Association of Tumor Pathological Response with the Use of Metformin During Neoadjuvant Chemoradiotherapy in Rectal and Esophageal/Gastroesophageal Cancer Patients: a Systematic Review and Meta-analysis

Purpose: Metformin has been reported to be associated with improved cancer prognosis when used in combination with chemotherapy and/or radiotherapy. In this study, we present a systematic review and meta-analyses of studies evaluating the association of tumor pathological response with the use of metformin during neoadjuvant chemoradiotherapy (NACRT) in rectal and esophageal/gastroesophageal cancer patients. Methods: We systematically searched databases for articles that compared concurrent metformin use with no metformin use in cancer patients treated with NACRT following the PRISMA 2020. The design and quality of the collected studies were reviewed, and meta-analyses were performed on the pathologic complete response (pCR) rate, tumor regression grade (TRG), T factor downstaging, and N factor downstaging. Results: Three databases were searched, and 220 papers were screened. Five retrospective cohort study papers were eligible for the meta-analysis, with a total of 2041 patients. The included papers contained only rectal and esophageal/gastroesophageal cancers. In the metformin group, the pCR rate was 26% [20–32%], and metformin was associated with the pCR rate (odds ratio [OR] = 0.51 [0.34–0.76], p < 0.01). Meta-regression analysis of the pCR rate showed a positive correlation with adenocarcinoma (coefficient = 0.13 [0.02–0.25], p = 0.03) and fluoropyrimidine anticancer drug use (coefficient = 0.01 [0.001–0.02], p = 0.03). Conclusions: The results suggest that metformin is associated with pCR rate when used in combination with NACRT. The association of metformin and pCR rate in combination with fluoropyrimidine anticancer drugs was observed mostly for adenocarcinoma patients.