Evaluating the Efficacy and Safety of TACE Combined with Iodine-125 Brachytherapy Versus TACE Monotherapy for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

<b>Background/Objectives:</b> This review and meta-analysis assessed whether combining transarterial chemoembolization (TACE) with iodine-125 brachytherapy (I-125 brachytherapy) offers greater efficacy and safety than TACE alone in treating hepatocellular carcinoma (HCC). <b>Methods:</b> PubMed, EMBASE, the Cochrane Library, Scopus, and Web of Science were searched for articles published between 1 January 2010 and 30 November 2023. Eligible studies compared TACE with and without I-125 brachytherapy from randomized controlled trials (RCTs) and non-randomized comparative studies published in English. The primary outcome was overall survival (OS) at 1, 2, and 3 years. The secondary outcomes included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and adverse events. ROB-2 and ROBINS-I tools were used to assess study quality. <b>Results:</b> Eighteen studies (<i>n</i> = 1872 patients) were included. All 18 studies originated from China, with the majority being retrospective cohorts (<i>n</i> = 16), one non-randomized prospective study, and one RCT. Compared with TACE alone, TACE + I-125 brachytherapy significantly improved OS at 1 year (OR = 3.64, 95% CI: 2.92-4.55), 2 years (OR = 3.93, 95% CI: 2.29-6.77), and 3 years (OR = 4.12, 95% CI: 2.24-7.56). The tumor response rates, including the ORR and DCR, were also significantly higher in the combination group. Subgroup analysis revealed that the survival benefit was maintained in studies without systemic chemotherapy (OR = 3.68, 95% CI: 2.89-4.70) and in studies with systemic chemotherapy (OR = 4.13, 95% CI: 1.69-10.09). Although larger effect estimates were observed with low-dose I-125 brachytherapy (<80 Gy; OR = 8.55, 95% CI: 4.32-16.92) compared to high-dose (≥100 Gy; OR = 2.87, 95% CI: 2.05-4.00), this finding is hypothesis-generating rather than conclusive and should be interpreted cautiously as it is based on only three studies. Adverse event rates were comparable between groups. GRADE assessment indicated low to very low certainty for all outcomes, primarily due to the retrospective nature of most included studies. <b>Conclusions:</b> TACE combined with I-125 brachytherapy was associated with improved survival and tumor response without a statistically significant increase in adverse events. High-quality, multicenter RCTs are warranted to confirm these results.