School of Medicine, Baylor College of Medicine, Houston, Texas.
Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston.
JAMA Oncol. 2023 Jul 1;9(7):930-937. doi: 10.1001/jamaoncol.2023.0998.
The use of second-generation antiandrogens (AAs) in the treatment of prostate cancer is increasing. Retrospective evidence suggests an association between second-generation AAs and adverse cognitive and functional outcomes, but further data from prospective trials are needed.
To examine whether evidence from randomized clinical trials (RCTs) in prostate cancer supports an association between second-generation AAs and cognitive or functional toxic effects.
PubMed, EMBASE, and Scopus (inception to September 12, 2022).
Randomized clinical trials of second-generation AAs (abiraterone, apalutamide, darolutamide, or enzalutamide) among individuals with prostate cancer that reported cognitive toxic effects, asthenic toxic effects (eg, fatigue, weakness), or falls were evaluated.
Study screening, data abstraction, and bias assessment were completed independently by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Enhancing the Quality and Transparency of Health Research reporting guidelines. Tabular counts for all-grade toxic effects were determined to test the hypothesis formulated before data collection.
Risk ratios (RRs) and SEs were calculated for cognitive toxic effects, asthenic toxic effects, and falls. Because fatigue was the asthenic toxic effect extracted from all studies, data on fatigue are specified in the results. Meta-analysis and meta-regression were used to generate summary statistics.
The systematic review included 12 studies comprising 13 524 participants. Included studies had a low risk of bias. An increased risk of cognitive toxic effects (RR, 2.10; 95% CI, 1.30-3.38; P = .002) and fatigue (RR, 1.34; 95% CI, 1.16-1.54; P < .001) was noted among individuals treated with second-generation AAs vs those in the control arms. The findings were consistent in studies that included traditional hormone therapy in both treatment arms for cognitive toxic effects (RR, 1.77; 95% CI, 1.12-2.79; P = .01) and fatigue (RR, 1.32; 95% CI, 1.10-1.58; P = .003). Meta-regression supported that, across studies, increased age was associated with a greater risk of fatigue with second-generation AAs (coefficient, 0.75; 95% CI, 0.04-0.12; P < .001). In addition, the use of second-generation AAs was associated with an increased risk of falls (RR, 1.87; 95% CI, 1.27-2.75; P = .001).
The findings of this systematic review and meta-analysis suggest that second-generation AAs carry an increased risk of cognitive and functional toxic effects, including when added to traditional forms of hormone therapy.
第二代抗雄激素（AA）在前列腺癌治疗中的应用正在增加。回顾性证据表明，第二代 AA 与认知和功能不良结局之间存在关联，但需要来自前瞻性试验的进一步数据。
检查前列腺癌随机临床试验（RCT）的证据是否支持第二代 AA 与认知或功能毒性作用之间存在关联。
PubMed、EMBASE 和 Scopus（从开始到 2022 年 9 月 12 日）。
评估了在前列腺癌患者中使用第二代 AA（阿比特龙、阿帕鲁胺、达罗鲁胺或恩扎鲁胺）的 RCT，这些研究报告了认知毒性作用、虚弱毒性作用（例如疲劳、虚弱）或跌倒。
两名审查员独立完成了研究筛选、数据提取和偏倚评估，遵循系统评价和荟萃分析的首选报告项目以及增强健康研究报告的质量和透明度指南。为了检验在数据收集之前提出的假设，确定了所有级别毒性作用的风险比（RR）和 SE。
计算了认知毒性作用、虚弱毒性作用和跌倒的 RR 和 SE。由于疲劳是所有研究中提取的虚弱毒性作用，因此在结果中指定了与疲劳相关的数据。使用荟萃分析和荟萃回归生成汇总统计数据。
系统评价包括 12 项研究，共纳入 13524 名参与者。纳入的研究具有低偏倚风险。与对照组相比，第二代 AA 治疗的个体发生认知毒性作用（RR，2.10；95%CI，1.30-3.38；P=0.002）和疲劳（RR，1.34；95%CI，1.16-1.54；P<0.001）的风险增加。在包括传统激素治疗的研究中，第二代 AA 治疗与认知毒性作用（RR，1.77；95%CI，1.12-2.79；P=0.01）和疲劳（RR，1.32；95%CI，1.10-1.58；P=0.003）的相关性一致。荟萃回归支持在研究中，随着年龄的增长，第二代 AA 与疲劳的风险增加相关（系数，0.75；95%CI，0.04-0.12；P<0.001）。此外，第二代 AA 的使用与跌倒风险增加相关（RR，1.87；95%CI，1.27-2.75；P=0.001）。
本系统评价和荟萃分析的结果表明，第二代 AA 具有认知和功能毒性作用的风险增加，包括当添加到传统形式的激素治疗中时。
