Metformin Use is Associated With Improved Response to Neoadjuvant Chemoradiation in Esophageal Adenocarcinoma

Abstract

The vast majority of patients with esophageal carcinoma succumb to their disease, and there has been little improvement in outcomes in the past decade. The anti-diabetic agent metformin has been investigated both as a chemopreventative agent, as well as possible addition to current chemotherapeutics. However, little work has been done examining the role of metformin in radiosensitization. In the current study, the PET and pathologic response rate of esophageal cancer patients treated with neoadjuvant chemoradiation (CRT) were examined in patients taking metformin during therapy. Two hundred eighty-five patients treated with concurrent chemoradiation (CRT) followed by esophagectomy for esophageal adenocarcinoma from 1997 - 2012 were included in the study, including 29 diabetics taking metformin at the time of radiation, 21 diabetics not taking metformin and 235 non-diabetics. Pre- and post- treatment PET scans were available for 204 patients. Maximum SUV values of the tumor were recorded for both scans. Pathologic response was graded at the time of surgery. PET and pathologic CR rates were compared using both the chi-square statistic as well as ANOVA with post-hoc LSD analysis. Multivariate logistic regression analysis was performed to control for predictors of pathologic complete response (CR) after CRT. The overall rate of pathologic CR for the study population was 20%. The pathologic CR rate was higher in patients taking metformin (34.5%), compared to diabetic patients not taking metformin (4.8%, p = 0.01) and nondiabetic patients (19.6%, p = 0.05). Analysis of only patients taking metformin showed that daily doses ≥1,500 mg trended toward improved pathologic CR rates (p = 0.07). No significant difference was seen in pre-CRT tumor maximum SUV (p = 0.88); however, post-CRT tumor maximum SUV was significantly decreased in patients taking metformin (p = 0.02). On multivariate logistic regression, metformin use was independently associated with pathologic CR (p = 0.04). Metformin use was also associated with decreased in-field loco-regional failure following radiation (p = 0.05). The use of metformin is associated with increased response to CRT in esophageal cancer in a dose-dependent manner and may be a sensitizer to this therapy.