Background: The use of trastuzumab has proven to be a successful strategy in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer; however, it is associated with an increased risk of cardiac dysfunction. We performed an up-to-date, comprehensive meta-analysis to clarify the risk of congestive heart failure (CHF) in patients with early breast cancer receiving different durations of adjuvant trastuzumab with the longest-term follow-up.
Methods: Eligible studies included randomized control trials of HER2-positive early breast cancer patients with or without trastuzumab in adjuvant chemotherapy. Adequate reporting of CHF data were required for inclusion. Statistical analyses were conducted to calculate the overall incidence, relative risk (RR), and 95% confidence interval (CI) by use of a fixed-effects model.
Results: Six randomized control trials including 18,111 patients were identified. The overall incidence of high-grade CHF in patients treated with trastuzumab versus placebo was 1.44% (95% CI, 0.79%-2.64%) and the RR was 3.19 (95% CI, 2.03-5.02; p < .00001). In subgroup analysis, the difference in CHF incidence failed to achieve significance. The RR for 8 mg/kg trastuzumab (high dose) was greater than that for 4 mg/kg (low dose) (RR, 6.79, 95% CI, 2.03-22.72, p = .0001; versus RR, 2.64; 95% CI, 1.61-4.32; p = .002). Additionally, higher RRs were observed for patients receiving trastuzumab for 1 year (RR, 3.29; 95% CI, 2.07-5.25) and 2 years (RR, 9.54; 95%CI, 2.19-41.43), but not 9 weeks (RR, 0.50; 95% CI, 0.05-5.49) compared with control groups. No evidence of publication bias was observed.
Conclusion: Adjuvant trastuzumab therapy was strongly associated with an increased risk of significant CHF in patients with early breast cancer, particularly in 2-year use.
Implications for practice: This comprehensive meta-analysis evaluated the risk of congestive heart failure with a usage profile of adjuvant trastuzumab in patients with early breast cancer. Before initiating treatment with trastuzumab, a risk-benefit analysis for individual patients should be critically evaluated, considering that the prognosis is closely related to drug dose and duration of use. Cardiac function should be monitored throughout the treatment period and also during follow-up. Thus, early identification of trastuzumab-related cardiac dysfunction can allow effective medical intervention, elimination of symptoms, recovery of function, and continuation of trastuzumab therapy.
摘要
背景. 已证实曲妥珠单抗用于治疗人类表皮生长因子受体 2 (HER2) 阳性乳腺癌患者是成功的策略, 但该药与心功能不全发生风险升高有关。我们开展了一项最新的全面 meta 分析, 旨在明确接受不同疗程的曲妥珠单抗辅助治疗的早期乳腺癌患者在最长时间的随访中发生充血性心力衰竭 (CHF) 的风险。
方法. 符合标准的研究包括在 HER2 阳性早期乳腺癌患者中开展的辅助化疗联合或不联合曲妥珠单抗治疗的随机对照临床试验。入选标准要求研究充分报告 CHF 数据。统计学分析中, 使用固定效应模型计算总发生率、相对危险度 (RR) 和95%置信区间 (CI) 。
结果. 共识别出 6 项随机对照临床试验, 涉及 18111 例患者。曲妥珠单抗与安慰剂相比, 高等级 CHF 的总发生率为 1.44%(95%CI: 0.79%∼2.64%), RR 为 3.19(95%CI: 2.03∼5.02, P<0.00001)。在亚组分析中, CHF 发生率差异未能达到具有统计学意义的水平。曲妥珠单抗 8 mg/kg (高剂量) 的 RR 大于 4 mg/kg (低剂量), RR 分别为 6.79 (95%CI: 2.03∼22.72, P=0.0001) 和 2.64 (95%CI: 1.61∼4.32, P=0.002)。此外, 与对照组患者相比, 接受曲妥珠单抗 1 年和 2 年治疗的患者 RR 较高, 1 年 RR 为 3.29 (95%CI: 2.07∼5.25), 2 年 RR 为 9.54(95%CI: 2.19∼41.43), 而接受 9 周治疗的 RR 则较低 (0.50, 95%CI: 0.05∼5.49)。没有证据显示存在发表偏倚。
结论. 曲妥珠单抗辅助治疗与早期乳腺癌患者中有意义的CHF风险升高具有强相关性, 尤其是接受2年治疗的患者。The Oncologist 2016;21:547–554
对临床实践的提示: 本项全面 meta 分析在早期乳腺癌患者中评价了曲妥珠单抗辅助治疗在不同用量下的充血性心力衰竭发生风险。考虑到曲妥珠单抗给药剂量和疗程与预后密切相关, 因此在开始曲妥珠单抗治疗前, 应严格评价每名患者的风险获益分析。在整个治疗阶段和随访期间应密切监测心功能。因此, 早期鉴别出曲妥珠单抗相关的心功能不全可以进行有效的医学干预, 以减少症状和恢复功能, 并且继续曲妥珠单抗治疗。
Keywords: Adjuvant; Breast cancer; Congestive heart failure; HER2; Meta-analysis; Trastuzumab.
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