title: Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality.
abstract: BACKGROUND
  In vitro data and early clinical results suggest that metformin has desirable antineoplastic effects and has a theoretical benefit on castration-resistant prostate cancer (CRPC).
  
  
  OBJECTIVE
  To determine whether the use of metformin would be associated with improved clinical outcomes and a reduction in the development of CRPC.
  
  
  METHODS
  Data from 2901 consecutive patients (157 metformin, 162 diabetic non-metformin, and 2582 nondiabetic) with localized prostate cancer treated with external-beam radiation therapy from 1992 to 2008 were collected from a single institution in the United States.
  
  
  METHODS
  Use of metformin in localized prostate cancer.
  
  
  METHODS
  Univariate and multivariate regression models utilizing k-sample, Fine and Gray, Cox regression, log-rank, and Kaplan-Meier methods to assess prostate-specific antigen-recurrence-free survival (PSA-RFS), distant metastases-free survival (DMFS), prostate cancer-specific mortality (PCSM), overall survival (OS), and development of CRPC.
  
  
  CONCLUSIONS
  With a median follow-up of 8.7 yr, the 10-yr actuarial rates for metformin, diabetic non-metformin, and nondiabetic patients for PCSM were 2.7%, 21.9%, and 8.2% (log-rank p ≤ 0.001), respectively. Metformin use independently predicted (correcting for PSA, T stage, Gleason score, age, diabetic status, and androgen-deprivation therapy use) improvement in all outcomes compared with the diabetic non-metformin group; PSA-RFS (hazard ratio [HR]: 1.99 [1.24-3.18]; p=0.004), DMFS (adjusted HR: 3.68 [1.78-7.62]; p<0.001), and PCSM (HR: 5.15 [1.53-17.35]; p=0.008). Metformin use was also independently associated with a decrease in the development of CRPC in patients experiencing biochemical failure compared with diabetic non-metformin patients (odds ratio: 14.81 [1.83-119.89]; p=0.01). The retrospective study design was the primary limitation of the study.
  
  
  CONCLUSIONS
  To our knowledge, our results are the first clinical data to indicate that metformin use may improve PSA-RFS, DMFS, PCSM, OS, and reduce the development of CRPC in prostate cancer patients. Further validation of metformin's potential benefits is warranted.
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Spratt
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Zumsteg
authors.forename: Xin
authors.initials: X
authors.lastname: Pei
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zelefsky
mesh_terms: D000368:Aged; D000726:Androgen Antagonists / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D009919:Orchiectomy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D012189:Retrospective Studies; D016019:Survival Analysis; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D008687:Metformin