张清树 陈瑞祥 温瑾 夏从龙 何姣 赵倩

摘 要 目的：系統评价免疫检查点抑制剂（ICIs）单用或联合常规化疗药物用于非小细胞肺癌（NSCLC）患者致非免疫相关不良事件（irAEs）的发生情况，为临床用药提供循证参考。方法：计算机检索PubMed、Cochrane 图书馆、Embase、中国知网、中国生物医学文献数据库、维普网和万方数据等，检索时限均为建库至2020年10月。收集ICIs单用或联合常规化疗药物（试验组）对比常规化疗药物或安慰剂联合常规化疗药物（对照组）的随机对照试验（RCT）。筛选文献、提取数据后，采用Cochrane系统评价员手册5.1.0推荐的偏倚风险评估工具对纳入文献质量进行评价，采用Rev Man 5.3和Stata 15.0软件进行Meta分析;采用Stata 15.0软件进行敏感性分析;采用倒漏斗图和Eggers检验进行发表偏倚分析。结果：共纳入20项RCT，共计12 283例患者。Meta分析结果显示，试验组患者总体所有级别和总体重度AEs发生率、贫血发生率、中性粒细胞减少症、呕吐、脱发发生率以及所有级别血小板减少症、恶心、周围神经病变发生率均显著低于对照组（P<0.05）;而两组患者终止治疗、死亡、重度血小板减少症、重度恶心和重度周围神经病变发生率以及所有级别和重度腹泻发生率比较，差异均无统计学意义（P>0.05）。亚组分析结果显示，试验组单用ICIs患者的总体所有级别和总体重度AEs发生率、贫血发生率、中性粒细胞减少症发生率、血小板减少症发生率、临床相关症状发生率（除重度腹泻外）以及终止治疗发生率、死亡发生率均显著低于对照组（P<0.05）;而试验组使用ICIs+化疗患者的终止治疗发生率、死亡发生率以及所有级别恶心、呕吐、腹泻、脱发和重度腹泻发生率均显著高于对照组（P<0.05）。敏感性分析支持上述结果;发表偏倚分析结果显示，本研究存在发表偏倚的可能性较小。结论：对于NSCLC患者，ICIs在治疗相关AEs、血液系统毒性和临床相关症状方面的安全性优于常规化疗药物或安慰剂联合常规化疗药物;但当其联合常规化疗药物时，因AEs终止治疗和死亡的风险以及所有级别恶心、呕吐、腹泻、脱发及重度腹泻的风险将有所增加。

关键词 非小细胞肺癌;免疫检查点抑制剂;非免疫相关不良事件;安全性;Meta分析

ABSTRACT   OBJECTIVE： To systematically evaluate the occurrence of non-immune related adverse events （AEs） caused by immune checkpoint inhibitors （ICIs） alone or combined with routine chemotherapy in the treatment of non-small cell lung cancer （NSCLC）， and to provide evidence-based reference for clinical medication. METHODS： Retrieved from PubMed， Cochrane Library， Embase， CNKI， CBM， VIP and Wanfang database during the inception to Oct. 2020， randomized controlled trials （RCT） about ICIs alone or combined with routine chemotherapy （trial group） versus routine chemotherapy or placebo combined with routine chemotherapy （control group） were collected. After literature screening and data extraction， the quality of included literatures were evaluated with bias risk evaluation tool recommended by Cochrane systematic evaluator manual 5.1.0. Meta-analysis was performed by using Rev Man 5.3 software and Stata 15.0 software. Sensitivity analysis was conducted with Stata 15.0 software. Inverted funnel plot and Eggers test were used to analyze publication bias. RESULTS： A total of 20 RCTs were included， involving 12 283 patients. Results of Meta-analysis showed that the incidence of all grades and severe AEs， anemia， neutropenia， vomiting and alopecia as well as the incidence of thrombocytopenia， nausea and peripheral neuropathy in all grades of trial group were all significantly lower than control group （P<0.05）. There was no statistical significance in the incidence of termination of treatment， death， severe thrombocytopenia， severe nausea and severe peripheral neuropathy or all grades and severe diarrhea between 2 groups （P>0.05）. Subgroup analysis showed that the incidence of all grade and total severe AEs， the incidence of anemia， neutropenia， thrombocytopenia， clinically relevant symptoms （except for severe diarrhea）， termination of treatment and death of patients receiving ICIs alone in trial group were significantly lower than control group （P<0.05）. The incidence of ermination of treatment and death， the incidence of nausea， vomiting， diarrhea and alopecia in all grade， severe diarrhea of patients receiving ICIs and chemotherapy in trial group were all significantly higher than control group （P<0.05）. Sensitivity analysis supported the above results. Analyze publication bias results showed that the possibility of publication bias in this study was small. CONCLUSIONS： For NSCLC patients， the safety of ICIs is better than that of routine chemotherapy or placebo combined with routine chemotherapy in the treatment-related AEs， hematologic toxicity and clinically relevant symptoms; however， the risks of treatment discontinuation， AEs-induced deaths， and all-grade nausea， vomiting， diarrhea， alopecia and severe diarrhea will be increased in the ICIs combined with routine chemotherapy.

KEYWORDS   Non-small cell lung cancer; Immune checkpoint inhibitors; Non-immune related adverse events; Safety; Meta-analysis

肺癌是常见的恶性肿瘤之一，也是全球发病率和病死率最高的肿瘤[1]。非小细胞肺癌（NSCLC）是肺癌的一种类型，属于一种异质性肿瘤，包括腺癌、鳞癌和大细胞癌。……