TACE plus systemic therapy versus TACE alone for unresectable, non-metastatic hepatocellular carcinoma: meta-analysis and trial sequential analysis from randomized controlled trials

Introduction: Transarterial chemoembolization (TACE) is the standard treatment for unresectable, non-metastatic 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 (PFS), 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, p = 0.008), with TSA confirming the statistical reliability of the evidence. TACE + S also significantly improved TTP based on mRECIST (HR = 0.63, 95% CI 0.54–0.74, p < 0.001) and ORR by RECIST 1.1 (Relative Risk [RR] = 1.44, 95% CI 1.22–1.70, p < 0.001). Subgroup analysis showed a more pronounced OS benefit in patients with HBV-related HCC (HR = 0.69, p = 0.009). However, the combination strategy was associated with a significantly higher incidence of both all-grade and grade ≥ 3 treatment-related AEs, though no treatment-related deaths were reported. Conclusions: In patients with unresectable, non-metastatic HCC, the combination of TACE and systemic therapy provides superior overall survival, 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 adverse events is notable, this approach remains a viable option, underscoring the necessity for careful patient selection and proactive management strategies.