title: (Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial.
abstract: OBJECTIVE
  We aimed to assess the safety and efficacy of metformin for treating patients with metastatic pancreatic cancer and to identify endocrine and metabolic phenotypic features or tumor molecular markers associated with sensitivity to metformin antineoplastic action.
  
  
  METHODS
  We designed an open-label, randomized, phase II trial to assess the efficacy of adding metformin to a standard systemic therapy with cisplatin, epirubicin, capecitabine, and gemcitabine (PEXG) in patients with metastatic pancreatic cancer. Patients ages 18 years or older with metastatic pancreatic cancer were randomly assigned (1:1) to receive PEXG every 4 weeks in combination or not with 2 g oral metformin daily. The primary endpoint was 6-months progression-free survival (PFS-6) in the intention-to-treat population.
  
  
  RESULTS
  Between August 2010 and January 2014, we randomly assigned 60 patients to receive PEXG with (n = 31) or without metformin (n = 29). At the preplanned interim analysis, the study was ended for futility. PFS-6 was 52% [95% confidence interval (CI), 33-69] in the control group and 42% (95% CI, 24-59) in the metformin group (P = 0.61). Furthermore, there was no difference in disease-free survival and overall survival between groups. Despite endocrine metabolic modifications induced by metformin, there was no correlation with the outcome. Single-nucleotide polymorphism rs11212617 predicted glycemic response, but not tumor response to metformin. Gene expression on tumor tissue did not predict tumor response to metformin.
  
  
  CONCLUSIONS
  Addition of metformin at the dose commonly used in diabetes did not improve outcome in patients with metastatic pancreatic cancer treated with standard systemic therapy. See related commentary by Yang and Rustgi, p. 1031.
authors.affiliation: Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. piemonti.lorenzo@hsr.it reni.michele@hsr.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Reni
authors.affiliation: Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Dugnani
authors.affiliation: Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cereda
authors.affiliation: Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Belli
authors.affiliation: Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Balzano
authors.affiliation: Department of Radiology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Nicoletti
authors.affiliation: Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Liberati
authors.affiliation: Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pasquale
authors.affiliation: Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Scavini
authors.affiliation: Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Maggiora
authors.affiliation: Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Sordi
authors.affiliation: Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Lampasona
authors.affiliation: Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Domenica
authors.initials: D
authors.lastname: Ceraulo
authors.affiliation: Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Di Terlizzi
authors.affiliation: Department of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.affiliation: Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Falconi
authors.affiliation: Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy. piemonti.lorenzo@hsr.it reni.michele@hsr.it.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000069287:Capecitabine / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D015251:Epirubicin; D000069287:Capecitabine; D008687:Metformin; D002945:Cisplatin; D000093542:Gemcitabine