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

项目摘要/摘要 非小细胞肺癌(NSCLC)是最常见的肺癌形式，约占 占所有肺癌的85%，这是最致命的癌症之一。标准的非小细胞肺癌治疗包括 手术、免疫治疗、化疗和放射治疗。放射治疗可以通过以下两种方式之一进行 光子或质子；然而，胸部的这两种放射治疗都会导致心脏损伤。到目前为止， 目前还没有可用的临床工具来指导医生根据患者的需求选择最佳类型的放射治疗 个人辐射所致心脏损伤的风险。计划放射治疗，正常组织并发症 概率(NTCP)模型是常用的模型，考虑了几何形状或 肿瘤和非肿瘤组织之间的体积，以及组织剂量限制。然而，这些患者 依赖于人口的模型仅基于光子放射治疗数据(不是质子)，不考虑 器官亚结构的辐射易损性差异，不考虑个体非小细胞肺癌患者的 特定毒性的风险(例如，心脏毒性)。因此，这项提议验证了这样的假设，即化学辐射- 相关的心脏毒性可以通过优化剂量和个体先前存在的心血管风险来最小化。 分层以选择适当的辐射方式。先前存在的心血管危险因素，例如 个体遗传倾向、心脏损伤血液生物标志物和血管钙化程度将是 与AIM中放化疗相关的心脏毒性和总生存期(OS)相关1。 现有的心血管危险因素将从前瞻性、随机化的两个方面进行回顾性收集 光子与质子的比较，以及来自登记试验的比较，该试验包括未纳入质子治疗的患者 进入随机试验。先前存在的心血管事件与放射治疗之间的关联- 中介的心脏事件以及OS将被用作参数来生成独一无二的NTCP模型 (目标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。在模型实施过程中，两个最大优化辐射 将为每个登记的患者制定治疗计划：1)使用标准的基于人群的剂量限制； 2)使用基于个体风险的个性化剂量约束。预定义的NTCP目标将设置为 评估两个计划。如果个性化计划将NTCP目标提高15%，患者将使用 个性化的计划。模型的性能将使用数据进行持续评估和改进 从审判中积累起来的。这个拟议项目的长期目标是将心血管疾病降至最低 在优化非小细胞肺癌患者预后的同时，基于并发后单个患者心脏损伤的风险 放射治疗方法和技术的多变量模型选择。预防 癌症患者的心血管损伤使个人可以活得更长，更有成就感的生活是直接的 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.