Introduction This sy stematic review and meta-analysis aimed to evaluate the efficacy and safety of TACE combined with I-125 brachytherapy versus TACE alone in Hepatocellular carcinoma (HCC) patients. Methods Following the PRISMA guidelines, we searched databases, including PubMed, EMBASE, the Cochrane Library, Scopus, Web of Science, and grey literature, for articles published between January 1, 2010 and November 30, 2023. Eligible studies compared TACE with and without I-125 brachytherapy, from randomized controlled trials (RCTs) and non-randomized comparative studies. Primary outcomes were overall survival (OS) at 1, 2, and 3 years. Secondary outcomes comprised progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and adverse events. Data extraction and quality assessment were conducted using Covidence software and validated risk-of-bias tools. Meta-analyses were performed using Stata. Results Eighteen studies (n=1,872 patients) were included. TACE + I-125 brachytherapy significantly improved OS at 1 year (OR: 1.30, 95%; CI: 1.05–1.56), 2 years (OR: 1.02, 95%; CI: 0.65–1.39), and 3 years (OR: 1.28, 95%; CI: 0.85–1.71) compared to TACE alone. Tumor response rates, including overall response rate (ORR: 1.74, 95%; CI: 0.65–2.83) and disease control rate (DCR: 1.04, 95%; CI: 0.07–2.01), were also significantly higher in the combination group. Subgroup analyses showed consistent OS outcomes between higher and lower doses of I-125. Adverse event rates were insignificant and comparable between groups. Conclusion TACE combined with I-125 brachytherapy enhances survival and tumor response without increasing adverse events, offering a promising strategy for managing advanced HCC. Further RCTs are warranted to confirm these findings.

Background/Objectives: 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). Methods: 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. Results: Eighteen studies (n = 1872 patients) were included. All 18 studies originated from China, with the majority being retrospective cohorts (n = 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. Conclusions: 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.