Zhang Yixi, La Bin, Liang Baosheng, Gu Yangchun
Department of Biostatistics, School of Public Health, Peking University, Beijing 100191, China.
School of Public Health, Peking University, Beijing 100191, China.
Life (Basel). 2021 Nov 22;11(11):1277. doi: 10.3390/life11111277.
to evaluate the risk of treatment-related adverse events of different severity and different system with PD-1 or PD-L1 inhibitors.
randomized controlled trials (RCTs) that using PD-1/PD-L1 for cancer treatment were searched in the PubMed, Embase, Cochrane Library, and Web of Science from 1 January 2019 to 31 May 2021. Adverse events data were extracted from clinical trials website or original article by two authors separately. Meta-analysis was used to determine risk ratio (RR) and 95% confidence interval (95% CI) of adverse events in PD-1/PD-L1 inhibitors groups compared to that of control groups. Subgroup analyses were also performed.
a total of 5,807 studies were initially identified and after exclusion, 41 studies were included in meta-analysis. All the trials were international multicenter, randomized, phase II/III clinical trials, with the median follow-up of 27.5 months on average. Analysis of all grade adverse events showed that PD-1/PD-L1 inhibitors treatment significantly increased the risk of immune-related adverse events, including pruritus (RR: 2.34, 95% CI: 1.85-2.96), rash (RR: 1.53, 95% CI: 1.25-1.87), ALT elevation (RR 1.54, 95% CI 1.23-1.92), AST elevation (AST: RR 1.49, 95% CI 1.20-1.85), hepatitis (RR: 3.54, 95% CI: 1.96-6.38) and hypothyroid (RR: 5.29, 95% CI: 4.00-6.99) compared with that of control group. Besides that, PD-1/PD-L1 inhibitors were associated with higher risk of adverse events related to respiratory system including cough (RR: 1.33, 95% CI: 1.21-1.48), dyspnea (RR:1.23, 95% CI: 1.12-1.35) and chest pain (RR: 1.26, 95% CI: 1.07-1.47) compared with that of control groups in our meta-analysis and the dyspnea was taken high risk both in all grade and grade 3 or higher (RR: 1.55, 95% CI: 1.13-2.12). The risk of arthralgia was increased with PD-1/PD-L1 inhibitors (RR: 1.27, 95% CI: 1.10-1.47). Although the risk of myalgia was similar with PD-1/PD-L1 inhibitors and control groups, under subgroup analysis, PD-1/PD-L1 inhibitors decreased the risk of myalgia (RR: 0.56, 95% CI: 0.45-0.70) compared with that of chemotherapy.
our results provide clear evidence that the risk of treatment-related adverse events in PD-1 or PD-L1 varies widely in different system. In particular, when using PD-1/PD-L1 inhibitors for oncology treatment, besides the common immune-related adverse events like pruritus, rash, hepatitis, and hypothyroid, the respiratory disorders and musculoskeletal disorders, such as cough, dyspnea, arthralgia, and myalgia, should also be taken into consideration.
评估使用PD-1或PD-L1抑制剂时不同严重程度和不同系统的治疗相关不良事件风险。
于2019年1月1日至2021年5月31日在PubMed、Embase、Cochrane图书馆和Web of Science中检索使用PD-1/PD-L1进行癌症治疗的随机对照试验（RCT）。由两名作者分别从临床试验网站或原始文章中提取不良事件数据。采用荟萃分析确定PD-1/PD-L1抑制剂组与对照组相比不良事件的风险比（RR）和95%置信区间（95%CI）。还进行了亚组分析。
初步识别出共5807项研究，排除后41项研究纳入荟萃分析。所有试验均为国际多中心、随机、II/III期临床试验，平均中位随访时间为27.5个月。对所有级别的不良事件分析表明，与对照组相比，PD-1/PD-L1抑制剂治疗显著增加了免疫相关不良事件的风险，包括瘙痒（RR：2.34，95%CI：1.85-2.96）、皮疹（RR：1.53，95%CI：1.25-1.87）、谷丙转氨酶升高（RR 1.54，95%CI 1.23-1.92）、谷草转氨酶升高（AST：RR 1.49，95%CI 1.20-1.85）、肝炎（RR：3.54，95%CI：1.96-6.38）和甲状腺功能减退（RR：5.29，95%CI：4.00-6.99）。除此之外，在我们的荟萃分析中，与对照组相比，PD-1/PD-L1抑制剂与呼吸系统相关不良事件的较高风险相关，包括咳嗽（RR：1.33，95%CI：1.21-1.48）、呼吸困难（RR：1.23，95%CI：1.12-1.35）和胸痛（RR：1.26，95%CI：1.07-1.47），并且呼吸困难在所有级别以及3级或更高级别中均为高风险（RR：1.55，95%CI：1.13-2.12）。使用PD-1/PD-L1抑制剂会增加关节痛风险（RR：1.27，95%CI：1.10-1.47）。虽然使用PD-1/PD-L1抑制剂与对照组的肌痛风险相似，但在亚组分析中，与化疗相比，PD-1/PD-L1抑制剂降低了肌痛风险（RR：0.56，95%CI：0.45-0.70）。
我们的结果提供了明确证据，表明PD-1或PD-L1治疗相关不良事件的风险在不同系统中差异很大。特别是，在使用PD-1/PD-L1抑制剂进行肿瘤治疗时，除了瘙痒、皮疹、肝炎和甲状腺功能减退等常见的免疫相关不良事件外，还应考虑呼吸系统疾病和肌肉骨骼疾病，如咳嗽、呼吸困难、关节痛和肌痛。
