Mechanistic Risk Prediction of Radiation Therapy Cardiotoxicity

摘要 肺癌既是全球最常见的癌症，也是美国癌症死亡的主要原因。而当 放射治疗(RT)是一种对许多癌症非常有效的治疗方法，胸部放射治疗增加了患癌症的风险 心血管(CV)发病率和死亡率限制了癌症控制和生存方面的关键进展。尽管 这个问题的重要性，我们对RT如何导致CV毒性以及生物学上的 以及作用机制和患者中CV毒性的预测因素。基本问题包括：如何 RT是否影响CV毒性的机制、生物学和影像标志物？哪个心脏辐射剂量-体积 参数与心血管毒性有关吗？生物标记物的基线水平或早期变化，成像 测量方法和辐射剂量体积参数确定有心血管不良临床结果风险的患者？我们的 初步数据表明，胸部RT会导致炎症、氧化应激、微血管功能障碍和 患者的心血管功能较差。我们将通过对这些途径的详细描述来扩展这些发现 来自加州大学的非小细胞肺癌患者的多中心纵向前瞻性队列研究 宾夕法尼亚州、华盛顿大学和布里格姆妇女医院接受了最终的胸科治疗 为了治疗目的而进行的放化疗。鉴于肺癌的高患病率，我们将重点放在肺癌上 RT在癌症控制中的作用，与RT相关的心血管发病率和死亡率，以及高RT 输送到心脏的剂量。我们的总体目标是确定RT是否会导致早期的亚临床CV功能障碍 使用高度敏感的、定量的生物和功能测量；了解心脏剂量-体积 参数影响这些异常；并在风险预测中发展多标记策略。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 心血管应激、炎症和血管功能障碍的生物标志物，并确定与放射治疗剂量的关系。 音量测量。在目标2中，我们将量化心血管功能成像衍生测量中与RT相关的变化 和灌注，并确定与RT剂量-体积测量的相关性。在目标3中，我们将确定 生物学、影像和RT剂量-体积测量作为不良心血管结局指标的预后价值。通过 使用深度CV表型的创新方法来识别高危个体，我们将使交付个性化 这将有助于提高RT和有针对性的心脏保护干预效果，并最终改善患者的心血管状况和整体预后。我们 将利用我们在接受心脏毒性治疗的癌症患者精确表型方面的经验来 应对NIH PA 19-112，解决高度优先的研究空白。

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.