Efficacy and safety of immune checkpoint inhibitors for hepatocellular carcinoma patients with macrovascular invasion or extrahepatic spread: a systematic review and meta-analysis of 54 studies with 6187 hepatocellular carcinoma patients

Background and aims The impacts of macrovascular invasion (MVI) or extrahepatic spread (EHS) on the efficacy and safety of immune checkpoint inhibitors (ICIs) among hepatocellular carcinoma (HCC) patients remain unclear. Thus, we conducted a systematic review and meta-analysis to clarify whether ICI therapy is a feasible treatment option for HCC with MVI or EHS. Methods Eligible studies published before September 14, 2022, were retrieved. In this meta-analysis, the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and occurrence of adverse events (AEs) were outcomes of interest. Results Fifty-four studies involving 6187 individuals were included. The findings indicated that the presence of EHS in ICI-treated HCC patients may indicate an inferior ORR (OR 0.77, 95% CI 0.63–0.96), but may not significantly affect the PFS (multivariate analyses: HR 1.27, 95% CI 0.70–2.31) and OS (multivariate analyses: HR 1.23, 95% CI 0.70–2.16). Additionally, the presence of MVI in ICI-treated HCC patients may not have significant prognostic impact on ORR (OR 0.84, 95% CI 0.64–1.10), but may indicate inferior PFS (multivariate analyses: HR 1.75, 95% CI 1.07–2.84) and OS (multivariate analyses: HR 2.03, 95% CI 1.31–3.14). The presence of EHS or MVI in ICI-treated HCC patients may not significantly impact the occurrence of any serious immune-related adverse events (irAEs) (grades ≥ 3) (EHS: OR 0.44, 95% CI 0.12–1.56; MVI: OR 0.68, 95% CI 0.24–1.88). Conclusion The presence of MVI or EHS in ICI-treated HCC patients may not significantly impact the occurrence of serious irAEs. However, the presence of MVI (but not EHS) in ICI-treated HCC patients may be a significant negative prognostic factor. Therefore, ICI-treated HCC patients with MVI warrant more attention.