Introduction: To investigate the incidence and spectrum of adverse events in unresectable hepatocellular carcinoma (HCC) patients treated with immune checkpoint inhibitors (ICIs) or ICI-based combinations. Methods: The study protocol was prospectively registered on PROSPERO (CRD42022319255). We searched PubMed, EMBASE, and the Cochrane Library for published clinical trials from database inception to April 22, 2022. Studies that included at least one group of unresectable HCC patients treated with ICIs or ICI-based combinations and reported the incidence or spectrum of treatment-related adverse events (trAEs) or immune-related adverse events (irAEs) were eligible. The incidence and spectra of all-grade and grade ≥3 trAEs were the primary outcomes. The profiles of irAEs, the incidence of trAEs leading to treatment discontinuation, and treatment-related mortalities were additional outcomes. We applied random-effects models to pool the incidence and spectra of adverse events. Subgroup analyses and meta-regression were performed. Results: The literature search identified 2464 records. Twenty studies (4146 participants with HCC) met the eligibility criteria. The pooled incidences of all-grade trAEs, grade ≥3 trAEs, all-grade irAEs, and grade≥3 irAEs were 80.1% (95% CI 73.8-85.2), 35.4% (95% CI 27.2-44.6), 31.1% (95% CI 21.0-43.5), and 6.6% (95% CI 3.6-11.8), respectively. ICIs plus oral targeted agents (all-grade OR=17.07, 95% CI 6.05-48.16, P<0.001; grade ≥3 OR=9.35, 95% CI 4.53-19.29, P<0.001) and ICIs plus intravenous targeted agents (all-grade OR=4.91, 95% CI 1.80-13.42, P=0.003; grade ≥3 OR=4.21, 95% CI 1.42-12.48, P=0.012) were associated with increased trAEs compared with monotherapy. The all-grade trAEs with the highest pooled incidences were reactive capillary endothelial proliferation (49.2%, 95% CI 26.3-72.3), neutropenia (34.6%, 95% CI 17.1-57.5), and proteinuria (32.8%, 95% CI 19.8-49.2). The grade ≥3 trAEs with highest pooled incidences were hypertension (11.1%, 95% CI 4.0-29.0), neutropenia (10.5%, 95% CI 7.0-15.4), and aspartate aminotransferase increased (7.7%, 95% CI 6.3-9.4). The pooled incidence of trAEs leading to treatment discontinuation was 8.0% (95% CI 6.0-10.5), and the overall incidence of treatment-related mortalities was 1.1%. Conclusions: This study comprehensively summarized the incidence and spectrum of trAEs in unresectable HCC patients receiving ICIs or ICI-based combinations in clinical trials. The results from this study will provide a useful reference to guide clinical practice.


中文翻译：

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前瞻性临床试验中基于免疫检查点抑制剂治疗不可切除肝细胞癌的不良事件：系统评价和荟萃分析

简介：旨在调查接受免疫检查点抑制剂 (ICI) 或基于 ICI 的组合治疗的不可切除肝细胞癌 (HCC) 患者的不良事件发生率和范围。方法：研究方案在 PROSPERO (CRD42022319255) 上进行了前瞻性注册。我们在 PubMed、EMBASE 和 Cochrane 图书馆中搜索了从数据库创建到 2022 年 4 月 22 日的已发表临床试验。研究包括至少一组接受 ICI 或基于 ICI 的组合治疗的不可切除的 HCC 患者，并报告了治疗的发生率或范围-相关不良事件（trAEs）或免疫相关不良事件（irAEs）符合条件。所有等级和≥3 级 trAE 的发生率和谱是主要结果。irAE 的概况，导致治疗中断的 trAE 的发生率，和治疗相关的死亡率是额外的结果。我们应用随机效应模型来汇总不良事件的发生率和范围。进行了亚组分析和荟萃回归。结果：文献检索共检索到2464条记录。20 项研究（4146 名 HCC 参与者）符合资格标准。所有级别 trAE、≥3 级 trAE、所有级别 irAE 和≥3 级 irAE 的合并发生率为 80.1%（95% CI 73.8-85.2）、35.4%（95% CI 27.2-44.6）、31.1%（ 95% CI 21.0-43.5) 和 6.6% (95% CI 3.6-11.8)。ICIs 加口服靶向药物（所有等级 OR=17.07，95% CI 6.05-48.16，P<0.001；≥3 级 OR=9.35，95%CI 4.53-19.29，P<0.001）和 ICIs 加静脉靶向药物（所有-等级 OR=4.91，95% CI 1.80-13.42，P=0.003；等级 ≥3 OR=4.21，95% CI 1.42-12.48，P=0。012) 与单一疗法相比增加了 trAE。汇总发生率最高的所有级别 trAE 是反应性毛细血管内皮增生（49.2%，95% CI 26.3-72.3）、中性粒细胞减少症（34.6%，95% CI 17.1-57.5）和蛋白尿（32.8%，95% CI 19.8） -49.2)。汇总发生率最高的 3 级及以上 trAE 为高血压（11.1%，95% CI 4.0-29.0）、中性粒细胞减少症（10.5%，95% CI 7.0-15.4）和天冬氨酸转氨酶升高（7.7%，95% CI 6.3-9.4） ). 导致治疗中断的 trAE 的合并发生率为 8.0%（95% CI 6.0-10.5），治疗相关死亡率的总发生率为 1.1%。结论：本研究全面总结了在临床试验中接受 ICI 或基于 ICI 的组合的不可切除 HCC 患者的 trAE 的发生率和范围。