Longitudinal Cardiotoxicity in Adult Survivors Childhood Cancer

描述(申请人提供)：有必要对儿童癌症的老年成年幸存者进行全面、客观的心脏评估，以确定：1)成年后心功能障碍的发生率和发展轨迹，以及2)早期发现迟发性心功能障碍的理想筛查工具。80%的被诊断为儿童恶性肿瘤的儿童将成为癌症的5年幸存者，其中超过50%的幸存者接受了蒽环类化疗药物和/或心脏定向放射治疗(RT)的治疗。蒽环类药物和/或心脏RT暴露与迟发性心脏毒性的发展(暴露1年后)之间存在着明确的联系。然而，大多数已发表的文献报道，儿童癌症幸存者的这一结果仅限于治疗后随访不到15年的临床队列。由于儿科机构一直无法将儿童癌症幸存者追踪到成年，随着幸存者年龄的增长，心功能的轨迹还没有得到充分的记录。此外，目前心脏毒性的标准测量(超声心动图的射血分数)很可能在进展为左心衰竭的自然历史中检测到毒性。需要新的超声心动图方法来早期发现。我们提出了一项横断面研究，将比较一种新的局部心肌功能障碍的超声心动图测量方法(应变)和传统的超声心动图(射血分数)，以评估810名接受蒽环类药物化疗和/或心脏定向放射治疗的儿童癌症患者和484名对照组的心脏毒性。我们假设，与射血分数的标准测量相比，异常应变测量与功能容量降低(最大摄氧量)的相关性更强。在这项研究之前10年有超声心动图评估的成年人亚群(n=170)，将评估成年后心功能的纵向轨迹。对这一人群的纵向评估将为成年早期心脏功能下降的轨迹和速度提供证据，从而为这一人群的筛查建议提供额外的证据。此外，这一应用将验证一种新的检测心脏毒性的新方法(心肌应变)。到目前为止，这样的研究还没有完成，因为儿科癌症机构在长期保留和评估大量成年幸存者队列时遇到了许多障碍。圣犹大终身队列的独特资源允许进行这样的研究，该队列由机构资助，由4000名成年幸存者组成，并进行终身随访。结果将为未来的研究提供基础，使用早期检测(菌株)来针对人群进行干预，以预防暴露于蒽环类药物/RT的儿童癌症幸存者的心力衰竭。

DESCRIPTION (provided by applicant): There is a need for comprehensive, objective cardiac evaluation of aging adult survivors of childhood cancer to determine: 1) the prevalence and trajectory of cardiac dysfunction in adulthood, and 2) ideal screening instruments for early detection of late-onset cardiac dysfunction. Eighty percent of children diagnosed with a pediatric malignancy will become 5-year survivors of their cancer, and more than 50% of these survivors received treatment with the anthracycline class of chemotherapeutic agents and/or cardiac-directed radiation therapy (RT). There is a well established association between anthracycline and/or cardiac RT exposure and the development of late-onset cardiotoxicity (>1 year from exposure). However, most published literature reporting this outcome among childhood cancer survivors is limited to clinical cohorts followed for less than 15 years post treatment. As pediatric institutions have been unable to follow childhood cancer survivors into adulthood, the trajectory of cardiac function has not been adequately documented as survivors age. Furthermore, the current standard measure of cardiotoxicity (ejection fraction by echocardiogram) likely detects toxicity late in the natural history of the progression to left ventricular failure. Novel echocardiographic methods for early detection are needed. We propose a cross-sectional study that will compare a novel echocardiographic measure of regional myocardial dysfunction (strain), to traditional echocardiography (ejection fraction) for evaluation of cardiac toxicity in 810 adults treated with anthracycline chemotherapy and/or cardiac-directed RT for childhood cancer and 484 controls. We hypothesize that abnormal strain measures will be more strongly associated with reduced functional capacity (VO2 max) than the standard measure of ejection fraction. A sub-population (n=170) of adults with previous echocardiographic evaluation 10 years prior to this study will be assessed for longitudinal trajectory of cardiac function in adulthood. Longitudinal assessment of this population will provide evidence for the trajectory and rate of cardiac decline in early adulthood, thus providing additional evidence for screening recommendations in this population. Furthermore, this application will validate a novel modality (myocardial strain) for early detection of cardiac toxicity. To date, such a study has not been done because of numerous barriers encountered in long-term retention and assessment of a large cohort of adult survivors by a pediatric cancer institution. The unique resource of the St. Jude Lifetime Cohort, an institutionally funded cohort of >4,000 adult survivors with lifetime follow-up, allows for such a study. Results will provide a foundation for future research using early detection (strain) to target a population for intervention approaches that may prevent heart failure in anthracycline/RT-exposed childhood cancer survivors.