TACE plus tyrosine kinase inhibitors and immune checkpoint inhibitors versus TACE plus tyrosine kinase inhibitors for the treatment of patients with hepatocellular carcinoma: a meta-analysis and trial sequential analysis

Background: We conducted a meta-analysis and trial sequential analysis (TSA) to compare the therapeutic efficacy and adverse events (AEs) between the following treatment strategies for patients with hepatocellular carcinoma (HCC): TACE plus tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) (TACE + T + I) versus TACE plus TKIs (TACE + T). Methods: We systematically searched PubMed, the Web of Science, the Cochrane Library, and Embase for studies comparing TACE + T + I and TACE + T for the treatment of BCLC intermediate- or advanced-stage HCC. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and AEs were included as outcomes. We used a fixed- or random-effects model based on the results of a heterogeneity evaluation and performed a meta-analysis using Review Manager 5.3 and Stata 16.0. We then carried out the TSA. Results: Five studies examining a total of 425 patients were included in this study. Our meta-analysis revealed that, compared to TACE + T, TACE + T + I significantly improved the ORR (risk ratio [RR] = 1.53, 95% confidence interval [CI] = 1.27–1.85, p < 0.01) and extended both the median PFS (mean difference [MD] = 4.51 months, 95% CI = 2.16–6.87, p < 0.01) and median OS (MD = 5.75 months, 95% CI = 4.03–7.48, p < 0.01). These results were tested to be true by the TSA without requiring a larger information size. Among AEs, hypertension tended to occur more often in patients treated with TACE + T + I than in those treated with TACE + T (RR = 1.58, 95% CI = 1.05–2.40, p < 0.05). However, the TSA suggested that additional cases are necessary to confirm this difference. Regarding the other AEs, no significant differences were detected between the two groups. Conclusion: TACE + T + I showed better effects on the ORR, PFS, and OS than TACE + T as a treatment for BCLC stages B and C HCC, without an obvious increase in the AEs. Based on these findings, well-designed, large RCTs are suggested.