Transarterial Chemoembolization plus Systemic Therapy versus Transarterial Chemoembolization alone for Unresectable, Nonmetastatic Hepatocellular Carcinoma: Meta-Analysis and Trial Sequential Analysis from Randomized Controlled Trials.

Introduction: Transarterial chemoembolization (TACE) is the standard treatment for unresectable, nonmetastatic hepatocellular carcinoma (HCC). Although adding systemic therapies (TACE + S) is hypothesized to mitigate TACE-induced angiogenesis and enhance efficacy, the definitive clinical advantage of TACE + S over TACE monotherapy, particularly with respect to overall survival (OS), remains uncertain. We aimed to comprehensively evaluate the efficacy and safety of this combination using a rigorous meta-analysis and trial sequential analysis (TSA). Methods: We systematically searched major databases for randomized controlled trials (RCTs) comparing TACE + S versus TACE alone or TACE plus placebo in patients with unresectable HCC without macrovascular invasion or extrahepatic metastasis. The primary outcome was OS; secondary outcomes included progression-free survival, time to progression (TTP), objective response rate (ORR), and adverse events (AEs). TSA was employed to assess the statistical reliability of findings and the adequacy of the cumulative evidence across all outcomes. Results: A total of 10 RCTs comprising 2,296 patients were included. Compared with TACE alone/placebo, TACE + S demonstrated a statistically significant improvement in OS (hazard ratio [HR] = 0.83, 95% CI: 0.73-0.95, Conclusion: In patients with unresectable, nonmetastatic HCC, the combination of TACE and systemic therapy provides superior OS, more favorable tumor control, and delayed disease progression compared with TACE monotherapy. These significant benefits are particularly pronounced in the HBV-associated HCC population. While the increased risk of AEs is notable, this approach remains a viable option, underscoring the necessity for careful patient selection and proactive management strategies.