Targeted Oncology

, Volume 7, Issue 3, pp 169–172

New treatment options with cytotoxic agents in neuroendocrine tumours

  • Pascal Hammel
  • Olivia Hentic
  • Cindy Neuzillet
  • Sandrine Faivre
  • Eric Raymond
  • Philippe Ruszniewski


There are numerous treatment options for patients with advanced digestive neuroendocrine tumours (NETs). Medical treatment includes systemic chemotherapies, targeted therapies, somatostatin analogs, liver-directed therapies such as (chemo)embolization or thermoablation, and peptide receptor radionuclide therapy. Cytotoxic chemotherapies can help control tumour progression in patients with non-resectable tumours and may improve symptoms by reducing tumour bulk. In addition, tumour response is usually greater than that obtained with targeted therapies. This should be taken into consideration in neoadjuvant strategies. Efficacy of temozolomide depends on the O6 methylguanine DNA methyl transferase status, and thus, this drug will likely have to be considered in the future in patients with a favourable enzyme profile. Because numerous treatment options are available for patients with advanced digestive NETs, and thanks to their long survival, successive drugs should be used. Careful attention should be paid to the adverse events in order to maintain the quality of life in these patients who have with a long life expectancy.


Neuroendocrine Tumour Digestive Pancreas Carcinoid Chemotherapy Streptozotocin Temozolomide MGMT 


  1. 1.
    Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C et al (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364:501–513PubMedCrossRefGoogle Scholar
  2. 2.
    Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E et al (2011) RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514–523PubMedCrossRefGoogle Scholar
  3. 3.
    Baudin E, Ducreux M (2011) Chemotherapy of endocrine tumours. In: Thoracic and digestive endocrine tumours. Springer, Paris, pp 215–232Google Scholar
  4. 4.
    Broder LR, Carter SK (1973) Pancreatic islet cell carcinoma. Results of therapy with streptozotocin in 52 patients. Ann Intern Med 79:108–118PubMedGoogle Scholar
  5. 5.
    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 326:519–523PubMedCrossRefGoogle Scholar
  6. 6.
    Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R et al (2004) Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 22:4762–4771PubMedCrossRefGoogle Scholar
  7. 7.
    Moertel CG, Hanley JA (1979) Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Clin Trials 2:327–334PubMedGoogle Scholar
  8. 8.
    Engstrom PF, Lavin PT, Moertel CG, Folsch E, Douglass HO Jr (1984) Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol 2:1255–1259PubMedGoogle Scholar
  9. 9.
    de Herder WW, Niederle B, Scoazec JY, Pauwels S, Kloppel G, Falconi M, Frascati Consensus Conference, European Neuroendocrine Tumor Society et al (2006) Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendocrinology 84:183–188PubMedCrossRefGoogle Scholar
  10. 10.
    Rindi G, Herder WW, O’Toole D, Wiedenmann B (2008) Consensus guidelines for the management of patients with digestive neuroendocrine tumors: the second event and some final considerations. Neuroendocrinology 87:5–7PubMedCrossRefGoogle Scholar
  11. 11.
    Kulke MH, Anthony LB, Bushnell DL, de Herder WW, Goldsmith SJ, Klimstra DS, North American Neuroendocrine Tumor Society (NANETS) et al (2010) NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas 39:735–752PubMedCrossRefGoogle Scholar
  12. 12.
    Boudreaux JP, Klimstra DS, Hassan MM, Woltering EA, Jensen RT, Goldsmith SJ, North American Neuroendocrine Tumor Society (NANETS) et al (2010) The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the jejunum, ileum, appendix, and cecum. Pancreas 39:753–766PubMedCrossRefGoogle Scholar
  13. 13.
  14. 14.
    Brixi-Benmansour H, Jouve JL, Mitry E, Bonnetain F, Landi B, Hentic O et al (2011) Phase II study of first-line FOLFIRI for progressive metastatic well-differentiated pancreatic endocrine carcinoma. Dig Liver Dis 43:912–916PubMedCrossRefGoogle Scholar
  15. 15.
    Cassier PA, Walter T, Eymard B, Ardisson P, Perol M, Paillet C et al (2009) Gemcitabine and oxaliplatin combination chemotherapy for metastatic well-differentiated neuroendocrine carcinomas: a single-center experience. Cancer 115:3392–3399PubMedCrossRefGoogle Scholar
  16. 16.
    Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A et al (2006) Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 24:401–406PubMedCrossRefGoogle Scholar
  17. 17.
    Kulke MH, Bendell J, Kvols L, Picus J, Pommier R, Yao J (2011) Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumors. J Hematol Oncol 4:29PubMedCrossRefGoogle Scholar
  18. 18.
    Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT et al (2011) First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 117:268–275PubMedCrossRefGoogle Scholar
  19. 19.
    Kulke MH, Hornick JL, Frauenhoffer C, Hooshmand S, Ryan DP, Enzinger PC et al (2009) O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res 15:338–345PubMedCrossRefGoogle Scholar
  20. 20.
    Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H et al (2007) Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res 13:2986–2991PubMedCrossRefGoogle Scholar
  21. 21.
    Maire F, Hammel P, Faivre S, Hentic O, Yapur L, Larroque B et al (2009) Temozolomide: a safe and effective treatment for malignant digestive endocrine tumors. Neuroendocrinology 90:67–72PubMedCrossRefGoogle Scholar
  22. 22.
    Hammel P, Hentic O, Cros J, Rebours V, Zappa M, Maire F et al (2012) Methyguanine DNA methyltransferase (MGMT) expression to predict response to temozolomide (TMZ) in patients with digestive neuroendocrine tumors (NETs). J Clin Oncol 30(suppl; abstr 4133)Google Scholar
  23. 23.
    Fine R, Fogelman D, Schreibman S (2005) Effective treatment of neuroendocrine tumors with temozolomide and capecitabine. J Clin Oncol 23(16S):4216Google Scholar
  24. 24.
    Murakami J, Lee YJ, Kokeguchi S, Tsujigiwa H, Asaumi J, Nagatsuka H et al (2007) Depletion of O6-methylguanine-DNA methyltransferase by O6-benzylguanine enhances 5-FU cytotoxicity in colon and oral cancer cell lines. Oncol Rep 17:1461–1467PubMedGoogle Scholar
  25. 25.
    Koumarianou A, Antoniou S, Kanakis G, Economopoulos N, Rontogianni D, Ntavatzikos A et al (2012) Combination treatment with metronomic temozolomide, bevacizumab and long-acting octreotide for malignant neuroendocrine tumours. Endocr Relat Cancer 19:L1–L4PubMedCrossRefGoogle Scholar
  26. 26.
    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 68:227–232PubMedCrossRefGoogle Scholar
  27. 27.
    Mitry E, Baudin E, Ducreux M, Sabourin JC, Rufie P, Aparicio T et al (1999) Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin. Br J Cancer 81:1351–1355PubMedCrossRefGoogle Scholar
  28. 28.
    Fjallskog ML, Granberg DP, Welin SL, Eriksson C, Oberg KE, Janson ET et al (2001) Treatment with cisplatin and etoposide in patients with neuroendocrine tumors. Cancer 92:1101–1107PubMedCrossRefGoogle Scholar
  29. 29.
    Ahlman H, Nilsson O, McNicol AM, Ruszniewski P, Niederle B, Ricke J et al (2008) Poorly-differentiated endocrine carcinomas of midgut and hindgut origin. Neuroendocrinology 87:40–46PubMedCrossRefGoogle Scholar
  30. 30.
    Bettini R, Boninsegna L, Mantovani W, Capelli P, Bassi C, Pederzoli P et al (2008) Prognostic factors at diagnosis and value of WHO classification in a mono-institutional series of 180 non-functioning pancreatic endocrine tumours. Ann Oncol 19:903–908PubMedCrossRefGoogle Scholar
  31. 31.
    Nilsson O, Van Cutsem E, Delle Fave G, Yao JC, Pavel ME, McNicol AM et al (2006) Poorly differentiated carcinomas of the foregut (gastric, duodenal and pancreatic). Neuroendocrinology 84:212–215PubMedCrossRefGoogle Scholar
  32. 32.
    Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund PJ et al (2012) Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal poorly differentiated neuroendocrine carcinoma: the NORDIC NEC study. J Clin Oncol 30(suppl; abstr 4133)Google Scholar
  33. 33.
    Hentic O, Hammel P, Rebours V, Dreyer C, Maire F, Vullierme MP et al (2009) FOLFIRI regimen as second-line chemotherapy after failure of vepeside-cisplatinum in poorly differentiated digestive neuroendocrine carcinoma: a potentially efficient treatment. Gastroenterol Clin Biol Gastroenterol Clin Biol 33:A171CrossRefGoogle Scholar
  34. 34.
    Welin S, Sorbye H, Sebjornsen S, Knappskog S, Busch C, Oberg K (2011) Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy. Cancer 117:4617–4622PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Pascal Hammel
    • 1
  • Olivia Hentic
    • 1
  • Cindy Neuzillet
    • 1
  • Sandrine Faivre
    • 2
  • Eric Raymond
    • 2
  • Philippe Ruszniewski
    • 1
  1. 1.Service de Gastroenterologie-PancreatologieHôpital Beaujon, AP-HP, Faculté Denis Diderot (Paris VII)ClichyFrance
  2. 2.Oncology UnitHôpital Beaujon, AP-HP, Faculté Denis Diderot (Paris VII)ClichyFrance

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