免疫检查点抑制剂联合方案对比单药方案治疗相关不良反应荟萃分析

Meta-analysis of the adverse reactions related to immune checkpoint inhibitor combination therapy versus monotherapy

目的探索免疫检查点抑制剂单药或者联合方案治疗实体瘤的免疫相关不良反应发生率和严重程度的差别。方法检索2018年1月至2021年12月PubMed、Corchrane Library、Web of Science数据库有关免疫治疗联合化疗(或贝伐单抗)对比免疫治疗单药治疗实体瘤临床研究相关文献,研究指标为不良反应;采用相对危险度(RR)和风险比(HR)为效应量,各效应量以95%置信区间表示,采用R 4.1.2统计学软件进行meta分析。结果共纳入11项临床研究,免疫治疗联合化疗相比免疫单药会增加呼吸道感染、转氨酶增加、谷草转氨酶增高、碱性磷酸酶增高、背痛发生率,会增加甲状腺功能减退3级以上不良反应的发生率,免疫单药组中腹水、脱水发生率高于联合治疗组,其中口咽痛、脱水3级以上不良反应发生率明显升高。相比免疫单药组,免疫治疗联合贝伐单抗组发生皮肤不良反应、白细胞减少、高血压、蛋白尿、出血、低镁血症、味觉障碍、体重下降、鼻窦炎、疼痛、腹痛、高钾血症、关节痛、丙氨酸氨基转移酶、腹泻、便秘、呕吐、恶心等明显更高。结论免疫治疗联合化疗治疗相比单药能增加呼吸道感染、肝功能异常和背痛的发生率,甲状腺功能减退严重不良反应发生率升高;联合化疗也减少了部分不良反应。免疫治疗联合贝伐单抗治疗相比免疫治疗单药增加了皮肤相关不良反应等,增加了部分贝伐单抗不良反应如:高血压、蛋白尿、出血。免疫联合治疗可以在一定程度上缓解免疫单药不良反应,但也为治疗安全性带来了新问题。

Objective To explore the differences in the incidence and severity of immune-related adverse reactions to immunotherapy monotherapy or combined chemotherapy(or Bevacizumab)for solid tumors.Methods The literature related to clinical studies of immunotherapy combination regimens(chemotherapy or Bevacizumab)versus immunotherapy monotherapy or immunotherapy combination versus immunotherapy monotherapy for solid tumors from PubMed,Corchrane Library,and Web of Science databases between January 2018 and December 2021 were searched.The study metrics were adverse effects,relative risk(RR)and hazard ratios(HR)were used as effect sizes,and each effect size was expressed with 95%confidence intervals,and Meta-analysis was performed with R 4.1.2 statistical software.Results A total of 11 clinical studies were included.The results showed that immunotherapy combined with chemotherapy increased the incidence of respiratory tract infection,increased aminotransferase,increased aspartate aminotransferase,increased alkaline phosphatase and back pain compared with immunotherapy monotherapy,and increased the incidence of hypothyroidism grade 3 or higher adverse reactions.The incidence of ascites and dehydration was higher than that in the combined treatment group,of which the incidence of oral sore throat and dehydration grade 3 or higher adverse reactions was significantly increased.Compared with the immune single group,the immune combined with Bevacizumab group had significant skin adverse reactions,leukopenia,hypertension,proteinuria,bleeding,hypomagnesemia,dysgeusia,weight loss,sinusitis,pain,abdominal pain,hyperkalemia,arthralgia,alanine aminotransferase,diarrhea,constipation,vomiting,and nausea.Conclusion Immunotherapy combined with chemotherapy treatment increased the incidence of respiratory infections,liver function abnormalities and back pain adverse reactions and increased the incidence of serious adverse reactions of hypothyroidism compared to monotherapy,combined chemotherapy also reduced some of the adverse reactions.Immunotherapy combined with Bevacizumab treatment increased skin-related adverse reactions etc.,compared with immunotherapy monotherapy,and increased some of the Bevacizumab adverse reactions such as:hypertension,proteinuria,and bleeding.Immunotherapy can alleviate the adverse reactions of immunization to a certain extent,but it also brings new issues to the safety of treatment.