Longitudinal Cardiotoxicity in Adult Survivors Childhood Cancer

描述（由申请人提供）：需要对儿童癌症的老年成年幸存者进行全面、客观的心脏评价，以确定：1）成年期心功能不全的患病率和轨迹，以及2）早期检测迟发性心功能不全的理想筛查工具。80%被诊断患有儿科恶性肿瘤的儿童将成为癌症的5年存活者，其中超过50%的存活者接受了蒽环类化疗药物和/或心脏定向放射治疗（RT）。蒽环类药物和/或心脏RT暴露与迟发性心脏毒性（暴露后>1年）的发生之间存在明确的相关性。然而，大多数已发表的文献报告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跟踪儿童癌症幸存者到成年，心脏功能的轨迹没有充分记录幸存者的年龄。此外，目前心脏毒性的标准测量（超声心动图射血分数）可能在进展为左心室衰竭的自然史晚期检测到毒性。需要新的超声心动图方法进行早期检测。我们提出了一项横断面研究，将比较一种新的超声心动图测量局部心肌功能不全（应变），传统的超声心动图（射血分数），在810名接受蒽环类药物化疗和/或心脏定向RT治疗儿童癌症的成人和484名对照组中评估心脏毒性。我们假设，异常应变措施将更强烈地与降低功能容量（最大摄氧量）比射血分数的标准措施。将评估在本研究前10年接受过既往超声心动图评价的成人亚群（n=170）成年期心脏功能的纵向轨迹。对该人群的纵向评估将为成年早期心脏功能下降的轨迹和速率提供证据，从而为该人群的筛查建议提供额外证据。此外，该应用将验证用于早期检测心脏毒性的新模式（心肌应变）。到目前为止，这样的研究还没有完成，因为在长期保留和评估一个大型队列的成人幸存者的儿科癌症机构遇到了许多障碍。圣裘德终身队列的独特资源，一个由机构资助的队列，有超过4,000名成年幸存者进行终身随访，允许这样的研究。结果将为未来的研究提供基础，使用早期检测（应变）针对人群进行干预方法，可以预防蒽环类药物/RT暴露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.