Survival Benefit of Metformin as an Adjuvant Treatment for Head and Neck Cancer: A Systematic Review and Meta-Analysis

Background/Aims: The relationship between the efficacy of metformin and the prognosis of patients with head and neck cancer (HNC) was still unclear. This study aims to clarify the prognostic value of metformin treatment using meta-analysis. Methods: Studies related to HNC prognosis and metformin were searched in Cochrane Library, Embase, LILACS, MEDLINE and PubMed databases. A meta-analysis was performed to evaluate the association between metformin therapy and the prognosis of HNC on overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS) and whether article quality, comorbidities, age, region or smoking had an influence on the prognosis of metformin treatment. Pooled hazard ratio (HR) and 95% confidence interval (CI) were analyzed to assess the effect. Results: Eleven eligible studies involving 14,694 participants were included. Metformin increased the OS (HR = 0.87, 95% CI: 0.76–0.99), but failed on DFS (HR = 0.67, 95% CI: 0.40–1.09) or DSS (HR = 0.69, 95% CI: 0.41–1.14) in HNC patients. Subgroup analysis showed metformin was associated with improved OS (HR = 0.66, 95% CI: 0.49–0.88), DFS (HR = 0.49, 95% CI: 0.26–0.92) and DSS (HR = 0.38, 95% CI: 0.22–0.65) in studies with higher Newcastle-Ottawa Scale (NOS) scores. Subgroup analysis of age indicated that patients younger than 65 years (OS, HR = 0.67, 95% CI: 0.49–0.92) were more likely to benefit from metformin treatment. Subgroup analysis of comorbidities showed metformin significantly improved patient outcomes in studies without adjusted for comorbidities (OS, HR = 0.66, 95% CI: 0.51–0.85; DSS, HR = 0.38, 95% CI: 0.22–0.65), but not in studies that adjusted for comorbidities. Conclusions: Metformin improved the prognosis of HNC patients as an adjuvant therapy, especially in those with higher NOS scores. Age and comorbidities of HNC patients influenced the therapeutic effect of metformin. Further well-conducted investigations are needed.