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Treatment of gastroenteropancreatic neuroendocrine tumors

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Abstract

Neuroendocrine tumors are rare; thus, individual experience with the diagnosis and treatment of these tumors is mostly low, except in specialized centers. For histological diagnosis, standards have been described recently. Pathological classification and clinical staging influence diagnostic and therapeutic decisions. This chapter aims at demonstrating the importance of pathological and clinical classification of neuroendocrine tumors on therapeutic decisions, indicating the appropriate therapy for different stages of the disease. Surgical therapy will be discussed shortly, including palliative surgical strategies. However, the focus of the manuscript is medical therapy. Biotherapy, its effects, and remaining uncertainties are presented as well as different chemotherapeutic schemes. Finally, new options of palliative medical therapies like kinase inhibitors and anti-angiogenetic drugs will be discussed.

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References

  1. Anthony L, Johnson D, Hande K, Shaff M, Winn, S, Krozely M, Oates J (1993) Somatostatin analogue phase I trials in neuroendocrine neoplasms. Acta Oncol 32:217–223

    Article  PubMed  CAS  Google Scholar 

  2. Aparicio T, Ducreux M, Baudin E, Sabourin JC, De Baere T, Mitry E, Schlumberger M, Rougier P (2001) Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours. Eur J Cancer 37:1014–1019

    Article  PubMed  CAS  Google Scholar 

  3. Arnold R, Benning R, Neuhaus C, Rolwage M, Trautmann ME (1993a) Gastroenteropancreatic endocrine tumours: effect of Sandostatin on tumour growth. The German Sandostatin Study Group. Digestion 54(Suppl 1):72–75

    PubMed  Google Scholar 

  4. Arnold R, Neuhaus C, Benning R, Schwerk WB, Trautmann ME, Joseph K, Bruns C (1993b) Somatostatin analog sandostatin and inhibition of tumor growth in patients with metastatic endocrine gastroenteropancreatic tumors. World J Surg 17:511–519

    Article  PubMed  CAS  Google Scholar 

  5. Arnold R, Trautmann ME, Creutzfeldt W, Benning R, Benning M, Neuhaus C, Jurgense, R, Stein K, Schafer H, Bruns C, Dennler HJ (1996) Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumours. Gut 38:430–438

    Article  PubMed  CAS  Google Scholar 

  6. Bajetta E, Rimassa L, Carnaghi C, Seregni E, Ferrari L, Di Bartolomeo M, Regalia E, Cassata A, Procopio G, Mariani L (1998) 5-Fluorouracil, dacarbazine, and epirubicin in the treatment of patients with neuroendocrine tumors. Cancer 83:372–378

    Article  PubMed  CAS  Google Scholar 

  7. Bajetta E, Ferrari L, Procopio G, Catena L, Ferrario E, Martinetti A, Di Bartolomeo M, Buzzoni R, Celio L, Vitali M, Beretta E, Seregni E, Bombardieri E (2002) Efficacy of a chemotherapy combination for the treatment of metastatic neuroendocrine tumours. Ann Oncol 13:614–621

    Article  PubMed  CAS  Google Scholar 

  8. Bukowski RM, Tangen C, Lee R, Macdonald JS, Einstein AB Jr, Peterson R, Fleming TR (1992) Phase II trial of chlorozotocin and fluorouracil in islet cell carcinoma: a Southwest Oncology Group study. J Clin Oncol 10:1914–1918

    PubMed  CAS  Google Scholar 

  9. Carr K, Yao J, Rashid A, Yeung SC, Szklaruk J, Baker J, Vauthey JN, Curley S, Ellis L, Ajani JA (2004) A phase II trial of imatinib in patients with advanced carcinoid tumor. J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition), 22(14S):4124

  10. Cheng PN, Saltz LB (1999) Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma. Cancer 86:944–948

    Article  PubMed  CAS  Google Scholar 

  11. Dasgupta P (2004) Somatostatin analogues: multiple roles in cellular proliferation, neoplasia, and angiogenesis. Pharmacol Ther 102:61–85

    Article  PubMed  CAS  Google Scholar 

  12. De Herder WW, Niederle B, Scoazec JY, Pauwels S, Kloppel G, Falconi M, Kwekkeboom DJ, Oberg K, Eriksson B, Wiedenmann B, Rindi G, O’Toole D, Ferone D (2006) Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendocrinology 84:183–188

    Article  PubMed  CAS  Google Scholar 

  13. Detjen KM, Welzel M, Farwig K, Brembeck FH, Kaiser A, Riecken EO, Wiedenmann B, Rosewicz S (2000) Molecular mechanism of interferon alfa-mediated growth inhibition in human neuroendocrine tumor cells. Gastroenterology 118:735–748

    Article  PubMed  CAS  Google Scholar 

  14. Di Bartolomeo M, Bajetta E, Bochicchio AM, Carnaghi C, Somma L, Mazzaferro V, Visini M, Gebbia V, Tumolo S, Ballatore P (1995) A phase II trial of dacarbazine, fluorouracil and epirubicin in patients with neuroendocrine tumours. A study by the Italian Trials in Medical Oncology (I.T.M.O.) Group. Ann Oncol 6:77–79

    PubMed  Google Scholar 

  15. Di Bartolomeo M, Bajetta E, Buzzoni R, Mariani L, Carnaghi C, Somma L, Zilembo N, Di Leo A (1996) Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors. A study by the Italian Trials in Medical Oncology Group. Cancer 77:402–408

    Article  PubMed  Google Scholar 

  16. Dirix LY, Vermeulen PB, Fierens H, De Schepper B, Corthouts B, Van Oosterom AT (1996) Long-term results of continuous treatment with recombinant interferon-alpha in patients with metastatic carcinoid tumors—an antiangiogenic effect? Anticancer Drugs 7:175–181

    Article  PubMed  CAS  Google Scholar 

  17. Doberauer C, Mengelkoch B, Kloke O, Wandl U, Niederle N (1991) Treatment of metastatic carcinoid tumors and the carcinoid syndrome with recombinant interferon alpha. Acta Oncol 30:603–605

    Article  PubMed  CAS  Google Scholar 

  18. Ducreux M, Ruszniewski P, Chayvialle JA, Blumberg J, Cloarec D, Michel H, Raymond JM, Dupas JL, Gouerou H, Jian R, Genestin E, Hammel P, Rougier P (2000) The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors. Am J Gastroenterol 95:3276–3281

    Article  PubMed  CAS  Google Scholar 

  19. Engstrom PF, Lavin PT, Moerte, CG, Folsch E, Douglass HO Jr (1984) Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol 2:1255–1259

    PubMed  CAS  Google Scholar 

  20. Eriksson B, Skogseid B, Lundqvist G, Wide L, Wilander E, Oberg K (1990) Medical treatment and long-term survival in a prospective study of 84 patients with endocrine pancreatic tumors. Cancer 65:1883–1890

    Article  PubMed  CAS  Google Scholar 

  21. Eriksson B, Renstrup J, Imam H, Oberg K (1997) High-dose treatment with lanreotide of patients with advanced neuroendocrine gastrointestinal tumors: clinical and biological effects. Ann Oncol 8:1041–1044

    Article  PubMed  CAS  Google Scholar 

  22. Falconi M, Plockinger U, Kwekkeboom DJ, Manfredi R, Korner M, Kvols L, Pape UF., Ricke J, Goretzki PE, Wildi S, Steinmuller T, Oberg K, Scoazec JY (2006) Well-differentiated pancreatic nonfunctioning tumors/carcinoma. Neuroendocrinology 84:196–211

    Article  PubMed  CAS  Google Scholar 

  23. Faiss S, Pape UF., Bohmig M, Dorffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B (2003) 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 21:2689–2696

    Article  PubMed  CAS  Google Scholar 

  24. Frame J, Kelsen D, Kemeny N, Cheng E, Niedzwiecki D, Heelan R, Lippermann R (1988) A phase II trial of streptozotocin and adriamycin in advanced APUD tumors. Am J Clin Oncol 11:490–495

    Article  PubMed  CAS  Google Scholar 

  25. Hobday TJ, Holen K, Donehower R, Camoriano J, Kim G, Picus J, Philip P, Lloyd R, Mahoney M, Erlichman C (2006) A phase II trial of gefitinib in patients (pts) with progressive metastatic neuroendocrine tumors (NET): a phase II consortium (P2C) study. J Clin Oncol, ASCO Annual Meeting Proceedings Part I, 24(18S):4043

  26. Hobday TJ, Rubin J, Goldberg R, Erlichman C, Lloyd R (2003) Molecular markers in metastatic gastrointestinal neuroendocrine tumors. Proc Am Soc Clin Oncol 22:269

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  28. Jacobsen MB, Hanssen LE, Kolmannskog F, Schrumpf E, Vatn MH, Bergan A (1995) Interferon-alpha 2b, with or without prior hepatic artery embolization: clinical response and survival in mid-gut carcinoid patients. The Norwegian carcinoid study. Scand J Gastroenterol 30:789–796

    Article  PubMed  CAS  Google Scholar 

  29. Janson ET, Ronnblom L, Ahlstrom H, Grander D, Alm G, Einhorn S, Oberg K (1992) Treatment with alpha-interferon versus alpha-interferon in combination with streptozocin and doxorubicin in patients with malignant carcinoid tumors: a randomized trial. Ann Oncol 3:635–638

    PubMed  CAS  Google Scholar 

  30. Jensen RT, Niederle B, Mitry E, Ramage JK, Steinmuller T, Lewington V, Scarpa A, Sundin A, Perren A, Gross D, O’Connor JM, Pauwels S, Kloppel G (2006a) Gastrinoma (duodenal and pancreatic). Neuroendocrinology 84:173–182

    Article  PubMed  CAS  Google Scholar 

  31. Jensen RT, Rindi G, Arnold R, Lopes JM, Brandi ML, Bechstein WO, Christ E, Taal BG, Knigge U, Ahlman H, Kwekkeboom DJ, O’Toole D (2006b) Well-differentiated duodenal tumor/carcinoma (excluding gastrinomas). Neuroendocrinology 84:165–172

    Article  PubMed  CAS  Google Scholar 

  32. Kaltsas GA, Mukherjee JJ, Isidori A, Kola B, Plowman PN, Monson JP, Grossman AB, Besser GM (2002) Treatment of advanced neuroendocrine tumours using combination chemotherapy with lomustine and 5-fluorouracil. Clin Endocrinol (Oxf) 57:169–183

    Article  CAS  Google Scholar 

  33. Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, Yao JC (2004) Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 22:4762–4771

    Article  PubMed  CAS  Google Scholar 

  34. Kulke MH, Lenz HJ, Meropol NJ, Posey J, Picus J, Ryan DP, Bergsland E, Stuart K, Baum CM, Fuchs Cs (2005) Results of a phase II study with sunitinib malate (SU11248) in patients with advanced neuroendocrine tumours (NETs). Eur J Cancer 3:406

    Google Scholar 

  35. Kulke M, Bergsland E, Ryan D, Enzinger P, Lynch T, Zhu A, Meyerhardt J, Heymach J, Fogler W, Sidor C, Michelini A, Kinsella K, Venook A, Fuchs C (2006) Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors. J Clin Oncol 24:3555–3561

    Article  PubMed  CAS  Google Scholar 

  36. Kulke MH, Stuart K, Earle C, Bhargava P, Clark J, Enzinger PC, Meyerhardt J, Attawia M, Lawrence C, Fuchs C (2006a) A phase II study of temozolomide and bevacizumab in patients with advanced neuroendocrine tumors. J Clin Oncol, ASCO Annual Meeting Proceedings Part I, 24(18S):4044

  37. Kulke MH, Stuart K, Enzinger Pc, Ryan Dp, Clark Jw, Muzikansky A, Vincitore M, Michelini A, Fuchs Cs (2006b) Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 24:401–406

    Article  PubMed  CAS  Google Scholar 

  38. Lamberts SW, Krenning EP, Reubi JC (1991) The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocr Rev 12:450–482

    Article  PubMed  CAS  Google Scholar 

  39. Moertel CG, Hanley JA (1979) Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Clin Trials 2:327–334

    PubMed  CAS  Google Scholar 

  40. Moertel CG, Hanley JA, Johnson LA (1980) Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med 303:1189–1194

    Article  PubMed  CAS  Google Scholar 

  41. Moertel CG, O’Connell MJ, Reitemeier RJ, Rubin J (1984) Evaluation of combined cyclophosphamide and methotrexate therapy in the treatment of metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Treat Rep 68:665–667

    PubMed  CAS  Google Scholar 

  42. Moertel CG, Rubin J, Kvols LK (1989) Therapy of metastatic carcinoid tumor and the malignant carcinoid syndrome with recombinant leukocyte A interferon. J Clin Oncol 7:865–868

    PubMed  CAS  Google Scholar 

  43. Moertel CG, Kvols LK, O’Connell MJ, Rubin J (1991) Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 68:227–232

    Article  PubMed  CAS  Google Scholar 

  44. Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D (1992) Streptozocin–doxorubicin, streptozocin–fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 326:519–523

    Article  PubMed  CAS  Google Scholar 

  45. Oberg K (1992) The action of interferon alpha on human carcinoid tumours. Semin Cancer Biol 3:35–41

    PubMed  CAS  Google Scholar 

  46. Oberg K (1994) Endocrine tumors of the gastrointestinal tract: systemic treatment. Anticancer Drugs 5:503–519

    Article  PubMed  CAS  Google Scholar 

  47. Oberg K, Eriksson B (1989) Medical treatment of neuroendocrine gut and pancreatic tumors. Acta Oncol 28:425–431

    Article  PubMed  CAS  Google Scholar 

  48. Oberg K, Eriksson B (1991) The role of interferons in the management of carcinoid tumours. Br J Haematol 79(suppl 1):74–77

    Article  PubMed  Google Scholar 

  49. O’Toole D, Salazar R, Falconi M, Kaltsas G, Couvelard A., De Herder WW, Hyrdel R, Nikou G., Krenning E, Vullierme MP, Caplin M, Jensen R, Eriksson B (2006) Rare functioning pancreatic endocrine tumors. Neuroendocrinology 84:189–195

    Article  PubMed  CAS  Google Scholar 

  50. Panzuto F, Di Fonzo M, Iannicelli E, Sciuto R, Maini CL, Capurso G, Milione M, Cattaruzza MS, Falconi M, David V, Ziparo V, Pederzoli P, Bordi C, Fave GD (2006) Long-term clinical outcome of somatostatin analogues for treatment of progressive, metastatic, well-differentiated entero-pancreatic endocrine carcinoma. Ann Oncol 17:461–466

    Article  PubMed  CAS  Google Scholar 

  51. Pavel ME, Baum U, Hahn EG, Hensen J (2005) Doxorubicin and streptozotocin after failed biotherapy of neuroendocrine tumors. Int J Gastrointest Cancer 35:179–185

    Article  PubMed  CAS  Google Scholar 

  52. Plöckinger U, Perez-Canto A, Emde C, Liehr RM, Hopfenmuller W, Quabbe HJ (1998) Effect of the somatostatin analog octreotide on gastric mucosal function and histology during 3 months of preoperative treatment in patients with acromegaly. Eur J Endocrinol 139:387–394

    Article  PubMed  Google Scholar 

  53. Plöckinger U, Rindi G, Arnold R, Eriksson B, Krenning EP, De Herder WW, Goede A, Caplin M, Oberg K, Reubi JC, Nilsson O, Delle Fave G, Ruszniewski P, Ahlman H, Wiedenmann B (2004) Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuroendocrinology 80:394–424

    Article  PubMed  CAS  Google Scholar 

  54. Plöckinger U (2007) Diagnosis and treatment of gastric neuroendocrine tumours. In: Wiedenmann B, Niederle B (eds) Hypergastrinemia—diagnosis and treatment. Wien Klin Wochenschr (in press)

  55. Ramanathan RK, Cnaan A, Hahn RG, Carbone PP, Haller DG (2001) Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282. Ann Oncol 12:1139–1143

    Article  PubMed  CAS  Google Scholar 

  56. Ricci S, Antonuzzo A, Galli L, Orlandini C, Ferdeghini M, Boni G, Roncella M, Mosca F, Conte PF (2000) Long-acting depot lanreotide in the treatment of patients with advanced neuroendocrine tumors. Am J Clin Oncol 23:412–415

    Article  PubMed  CAS  Google Scholar 

  57. Rivera E, Ajani JA (1998) Doxorubicin, streptozocin, and 5-fluorouracil chemotherapy for patients with metastatic islet-cell carcinoma. Am J Clin Oncol 21:36–38

    Article  PubMed  CAS  Google Scholar 

  58. Ruszniewski P, Delle Fave G, Cadiot G, Komminoth P, Chung D, Kos-Kudla B, Kianmanesh R, Hochhauser D, Arnold R, Ahlman H, Pauwels S, Kwekkeboom DJ, Rindi G (2006) Well-differentiated gastric tumors/carcinomas. Neuroendocrinology 84:158–164

    Article  PubMed  CAS  Google Scholar 

  59. Schober C, Schmoll E, Schmoll HJ, Poliwoda H, Schuppert F, Stahl M, Bokemeyer C, Wilke H, Weiss J (1992) Antitumour effect and symptomatic control with interferon alpha 2b in patients with endocrine active tumours. Eur J Cancer 28A:1664–1666

    Article  PubMed  CAS  Google Scholar 

  60. Shah T, Caplin M (2005) Endocrine tumours of the gastrointestinal tract. Biotherapy for metastatic endocrine tumours. Best Pract Res Clin Gastroenterol 19:617–636

    Article  PubMed  CAS  Google Scholar 

  61. Smith DB, Scarffe JH, Wagstaff J, Johnston RJ (1987) Phase II trial of rDNA alfa 2b interferon in patients with malignant carcinoid tumor. Cancer Treat Rep 71:1265–1266

    PubMed  CAS  Google Scholar 

  62. Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG (2005) 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 23:4897–4904

    Article  PubMed  CAS  Google Scholar 

  63. Thomas Al, Morgan B, Horsfield MA, Higginson A, Kay A, Lee L, Masson E, Puccio-Pick M, Laurent D, Steward WP (2005) Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J Clin Oncol 23:4162–4171

    Article  PubMed  Google Scholar 

  64. Tiensuu Janson EM, Ahlstrom H, Andersson T, Oberg KE (1992) Octreotide and interferon alfa: a new combination for the treatment of malignant carcinoid tumours. Eur J Cancer 28A:1647–1650

    Article  PubMed  CAS  Google Scholar 

  65. Tomassetti P, Migliori M, Gullo L (1998) Slow-release lanreotide treatment in endocrine gastrointestinal tumors. Am J Gastroenterol 93:1468–1471

    Article  PubMed  CAS  Google Scholar 

  66. Tomassetti P, Migliori M, Corinaldesi R, Gullo L (2000) Treatment of gastroenteropancreatic neuroendocrine tumours with octreotide LAR. Aliment Pharmacol Ther 14:557–560

    Article  PubMed  CAS  Google Scholar 

  67. Von Schrenck T, Howard JM, Doppman JL, Norton JA, Maton PN, Smith FP, Vinayek R, Frucht H, Wank SA, Gardner JD (1988) Prospective study of chemotherapy in patients with metastatic gastrinoma. Gastroenterology 94:1326–1334

    Google Scholar 

  68. Wymenga AN, Eriksson B, Salmela PI, Jacobsen MB, Van Cutsem EJ, Fiasse RH, Valimaki MJ, Renstrup J, De Vries EG, Oberg KE (1999) Efficacy and safety of prolonged-release lanreotide in patients with gastrointestinal neuroendocrine tumors and hormone-related symptoms. J Clin Oncol 17:1111

    PubMed  CAS  Google Scholar 

  69. Yao J, Ng C, Hoff PM, Phan A, Hess K, Chen H, Wang X, Abbruzzese J, Ajani JA (2005) Improved progression free survival (PFS), and rapid, sustained decrease in tumor perfusion among patients with advanced carcinoid treated with bevacizumab. J Clin Oncol, ASCO Annual Meeting Proceedings Part I, 23(6S):4007

    Google Scholar 

  70. Yao J, Phan A, Chang D, Jacobs C, Mares J, Rashid A, Meric-Bernstam F (2006) Phase II study of RAD001 (everolimus) and depot octreotide (sandostatin LAR) in patients with advanced low grade neuroendocrine carcinoma (LGNET). J Clin Oncol, ASCO Annual Meeting Proceedings Part I, 24(18S):4042

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Plöckinger, U., Wiedenmann, B. Treatment of gastroenteropancreatic neuroendocrine tumors. Virchows Arch 451 (Suppl 1), 71–80 (2007). https://doi.org/10.1007/s00428-007-0446-z

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