Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, People's Republic of China.
Oncologist. 2021 Dec;26(12):e2239-e2246. doi: 10.1002/onco.13940. Epub 2021 Aug 31.
Immune-related adverse events (irAEs) are of great interest and importance in clinical practice, and many deficiencies and controversies have been noted in the reporting of irAEs. Herein, we aimed to evaluate the current status of irAE reporting in randomized controlled clinical trials (RCTs) of PD-1/PD-L1 inhibitors and to attempt to explain and solve the current pitfalls associated with this reporting.
We conducted a systematic review across multiple databases, including PubMed, Web of Science, Embase, and the Cochrane Library. The RCTs that compared PD-1/PD-L1 inhibitors with standard treatments were included. The Harms extension of the Consolidated Standards of Reporting Trials (CONSORT) was used to evaluate the completeness of irAE reporting.
A total of 44 articles and 23,759 patients were included in the analysis. The terminology of the irAEs changed over time (p = .01) and was different among immune checkpoint inhibitors (ICIs) (p = .005). Twenty-two of the studies provided a definition of irAE, but only four of them concretely addressed this definition. The incidence of any grade of irAEs ranged from 16.9% to 96%, whereas grade 3-4 irAE ranged from 2% to 23%. The RCTs with combined therapy exhibited a higher incidence of grade 3-4 irAEs (p = .012). Thirty-two studies reported irAEs in the control arms, whereas seven studies reported irAEs only in the experimental arms. Respiratory, endocrine, and gastrointestinal disorders were the most commonly reported irAEs. IrAEs were generally neglected in the introduction or conclusion sections in all of the study reviews and were never subjected to subgroup analyses. Moreover, withdrawals due to severe irAEs, as well as clarifications of the irAE collection methods, were also poorly reported. RCTs using combination therapies in the experimental arms were associated with a higher reporting quality (p = .032). However, the completeness of the reporting did not improve over the last 5 years (p = .076).
The reporting of irAEs was inadequate, and there are still inconsistencies and controversies in the reporting of irAEs. In the future, authors should be encouraged to adhere to the Harms extension of the CONSORT statement.
PD-1/PD-L1 inhibitors profoundly changed the landscape of cancer treatment, and thousands of randomized controlled clinical trials (RCTs) were active or completed over the past decade. However, different from chemotherapy or targeted therapy, the profile of immune-related adverse effects (irAE) was unique. An understanding of irAEs is developed mainly from clinical trials; however, inconsistencies and controversies between trials were noted. This study primarily reviewed the evolution of irAE terminology and definitions and evaluated the reporting quality of each RCT. It was found that RCTs using combined immunotherapy were associated with higher quality of irAE reporting. This article identifies the controversies and deficiencies in current irAE reporting and provides possible explanations and suggestions for these inadequacies.
免疫相关不良事件（irAEs）在临床实践中备受关注，其报告存在诸多不足和争议。本研究旨在评估 PD-1/PD-L1 抑制剂随机对照临床试验（RCT）中 irAE 报告的现状，并尝试解释和解决当前报告中存在的问题。
我们对多个数据库（包括 PubMed、Web of Science、Embase 和 Cochrane Library）进行了系统检索，纳入了比较 PD-1/PD-L1 抑制剂与标准治疗的 RCT。采用 CONSORT 扩展的危害报告评估 irAE 报告的完整性。
共纳入 44 篇文章和 23759 例患者。irAE 的术语随时间变化（p=0.01）且在免疫检查点抑制剂（ICI）之间存在差异（p=0.005）。22 项研究提供了 irAE 的定义，但仅有 4 项具体说明了该定义。任何级别 irAE 的发生率为 16.9%至 96%，而 3-4 级 irAE 的发生率为 2%至 23%。联合治疗的 RCT 中 3-4 级 irAE 的发生率更高（p=0.012）。32 项研究报告了对照组的 irAE，而 7 项研究仅报告了实验组的 irAE。最常见的 irAE 为呼吸系统、内分泌系统和胃肠道疾病。所有研究综述的引言或结论部分通常忽略 irAE，且从未进行亚组分析。此外，严重 irAE 导致的退出以及 irAE 收集方法的澄清也很少报告。实验组采用联合治疗的 RCT 报告质量更高（p=0.032）。然而，过去 5 年中报告的完整性并未提高（p=0.076）。
irAE 的报告不充分，irAE 的报告仍存在不一致和争议。未来，应鼓励作者遵守 CONSORT 声明的危害扩展。
PD-1/PD-L1 抑制剂极大地改变了癌症治疗的格局，过去十年间有数千项随机对照临床试验（RCT）正在进行或已完成。然而，与化疗或靶向治疗不同，免疫相关不良事件（irAE）的特征是独特的。对 irAE 的认识主要来自临床试验，但临床试验之间存在不一致和争议。本研究主要回顾了 irAE 术语和定义的演变，并评估了每个 RCT 的报告质量。结果发现，联合免疫治疗的 RCT 与更高质量的 irAE 报告相关。本文确定了当前 irAE 报告中的争议和不足，并对这些不足提出了可能的解释和建议。
