乳腺癌化疗患者心脏保护策略比较

　　几十年来，蒽环类化疗方案一直是治疗乳腺癌的主要方法。然而，蒽环类可能引起轻微或严重的短期或长期毒性反应。其中，心脏毒性反应是众所周知的并发症，所致心脏收缩期左室射血分数降低可导致治疗中断或终止，并可增加死亡风险。若干研究已经分别证实血管紧张素转换酶抑制剂或血管紧张素II受体阻滞剂、β受体阻滞剂可以预防心脏重构并降低心功能不全患者死亡风险。不过，其中哪种心脏保护策略效果最好，目前仍然存在争议。

　　2021年8月26日，《美国医学会杂志》肿瘤学分册在线发表意大利佛罗伦萨大学卡雷奇医院、托斯卡纳大区中心医院、佛罗伦萨癌症预防与临床研究网络研究所、都灵大学医院、维西利亚医院、里窝那医院的SAFE2014研究报告，探讨了心脏保护药物能否减少早期乳腺癌蒽环类化疗患者的亚临床（无症状）心脏损伤。

SAFE2014 (NCT02236806): Cardiotoxicity Prevention in Breast Cancer Patients Treated With Anthracyclines and/or Trastuzumab: Role of ACE Inhibitors and Beta Blockers as Cardiotoxicity Prevention in Breast Cancer Patients Treated With (Neo)Adjuvant Anthracyclines and/or Trastuzumab: a Four Arm, Placebo Control, Randomized Trial

　　该全国多中心四组双盲安慰剂随机对照三期临床研究于2015年7月～2020年6月从全国8个肿瘤科入组既往未被诊断心血管疾病的早期乳腺癌术前或术后蒽环类全身化疗患者174例（年龄24～75岁，中位48岁）按1∶1∶1∶1的比例随机分为四组：安慰剂组42例、雷米普利组43例、比索洛尔组45例、雷米普利＋比索洛尔组43例。从化疗启动开始分别给予12个月安慰剂、雷米普利每天5毫克、比索洛尔每天5毫克、雷米普利每天5毫克＋比索洛尔每天5毫克，12个月时完成心脏评定。2020年进行预设中期分析。主要终点为根据标准和三维超声心动图测定心脏收缩期的左室射血分数（心肌功能指标）和整体纵向应变（心肌应变指标）。

　　结果，12个月时，安慰剂组、雷米普利组、比索洛尔组、雷米普利＋比索洛尔组相比：

• 左室射血分数：降低4.4%、降低3.0%、降低1.9%、降低1.3%（P=0.01）

• 总体纵向应变：降低6.0%、降低1.5%、降低0.6%、提高0.1%（P<0.001）

• 左室射血分数降低≥10%：8例、5例、5例、3例（19%、11.5%、11.4%、6.8%）

• 总体纵向应变降低≥10%：15例、7例、6例、6例（35.7%、15.9%、13.6%、13.6%，P=0.03）

　　因此，该全国多中心小样本四组双盲安慰剂随机对照三期临床研究中期结果分析表明，对于早期乳腺癌蒽环类化疗患者，心脏保护药物策略耐受性良好，可以预防癌症治疗相关左室射血分数下降和心脏重构，故有必要进一步开展大样本研究进行验证。

JAMA Oncol. 2021 Aug 26. Online ahead of print.

Cardioprotective Strategy for Patients With Nonmetastatic Breast Cancer Who Are Receiving an Anthracycline-Based Chemotherapy: A Randomized Clinical Trial.

Livi L, Barletta G, Martella F, Saieva C, Desideri I, Bacci C, Del Bene MR, Airoldi M, Amoroso D, Coltelli L, Scotti V, Becherini C, Visani L, Salvestrini V, Mariotti M, Pedani F, Bernini M, Sanchez L, Orzalesi L, Nori J, Bianchi S, Olivotto I, Meattini I.

University of Florence, Florence, Italy; Careggi University Hospital, Florence, Italy; Azienda USL Toscana Centro, Florence, Italy; Institute for Cancer Research Prevention and Clinical Network, Florence, Italy; Città della Salute e della Scienza University Hospital, Turin, Italy; Ospedale Versilia, Lido di Camaiore, Lucca, Italy; Livorno Hospital, Azienda USL Toscana Nord Ovest, Livorno, Italy.

This randomized clinical trial examines the use of a cardioprotective strategy in preventing subclinical cardiac damage caused by anthracycline-based chemotherapy in Italian women with breast cancer.

QUESTION: Can pharmacological cardioprevention avoid subclinical damage in patients with breast cancer who are undergoing cardiotoxic therapy?

FINDINGS: In this randomized clinical trial of 262 patients with breast cancer, 174 of whom were analyzed, at 12 months, left ventricular ejection fraction as evaluated by 3-dimensional echocardiography worsened by 4.4% in the placebo arm and 3%, 1.9%, 1.3% in the ramipril, bisoprolol, and ramipril plus bisoprolol arms, respectively. Global longitudinal strain worsened by 6.0% in the placebo arm and 1.5% and 0.6% in the ramipril and bisoprolol arms, respectively, whereas it was unchanged (0.1% improvement) in the ramipril plus bisoprolol arm.

MEANING: The results of this trial suggest that during cardiotoxic therapy for breast cancer, the use of pharmacological cardioprevention may be warranted.

IMPORTANCE: Several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients who are receiving cardiotoxic therapies. However, the optimal approach still represents a controversial issue.

OBJECTIVE: To determine whether pharmacological cardioprevention could reduce subclinical heart damage in patients with breast cancer who are being treated with anthracycline-based chemotherapy.

DESIGN, SETTING, AND PARTICIPANTS: The SAFE trial was a 4-arm, randomized, phase 3, double-blind, placebo-controlled, national multicentric study conducted at 8 oncology departments in Italy. It was a prespecified interim analysis on the first 174 patients who had completed cardiac assessment at 12 months. The study recruitment was conducted between July 2015 and June 2020. The interim analysis was performed in 2020. Patients were eligible for trial inclusion if they had indication to receive primary or postoperative systemic therapy using an anthracycline-based regimen. Patients with a prior diagnosis of cardiovascular disease were excluded.

INTERVENTIONS: Cardioprotective therapy (bisoprolol, ramipril, or both drugs compared with placebo) was administered for 1 year from the initiation of chemotherapy or until the end of trastuzumab therapy in case of ERBB2-positive patients. Doses for all groups were systematically up-titrated up to the daily target dose of bisoprolol (5 mg, once daily), ramipril (5 mg, once daily), and placebo, if tolerated.

MAIN OUTCOMES AND MEASURES: The primary end point was defined as detection of any subclinical impairment (worsening ≥10%) in myocardial function and deformation measured with standard and 3-dimensional (3D) echocardiography, left ventricular ejection fraction (LVEF), and global longitudinal strain (GLS).

RESULTS: The analysis was performed on 174 women (median age, 48 years; range, 24-75 years) who had completed a cardiological assessment at 12 months and reached the end of treatment. At 12 months, 3D-LVEF worsened by 4.4% in placebo arm and 3.0%, 1.9%, 1.3% in the ramipril, bisoprolol, ramipril plus bisoprolol arms, respectively (P = .01). Global longitudinal strain worsened by 6.0% in placebo arm and 1.5% and 0.6% in the ramipril and bisoprolol arms, respectively, whereas it was unchanged (0.1% improvement) in the ramipril plus bisoprolol arm (P < .001). The number of patients showing a reduction of 10% or greater in 3D-LVEF was 8 (19%) in the placebo arm, 5 (11.5%) in the ramipril arm, 5 (11.4%) in the bisoprolol, arm and 3 (6.8%) in the ramipril plus bisoprolol arm; 15 patients (35.7%) who received placebo showed a 10% or greater worsening of GLS compared with 7 (15.9; ramipril), 6 (13.6%; bisoprolol), and 6 (13.6%; ramipril plus bisoprolol) (P = .03).

CONCLUSIONS AND RELEVANCE: The interim analysis of this randomized clinical trials suggested that cardioprotective pharmacological strategies in patients who were affected by breast cancer and were receiving an anthracycline-based chemotherapy are well tolerated and seem to protect against cancer therapy-related LVEF decline and heart remodeling.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02236806

PMID: 34436523

DOI: 10.1001/jamaoncol.2021.3395