Abstract
INTRODUCTION: Transarterial chemoembolization (TACE), anti-angiogenic drugs (AADs), and immune checkpoint inhibitors (ICIs) are common therapies for hepatocellular carcinoma (HCC). Despite proven benefits of combined regimens, optimal sequencing remains unclear. This network meta-analysis evaluates safety and efficacy of therapeutic sequences in intermediate-advanced HCC. METHODS: We conducted a comprehensive search of multiple databases, including PubMed, Cochrane Library, Web of Science, and EMBASE, for studies published until February 1, 2025. Cochrane's tools and the Newcastle-Ottawa Scale were used to assess the evaluation of bias. We performed data compilation and conducted a network meta-analysis to compare the relative efficacy of different treatments. RESULTS: A total of 56 studies (10,456 patients) evaluated 11 therapeutic sequences. Survival outcomes favored TACE-AADs-ICIs (TAI), which ranked highest for overall survival (OS: SUCRA 90.0%) and progression-free survival (PFS: SUCRA 91.3%). Tumor responses differed significantly across regimens: TACE-ICIs (TI) achieved the highest probability of complete response rate (CRR: SUCRA 83.9%), while AADs-ICIs-TACE (AIT) ranked first in objective response rate (ORR: SUCRA 85.8%). Notably, ICIs-AADs (IA) achieved superior disease control rate (DCR: SUCRA 88.1%). ICIs monotherapy (I) was associated with the lowest incidence of grade ≥ 3 adverse events (AEs: SUCRA 11.7%). CONCLUSION: Our comprehensive network meta-analysis establishes a multidimensional efficacy-safety profile for sequential therapies in intermediate and advanced HCC management. TACE-initiated sequences (TAI/TIA) optimize survival (OS/PFS: SUCRA > 90%), while systemic-first regimens (AIT/IA) maximize tumor response (ORR/DCR: SUCRA > 85%). ICIs monotherapy exhibits the safest profile. Further clinical studies are warranted to determine optimal treatment sequencing for intermediate and advanced HCC.