Dexrazoxane and Prevention of Anthracycline-Related Cardiomyopathy

右雷佐生与蒽环类药物相关心肌病的预防

• 批准号: 10656913
• 负责人: Eric Jessen Chow
• 金额: $ 45.56万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-05 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10656913
• 关键词: Dexrazoxane; Prevention; Anthracycline; Related; Cardiomyopathy

PROJECT SUMMARY Five-year survival among children with cancer now exceeds 80%. Late cardiovascular disease, including cancer therapy-related cardiomyopathy/heart failure (CHF), has now become the leading non-cancer cause of premature morbidity and mortality among childhood cancer survivors. Anthracycline and related drugs have been well-documented to be the single most important risk factor associated with subsequent development of CHF among cancer survivors. Anthracyclines, despite their known cardiotoxicity, continue to be an integral part of many contemporary pediatric cancer treatment protocols. Dexrazoxane (DRZ) is an EDTA-like bisdioxopiperazine that decreases oxygen free radicals via intracellular iron chelation, and is FDA-approved for use as a cardioprotectant in adults being treated with high-dose anthracyclines for breast cancer. The American Society of Clinical Oncology recommends considering its use for all adults exposed to high doses of anthracyclines. However, concerns regarding DRZ’s safety and efficacy have limited its use in children. Four national phase 3 clinical trials that featured upfront DRZ randomization were conducted among more than 1,200 children with leukemias and lymphomas from 1995-2001. Patients were treated with a range of anthracycline (specifically, doxorubicin) doses still commonly used today. While some short- and intermediate- term data up to 5-years from these trials suggest that DRZ-exposed children had less acute cardiotoxicity and pathologic left ventricular remodeling, longer term data are lacking. The proposed research will attempt to ascertain long-term cardiovascular health in this population of childhood cancer survivors now that 15-20 years have elapsed since cancer diagnosis. Specifically, we will leverage the study infrastructure we have developed within the Children’s Oncology Group (COG; a member of the NCI’s National Clinical Trials Network) in order to prospectively ascertain current cardiac function via echocardiography and overall cardiovascular health among at least 200 survivors. This sample size will allow us to definitively determine if survivors randomized to DRZ have decreased markers of CHF compared with those treated on the standard non-DRZ arms. We will then combine prospective echocardiographic data with archived data collected by the original clinical trialists and those available from participating COG institutions to examine whether DRZ exposure is associated with a differential trajectory of echocardiographic change over time. Finally, we will deploy a variety of approaches, including use of administrative and insurance databases, to capture long-term adverse health outcomes from almost the entire study population. We believe successful completion of the proposed research will allow us to determine whether DRZ provides long-term cardioprotection, with immediate clinical implications for current patients and drug regulatory policy.

项目摘要 癌症儿童的五年生存率现在超过80％。晚期心血管疾病，包括 癌症治疗相关的心肌病/心力衰竭（CHF）现已成为主要的非癌症原因 儿童癌症生存的过早发病率和死亡率。蒽环类药物和相关药物具有 有充分记录是与随后发展相关的最重要的危险因素 癌症存活中的CHF。蒽环类药物尽管已知心脏毒性，但仍然是不可或缺的一部分 在许多当代小儿癌症治疗方案中。右旋唑烷（DRZ）是类似EDTA的样子 双氧杂嗪通过细胞内铁螯合减少氧气自由基，并被FDA批准用于 用大剂量蒽环类药物治疗的成年人用作心脏保护剂。这 美国临床肿瘤学会建议考虑其用于所有暴露于高剂量的成年人 蒽环类动物。但是，对DRZ的安全性和效率的担忧限制了其在儿童中的使用。四个 国家第三阶段的3临床试验进行了前期DRZ随机化的特征 从1995- 2001年开始有1,200名白血病和淋巴瘤儿童。患者接受了一系列治疗 邻苯二霉（特别是阿霉素）剂量今天仍然常用。虽然短和中间 - 这些试验中最多5年的术语数据表明，暴露于DRZ的儿童的急性心脏毒性和 缺乏病理左心室重塑，长期数据。拟议的研究将尝试 确定15 - 20年的儿童期癌症人群中的长期心血管健康 自癌症诊断以来已经过去了。具体而言，我们将利用我们开发的研究基础设施 在儿童肿瘤学组（COG； NCI国家临床试验网络的成员）中 通过超声心动图和整体心血管健康，前瞻性确定当前的心脏功能 在至少200名冲浪者中。该样本量将使我们能够确定确定冲浪者是否随机 与在标准非DRZ臂上处理的CHF标记相比，DRZ的标记率降低了。我们将 然后将前瞻性超声心动图数据与原始临床试验者收集的存档数据相结合 以及参与的齿轮机构可获得的那些，以检查DRZ暴露是否与 超声心动图随时间变化的差异轨迹。最后，我们将部署各种方法， 包括使用行政和保险数据库，以捕获长期不良健康结果 几乎整个研究人群。我们认为，成功完成拟议的研究将使我们能够 确定DRZ是否提供长期心脏保护作用，对当前有立即的临床影响 患者和药物调节政策。

项目成果

Challenges associated with retrospective analysis of left ventricular function using clinical echocardiograms from a multicenter research study.

• DOI: 10.1111/echo.14983
• 发表时间: 2021-03
• 期刊: Echocardiography (Mount Kisco, N.Y.)
• 作者: Sachdeva R;Stratton KL;Cox DE;Armenian SH;Bhat A;Border WL;Leger KJ;Leisenring WM;Meacham LR;Sadak KT;Narasimhan S;Chow EJ;Nathan PC
• 通讯作者: Nathan PC