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Sunitinib in pancreatic neuroendocrine tumors

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Sunitinib is an oral multitarget tyrosine kinase inhibitor with potent antiangiogenic properties. Preclinical data have demonstrated that pancreatic neuroendocrine tumors depend on vascular endothelial growth factor receptors and platelet growth factor receptors-signaling pathways for tumor angiogenesis. Sunitinib has recently been approved for the treatment of patients with advanced, progressive pancreatic neuroendocrine tumors. Sunitinib has demonstrated clinically meaningful improvements in progression-free survival in a double-blinded randomized trial against placebo, setting progression-free survival as a valid endpoint for the evaluation of novel agents in patients with pancreatic neuroendocrine tumors. Although patients who progressed in this phase III trial were allowed to cross-over, a trend toward improvement in overall survival was also observed. In this trial, side effects reported with sunitinib were those previously reported in other tumor types, including hand–foot syndrome, diarrhea, and hypertension. This trial also investigated patient-reported outcome and showed that treatment with sunitinib did not affect quality of life of patient. Interestingly, this trial showed that sunitinib could be combined with somatostatin analogues without affecting the safety profile of either sunitinib or somatostatin analogues. Since the overall survival of patients with well-differentiated neuroendocrine tumors remains sufficiently long, it is worth considering using alternate sequences of targeted therapy (such as everolimus) and chemotherapy to optimize the care of patients with advanced diseases. The optimal sequence for using chemotherapy, everolimus, and sunitinib will remain to be established in clinical trials.

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References

  1. Halfdanarson TR, Rabe KG, Rubin J, Petersen GM (2008) Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol 19:1727–1733

    Article  PubMed  CAS  Google Scholar 

  2. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE et al (2008) One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26(18):3063–3072

    Article  PubMed  Google Scholar 

  3. Ballian N, Loeffler AG, Rajamanickam V, Norstedt PA, Weber SM, Cho CS (2009) A simplified prognostic system for resected pancreatic neuroendocrine neoplasms. HPB (Oxford) 11:422–428

    Article  Google Scholar 

  4. Knigge U, Hansen CP, Stadil F (2008) Interventional treatment of neuroendocrine liver metastases. Surgeon 6:232–239

    Article  PubMed  CAS  Google Scholar 

  5. Modlin IM, Pavel M, Kidd M, Gustafsson BI (2010) Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther 31:169–188

    PubMed  CAS  Google Scholar 

  6. Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M et al (2009) 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 27:4656–4663

    Article  PubMed  CAS  Google Scholar 

  7. 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 

  8. 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 

  9. Heng 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  Google Scholar 

  10. McCollum AD, Kulke MH, Ryan DP, Clark JW, Shulman LN, Mayer RJ et al (2004) Lack of efficacy of streptozocin and doxorubicin in patients with advanced pancreatic endocrine tumors. Am J Clin Oncol 27:485–488

    Article  PubMed  CAS  Google Scholar 

  11. Klöppel G, Anlauf M (2005) Epidemiology, tumour biology and histopathological classification of neuroendocrine tumours of the gastrointestinal tract. Best Pract Res Clin Gastroenterol 19:507–517

    Article  PubMed  Google Scholar 

  12. Inoue M, Hager JH, Ferrara N, Gerber HP, Hanahan D (2002) VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell 1:193–202

    Article  PubMed  CAS  Google Scholar 

  13. Fjällskog ML, Lejonklou MH, Oberg KE, Eriksson BK, Janson ET (2003) Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumors. Clin Cancer Res 9:1469–1473

    PubMed  Google Scholar 

  14. Yao VJ, Sennino B, Davis RB, Christensen J, Hu-Lowe D, Roberts G et al (2006) Combined anti-VEGFR and anti-PDGFR actions of sunitinib on blood vessels in preclinical tumor models. Eur J Cancer 4(12):27–28

    Google Scholar 

  15. Missiaglia E, Dalai I, Barbi S, Beghelli S, Falconi M, del la Peruta M et al (2010) Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol 28:245–255

    Article  PubMed  CAS  Google Scholar 

  16. Moreno A, Akcakanat A, Munsell MF, Soni A, Yao JC, Meric-Bernstam F (2008) Antitumor activity of rapamycin and octreotide as single agents or in combination in neuroendocrine tumors. Endocr Relat Cancer 15:257–266

    Article  PubMed  CAS  Google Scholar 

  17. Grothey A, Galanis E (2009) Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat Rev Clin Oncol 6(9):507–18

    Article  PubMed  CAS  Google Scholar 

  18. Rodallec M, Vilgrain V, Couvelard A, Rufat P, O'Toole D, Barrau V et al (2006) Endocrine pancreatic tumours and helical CT: contrast enhancement is correlated with microvascular density, histoprognostic factors and survival. Pancreatology 6:77–85

    Article  PubMed  CAS  Google Scholar 

  19. Couvelard A, O'Toole D, Turley H, Leek R, Sauvanet A, Degott C et al (2005) Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression. Br J Cancer 92:94–101

    Article  PubMed  CAS  Google Scholar 

  20. Chung DC, Smith AP, Louis DN, Graeme-Cook F, Warshaw AL, Arnold A (1997) A novel pancreatic endocrine tumor suppressor gene locus on chromosome 3p with clinical prognostic implications. J Clin Invest 100:404–410

    Article  PubMed  CAS  Google Scholar 

  21. Moore PS, Missiaglia E, Antonello D, Zamò A, Zamboni G, Corleto V et al (2001) Role of disease-causing genes in sporadic pancreatic endocrine tumors: MEN1 and VHL. Genes Chromosomes Cancer 32:177–181

    Article  PubMed  CAS  Google Scholar 

  22. Schmitt AM, Schmid S, Rudolph T, Anlauf M, Prinz C, Klöppel G et al (2009) VHL inactivation is an important pathway for the development of malignant sporadic pancreatic endocrine tumors. Endocr Relat Cancer 16:1219–1227

    Article  PubMed  CAS  Google Scholar 

  23. Couvelard A, Deschamps L, Rebours V, Sauvanet A, Gatter K, Pezzella F et al (2008) Overexpression of the oxygen sensors PHD-1, PHD-2, PHD-3, and FIHIs associated with tumor aggressiveness in pancreatic endocrine tumors. Clin Cancer Res 14:6634–6639

    Article  PubMed  CAS  Google Scholar 

  24. Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A et al (2011) DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331:1199–1203

    Article  PubMed  CAS  Google Scholar 

  25. Hanahan D (1985) Heritable formation of pancreatic β-cells: tumors in transgenic mice harboring recombinant insulin/simian virus 40 oncogenes. Nature 215:115–122

    Article  Google Scholar 

  26. Lopez T, Hanahan D (2002) Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 1:339–353

    Article  PubMed  CAS  Google Scholar 

  27. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K et al (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744

    Article  PubMed  CAS  Google Scholar 

  28. Joyce JA, Laakkonen P, Bernasconi M, Bergers G, Ruoslahti E, Hanahan D (2003) Stage-specific vascular markers revealed by phage display in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 4:393–403

    Article  PubMed  CAS  Google Scholar 

  29. Bergers G, Javaherian K, Lo KM, Folkman J, Hanahan D (1999) Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284:808–812

    Article  PubMed  CAS  Google Scholar 

  30. Parangi S, O'Reilly M, Christofori G, Holmgren L, Grosfeld J, Folkman J et al (1996) Antiangiogenic therapy of transgenic mice impairs de novo tumor growth. Proc Natl Acad Sci USA 93:2002–2007

    Article  PubMed  CAS  Google Scholar 

  31. Chiu CW, Nozawa H, Hanahan D (2010) Survival benefit with proapoptotic molecular and pathologic responses from dual targeting of mammalian target of rapamycin and epidermal growth factor receptor in a preclinical model of pancreatic neuroendocrine carcinogenesis. J Clin Oncol 28:4425–4433

    Article  PubMed  CAS  Google Scholar 

  32. 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 364:501–513

    Article  PubMed  CAS  Google Scholar 

  33. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E et al (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514–523

    Article  PubMed  CAS  Google Scholar 

  34. Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8:299–309

    Article  PubMed  CAS  Google Scholar 

  35. Marijon H, Dokmak S, Paradis V, Zappa M, Bieche I, Bouattour M et al (2011) Epithelial-to-mesenchymal transition and acquired resistance to sunitinib in a patient with hepatocellular carcinoma. J Hepatol 54:1073–1078

    Article  PubMed  CAS  Google Scholar 

  36. Faivre S, Demetri G, Sargent W, Raymond E (2007) Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 6:734–745

    Article  PubMed  CAS  Google Scholar 

  37. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D (2003) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111:1287–1295

    PubMed  CAS  Google Scholar 

  38. Tuveson D, Hanahan D (2011) Translational medicine: cancer lessons from mice to humans. Nature 471:316–317

    Article  PubMed  CAS  Google Scholar 

  39. Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N et al (2006) Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 24:25–35

    Article  PubMed  CAS  Google Scholar 

  40. Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J et al (2008) Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 26:3403–3410

    Article  PubMed  CAS  Google Scholar 

  41. Turner NC, Strauss SJ, Sarker D, Gillmore R, Kirkwood A, Hackshaw A et al (2010) Chemotherapy with 5-fluorouracil, cisplatin and streptozocin for neuroendocrine tumours. Br J Cancer 102:1106–1112

    Article  PubMed  CAS  Google Scholar 

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Disclosures

Consultancy Pfizer (ER, SF, PH, PhR), grant support for research Pfizer (ER, SF PH, PhR), consultancy Novartis (ER, SF, PH, PhR), grant support for research Novartis (ER, SF, PH, PhR)

Conflict of interest statement

Eric Raymond, Sandrine Faivre, Pascal Hammel, Philippe Rusniewski declare grants support for research from PFIZER and NOVARTIS and consultancy for Novartis. All other authors of this manuscript have not conflict of interest

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Authors and Affiliations

  1. Department of Medical Oncology (INSERM U728–Paris 7 Diderot University), Beaujon University Hospital, 100 boulevard du Général Leclerc, 92110, Clichy, France

    Eric Raymond, Chantal Dreyer, Christian Maatescu & Sandrine Faivre

  2. Department of Gastro-entero-pancreatology, Beaujon University Hospital, 100 boulevard du Général Leclerc, 92110, Clichy, France

    Pascal Hammel, Olivia Hentic & Philippe Ruszniewski

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Correspondence to Eric Raymond.

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Financial support

This work was supported by the Foundation Nelia and Amadeo Barleta (FNAB) and by the Association d’Aide à la Recherche et à l’Enseignement en Cancérologie (AAREC).

Other notes

Information for this review was compiled by searching PubMed and MEDLINE databases for articles published until May 2011. Only articles published in English were considered. The search terms used included “pancreatic neuroendocrine tumor” in association with the search terms: “angiogenesis,” “VEGFR,” “PDGFR,” “sunitinib,” “everolimus,” “bevacizumab,” “mTOR inhibitors,” “rapamycin,” “rapalogues,” “temozolomide,” “streptozotocin,” “somatostatin analogs,” “IGF1-R inhibitor,” “natural product,” “metastatic,” “clinical trial,” “islet cell carcinomas,” “carcinoid tumors,” “targeted therapy,” “cytotoxic therapy,” and “prognosis.” Full articles were obtained, and references were checked for additional material and references when appropriate. Selected articles from a personal collection were also considered.

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Raymond, E., Hammel, P., Dreyer, C. et al. Sunitinib in pancreatic neuroendocrine tumors. Targ Oncol 7, 117–125 (2012). https://doi.org/10.1007/s11523-012-0220-2

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