Risk prediction and longitudinal assessment of cardiotoxicity and functional capacity trajectory in NSCLC patients

项目总结/摘要 非小细胞肺癌（NSCLC）是最常见的肺癌形式，约占 85%的肺癌是最致命的癌症之一。标准NSCLC治疗包括 手术、免疫疗法、化学疗法和放射疗法。放射治疗可以通过以下方式进行： 光子或质子;然而，这两种类型的胸部放射治疗都可能导致心脏损伤。到目前为止， 不存在可用的临床工具来指导医生根据放射治疗的最佳类型选择放射治疗。 辐射介导的心脏损伤的风险。计划放射治疗，正常组织并发症 概率（NTCP）模型通常使用，并考虑几何形状或 肿瘤和非肿瘤组织之间的体积以及组织剂量约束。然而，这些患者 人口依赖模型仅基于光子放射治疗数据（而不是质子），不考虑 器官亚结构的辐射易损性差异，不考虑个体NSCLC患者的 特定毒性的风险（例如，心脏毒性）。因此，这项提议检验了放化疗的假设- 相关心脏毒性可通过剂量优化和个体既存心血管风险最小化- 分层以选择合适的放射方式。预先存在的心血管风险因素，如 个体遗传易感性、心脏损伤血液生物标志物和血管钙化程度将被 与目标1中的放化疗相关心脏毒性和总生存期（OS）相关。数据显示， 现有的心血管危险因素将从两个前瞻性、随机、 光子与质子的比较，来自一项登记研究，其中包括未入组的质子治疗患者 进入随机试验。既存心血管事件与放射治疗之间的关联- 介导的心脏事件以及OS将用作参数，以生成独一无二的NTCP模型 (Aim 2）。在目标3中，将开发一项前瞻性队列登记试验，以纵向评估心脏功能， 心脏健康和模型实施。在模型实施期间，两个最大优化辐射 将为每名入选患者制定治疗计划：1）使用标准的基于人群的剂量限制; 以及2）使用基于个体风险的个性化剂量约束。预定义的NTCP目标将被设置为 评估这两个计划。如果个性化计划将NTCP目标提高15%，则患者将使用 个性化的计划。将利用这些数据不断评估和改进模型性能 从审判中积累起来的。本拟议项目的长期目标是尽量减少心血管疾病 同时优化NSCLC患者结局，基于个体患者并发心脏损伤后的风险 通过放射治疗方式和技术的多变量模型选择化放疗。防止 癌症患者的心血管损伤，使个人可以活得更长，更充实的生活是直接的 与国家癌症研究所和国家心肺血液研究所的使命保持一致。

Project Summary/Abstract Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer, accounting for approximately 85% of all lung cancers, which is one of the deadliest types of cancers. Standard NSCLC treatments include surgery, immunotherapy, chemotherapy, and radiation therapy. Radiation therapy can be delivered by either photons or protons; however, both types of radiation therapy to the chest can result in cardiac injury. To date, no available clinical tool exists to guide physicians in choosing the best type of radiation therapy according to an individual’s risk for radiation-mediated cardiac injury. To plan radiation therapy, normal tissue complication probability (NTCP) models are commonly used and take into consideration differences in geometric shape or volumes between tumor and non-tumor tissue, as well as tissue dose constraints. However, these patient population-reliant models are based only on photon radiation therapy data (not proton), do not consider the differences in radiation vulnerability of organ substructures, and do not consider the individual NSCLC patient’s risk for a specific toxicity (e.g., cardiac toxicity). Hence, this proposal tests the hypothesis that chemoradiation- related cardiac toxicity can be minimized by dose optimization and individual pre-existing cardiovascular risk- stratification for choosing appropriate radiation modality. Pre-existing cardiovascular risk factors, such as individual genetic predisposition, cardiac injury blood biomarkers, and extent of vascular calcification will be correlated with chemoradiation-associated cardiac toxicity and overall survival (OS) in Aim 1. Data on pre- existing cardiovascular risk factors will be retrospectively collected from two prospective, randomized comparisons of photons vs. protons and from a registry trial, which included proton-treated patients not enrolled into the randomized trial. Associations between pre-existing cardiovascular events and radiation therapy- mediated cardiac events as well as OS will be used as parameters to generate a one-of-a-kind NTCP model (Aim 2). In Aim 3, a prospective cohort registration trial will be developed to longitudinally assess cardiac function, cardiac fitness, and model implementation. During model implementation, two maximally optimized radiation therapy plans for each enrolled patient will be developed: 1) using standard population-based dose constraints; and 2) using personalized dose constraints based on individual risk. A predefined NTCP goal will be set to evaluate both plans. If the personalized plan improves the NTCP goal by 15%, the patient will be treated using the personalized plan. The model performance will be continuously assessed and improved using the data accumulated from the trial. The long-term objectives of this proposed project are to minimize cardiovascular injury while optimizing NSCLC patient outcomes, based on individual patient risk to cardiac injury after concurrent chemoradiation therapy by multivariable model selection of radiation therapy modality and technique. Preventing cardiovascular injury in cancer patients so that individuals can live longer, and more fulfilling lives is in direct alignment with the mission of both the National Cancer Institute and the National Heart, Lung, and Blood Institute.