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 chemoradia...