Dexrazoxane and Prevention of Anthracycline-Related Cardiomyopathy

项目摘要 癌症儿童的五年存活率现在超过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），现在已经成为癌症的主要非癌症原因。 儿童癌症幸存者的过早发病率和死亡率。蒽环类药物及相关药物 已被充分记录为与随后的发展相关的单一最重要的风险因素， 癌症幸存者中的CHF。蒽环类药物，尽管它们已知的心脏毒性，仍然是一个组成部分， 许多当代儿科癌症治疗方案。Dexrazoxane（DRZ）是一种EDTA类药物， 双二氧代哌嗪，通过细胞内铁螯合作用减少氧自由基，FDA批准用于 在接受高剂量蒽环类药物治疗乳腺癌的成人中用作心脏保护剂。的 美国临床肿瘤学会建议所有暴露于高剂量的 蒽环类然而，对DRZ安全性和有效性的担忧限制了其在儿童中的使用。四 在超过100名患者中进行了以预先DRZ随机化为特征的国家III期临床试验， 1995-2001年，1 200名儿童白血病和淋巴瘤患者。患者接受了一系列 蒽环类抗生素（特别是多柔比星）剂量仍然普遍使用的今天。一些短期和中期的- 这些试验长达5年的长期数据表明，暴露于DRZ的儿童急性心脏毒性较小， 病理性左心室重构，长期数据缺乏。拟议的研究将试图 确定15-20岁儿童癌症幸存者的长期心血管健康状况， 自癌症诊断以来，具体而言，我们将利用我们开发的研究基础设施 在儿童肿瘤学小组（COG; NCI国家临床试验网络的成员）中， 通过超声心动图前瞻性确定当前心脏功能和总体心血管健康状况 至少200名幸存者。这一样本量将使我们能够明确确定幸存者是否随机分配到 与标准非DRZ组相比，DRZ组CHF标志物减少。我们将 然后将联合收割机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结合起来 以及参与COG机构提供的资料，以检查DRZ暴露是否与 超声心动图随时间变化的不同轨迹。最后，我们将部署各种方法， 包括使用行政和保险数据库，以捕捉长期不利的健康结果， 几乎所有的研究对象。我们相信，成功完成拟议的研究将使我们能够 确定DRZ是否提供长期的心脏保护作用，并对当前的 患者和药品监管政策。

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.