Mechanistic Risk Prediction of Radiation Therapy Cardiotoxicity

放射治疗心脏毒性的机制风险预测

• 批准号: 10442397
• 负责人: Bonnie Ky
• 金额: $ 72.55万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442397
• 关键词: Address; Affect; Biological; Biological Markers; Cancer Control; Cancer Etiology; Cancer Patient; Cardiac; Cardiomyopathies; Cardiotoxicity; Cardiovascular Physiology; Cardiovascular system; Cessation of life; Chest; Clinical; Cohort Studies; Collaborations; Coronary heart disease; Data; Disease; Dose; Functional disorder; Heart; Heart failure; High Prevalence; Hospitals; Image; In Vitro; Individual; Inflammation; Intervention; Longitudinal cohort; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Methods; Microvascular Dysfunction; Morbidity - disease rate; Multicenter Studies; Non-Small-Cell Lung Carcinoma; Oncology; Outcome; Oxidative Stress; Pathway interactions; Patient-Focused Outcomes; Patients; Pennsylvania; Perfusion; Phenotype; Prospective cohort; Radiation Dose Unit; Radiation Oncology; Radiation Therapy Oncology Group; Radiation therapy; Radiology Specialty; Randomized Clinical Trials; Research Priority; Risk; Role; Solid Neoplasm; Stress; Toxic effect; United States National Institutes of Health; Universities; Vascular Diseases; Washington; Woman; Work; cancer survival; cardioprotection; cardiovascular risk factor; chemoradiation; circulating biomarkers; effective therapy; experience; high risk; imaging biomarker; imaging study; improved; in vivo; innovation; mortality; multidisciplinary; patient subsets; prognostic value; radiation delivery; response; risk prediction; risk stratification

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.

抽象的 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。尽管 放射治疗（RT）是许多癌症的高效治疗，胸部RT的风险增加 心血管（CV）发病率和死亡率限制了癌症控制和存活中的关键收益。尽管有 这个问题的重要性，我们对RT如何导致CV毒性和生物学有限 患者CV毒性的功能机制和预测因子。基本问题包括：如何 RT会影响CV毒性的机械生物学和成像标记？哪个心脏辐射剂量量 参数与简历毒性有关？可以基线水平或生物标志物的早期变化，成像 措施和辐射剂量的体积参数确定患有不良CV临床结果风险的患者？我们的 初步数据表明胸腔RT导致炎症，氧化应激，微血管功能障碍和 患者的简历功能较差。我们将通过这些途径的详细表征扩展这些发现 在多中心的纵向前瞻性队列中，来自大学的非小细胞肺癌患者 宾夕法尼亚州，华盛顿大学和杨百翰和妇女医院接受了确定性的胸腔治疗 治疗意图的化学放疗。鉴于疾病的高患病率，我们专注于肺癌，这是重要的 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 剂量传递给心脏。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生物学和功能措施；了解心脏剂量体积 参数会影响这些异常；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AIM 1中，我们将评估循环的变化 简历应力，感染和血管功能障碍的生物标志物，并定义与RT剂量的关联 音量测量。在AIM 2中，我们将量化与RT相关的CV功能量度的变化 和灌注，并定义与RT剂量 - 体积测量的关联。在AIM 3中，我们将确定 生物学，成像和RT剂量体积量度的预后价值是广告CV结果的指标。经过 使用深度简历表型中的创新方法来识别高风险个人，我们将个性化交付 RT和针对性的心脏保护干预措施，并最终改善简历和整体患者预后。我们 将利用我们在接受心脏毒性疗法的癌症患者精确表型中的经验 解决了对NIH PA 19-112的高优先研究差距。