免疫检查点抑制剂引起甲状腺功能减退的网状meta分析

Immunological Checkpoint Inhibitors Cause Hypothyroidism：A Network Meta-analysis

关键词:  免疫检查点抑制剂  甲状腺功能减退  网状meta分析

Key words:  immunological checkpoint inhibitor  hypothyroidism  network meta-analysis

摘要:

目的 采用网状meta分析方法对免疫检查点抑制剂引起甲状腺功能减退的不良反应进行分析。方法 检索Embase、PubMed、Cochrane Library、CNKI、万方、维普中公开发表的随机对照试验。使用WinBUGS 1.4联合Stata 14.0软件进行数据分析。结果 共检索2 435篇文献，按照纳入排除标准纳入文献19篇，涉及12 253例患者，7种上市使用的免疫检查点抑制剂，数据提取过程中发现阿特珠单抗、avelumab、tremllimumab 3种免疫检查点抑制剂未出现甲状腺功能减退报告，剩余4种免疫检查点抑制剂的19种不同给药方案均有不同程度甲状腺功能减退报告。经网状meta计算得出，19种不同给药方案中引起甲状腺功能减退概率排序前3位依次为：纳武单抗3 mg·kg^-1，每2周给药1次，同时联合伊匹单抗1 mg·kg^-1，每6周给药1次，联合给药共4次（PrBest 90.1%，SUCRA 99.1%）；纳武单抗240 mg，每2周给药1次，共给药4次（PrBest 4.6%，SUCRA 92.8%）；德瓦鲁单抗10 mg·kg^-1，每2周给药1次（PrBest 1.9%，SUCRA 58.8%）。概率排序最低为伊匹单抗的3种给药方案，分别为3 mg·kg^-1，每3周给药1次，共给药4次；3 mg·（2 kg）^-1，每3周给药1次，共给药4次；10 mg·kg^-1，每3周给药1次，共给药4次（PrBest均为0，SUCRA分别为11.4%，11.5%，13.6%）。结论 联合给药方案（纳武单抗3 mg·kg^-1，每2周给药1次，同时联合伊匹单抗1 mg·kg^-1，每6周给药1次，联合给药共4次）存在较高的甲状腺功能减退风险。单药给药方案（纳武单抗240 mg每2周给药1次，共给药4次）的风险次之，伊匹单抗的3种给药方案排序均靠后，为较为安全品种。

Abstract:

OBJECTIVE To analyze the adverse reactions of immunological check-point inhibitors causing hypothyroidism by network meta-analysis. METHODS Search for randomized controlled trials published in Embase, PubMed, Cochrane Library, CNKI, Wanfang, and Weipu. Data analysis was performed using WinBUGS 1.4 in conjunction with Stata 14.0 software. RESULTS A total of 2 435 articles were searched and 19 articles were included in the inclusion exclusion criteria, involving 12 253 patients and seven kinds of immunological checkpoint inhibitors used in the market. During the data extraction process, three immunological checkpoint inhibitors of atezolizumab, avelumab, and tremllimumab were found to have no hypothyroidism report, and the remaining four immunological checkpoint inhibitors were administered in 19 different regimens. The top 3 rankings for the probability of hypothyroidism in 19 different dosing regimens were as followed:nivolumab 3 mg·kg^-1, once every 2 weeks+ipilimumab 1 mg·kg^-1, once every 6 weeks, four times of combined administration(PrBest 90.1%, SUCRA 99.1%), nivolumab 240 mg, once every 2 weeks, four times in total(PrBest 4.6%, SUCRA 92.8%), durvalumab 10 mg·kg^-1, once every 2 weeks(PrBest 1.9%, SUCRA 58.8%). The lowest dose schedule for probability ordering were ipilimumab 3 mg·kg^-1, once every three weeks, four times in total, ipilimumab 3 mg·(2 kg)^-1, once every three weeks, four times in total, ipilimumab 10 mg·kg^-1, once every three weeks, four times in total(all PrBest was 0, SUCRA were 11.4%, 11.5% and 13.6%). CONCLUSION The combined administeration of nivolumab 3 mg·kg^-1, once every 2 weeks+ipilimumab 1 mg·kg^-1, once every 6 weeks, four times of combined administration result in the highest probability of hypothyroidism, the second risk is nivolumab 240 mg, once every 2 weeks, four times in total. The three dosing regimens of ipilimumab are ranked lower and they are safer.