Patient-Level and Endpoint-Specific Clinico-Dosimetric Analysis of the Cardiac Base as a Mediator of Radiation Cardiotoxicity in Non-Small Cell Lung Cancer

Abstract

Cardiac disease is a dose-limiting toxicity in non-small cell lung cancer (NSCLC) radiation therapy. Radiation dose to the cardiac base is associated with poor overall survival in several clinical studies, but has not been validated in a non-dose escalated cohort, or with individual patient delineations. In this study we examined the impact of cardiac base dose on overall survival (OS) and cardiac events (CEs), and interrogated the relationships of the substructures comprising the heart base with OS and CEs. Patients with stage I-III NSCLC treated with curative-intent radiation therapy between 2015 and 2020 at a regional cancer center were identified. Clinical notes were examined for baseline patient, tumor and cardiac details, and both cancer and cardiac outcomes. Three cardiologists verified CEs. Cardiac delineations were completed using a validated deep learning-based autosegmentation tool. Cox and Fine and Gray regressions were undertaken for the risk of death and CEs respectively, accounting for pre-specified evidence-based dose metrics and clinically relevant cardiac covariates. Most patients received 55 Gy/20# (n = 461/478, 96%) without chemotherapy (58%), planned with VMAT (51%) or IMRT (20%). Pre-existing cardiovascular morbidity was common, with 78% having ≥2 risk factors, and 46% having >1 established cardiac disease. The median follow-up was 21.1 months. Dichotomized at the median, higher heart base Dmax was associated with poorer survival on Kaplan-Meier analysis (21.6 months (95% CI 19.3-24.9) versus 29.4 months (95% CI 21.6-36.6), p = 0.021), and remained significant when statistically compared in published multivariate models. In a multivariate analysis for pooled acute CEs, heart base Dmax was associated with CEs (HR 1.75, 95% CI 1.01-1.06, p = 0.04), but this was not the case for individual CEs. Using Fine and Gray models to account for the competing risk of death, left main coronary maximum dose was associated with atrial fibrillation (p = 0.024), proximal right coronary artery V15 (p = 0.023) and mean dose (p = 0.032), and the right atrium mean dose (p = 0.029) were associated with heart failure. No dose-volume metrics were significantly associated with acute coronary syndrome. None of the constituent base substructures dose were significantly associated with death. Dose to the heart base was associated with increased mortality and an increased pooled cardiac event rate. Accounting for endpoint-specific clinical covariates, only select constituent substructures of the heart base were associated with CEs and no substructures were independently associated with survival. Together, these findings are suggestive of possible interplay between the constituent base substructures in their mediation of radiation cardiotoxicity.