Dexrazoxane and Prevention of Anthracycline-Related Cardiomyopathy

项目总结 患癌症的儿童的五年存活率现在超过80%。晚期心血管疾病，包括 与癌症治疗相关的心肌病/心力衰竭(CHF)，现已成为 儿童癌症幸存者的过早发病率和死亡率。蒽环类药物和相关药物 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 癌症幸存者中的慢性心力衰竭。尽管已知对心脏有毒性，但蒽环类药物仍然是不可或缺的一部分 许多当代儿科癌症治疗方案。右旋氮杂环己烷(DRZ)是一种类似EDTA的化合物 双二氧哌嗪，通过细胞内铁螯合减少氧自由基，FDA批准用于 作为心脏保护剂，用于正在接受大剂量蒽环类药物治疗的乳腺癌成年人。这个 美国临床肿瘤学会建议考虑将其用于所有接触高剂量 蒽环类药物。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 以预先dRZ随机化为特征的国家3期临床试验在超过 1995-2001年间，有1200名儿童患有白血病和淋巴瘤。患者接受了一系列的治疗 今天仍然普遍使用的是蒽环素(具体地说是阿霉素)剂量。而一些短期和中期的- 这些试验的长达5年的长期数据表明，接触dRZ的儿童急性心脏毒性较小， 病理性左心室重构，缺乏更长期的数据。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 自从被诊断出癌症后就已经过去了。具体地说，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)内 通过超声心动图和整体心血管健康来前瞻性地确定当前的心功能 在至少200名幸存者中。这一样本量将使我们能够确定幸存者是否被随机分配到 与标准非dRZ组相比，DRZ组的CHF标志物降低。我们会 然后将预期的超声心动图数据与最初的临床试验人员收集的存档数据结合起来 以及从参与的COG机构获得的检查dRZ暴露是否与 超声心动图随时间变化的不同轨迹。最后，我们将部署多种方法， 包括使用行政和保险数据库，以获取来自 几乎是整个研究人群。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，对当前的临床影响 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.