Cumulative metformin use and its impact on survival in gastric cancer patients after gastrectomy

Objective: The aim of this study was to evaluate the association between metformin and survival of gastric cancer (GC) patients. Background: Metformin has recently received attention as a potential anticancer treatment. However, no study has shown the survival benefit of metformin for GC patients. Methods: A total of 1974 GC patients who underwent curative gastrectomy were compared for survival according to groups; 132 diabetic patients treated with metformin, 194 diabetic patients without metformin, and 1648 nondiabetic patients. Results: During the median follow-up period of 6.2 years (interquartile range, 4.7-7.8 years), 381 patients (19.3%) died, including 302 (15.3%) who died from GC. The non-diabetic patients had significantly better recurrence-free survival (RFS; P<0.0001), cancer-specific survival (CSS; P=0.006), and overall survival (OS; P<0.0001). However, the diabetic patients treated with metformin had a significantly better prognosis than those who were not (OS: hazard ratio [HR]=0.584, 95% confidence interval [CI], 0.369-0.926; CSS: HR=0.57, 95% CI, 0.334-0.975; RFS: HR=0.633, 95% CI, 0.410-0.977), and metformin treatment prolonged survival in diabetic patients to a rate comparable to that in non-diabetic patients. In multivariable analysis using the Cox proportional hazard model with time-dependent covariates, each cumulative 6 months of metformin use was significantly associated with a decreased risk of recurrence, cancer-specific mortality, and all-cause mortality (RFS: HR=0.864, 95% CI, 0.797-0.937; CSS: HR=0.865, 95% CI, 0.782-0.958; OS: HR 0.870, 95% CI, 0.801-0.945). Conclusions: The increased cumulative duration of metformin use decreased the recurrence, all-cause mortality, and cancer-specific mortality rates among GC patients with diabetes who underwent gastrectomy.