Metformin use and improved response to therapy in rectal cancer

Heath D Skinner, Christopher H Crane, Christopher R Garrett, Cathy Eng, George J Chang, John M Skibber, Miguel A Rodriguez-Bigas, Patrick Kelly, Vlad C Sandulache, Marc E Delclos, Sunil Krishnan, Prajnan Das, Heath D Skinner, Christopher H Crane, Christopher R Garrett, Cathy Eng, George J Chang, John M Skibber, Miguel A Rodriguez-Bigas, Patrick Kelly, Vlad C Sandulache, Marc E Delclos, Sunil Krishnan, Prajnan Das

Abstract

Locally advanced rectal cancer is commonly treated with chemoradiation prior to total mesorectal excision (TME). Studies suggest that metformin may be an effective chemopreventive agent in this disease as well as a possible adjunct to current therapy. In this study, we examined the effect of metformin use on pathologic complete response (pCR) rates and outcomes in rectal cancer. The charts of 482 patients with locally advanced rectal adenocarcinoma treated from 1996 to 2009 with chemoradiation and TME were reviewed. Median radiation dose was 50.4 Gy (range 19.8-63). Nearly, all patients were treated with concurrent 5-fluorouracil-based chemotherapy (98%) followed by adjuvant chemotherapy (81.3%). Patients were categorized as nondiabetic (422), diabetic not taking metformin (40), or diabetic taking metformin (20). No significant differences between groups were found in clinical tumor classification, nodal classification, tumor distance from the anal verge or circumferential extent, pretreatment carcinoembryonic antigen level, or pathologic differentiation. pCR rates were 16.6% for nondiabetics, 7.5% for diabetics not using metformin, and 35% for diabetics taking metformin, with metformin users having significantly higher pCR rates than either nondiabetics (P = 0.03) or diabetics not using metformin (P = 0.007). Metformin use was significantly associated with pCR rate on univariate (P = 0.05) and multivariate (P = 0.01) analyses. Furthermore, patients taking metformin had significantly increased disease-free (P = 0.013) and overall survival (P = 0.008) compared with other diabetic patients. Metformin use is associated with significantly higher pCR rates as well as improved survival. These promising data warrant further prospective study.

Keywords: Chemotherapy; metformin; radiation; rectal cancer.

Figures

Figure 1
Figure 1
Pathologic complete response (pCR) rates following chemoradiotherapy. (A) pCR rates among the different metformin use categories. *Significantly different from nondiabetic patients. +Significantly different from diabetic patients not taking metformin. (B) pCR rates stratified by hypoglycemic use. *Significantly different from nondiabetic patients. +Significantly different from patients using nonmetformin hypoglycemic, #Significantly different from patients treated with no medical management for their diabetes. P-values <0.05 were considered significant. Error bars denote standard error of the mean.
Figure 2
Figure 2
Survival outcomes and patterns of failure. (A) Overall survival, (B) disease-free survival, (C) locoregional control, and (D) time to distant metastasis.

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