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Novel Medical Therapies of Recurrent and Metastatic Gastroenteropancreatic Neuroendocrine Tumors

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Abstract

Neuroendocrine tumors (NETs) of the gastrointestinal tract and pancreas are slow-growing but commonly advanced malignancies with increasing incidence and prevalence. While locoregional disease can be effectively managed with resection, treatment of recurrent, progressive or metastatic disease has until recently been limited to palliative embolization and cytoreducitve surgery, with cytotoxic chemotherapeutic agents being the last resort. However, novel molecular targeted therapies inhibiting malignant cell proliferation and neoangiogenesis, as well as new cytotoxic chemotherapy drugs and somatostatin analogues, are all being investigated for their potential use in advanced neuroendocrine tumors. Long-acting release forms of octreotide have been shown to not only improve symptoms in carcinoid syndrome but to also delay progression of gastrointestinal NETs. On the other hand, phase III trials have demonstrated everolimus (with octreotide) and sunitinib to increase progression-free survival in pancreatic NETs. Use of bevacizumab has also shown promise in a phase II study, and results of an ongoing phase III trial comparing it to interferon are eagerly expected. Use of radiolabeled somatostatin analogues is still under investigation, though several phase II studies are encouraging. New cytotoxic agents, most notably temozolomide and capecitabine, are already in use, but their relative effectiveness compared to streptozocin in pancreatic NETs is yet to be determined.

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References

  1. Toumpanakis CG, Caplin ME. Molecular genetics of gastroenteropancreatic neuroendocrine tumors. Am J Gastroenterol. 2008;103:729–732.

    Article  PubMed  CAS  Google Scholar 

  2. Oberndorfer S. Karzinoid tumore des Dunndarms. Frankf Z Pathol. 1907;1:426–430.

    Google Scholar 

  3. Gosset A, Masson P. Tumeurs endocrines se l’appendice. Presse Med. 2009;25:237–240.

    Google Scholar 

  4. Arnold R. Endocrine tumours of the gastrointestinal tract. Introduction: definition, historical aspects, classification, staging, prognosis and therapeutic options. Best Pract Res Clin Gastroenterol. 2005;19:491–505.

    Article  PubMed  CAS  Google Scholar 

  5. Oberg K. Diagnosis and treatment of carcinoid tumors. Expert Rev Anticancer Ther. 2003;3:863–877.

    Article  PubMed  Google Scholar 

  6. Phan AT, Yao JC. Neuroendocrine tumors: current and future medical therapies. Curr Opin Endocrinol Diabetes Obes. 2009;16:72–78.

    Article  Google Scholar 

  7. Maggard MA, O’Connell JB, Ko CY. Updated population-based review of carcinoid tumors. Ann Surg. 2004;240:117–122.

    Article  PubMed  Google Scholar 

  8. Modlin I, Oberg K, Chung D, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008;9:61–72.

    Article  PubMed  CAS  Google Scholar 

  9. Yao J, 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;26:3063–3072.

    Article  PubMed  Google Scholar 

  10. Kulke M, Scherübl H. Accomplishments in 2008 in the management of gastrointestinal neuroendocrine tumors. Gastrointest Cancer Res. 2009;3(Suppl 2):S43–S47.

    Google Scholar 

  11. Pasieka JL. Carcinoid tumors. Surg Clin North Am. 2009;89:1123–1137.

    Article  PubMed  Google Scholar 

  12. Van Eeden S, Quaedvlieg PF, Taal BG, et al. Classification of low-grade neuroendocrine tumors of midgut and unknown origin. Hum Pathol. 2002;33:1126–1132.

    Article  PubMed  Google Scholar 

  13. Oberg K, Astrup L, Eriksson B, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine tumors (including bronchopulmonary and thymic neoplasms). Part I-general overview. Acta Oncol. 2004;43:617–625.

    Article  PubMed  Google Scholar 

  14. Kawahara M, Kammori M, Kanauchi H, et al. Immunohistochemical prognostic indicators of gastrointestinal carcinoid tumors. Eur J Surg Oncol. 2002;28:140–146.

    Article  PubMed  CAS  Google Scholar 

  15. Sökmensër C, Gedikoglu G, Uzunalimoglu B. Importance of proliferation markers in gastrointestinal carcinoid tumors: a clinicopathologic study. Hepatogastroenterology. 2001;48:720–723.

    Google Scholar 

  16. Ghevariya V. Carcinoid tumors of the gastrointestinal tract. South Med J. 2009;102:1032–1040.

    Article  PubMed  Google Scholar 

  17. Modlin IM, Kidd M, Latich I, et al. Current status of gastrointestinal carcinoids. Gastroenterology. 2005;128:1717–1751.

    Article  PubMed  Google Scholar 

  18. Kulke MH, Kim H, Clark JW, et al. A phase II trial of gemcitabine for metastatic neuroendocrine tumors. Cancer. 2004;101:934–939.

    Article  PubMed  CAS  Google Scholar 

  19. Oberg K, Norheim I, Lundqvist G, et al. Cytotoxic treatment in patients with malignant carcinoid tumors. Response to streptozocin—alone or in combination with 5-FU. Acta Oncol. 1987;26:429–432.

    Article  PubMed  CAS  Google Scholar 

  20. Oberg K, Kvols L, Caplin M, et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004;15:966–973.

    Article  PubMed  CAS  Google Scholar 

  21. Faiss S, Pape UF, Bohmig M, 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;21:2689–2696.

    Article  PubMed  CAS  Google Scholar 

  22. Kolby L, Persson G, Franzen S, Ahren B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003;90:687–693.

    Article  PubMed  CAS  Google Scholar 

  23. Eriksson B. New drugs in neuroendocrine tumors: rising of new therapeutic philosophies. Curr Opin Oncol. 2010;22:381–386.

    Article  PubMed  CAS  Google Scholar 

  24. Schnirer II, Yao JC, Ajani JA. Carcinoid—a comprehensive review. Acta Oncol. 2003;42:672–692.

    Article  PubMed  Google Scholar 

  25. Modlin IM, Kidd M, Drozdov I, et al. Pharmacothearpy of neuroendocrine cancers. Expert Opin Pharmacother. 2008;9:2617–2626.

    Article  PubMed  CAS  Google Scholar 

  26. Modlin IM, Pavel M, et al. Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther. 2010;31:169–188.

    PubMed  CAS  Google Scholar 

  27. Rinke A, Muller H, Schhade-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;27:4656–4663.

    Article  PubMed  CAS  Google Scholar 

  28. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology™ for Neuroendocrine Tumors V.1.2011. ©National Comprehensive Cancer Network, Inc 2011. All rights reserved. Accessed July 1, 2011. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES™, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

  29. 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;80:47–50.

    Article  PubMed  CAS  Google Scholar 

  30. Kvols L, Wiedenmann B, Oberg K, The SOM230 Carcinoid Study Group, 2006, 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. J Clin Oncol. 2006;24:198s.

    Google Scholar 

  31. Jaquet P, Gnerz G, Saveanu A, et al. Efficacy of chimeric molecules directed towards multiple somatostatin and dopamine receptors on inhibition of GH and prolactin secretion from GH and prolactin secretion from GH-secreting pituitary adenoma classified as partially responsive to somatostatin analog therapy. Eur J Endocrinol. 2005;153:135–141.

    Article  PubMed  CAS  Google Scholar 

  32. Hofland LJ, Lamberts SW. The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocr Rev. 2003;24:28–47.

    Article  PubMed  CAS  Google Scholar 

  33. Modlin IM, Moss SF, Chung DC, et al. Priorities for improving the management of gastroenteropancreatic neuroendocrine tumors. J Natl Cancer Inst. 2008;100:1282–1289.

    Article  PubMed  Google Scholar 

  34. Grozinsky-Glasberg S, Franchi G, Teng M, et al. Octreotide and the mTOR inhibitor RAD001 (everolimus) block proliferation and interact with the Akt-mTOR-p70S6K pathway in a neuro-endocrine tumour cell line. Neuroendocrinology. 2008;87:168–181.

    Article  PubMed  CAS  Google Scholar 

  35. Yao JC, Phan A, Chang D, 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;26:4311–4318.

    Article  PubMed  Google Scholar 

  36. 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;28:69–76.

    Article  PubMed  CAS  Google Scholar 

  37. Yao JC, Ricci S, Winkler RE, Pavel ME. Everolimus plus octreotide LAR versus placebo plus octreotide LAR in patients with advanced neuroendocrine tumors (NET): updated safety and efficacy results from RADIANT-2. J Clin Oncol. 2011;29:4011.

    Google Scholar 

  38. Yao JC, Shah MH, Ito T. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514–523.

    Article  PubMed  CAS  Google Scholar 

  39. Terris B, Scoazec J, Rubbia L, et al. Expression of vascular endothelial growth factor in digestive neuroendocrine tumors. Histopathology. 1998;32:133–138.

    Article  PubMed  CAS  Google Scholar 

  40. Zhang J, Jia Z, Li Q, et al. Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors. Cancer. 2007;109:1478–1486.

    Article  PubMed  CAS  Google Scholar 

  41. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting VEGF and PDGF receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003;9:327–337.

    PubMed  CAS  Google Scholar 

  42. O’Farrell AM, Abrams TJ, Yuen HA, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood. 2003;101:3597–3605.

    Article  PubMed  Google Scholar 

  43. Kulke M, Lenzy N, Meropol J, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol. 2008;26:3403–3410.

    Article  PubMed  CAS  Google Scholar 

  44. Raymond E, Raoul J, Niccoli P, et al. Phase III randomised, double-blind trial of sunitinib versus placebo in patients with progressive, well differentiated malignant islet cell tumours. 11th world congress on gastrointestinal cancer (ESMO 2009); Barcelona, Spain. 2009 June 30–July 03; Abtr 0013.

  45. Niccoli P, Raoul J, Bang Y, et al. Updated safety and efficacy results of the phase III trial of sunitinib (SU) versus placebo (PBO) for treatment of pancreatic neuroendocrine tumors (NET). J Clin Oncol. 2010;28:4000.

    Google Scholar 

  46. Vinik A, Bang Y, Raoul J, et al. Patient-reported outcomes (PROs) in patients (pts) with pancreatic neuroendocrine tumors (NET) receiving sunitinib (SU) in a phase III trial. J Clin Oncol. 2010;28:4003.

    Google Scholar 

  47. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561–566.

    Article  PubMed  CAS  Google Scholar 

  48. Kindmark H, Janson ET, Gustafsson B, et al. Five patients with malignant endocrine tumors tested with imatinib mesylate (Gleevec). Acta Oncol. 2010;49:100–101.

    Article  PubMed  Google Scholar 

  49. Yao J, Zhang J, Rashid A, et al. Clinical and in vitro studies of imatinib in advanced carcinoid tumors. Clin Cancer Res. 2007;13:234–240.

    Article  PubMed  CAS  Google Scholar 

  50. Hobday TJ, Rubin J, Holen K, et al. MCO44h, a phase II trial of sorafenib in patients with metastatic neuroendocrine tumors (NET): a phase II consortium (P2C) study. J Clin Oncol. 2007;25:4504.

    Article  Google Scholar 

  51. Yao J, Phan P, Hoss H, 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;26:1316–1323.

    Article  PubMed  CAS  Google Scholar 

  52. Yao JC, Phan AT, 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;28:4002.

    Article  Google Scholar 

  53. D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA. 1994;91:4082–4085.

    Article  PubMed  Google Scholar 

  54. Varker KA, Campbell J, Shah MH. Phase II study of thalidomide in patients with metastatic carcinoid and islet cell tumors. Cancer Chemother Pharmacol. 2008;61:661–668.

    Article  PubMed  CAS  Google Scholar 

  55. Sung M, Kvols L, Wolin E, et al. Phase II proof-of-concept study of atiprimoid in patients with advanced low-to intermediate-grade neuroendocrine carcinoma. J Clin Oncol. 2008;26:4611.

    Google Scholar 

  56. Tolcher A, Rothenberg M, Rodon J, et al. A phase I pharmakinetic and pharmacodynamic study of AMG 479, a fully monoclonal antibody against insulin-like growth factor type 1 receptor (IGF-IR) in advanced solid tumors. J Clin Oncol. 2007;25:3002.

    Article  Google Scholar 

  57. Anthony L, Chester M, Michael S, et al. Phase II open-label clinical trial of vatalanib (PTK/ZK) in patients with progressive neuroendocrine cancer. J Clin Oncol. 2008;26:14624.

    Google Scholar 

  58. Pavel M, Bartel C, Henck F, et al. Open-label, nonrandomized, multicenter phase II study evaluating the angiogenesis inhibitor PTK787/ZK222584 (PTK/ZK) in patients with advanced neuroendocrine carcinomas (NEC). J Clin Oncol. 2008;26:14684.

    Google Scholar 

  59. Forrer F, Valkema R, Kwekkeboom DJ, de Jong M, Krenning EP. Neuroendocrine tumors. Peptide receptor radionuclide therapy. Best Pract Res Clin Endocrinol Metab. 2007;21:111–129.

    Article  PubMed  CAS  Google Scholar 

  60. Valkema R, Pauwels S, Kvols LK, et al. Survival and response after peptide receptor radionuclide therapy with [90Y-DOTA0, Tyr3] octreotide in patients with advanced gastroenteropancreatic neuroendocrine tumors. Semin Nucl Med. 2006;36:147–156.

    Article  PubMed  Google Scholar 

  61. Kwekkeboom D, de Herder W, Kam B, et al. Treatment with the radiolabeled somatostatin analog [177Lu-DOTAO, Tyr3] octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26:2124–2130.

    Article  PubMed  CAS  Google Scholar 

  62. Cwikla JB, Sankowski A, Seklecka N, et al. Efficacy of radionuclide treatment DOTATATE Y-90 in patients with progressive metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs): a phase II study. Ann Oncol. 2010;21:787–794.

    Article  PubMed  CAS  Google Scholar 

  63. Kennedy AS, Dezarn WA, Mc Neillie P, et al. Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in 148 patients. Ann J Clin Oncol. 2008;31:271–279.

    Article  Google Scholar 

  64. Ekeblad S, Sundin A, Welin S, et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007;13:2986–2991.

    Article  PubMed  CAS  Google Scholar 

  65. 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;24:401–406.

    Article  PubMed  CAS  Google Scholar 

  66. Kunz PL, Kuo T, Zahn JM, et al. A phase II study of capecitabine, oxaliplatin, and bevacizumab for metastatic or unresectable neuroendocrine tumors. J Clin Oncol. 2010;28(15 Suppl):4104.

    Google Scholar 

  67. Papouchado B, Erickson LA, Rohlinger AL, et al. Epidermal growth factor receptor and activated epidermal growth factor receptor expression in gastrointestinal carcinoids and pancreatic endocrine carcinomas. Mod Pathol. 2005;18:1329–1335.

    Article  PubMed  CAS  Google Scholar 

  68. Hobday TJ, Holen K, Donehower R, et al. A phase II trial of gefitinib in patients (pts) with progressive metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study. J Clin Oncol. 2006;24:4043.

    Article  Google Scholar 

  69. O’Reilly M, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88:277–285.

    Article  PubMed  Google Scholar 

  70. Zatterstrom U, Felbor U, Fukai N, et al. Collagen XVIII/endostatin structure and functional role in angiogenesis. Cell Struct Funct. 2000;25:97–101.

    Article  PubMed  CAS  Google Scholar 

  71. Kulke MH, Bergsland EK, Ryan DP, et al. Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors. J Clin Oncol. 2006;24:3555–3561.

    Article  PubMed  CAS  Google Scholar 

  72. Kulke MH, Siu LL, Tepper JE, et al. Future directions in the treatment of neuroendocrine tumors: consensus report of the national cancer institute neuroendocrine tumor clinical trials planning meeting. J Clin Oncol. 2011;29:934–943.

    Article  PubMed  CAS  Google Scholar 

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Miljković, M.D., Girotra, M., Abraham, R.R. et al. Novel Medical Therapies of Recurrent and Metastatic Gastroenteropancreatic Neuroendocrine Tumors. Dig Dis Sci 57, 9–18 (2012). https://doi.org/10.1007/s10620-011-1854-0

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