Reducing risk of Anthracycline-related heart failure after childhood cancer

降低儿童癌症后与蒽环类药物相关的心力衰竭的风险

• 批准号: 9103021
• 负责人: Saro Armenian
• 金额: $ 66.99万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9103021
• 关键词: Address; Adrenergic beta-Antagonists; Adult; Age; Angiotensin-Converting Enzyme Inhibitors; Anthracyclines; Biological Markers; Blood; Cancer Survivor; Cardiac; Cardiotoxicity; Cardiovascular system; Caring; Cessation of life; Chest; Child; Childhood; Childhood Cancer Treatment; Clinical Trials Network; Coronary Arteriosclerosis; Coupled; Deterioration; Dimensions; Dose; Double-Blind Method; EFRAC; Early Intervention; Endocrine system; Enzyme Inhibition; Exposure to; Free Radical Formation; Galectin 3; Generations; Genetic Predisposition to Disease; Health; Heart Abnormalities; Heart failure; Hepatic; Image; Incidence; Individual; Injury; Interruption; Intervention; Left; Left Ventricular Dysfunction; Left Ventricular Function; Left Ventricular Remodeling; Life; Long-Term Survivors; Lymphoma; Malignant Childhood Neoplasm; Measures; Morbidity - disease rate; Myocardial; Myocardium; Natriuretic Peptides; Outcome; Patient Self-Report; Pediatric Oncology; Pediatric Oncology Group; Peptidyl-Dipeptidase A; Phase; Physiological; Placebo Control; Population; Prevention; Preventive Intervention; Randomized; Randomized Clinical Trials; Recording of previous events; Risk; Risk Reduction; Safety; Stress; Stroke; Survival Rate; Survivors; Thick; Time; Toxic effect; Ventricular; Ventricular Remodeling; Vulnerable Populations; base; carvedilol; chemotherapy; childhood cancer survivor; clinical efficacy; clinically relevant; high risk; improved; malignant breast neoplasm; mortality; oncology; patient population; premature; prevent; randomized placebo controlled trial; sarcoma; treatment adherence

 DESCRIPTION (provided by applicant): Childhood cancer survivors are at a 15-fold risk of developing heart failure (HF) compared to age-matched controls. There is a strong dose-dependent association between anthracyclines and risk of HF; the incidence approaches 20% at cumulative doses between 300-600 mg/m2, and exceeds 30% for doses >600 mg/m2. Outcome following HF is poor; 5-year survival rate is <50%. %. Nearly 60% of the childhood cancer survivors carry a history of prior anthracycline exposure. The growing number of survivors, coupled with the decades of life saved makes it imperative that we develop strategies to reduce the risk of HF in the vulnerable populations. Anthracycline cardiotoxicity is thought to be related to direct myocardial injury due to formation of free radicals, which initiates myocardia remodeling and subsequent left ventricular (LV) functional deterioration. ß-blockade or angiotensin-converting enzyme (ACE)-inhibition have been successfully used to prevent HF in adult non- oncology populations with asymptomatic LV dysfunction, as well as in pediatric non-oncology populations with genetic predisposition to HF, but with preserved cardiac function at the time of intervention. Increasing evidence supports the use of third generation ß-blockers such as carvedilol (combined ß1, ß 2, a1 blockade) to provide a comprehensive reversal of myocardial remodeling following exposure to high dose (HD)- anthracyclines (=300 mg/m2), when compared with the more selective ACE inhibitors. However, clinicians caring for childhood cancer survivors are reluctant to use these agents for prevention due in large part to the paucity of well-conducted randomized clinical trials that would provide the evidence for such an intervention. We propose a randomized, placebo-controlled trial of low-dose carvedilol (beta-blocker) in childhood cancer survivors treated with HD anthracyclines to determine the impact of a two-year course of carvedilol on LV Thickness-Dimension ratio (LV T-D) - an established echocardiographic marker of cardiac remodeling and HF risk in survivors of childhood cancer exposed to anthracyclines, and the primary endpoint for measuring efficacy in the study; additional echocardiographic (left ventricular: volume, ejection fraction [EF], mass/volume ratio, wall stress, systolic cardiac strain), functional (V02 Max), and blood biomarker (natriuretic peptides, galectin-3) measures of HF risk will be included as secondary endpoints. In addition, we plan to establish safety and tolerability of the two-year course of carvedilol in this populatio of survivors. The proposed intervention has the potential to significantly reduce ongoing cardiac injury via interruption of neuro-hormonal systems responsible for LV remodeling, resulting in improved cardiac function and decreased risk of HF. When completed, this study will provide critical information regarding plausible pharmacologic intervention for prevention of cardiac remodeling in anthracycline-exposed cancer survivors at highest risk for HF.

 描述（由申请人提供）：与年龄匹配的对照组相比，儿童癌症幸存者发生心力衰竭（HF）的风险为15倍。蒽环类药物与HF风险之间存在强烈的剂量依赖性相关性;累积剂量为300-600 mg/m2时，发生率接近20%，剂量>600 mg/m2时，发生率超过30%。HF后的预后较差，5年生存率<50%。%.近60%的儿童癌症幸存者有既往蒽环类药物暴露史。越来越多的幸存者，加上几十年来挽救的生命，使我们必须制定战略，以减少脆弱人群中HF的风险。蒽环类药物的心脏毒性被认为与自由基形成引起的直接心肌损伤有关，自由基的形成会引发心肌重塑和随后的左心室（LV）功能恶化。血管紧张素受体阻滞剂或血管紧张素转换酶（ACE）抑制剂已成功用于预防无症状LV功能障碍的成人非肿瘤人群以及有HF遗传易感性但在干预时心功能保留的儿科非肿瘤人群的HF。越来越多的证据支持使用第三代β受体阻滞剂如卡维地洛（联合β 1、β 2、α 1阻滞剂），与选择性更高的ACE抑制剂相比，可全面逆转暴露于高剂量（HD）蒽环类药物（=300 mg/m2）后的心肌重塑。然而，照顾儿童癌症幸存者的临床医生不愿意使用这些药物进行预防，这在很大程度上是由于缺乏进行良好的随机临床试验，为这种干预提供证据。我们提出了一个小剂量卡维地洛的随机、安慰剂对照试验（β-受体阻滞剂），以确定卡维地洛两年疗程对LV厚度-尺寸比（LV T-D）的影响-LV T-D是暴露于蒽环类药物的儿童癌症幸存者心脏重塑和HF风险的既定超声心动图标志物，也是测量研究疗效的主要终点; HF风险的其他超声心动图（左心室：容积、射血分数[EF]、质量/容积比、室壁应力、收缩期心脏应变）、功能（VO 2 Max）和血液生物标志物（利钠肽、半乳糖凝集素-3）测量将作为次要终点纳入。此外，我们计划在这组幸存者中确定卡维地洛两年疗程的安全性和耐受性。拟议的干预措施有可能通过中断负责LV重塑的神经激素系统来显著减少持续的心脏损伤，从而改善心脏功能并降低HF风险。完成后，本研究将提供关于合理的药物干预以预防蒽环类药物暴露的HF最高风险癌症幸存者心脏重塑的关键信息。