Optimal timing of combining sorafenib with trans-arterial chemoembolization in patients with hepatocellular carcinoma: A meta-analysis

Background: The combination therapy of trans-arterial chemoembolization (TACE) and sorafenib were proved to be one of the effective methods for intermediate and advanced hepatocellular carcinoma (HCC). Although it has been confirmed that the combination therapy can prolong survival for advanced HCC effectively, the therapeutic efficacy and safety are still controversial and the clinical value has not been determined. This meta-analysis aims to evaluate the efficacy and safety of combination therapy and discuss the optimal timing of combination for better clinical benefits. Data sources: PubMed, EMBASE, the Cochrane Library, MEDLINE, and Web of Science were systematically reviewed to search for relevant studies published before May 15, 2021. Studies comparing the efficacy and safety of TACE + sorafenib with TACE + placebo / alone were adopted. Two reviewers independently extracted study outcomes. The data were analyzed through fixed/random-effect meta-analysis models with Review Manager (Version 5. 3) software. Results: 7 randomized controlled trials (RCTs) were included with 1464 patients with unresectable HCC (734 in TACE + sorafenib group and 730 in TACE + placebo or alone group). Meta-analysis showed that objective response rate (ORR) and disease control rate (DCR) were slightly improved in TACE + sorafenib group (ORR: risk ratio = 1.24; 95% confidence interval: 1.08-1.42; P = 0.002; DCR: risk ratio = 1.09; 95% confidence interval: 1.01-1.18; P = 0.02). The combination therapy obviously improved time to progression (TTP) (hazard ratio: 0.73; 95% confidence interval: 0.55-0.96; P = 0.03) and progression-free survival (PFS) (hazard ratio 0.62; 95% confidence interval: 0.52-0.73, P < 0.00001) but not overall survival (OS) (hazard ratio: 0.93; 95% confidence interval: 0.59-1.46; P = 0.75) or time to untreatable progression (TTUP) (hazard ratio: 0.76; 95% confidence interval: 0.31-1.89; P = 0.56). In addition, the incidence of adverse reactions (AEs) in combination group were higher than TACE + placebo / alone group. Furthermore, the subgroup analysis showed that the heterogeneity of TTP was notably decreased (pre-TACE: P = 0.12, I2 = 48%; post-TACE: P = 0.58, I2 = 0%), and the hazard ratio was 0.59 (95% confidence interval: 0.51-0.68; P < 0.00001) in pre-TACE subgroup which indicated that combination before TACE significantly prolonged TTP but not in combination after TACE (hazard ratio: 0.88; 95% confidence interval: 0.62-1.24; P = 0.46). In term of AEs, sensitivity analysis indicated that the risk ratio for hand-foot skin reaction, diarrhea, rash/desquamation, and hypertension was 7.41, 2.58, 2.14, 1.55 in pre-TACE subgroup respectively and was 11.34, 3.26, 3.61, 4.11 in post-TACE subgroup respectively (All P < 0.05). Conclusion: The combination of TACE and sorafenib significantly can improve TTP and PFS, and reduce the level of risk of adverse reactions of unresectable HCC, especially in the combination before TACE.