract 4044.Google Scholar
  40. 40.
    Kulke MH, Lenz HJ, Meropol NJ, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol. 2008;26(20):3403–10.PubMedCrossRefGoogle Scholar
  41. 41.••
    Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501–13. This randomized, phase III study demonstrated an improvement in progression-free survival for patients with advanced pancreatic neuroendocrine tumor receiving sunitinib compared to placebo.Google Scholar
  42. 42.
    Vignot S, Faivre S, Aguirre D, et al. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol. 2005;16(4):525–37.PubMedCrossRefGoogle Scholar
  43. 43.
    Podsypanina K, Lee RT, Politis C, et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/− mice. Proc Natl Acad Sci USA. 2001;98(18):10320–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Wang L, Ignat A, Axiotis CA. Differential expression of the PTEN tumor suppressor protein in fetal and adult neuroendocrine tissues and tumors: progressive loss of PTEN expression in poorly differentiated neuroendocrine neoplasms. Appl Immunohistochem Mol Morphol. 2002;10(2):139–46.PubMedCrossRefGoogle Scholar
  45. 45.
    Duran I, Kortmansky J, Singh D, et al. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer. 2006;95(9):1148–54.PubMedCrossRefGoogle Scholar
  46. 46.
    Yao JC, Phan AT, Chang DZ, et al. 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;26(26):4311–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010;28(1):69–76.PubMedCrossRefGoogle Scholar
  48. 48.••
    Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514–23. The RADIANT-3 trial, a randomized, phase III study, demonstrated an improvement in progression-free survival for patients with advanced pancreatic neuroendocrine tumor receiving the mTOR inhibitor everolimus compared to placebo.Google Scholar
  49. 49.
    Yao J, Phan A, Fogleman D et al. Randomized run-in study of bevacizumab (B) and everolimus (E) in low- to intermediate-grade neuroendocrine tumors (LGNETs) using perfusion CT as functional biomarker. J Clin Oncol. 2010;28:15s, (suppl; abstr 4002) 2010.Google Scholar
  50. 50.
    Chan J, Mayer R, Jackson N et al. Phase I study of sorafenib in combination with everolimus (RAD001) in patients with advanced neuroendocrine tumors (NET). J Clin Oncol. 2010;28(suppl; abstr e14597) 2010.Google Scholar
  51. 51.
    Chan J, Ryan D, Fuchs C et al. Phase I study of pasireotide (SOM230) in combination with everolimus (RAD001) in patients (pts) with advanced neuroendocrine tumors (NET) in Gastrointestinal Cancers Symposium 2010; Orlando.Google Scholar
  52. 52.
    Yao J, NG C, Hoff P et al. Improved progression-free survival and rapid, sustained decrease in tumor perfusion among patients with advanced carcinoid treated with bevacizumab (abstract). J Clin Oncol. 2005;23(309s).Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Medical OncologyDana-Farber Cancer InstituteBostonUSA

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