肥胖是蒽环类和曲妥珠单抗对乳腺癌的心脏毒性风险因素：系统回顾与荟萃分析

　　2016年7月25日，美国临床肿瘤学会官方期刊《临床肿瘤学杂志》在线发表法国勃艮第大学医院、国家卫生与医学研究所、心脏代谢病理生理学与药理学实验室、乔治·弗朗索瓦·勒克莱尔癌症中心、意大利米兰欧洲肿瘤学研究所、美国纽约纪念斯隆-凯特林癌症中心的系统回顾与荟萃分析，发现肥胖是蒽环类和曲妥珠单抗治疗乳腺癌的心脏毒性风险因素。

　　代谢综合征患者的心血管疾病风险较高，但其化疗所致心脏疾病易感性未被充分报道，故该荟萃分析评估了乳腺癌患者肥胖或超重与蒽环类和蒽环类序贯曲妥珠单抗所致心脏毒性之间的相关性。

　　作者筛选出15项研究共8745例接受蒽环类和蒽环类序贯曲妥珠单抗治疗的乳腺癌患者，进行随机效应分析和网络荟萃分析，并评估发表偏倚。发表偏倚是临床医学文献一个广为人知的现象，即阳性研究结果发表机会更多，发表速度更快，所发表刊物影响因子更高。获得发表的研究是获取结论的主要依据，因此过分强调阳性结果可能造成误导。相对于那些带有故意伪造数据的已发表研究，被筛选掉的未发表研究可能更普遍，并更有可能对患者产生不利后果。

　　结果发现，肥胖并超重，与乳腺癌患者接受蒽环类和蒽环类序贯曲妥单抗方案后出现较高心脏毒性风险，有显著相关性。超重或肥胖（体重指数＞25kg/m²）、肥胖、超重的心脏毒性合并比值比分别为1.38（95%置信区间：1.06～1.80，I²=43%，N=8745）、1.47（95%置信区间：0.95～2.28，I²=47%，N=2615）、1.15（95%置信区间：0.83～1.58，I²=27%，N=2708）。该相关性独立于研究设计、发表年份、药物方案（蒽环类单药、蒽环类序贯曲妥珠单抗）或心脏毒性和超重或肥胖的定义。无发表偏倚证据，但是由于该分析中绝大部分研究未校正比值比，故无法将肥胖本身与肥胖相关心血管风险因素（如糖尿病和高血压）进行区分。

　　因此，根据绝大部分研究未校正比值比的分析结果表明，超重和肥胖是蒽环类和蒽环类序贯曲妥珠单抗心脏毒性的风险因素。

J Clin Oncol. 2016 Jul 25. [Epub ahead of print]

Obesity as a Risk Factor for Anthracyclines and Trastuzumab Cardiotoxicity in Breast Cancer: A Systematic Review and Meta-Analysis.

Charles Guenancia, Annick Lefebvre, Daniela Cardinale, Anthony F. Yu, Sylvain Ladoire, Francois Ghiringhelli, Marianne Zeller, Luc Rochette, Yves Cottin, Catherine Vergely.

University Hospital; Institut National de la Santé et de la Recherche Médicale, U866, Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques; Georges Francois Leclerc Cancer Center; Institut National de la Santé et de la Recherche Médicale, CRI-866, University of Burgundy, Dijon; University Hospital, Reims, France; European Institute of Oncology, Milan, Italy; Memorial Sloan Kettering Cancer Center, New York, NY.

PURPOSE: Patients with metabolic syndrome have a greater risk of cardiovascular disease, although their susceptibility to chemotherapy-induced cardiac disease is not well documented. The aim of this meta-analysis was to assess associations between obesity or being overweight and cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab in patients with breast cancer.

METHODS: We performed a random-effects analysis and a network meta-analysis and assessed publication bias. We included 15 studies and 8,745 patients with breast cancers who were treated with anthracyclines and sequential anthracyclines and trastuzumab.

RESULTS: Combination of obesity and being overweight was significantly associated with a greater risk of developing cardiotoxicity after anthracyclines and a sequential anthracyclines and trastuzumab regimen in patients with breast cancer. Pooled odds ratio for cardiotoxicity was 1.38 (95% CI, 1.06 to 1.80; I² = 43%; N = 8,745) for overweight or obesity (body mass index > 25 kg/m2), 1.47 (95% CI, 0.95 to 2.28; I² = 47%; n = 2,615) for obesity, and 1.15 (95% CI, 0.83 to 1.58; I² = 27%; n = 2,708) for overweight. Associations were independent of study design, year of publication, drug regimen (anthracyclines alone v sequential anthracyclines and trastuzumab), or definitions of cardiotoxicity and of overweight or obesity. There was no evidence of publication bias; however, we could not separate the contributions of obesity-related cardiovascular risk factors, such as diabetes and hypertension, from that of obesity itself in this largely unadjusted analysis.

CONCLUSION: Our findings in a largely unadjusted analysis suggest that overweight and obesity are risk factors for cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab.

DOI: 10.1200/JCO.2016.67.4846