Antitumor Activity of Metformin Combined with Locoregional Therapy for Liver Cancer: Evidence and Future Directions

SIMPLE SUMMARY: Existing therapies for hepatocellular carcinoma, although effective, often have limitations in their long-term efficacy. Metformin is increasingly being recognized for its anti-cancer properties and potential in augmenting the tumor response following locoregional therapy. This review analyzed existing comparative studies on combination therapy with metformin and found that metformin had the potential to augment the effects of current locoregional therapies for HCC management. ABSTRACT: This article aimed to examine the effect of metformin use on improving outcomes after liver-directed therapy in patients with HCC and identify future directions with the adjuvant use of and potential therapeutic agents that operate on similar mechanistic pathways. Databases were queried to identify pertinent articles on metformin’s use as an anti-cancer agent in HCC. Eleven studies were included, with five pre-clinical and six clinical studies. The mean overall survival (OS) and progression-free survival were both higher in the locoregional therapy (LRT) + metformin-treated groups. The outcome variables, including local tumor recurrence rate, reduction in HCC tumor growth and size, tumor growth, proliferation, migration and invasion of HCC cells, HCC cell apoptosis, DNA damage, and cell cycle arrest, showed favorable outcomes in the LRT + metformin-treated groups compared with LRT alone. This systemic review provides a strong signal that metformin use can improve the tumor response after locoregional therapy. Well-controlled prospective trials will be needed to elucidate the potential antitumor effects of metformin and other mTOR inhibitors.