Comparison of the efficacy of transarterial chemoembolization combined with different molecular targeted agents and/or immune checkpoint inhibitors for unresectable hepatocellular carcinoma: a systematic review and network meta-analysis.

BACKGROUND: Transarterial chemoembolization (TACE) combined with molecular targeted agents (MTAs) and/or immune checkpoint inhibitors (ICIs) has been increasingly used in patients with unresectable hepatocellular carcinoma (uHCC). However, the efficacy differences among these combination regimens have not been systematically compared. This study aimed to compare the efficacy of these treatment strategies and provide evidence for optimizing combination therapies in clinical practice. METHODS: PubMed, Embase, the Cochrane Library, and Web of Science were systematically searched up to February 26, 2026. Randomized controlled trials (RCTs) and cohort studies involving patients with uHCC were included. The interventions were TACE combined with MTAs and/or ICIs. The primary outcomes were overall survival (OS) and progression-free survival (PFS), while the secondary outcomes were objective response rate (ORR) and disease control rate (DCR). A frequentist network meta-analysis (NMA) with a random-effects model was performed, and treatment regimens were ranked using P-scores. This NMA was registered in PROSPERO (CRD420261350164). RESULTS: A total of 108 studies involving 19,761 patients and 26 treatment regimens were included, comprising 84 retrospective cohort studies and 24 RCTs. Compared with TACE alone, most combination regimens significantly improved patient outcomes. For OS, TACE + anlotinib + sintilimab (TACE + Anl + Sin), TACE + donafenib + toripalimab (TACE + Don + Tor), TACE + lenvatinib + tislelizumab (TACE + Len + Tis), TACE + sorafenib + camrelizumab (TACE + Sor + Cam), and TACE + apatinib + camrelizumab (TACE + Apa + Cam) were all significantly superior to TACE alone. P-score ranking showed that TACE + Anl + Sin was most likely to achieve the best OS outcome. For PFS, compared with TACE alone, TACE + Anl + Sin, TACE + Don + Tor, TACE + lenvatinib + pembrolizumab (TACE + Len + Pem), TACE + Len + Tis, and TACE + Apa + Cam significantly prolonged PFS. Among them, TACE + Len + Pem still showed strong benefit when compared with some triple-combination regimens and ranked first by P-score. For ORR, TACE + Len + Cam, TACE + Len + Tis, TACE + Anl + Sin, and TACE + Don + Tor all significantly improved ORR compared with TACE alone. Among these, TACE + Len + Cam had the highest P-score. For DCR, TACE + Len + Tis showed the best performance, while TACE + atezolizumab + bevacizumab (TACE + Ate + Bev), TACE + Anl + Sin, and TACE + Apa + Cam also demonstrated relatively high DCR. CONCLUSIONS: Compared with TACE alone, TACE combined with MTAs and ICIs can significantly improve outcomes in patients with uHCC. TACE + Anl + Sin, TACE + Len + Tis, and TACE + Apa + Cam may be promising treatment options, although more prospective studies are needed for further validation.