What question did this study set out to answer?

This study aims to evaluate how diabetes and metformin influence tumor response to total neoadjuvant therapy in advanced rectal cancer.

January 14, 2026

Impact of Metformin and Diabetes on Tumor Response to Total Neoadjuvant Therapy in Advanced Rectal Cancer: A Multicenter Retrospective Cohort Study

Key Points

This study aims to evaluate how diabetes and metformin influence tumor response to total neoadjuvant therapy in advanced rectal cancer.
Retrospective cohort study at three hospitals in South Australia from 2019 to 2025.
Included rectal cancer patients treated with total neoadjuvant therapy with curative intent.
Patients were categorized based on diabetes status and metformin use. Primary outcome measured was overall complete response rate.
Out of 244 patients, 44 (18.0%) had diabetes and 31 (12.7%) used metformin.
No significant difference in overall complete response rates between diabetic and non-diabetic patients.
Subgroup analysis indicated diabetic patients using metformin had a higher overall complete response rate (58.1% vs. 23.1%, p = 0.049).

Abstract

ABSTRACT Aim Diabetes mellitus (DM) is associated with impaired response to neoadjuvant chemoradiotherapy in rectal cancer. Metformin may enhance treatment response by improving tumor oxygenation and inhibiting cell growth and proliferation through activation of AMP‐activated protein kinase and downstream inhibition of mTOR and HIF‐1α pathways. However, the impact of DM and metformin use in patients receiving total neoadjuvant therapy (TNT) for advanced rectal cancer remains unknown. Objective This study evaluates the effect of DM and metformin use on overall complete response (oCR) after TNT. Methods This multicenter, retrospective cohort study included consecutive rectal cancer patients treated with TNT with curative intent at three South Australian hospitals between 2019 and 2025. Patients were grouped by diabetes status and metformin use. The primary outcome was the oCR rate, encompassing both clinical complete response (cCR) and pathological complete response (pCR) rates. The main secondary outcome was response at distant sites (complete M1 response). Results Among 244 patients who completed TNT, 44 (18.0%) were diabetic and 31 (12.7%) patients used metformin. No significant differences in response rates were observed between diabetic and nondiabetic groups: oCR (47.7%vs. 41.5%, p = 0.450), cCR (40.9% vs. 37.5%, p = 0.673), pCR (12.5% vs. 8.3%, p = 0.457), and M1 complete response (50% vs. 36.2%, p = 0.873). Similarly, no significant differences in oCR, cCR, pCR, or complete M1 response were observed between metformin users and non‐users. However, subgroup analysis of diabetic patients demonstrated that those taking metformin had a significantly higher oCR rate than those not taking metformin (58.1% vs. 23.1%, p = 0.049). Conclusion Diabetes and metformin use did not significantly affect tumor response rates in the overall cohort of patients with advanced rectal cancer treated with TNT. However, among diabetic patients, metformin use was associated with improved response to TNT. Given the retrospective design and limited sample size, large‐scale prospective studies are required to validate these findings.

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