Mechanistic Risk Prediction of Radiation Therapy Cardiotoxicity

摘要 肺癌是全球最常见的癌症，也是美国癌症死亡的主要原因。而 放射治疗（RT）是一种非常有效的治疗许多癌症，胸部RT携带的风险增加， 心血管（CV）发病率和死亡率，限制了癌症控制和生存的关键进展。尽管 由于这个问题的重要性，我们对RT如何导致CV毒性的理解有限， 以及患者中CV毒性的功能机制和预测因素。基本问题包括： RT是否影响CV毒性的机制生物学和成像标志物？哪种心脏辐射剂量体积 参数是否与CV毒性相关？基线水平或生物标志物、成像 测量和辐射剂量体积参数是否识别出存在CV不良临床结局风险的患者？我们 初步数据表明胸部RT导致炎症、氧化应激、微血管功能障碍， 患者的CV功能更差。我们将通过对这些通路的详细描述来扩展这些发现 在一个多中心、纵向前瞻性队列研究中，来自美国华盛顿大学的非小细胞肺癌患者， 宾夕法尼亚州，华盛顿大学和布里格姆妇女医院接受了明确的胸部 化疗和放疗以达到治疗目的。我们关注肺癌，因为疾病的高患病率， RT在癌症控制中的作用，与RT相关的伴随CV发病率和死亡率，以及高RT 输送到心脏的剂量。我们的总体目标是确定RT是否会导致早期亚临床CV功能障碍 使用高度敏感的定量生物和功能测量;了解心脏剂量-体积 参数影响这些异常;并制定风险预测中的多标记策略。我们的多- 中心纵向队列构成了所有目标的基础。在目标1中，我们将评估循环中的变化， CV应激、炎症和血管功能障碍的生物标志物，并确定与RT剂量的相关性- 量的措施。在目标2中，我们将量化CV功能成像衍生指标中的RT相关变化 和灌注，并定义与RT剂量体积测量的关联。在目标3中，我们将确定 生物学、影像学和RT剂量体积测量作为CV不良结局指标的预后价值。通过 使用创新的方法进行深度CV表型分析，以识别高风险个体，我们将个性化提供 RT和靶向心脏保护干预，并最终改善CV和整体患者结局。我们 将利用我们在接受心脏毒性治疗的癌症患者的精确表型分析方面的经验， 解决高优先级的研究差距，以响应NIH PA 19-112。

Abstract Lung cancer is both the most common cancer worldwide and the leading cause of cancer death in the US. While radiation therapy (RT) is a highly effective treatment for many cancers, thoracic RT carries an increased risk of cardiovascular (CV) morbidity and mortality that limit critical gains in cancer control and survival. Despite the significance of this problem, we have a limited understanding of how RT results in CV toxicity, and the biologic and functional mechanisms and predictors of CV toxicity in patients. Fundamental questions include: how does RT affect mechanistic biologic and imaging markers of CV toxicity? Which cardiac radiation dose-volume parameters are associated with CV toxicity? Can baseline levels or early changes in biomarkers, imaging measures and radiation-dose volume parameters identify patients at risk of adverse CV clinical outcomes? Our preliminary data suggest thoracic RT results in inflammation, oxidative stress, microvascular dysfunction, and worse CV function in patients. We will extend these findings through detailed characterization of these pathways in a multi-center, longitudinal prospective cohort of nonsmall cell lung cancer patients from the University of Pennsylvania, Washington University, and the Brigham and Women’s Hospital treated with definitive thoracic chemoradiation for curative intent. We focus on lung cancer given the high prevalence of disease, the important role of RT in cancer control, the concomitant CV morbidity and mortality associated with RT, and the high RT doses delivered to the heart. Our overall objective is to determine if RT results in early, subclinical CV dysfunction using highly sensitive, quantitative biologic and functional measures; understand how cardiac dose-volume parameters influence these abnormalities; and develop multi-marker strategies in risk prediction. Our multi- center longitudinal cohort forms the basis of all Aims. In Aim 1, we will evaluate the changes in circulating biomarkers of CV stress, inflammation and vascular dysfunction, and to define the associations with RT dose- volume measures. In Aim 2, we will quantify RT-related changes in imaging-derived measures of CV function and perfusion, and to define the associations with RT dose-volume measures. In Aim 3, we will determine the prognostic value of biologic, imaging, and RT dose-volume measures as indicators of adverse CV outcomes. By using innovative methods in deep CV phenotyping to identify high risk individuals, we will personalize the delivery of RT and targeted cardioprotective interventions, and ultimately improve CV and overall patient outcomes. We will leverage our experiences in precision phenotyping of cancer patients undergoing cardiotoxic therapy to address a high-priority research gap in response to NIH PA 19-112.