曲妥珠单抗致女性乳腺癌患者心脏毒性风险Meta分析

Risk of Cardiotoxicity Induced by Trastuzumab in Female Breast Cancer Patients:A Meta-Analysis

目的系统评价曲妥珠单抗治疗人表皮生长因子受体2(HER2)阳性乳腺癌女性患者的心脏毒性事件风险。方法计算机检索PubMed,Embase,The Cochrane Library,Web of Science,CBM及万方(WanFang)、维普(VIP)、中国知网(CNKI)、临床试验注册平台(clinicaltrials.gov)等数据库,以及美国临床肿瘤学会(ASCO)会议摘要,收集曲妥珠单抗对比不含曲妥珠单抗相关的随机对照试验(RCT)和观察性研究的中、英文文献,检索时限为自建库起至2020年2月。由2名研究者独立筛选文献、提取资料,采用Cochrane协作网推荐的手册和纽卡斯尔-渥太华量表(NOS)评价纳入研究的偏倚风险,采用STATA 16.0统计学软件进行Meta分析,以相对危险度(RR)为心脏毒性事件的效应分析统计量,采用倒漏斗图和Egger检验判断是否存在发表偏倚。结果纳入17项RCT和10项队列研究,分别有19 137例和78 198例患者。RCT和队列研究均表明,曲妥珠单抗显著增加了总心脏事件的发生风险[RR=1.92,95%CI(1.40,2.64),P <0.01]和[RR=2.45,95%CI(1.81,3.32),P <0.01]。RCT研究表明,曲妥珠单抗显著增加了左室射血分数(LVEF)下降风险[RR=1.66,95%CI(1.24,2.24),P <0.01],充血性心力衰竭(CHF)发生风险[OR=2.05,95%CI(1.63,2.59),P <0.01],Ⅲ级或Ⅳ级严重CHF发生风险[OR=3.52,95%CI(2.35,5.26),P <0.01]。亚组分析结果表明,曲妥珠单抗联合蒽环类药物显著增加LVEF下降和CHF的发生风险(P=0.024.0.001),且在用药后5年内LVEF下降和CHF的发生风险仍有增加(P均为0.001)。结论曲妥珠单抗可显著增加HER2阳性乳腺癌患者LVEF下降和CHF的发生风险,建议患者特别是高危人群在使用曲妥珠单抗治疗后的数年内定期监测心脏病学相关指标。

Objective To systematically review the risk of cardiotoxicity events induced by trastuzumab in the treatment of human epidermal growth factor receptor 2(HER2)-positive female breast cancer patients. Methods The databases of PubMed,Embase,The Cochrane Library,Web of Science,CBM,WanFang Data,VIP,CNKI,Clinicaltrials. gov,and the conference abstracts of the American Society of Clinical Oncology(ASCO) were searched to collect the trastuzumab versus non-trastuzumab related randomized controlled trials(RCTs) and the Chinese and English literature of observational studies without trastuzumab from the inception to February 2020. Two researchers independently screened the literature,extracted data and evaluated the bias risk included in the studies by the Cochrane Reviewers’ Handbook and the Newcastle-Oltawa Scale,STATA 16. 0 statistical software was used for the Meta-analysis. The relative risk(RR) was used as the effect analysis statistic of cardiotoxic events,and the inverted funnel diagram and Egger test were used to judge whether there was publication bias. Results A total of 17 RCTs and 10 cohort studies were included,with 19 137 patients and 78 198 patients,respectively. Both RCTs and cohort studies showed that trastuzumab significantly increased the overall risk of cardiac events [ RR = 1. 92,95% CI(1. 40,2. 64),P = 0. 001 ] and [ RR = 2. 45,95% CI(1. 81,3. 32),P = 0. 001 ]. RCT studies showed that trastuzumab significantly increased the risk of left ventricular ejection fraction(LVEF) reduction[ RR = 1. 66,95% CI(1. 24,2. 24),P < 0. 01],and the risk of congestive heart failure [ OR = 2. 05,95% CI(1. 63,2. 59 ],P < 0. 01 ],and the risk of grade Ⅲ or Ⅳ severe congestive heart failure [ OR = 3. 52,95% CI(2. 35,5. 26),P < 0. 01 ]. Subgroup analysis showed that trastuzumab combined with anthracyclines significantly increased the risk of LVEF reduction and congestive heart failure(P = 0. 024, 0. 001),and the risk of LVEF reduction and congestive heart failure still increased within five years after medication(P = 0. 001). Conclusion Trastuzumab can significantly increase the risk of LVEF and congestive heart failure in HER2-positive breast cancer patients. It is recommended that the cardiology-related indicators should be monitored regularly in patients,especially high-risk groups within a few years after trastuzumab treatment.