title: Efficacy and Safety of Everolimus in Extrapancreatic Neuroendocrine Tumor: A Comprehensive Review of Literature.
abstract: Everolimus, an oral mTOR (mammalian target of rapamycin) inhibitor, is currently approved for the treatment of progressive pancreatic neuroendocrine tumors (NETs). Although promising, only scattered data, often from nondedicated studies, are available for extrapancreatic NETs.
  
  
  
  A systematic review of the published data was performed concerning the use of everolimus in extrapancreatic NET, with the aim of summarizing the current knowledge on its efficacy and tolerability. Moreover, the usefulness of everolimus was evaluated according to the different sites of the primary.
  
  
  
  The present study included 22 different publications, including 874 patients and 456 extrapancreatic NETs treated with everolimus. Nine different primary sites of extrapancreatic NETs were found. The median progression-free survival ranged from 12.0 to 29.9 months. The median time to progression was not reached in a phase II prospective study, and the interval to progression ranged from 12 to 36 months in 5 clinical cases. Objective responses were observed in 7 prospective studies, 2 retrospective studies, and 2 case reports. Stabilization of the disease was obtained in a high rate of patients, ranging from 67.4% to 100%. The toxicity of everolimus in extrapancreatic NETs is consistent with the known safety profile of the drug. Most adverse events were either grade 1 or 2 and easy manageable with a dose reduction or temporary interruption and only rarely requiring discontinuation.
  
  
  
  Treatment with everolimus in patients with extrapancreatic NETs appears to be a promising strategy that is safe and well tolerated. The use of this emerging opportunity needs to be validated with clinical trials specifically designed on this topic.
  
  
  
  The present study reviewed all the available published data concerning the use of everolimus in 456 extrapancreatic neuroendocrine tumors (NETs) and summarized the current knowledge on the efficacy and safety of this drug, not yet approved except for pancreatic NETs. The progression-free survival rates and some objective responses seem promising and support the extension of the use of this drug. The site-by-site analysis seems to suggest that some subtypes of NETs, such as colorectal, could be more sensitive to everolimus than other primary NETs. No severe adverse events were usually reported and discontinuation was rarely required; thus, everolimus should be considered a valid therapeutic option for extrapancreatic NETs.
authors.affiliation: Thyroid and Parathyroid Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy afaggian@unina.it.
authors.forename: Antongiulio
authors.initials: A
authors.lastname: Faggiano
authors.affiliation: Endocrinology Unit, Garibaldi Nesima Medical Center, Catania, Italy.
authors.forename: Pasqualino
authors.initials: P
authors.lastname: Malandrino
authors.affiliation: Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Modica
authors.affiliation: District Hospital, Azienda Sanitaria Locale, Brindisi, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Agrimi
authors.affiliation: Endocrinology Unit, Azienda Sanitaria Locale Napoli 3, Naples, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Aversano
authors.affiliation: Unit of Internal Medicine, San Giovanni Bosco Hospital, Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bassi
authors.affiliation: Endocrinology Unit, Azienda Sanitaria Provinciale di Calabria, Reggio Calabria, Italy.
authors.forename: Ernesto A
authors.initials: EA
authors.lastname: Giordano
authors.affiliation: Biomedical Department of Internal and Specialist Medicine, Section of Endocrinology, University of Palermo, Palermo, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Guarnotta
authors.affiliation: Endocrinology Unit, Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, Italy.
authors.forename: Francesco A
authors.initials: FA
authors.lastname: Logoluso
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Messina
authors.affiliation: Azienda Ospedaliero-Universitaria "Ospedali Riuniti," Foggia, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Nicastro
authors.affiliation: Unit of Internal Medicine, San Gennaro Hospital, Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Nuzzo
authors.affiliation: Endocrinology Unit, SS Annunziata Hospital, Taranto, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Sciaraffia
authors.affiliation: Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Colao
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000188:drug therapy; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000188:drug therapy; D018572:Disease-Free Survival; D000068338:Everolimus / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007078:Ileal Neoplasms / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000401:mortality; D010673:Pheochromocytoma / Q000188:drug therapy; D013274:Stomach Neoplasms / Q000188:drug therapy; D013964:Thyroid Neoplasms / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus
keywords: Efficacy; Everolimus; Extrapancreatic neuroendocrine tumors; Neuroendocrine tumors; Safety