Top

Published in:

01-08-2007 | Review and Perspective

Treatment of gastroenteropancreatic neuroendocrine tumors

Authors: U. Plöckinger, B. Wiedenmann

Published in: Virchows Archiv | Special Issue 1/2007

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.

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 32:217–223PubMedCrossRef

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 37:1014–1019PubMedCrossRef

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):72–75PubMed

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 17:511–519PubMedCrossRef

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 38:430–438PubMedCrossRef

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 83:372–378PubMedCrossRef

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 13:614–621PubMedCrossRef

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 10:1914–1918PubMed

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 86:944–948PubMedCrossRef

11.

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

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 84:183–188PubMedCrossRef

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 118:735–748PubMedCrossRef

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 6:77–79PubMed

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 77:402–408PubMedCrossRef

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 7:175–181PubMedCrossRef

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 30:603–605PubMedCrossRef

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 95:3276–3281PubMedCrossRef

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 2:1255–1259PubMed

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 65:1883–1890PubMedCrossRef

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 8:1041–1044PubMedCrossRef

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 84:196–211PubMedCrossRef

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 21:2689–2696PubMedCrossRef

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 11:490–495PubMedCrossRef

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

27.

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

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 30:789–796PubMedCrossRef

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 3:635–638PubMed

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 84:173–182PubMedCrossRef

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 84:165–172PubMedCrossRef

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) 57:169–183CrossRef

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 22:4762–4771PubMedCrossRef

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

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 24:3555–3561PubMedCrossRef

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 24:401–406PubMedCrossRef

38.

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

39.

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

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 303:1189–1194PubMedCrossRef

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 68:665–667PubMed

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 7:865–868PubMed

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 68:227–232PubMedCrossRef

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 326:519–523PubMedCrossRef

45.

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

46.

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

47.

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

48.

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

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 84:189–195PubMedCrossRef

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 17:461–466PubMedCrossRef

51.

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

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 139:387–394PubMedCrossRef

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 80:394–424PubMedCrossRef

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 12:1139–1143PubMedCrossRef

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 23:412–415PubMedCrossRef

57.

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

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 84:158–164PubMedCrossRef

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:1664–1666PubMedCrossRef

60.

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

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 71:1265–1266PubMed

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 23:4897–4904PubMedCrossRef

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 23:4162–4171PubMedCrossRef

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:1647–1650PubMedCrossRef

65.

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

66.

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

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

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 17:1111PubMed

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

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

Title: Treatment of gastroenteropancreatic neuroendocrine tumors
Authors: U. Plöckinger
B. Wiedenmann
Publication date: 01-08-2007
Publisher: Springer-Verlag
Published in: Virchows Archiv / Issue Special Issue 1/2007
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-007-0446-z

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Treatment of gastroenteropancreatic neuroendocrine tumors

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Special Issue 1/2007

Siegfried Oberndorfer: a tribute to his work and life between Munich, Kiel, Geneva, and Istanbul

Neuroendocrine tumors (2007): Oberndorfer’s legacy

Peptide receptor expression in GEP-NET

Goblet cell carcinoids and other mixed neuroendocrine/nonneuroendocrine neoplasms

Hereditary neuroendocrine tumors of the gastroenteropancreatic system

Neuro-endocrine tumours of the lung. A review of relevant pathological and molecular data