Supplementary Material for: Transarterial Chemoembolization Combined with Lenvatinib for Hepatocellular Carcinoma: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Introduction: The treatment of hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) and lenvatinib individually has shown favorable outcomes, but there is currently no meta-analysis based on randomized controlled trials (RCTs) to investigate the efficacy and safety of this combined treatment for HCC. The aim of this study is to identify the efficacy and safety of TACE plus lenvatinib for the treatment of HCC. Methods: A systematic search of MEDLINE (via PubMed), the Cochrane Library, EMBASE, and the Web of Science was conducted on July 31, 2023. RCTs evaluating the efficacy and safety of TACE in combination with lenvatinib for the treatment of HCC were included. The risk of bias in the included studies was assessed using the Risk of Bias 2 tool. Outcome measures such as objective response rate (ORR), CR (complete remission), progression-free survival (PFS), overall survival (OS), and safety parameters were extracted from the included studies. Binary outcomes were analyzed using odds ratio (OR), risk ratio (RR), or hazard ratio (HR), while continuous variables were analyzed using mean difference (MD) or standardized MD (SMD) in Rstudio. The quality of the evidence was graded using the GRADE approach. Heterogeneity was considered significant when the I-squared was 50% or less. Results: Five RCTs involving 638 patients were included. The meta-analysis revealed that patients in the TACE plus lenvatinib group had a significantly higher mean ORR compared to the control group (OR: 3.65, 95% CI: 2.50–5.32, fixed effects model; OR: 3.58, 95% CI: 2.45–5.24, random effects model, I2 = 0, moderate quality). Specifically, 40.9% of patients in the TACE plus lenvatinib group achieved a PR, which was significantly higher than the control group (OR: 3.51, 95% CI: 2.41–5.13, fixed effects model; OR: 3.46, 95% CI: 2.36–5.07, random effects model, I2 = 0, moderate quality). The HR for OS was 0.47 (95% CI: 0.35–0.62, fixed effects model and random effects model, I2 = 0, moderate quality). The meta-analysis revealed that the TACE plus lenvatinib group had a significantly higher total adverse effects rate than the control group (OR: 1.86, 95% CI: 1.01–3.43, fixed effects model; OR: 1.85, 95% CI: 1.00–3.43, random effects model, I2 = 0, moderate quality). Conclusion: Our study suggests that the combination of TACE and lenvatinib in the treatment of HCC has shown promising results, with extended OS and improved ORR.

引言：单独采用经动脉化疗栓塞术（transarterial chemoembolization, TACE）或仑伐替尼（lenvatinib）治疗肝细胞癌（hepatocellular carcinoma, HCC）均已取得良好疗效，但目前尚无基于随机对照试验（randomized controlled trials, RCTs）的荟萃分析，探讨二者联合治疗HCC的有效性与安全性。本研究旨在明确TACE联合仑伐替尼治疗HCC的有效性及安全性。
方法：本研究于2023年7月31日对MEDLINE（通过PubMed检索）、考克兰图书馆（Cochrane Library）、EMBASE及Web of Science进行系统性检索。纳入评估TACE联合仑伐替尼治疗HCC的有效性与安全性的随机对照试验。采用偏倚风险2工具（Risk of Bias 2 tool）对纳入研究的偏倚风险进行评价。从纳入研究中提取客观缓解率（objective response rate, ORR）、完全缓解（complete remission, CR）、无进展生存期（progression-free survival, PFS）、总生存期（overall survival, OS）及安全性参数等结局指标。二分类结局采用比值比（odds ratio, OR）、相对危险度（risk ratio, RR）或风险比（hazard ratio, HR）进行分析，连续变量则采用RStudio中的均数差（mean difference, MD）或标准化均数差（standardized MD, SMD）进行分析。采用GRADE分级法对证据质量进行评级。当I²值≤50%时，认为存在显著异质性。
结果：共纳入5项RCTs，涉及638例患者。荟萃分析结果显示，TACE联合仑伐替尼组患者的平均客观缓解率显著高于对照组（固定效应模型：OR=3.65，95%CI：2.50~5.32；随机效应模型：OR=3.58，95%CI：2.45~5.24，I²=0，证据质量中等）。具体而言，TACE联合仑伐替尼组中有40.9%的患者达到部分缓解（partial remission, PR），该比例显著高于对照组（固定效应模型：OR=3.51，95%CI：2.41~5.13；随机效应模型：OR=3.46，95%CI：2.36~5.07，I²=0，证据质量中等）。总生存期的风险比为0.47（95%CI：0.35~0.62，固定效应模型与随机效应模型结果一致，I²=0，证据质量中等）。荟萃分析结果显示，TACE联合仑伐替尼组的总不良反应发生率显著高于对照组（固定效应模型：OR=1.86，95%CI：1.01~3.43；随机效应模型：OR=1.85，95%CI：1.00~3.43，I²=0，证据质量中等）。
结论：本研究表明，TACE联合仑伐替尼治疗肝细胞癌的疗效喜人，可延长患者总生存期并提高客观缓解率。