Combination therapy for advanced hepatocellular carcinoma: do we see the light at the end of the tunnel?

IMPORTANCE: Combination therapies of anti-PD-1 and anti-angiogenesis regimens are emerging rapidly and exhibit more promising anti-tumor efficacy for advanced hepatocellular carcinoma (HCC), and consistently it is the hotspot in clinical studies. OBJECTIVE: To elaborate several issues which are warranted further consideration as more regimens are being investigated in combination therapies. EVIDENCE REVIEW: We searched PubMed, MEDLINE, Cochrane Library and Google Scholar by 2021 February for publications on combination therapies for HCC. FINDINGS: Several clinical issues are worth reconsidering, such as the evaluation on appropriate primary endpoints in phase III clinical trials as for different practical problems, the translation of surrogate endpoint objective response rate (ORR) benefits into overall survival (OS) benefits, and whether conversion surgery contributes to initial expectations of long-term survival or not. New concepts in novel immunotherapy and targeted therapy in combination with loco-regional therapies may improve overall survival for HCC. CONCLUSIONS AND RELEVANCE FOR REVIEWS: Comprehensive understanding of the mechanism of immunotherapy and targeted therapy contributes to better prognosis of advanced HCC and more explorative combination therapies are needed.