Everolimus-based combination for the treatment of advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): biological rationale and critical review of published data
- 262 Downloads
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) comprise a heterogeneous group of diseases. Advanced GEP-NENs are considered distinct disease entity with limited treatments. In this review, we will explore the biological rationale and clinical data of everolimus-based combinations for advanced GEP-NENs. PubMed/Medline, the Cochrane Library, and Google Scholar were searched using the terms “GEP-NENs” and “everolimus” and “systemic therapy” and selecting English literature only. Outcomes of interest included progression-free survival and overall survival (PFS and OS), toxicities, and tumor response. A total of 14 potentially relevant trials were initially identified, of which five studies were excluded. Hence, nine trials including 699 patients were included. Median PFS was reported in four out of the nine studies ranging from 14.6 to 16.4 months. The disease control rate was reported in all studies, and it ranged from 75 to 93 %. Frequently reported grade 3/4 toxicities were elevated transaminases, hyperglycemia, and hematologic toxicities. The presence of clinical and statistical heterogeneity of the primary studies precludes reliable evidence-based conclusions. Further well-conducted randomized controlled trials are awaited to better evaluate the treatment of GEP-NENs.
KeywordsEverolimus Systemic treatment Neuroendocrine neoplasms
Conflicts of interest
OA: Provided the idea and study design and collected the data and wrote the manuscript.
MF: Collected the data and revised the manuscript.
- 6.Rindi GUIDO, Falconi M, Klersy C, Albarello L, Boninsegna L, Buchler MW, et al. TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst. 2012;104(10):764–77.Google Scholar
- 7.Plockinger U, Rindi G, Arnold R, Eriksson B, Krenning EP, de Herder WW, et al. Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuroendocrinology. 2004;80(6):394–424. doi: 10.1159/000085237.CrossRefPubMedGoogle Scholar
- 20.Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2008;13:2278–87.Google Scholar
- 24.Pinato DJ, Tan TM, Toussi ST, Ramachandran R, Martin N, Meeran K, et al. An expression signature of the angiogenic response in gastrointestinal neuroendocrine tumours: correlation with tumour phenotype and survival outcomes. Br J Cancer. 2014;110(1):115–22. doi: 10.1038/bjc.2013.682. Epub 2013 Nov 14.CrossRefPubMedGoogle Scholar
- 25.Kuiper P, Hawinkels LJ, de Jonge-Muller ES, Biemond I, Lamers CB, Verspaget HW. Angiogenic markers endoglin and vascular endothelial growth factor in gastroenteropancreatic neuroendocrine tumors. World J Gastroenterol. 2011;17(2):219–25. doi: 10.3748/wjg.v17.i2.219.CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Kasuya K, Nagakawa Y, Suzuki M, et al. Anti-vascular endothelial growth factor antibody single therapy for pancreatic neuroendocrine carcinoma exhibits a marked tumor growth-inhibitory effect. Exp Thermal Med. 2011;2(6):1047–52. Epub 2011 Sep 5.Google Scholar
- 29.Kasuya K, Nagakawa Y, Suzuki M, et al. Combination therapy of gemcitabine or oral S-1 with the anti-VEGF monoclonal antibody bevacizumab for pancreatic neuroendocrine carcinoma. Exp Thermal Med. 2012;3(4):599–602. Epub 2012 Jan 18.Google Scholar
- 33.Grozinsky-Glasberg S, Franchi G, Teng M, Leontiou CA, Dalino P, Salahuddin N, 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. 2007;87(3):168–81.CrossRefPubMedGoogle Scholar
- 35.Tejani MA, Saif MW. Pancreatic neuroendocrine tumors: does chemotherapy work? J Pancreas. 2014;15(2):132–4.Google Scholar
- 36.Lamarca A, Hubner RA, Valle JW. Looking beyond chemotherapy in patients with advanced, well-differentiated, pancreatic neuroendocrine tumors. J Oncol Pathol. 2014;2(1):15–25.Google Scholar
- 37.André N, Carré M, Pasquier E. Metronomics: towards personalized chemotherapy? Nat Rev Clin Oncol. 2014;11:413–31.Google Scholar
- 38.Yao JC, Shah M, Panneerselvam A, Chen D, Stergiopoulos S, Ito T, et al. The VEGF pathway in pancreatic neuroendocrine tumors: prognostic and predictive capacity of baseline biomarker levels on efficacy of everolimus analyzed from the radiant-3 study. Pancreas. 2013;42(2):386–7.Google Scholar
- 39.Hobday T, Rubin J, Holen K, et al. MC044 h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): a phase II consortium (P2C) study. J Clin Oncol. 2007;25(18):4504.Google Scholar
- 42.Bajetta E, Catena L, Fazio N, Pusceddu S, Biondani P, Blanco G, et al. Everolimus in combination with octreotide long-acting repeatable in a first-line setting for patients with neuroendocrine tumors: An ITMO group study. Cancer. 2014;120(16):2457–63.Google Scholar
- 45.Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011;378(9808):2005–12.CrossRefPubMedGoogle Scholar
- 46.Yao J, Phan A, Hess K, Fogelman D, Jacobs C, Dagohoy C et al. (2010) Randomized run-in study of Bevacizumab and everolimus in low to intermediate- grade neuroendocrine tumor (lgneTs) using perfusion CT (pCT) as functional biomarker. http://www.nanets.net/nanets_cd/2010/pdfs/C36.pdf. Accessed 29 April 2014.
- 47.Dasari A, Phan A, Gupta S, Hess KR, Culotta KS, Rashid A, et al. A phase I study of the anti-IGF-1R monoclonal antibody (MoAb), IMC-A12 (I), and everolimus (E) in well-differentiated neuroendocrine tumors (WD NET). J Clin Oncol. 2014;32(23):8. MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA: AMER SOC CLINICAL ONCOLOGY.Google Scholar
- 48.Bergsland EK, Watt L, Ko AH, Tempero MA, Korn WK, Kelley RK. A phase II study to evaluate the safety and efficacy of RAD001 plus erlotinib in patients with well-differentiated neuroendocrine tumors (NET). J Clin Oncol. 2012;30 Suppl 4:abstr 285.Google Scholar
- 50.Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, 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(28):4656–63.CrossRefPubMedGoogle Scholar
- 51.Abdel-Rahman O, Fouad M. Risk of mucocutaneous toxicities in patients with solid tumors treated with everolimus; a systematic review and meta-analysis. Expert Rev Anticancer Ther. 2014;14(12):1529-36.Google Scholar
- 52.Raymond, E., Niccoli-Sire, P., Bang, Y., Borbath, I., Lombard-Bohas, C., & Valle, J. W. (2010, January) Updated results of the phase III trial of sunitinib (SU) versus placebo (PBO) for treatment of advanced pancreatic neuroendocrine tumors (NET). In ASCO 2010 Gastrointestinal Cancers Symposium Abstract (Vol. 127).Google Scholar
- 55.Marciello F, Di Somma C, Del Prete M, Marotta V, Ramundo V, Carratu A, et al. Combined biological therapy with lanreotide autogel and cabergoline in the treatment of MEN-1-related insulinomas. Endocrine. 2014;46:678–81.Google Scholar
- 58.Abdel-Rahman O. Vascular endothelial growth factor (VEGF) pathway and neuroendocrine neoplasms (NENs): prognostic and therapeutic considerations. Tumor Biol. 2014;35(11):10615–25.Google Scholar