The effect of metformin on cancer-specific survival outcomes in diabetic patients undergoing radical cystectomy for urothelial carcinoma of the bladder

Madhur Nayan; Bimal Bhindi; Julie L Yu; Thomas Hermanns; Aza Mohammed; Robert J Hamilton; Antonio Finelli; Michael A S Jewett; Alexandre R Zlotta; Neil E Fleshner; Girish S Kulkarni

doi:10.1016/j.urolonc.2015.05.024

The effect of metformin on cancer-specific survival outcomes in diabetic patients undergoing radical cystectomy for urothelial carcinoma of the bladder

Urol Oncol. 2015 Sep;33(9):386.e7-13. doi: 10.1016/j.urolonc.2015.05.024. Epub 2015 Jun 19.

Affiliations

¹ Department of Surgery, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada; Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada. Electronic address: madhur.nayan@mail.utoronto.ca.
² Department of Surgery, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada; Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada.
³ Faculty of Medicine, University of Toronto, Toronto, Canada.
⁴ Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Canada.

PMID: 26097049
DOI: 10.1016/j.urolonc.2015.05.024

Abstract

Purpose: Metformin, a first-line oral therapy for diabetes, has anticancer properties. Our objective was to evaluate the association between metformin use and oncologic outcomes in diabetic patients undergoing radical cystectomy (RC) for bladder cancer (BC).

Methods: A single-institution retrospective cohort (January 1997-June 2013) of diabetic patients undergoing RC was assembled. Medication use was assessed at time of surgery. Outcome measures were recurrence-free survival (RFS), BC-specific survival (BCSS), and overall survival (OS). Multivariable Cox proportional hazards models were used. To create parsimonious models, the change of estimate approach (10% threshold) was used as a variable selection strategy for final model inclusion separately for each outcome measure.

Results: Of 421 patients, 85 (20%) had diabetes. There were 39 (46%) patients on metformin therapy. Among diabetic patients, there were 21 patients with BC recurrence, 16 who died of BC, and 30 who died overall. In univariate analyses, metformin use among diabetic patients was associated with improved RFS (hazard ratio = 0.54, 95% CI: 0.33-0.88, P = 0.013) and trended toward improved BCSS (hazard ratio = 0.65, 95% CI: 0.40-1.07, P = 0.087), but not with OS (P = 0.87). In multivariable models, metformin use among diabetic patients was associated with significantly improved RFS (adjusted hazard ratio = 0.38, 95% CI: 0.20-0.72, P = 0.003) and BCSS (adjusted hazard ratio = 0.57, 95% CI: 0.35-0.91, P = 0.019), but not with OS (P = 0.89). Use of other oral hypoglycemic agents or insulin was not associated with oncologic outcomes.

Conclusions: Our study is among the first to report an association between metformin use and improved RFS and BCSS in diabetic patients undergoing RC. Given its low cost and demonstrated safety among nondiabetic patients, further studies are warranted to evaluate potential therapeutic and preventive roles of metformin in BC.

Keywords: Cystectomy; Metformin; Mortality; Patient outcome assessment; Urinary bladder neoplasms.

MeSH terms

Aged
Carcinoma, Transitional Cell / mortality*
Carcinoma, Transitional Cell / surgery
Cohort Studies
Cystectomy
Diabetes Mellitus / drug therapy*
Disease-Free Survival
Female
Humans
Hypoglycemic Agents / therapeutic use*
Kaplan-Meier Estimate
Male
Metformin / therapeutic use*
Middle Aged
Proportional Hazards Models
Retrospective Studies
Urinary Bladder Neoplasms / mortality*
Urinary Bladder Neoplasms / surgery

Substances

Hypoglycemic Agents
Metformin