Metformin enhances the pathological response in nondiabetic patients with rectal cancer undergoing neoadjuvant...

This randomized, single-blind controlled pilot phase II trial evaluated whether adding metformin to neoadjuvant chemoradiotherapy (nCRT) increases pathological complete response (pCR) rates in nondiabetic patients with locally advanced rectal adenocarcinoma. Eighty-five nondiabetic patients treated between May 2024 and June 2025 were randomized to receive standard nCRT-radiotherapy 50.4 Gy in 28 daily fractions with concurrent oral capecitabine 825 mg/m² twice daily (group A, n = 43)-or the same regimen plus oral metformin 1000 mg twice daily (group B, n = 42). Metformin was started 1 to 2 weeks before nCRT and continued until 30 days after completion. The primary endpoint was pCR, defined as the absence of residual tumor in the resected specimen; a composite endpoint combining pCR and clinical complete response (cCR) was also assessed. Group B achieved a significantly higher pCR rate than group A (28% vs 9%, P = .010). The combined pCR/cCR outcome was likewise superior in the metformin group (38% vs 14%, P = .011). In multivariable logistic regression adjusting for potential confounders, metformin remained an independent predictor of combined pCR/cCR (adjusted odds ratio 3.98, P = .031). Metformin added to nCRT appears to enhance tumor response and early clinical outcomes in nondiabetic patients with locally advanced rectal cancer and may represent a low-cost, low-toxicity radiosensitizer. Larger, long-term studies are warranted to confirm these findings and clarify their impact on survival and recurrence. The study was registered at ClinicalTrials.gov Identifier: NCT06728982. SIGNIFICANCE STATEMENT: This randomized trial shows that adding the common antidiabetic drug metformin to standard preoperative chemoradiotherapy significantly increases complete tumor response rates in nondiabetic patients with locally advanced rectal cancer. These findings highlight a simple, low-cost radiosensitizing strategy that could improve downstaging, organ preservation, and long-term outcomes if confirmed in larger studies.