Investigating Dosimetry and Imaging Biomarkers for Prediction of Major Adverse Cardiac Events Following Locally Advanced Non-Small Cell Lung Cancer Radiotherapy

Abstract

Thoracic radiotherapy (RT) may confer major adverse cardiac events (MACE) following treatment. Mean heart dose positively associates with MACE and recent studies show cardiac substructure dosimetry improves MACE prediction. Use of imaging biomarkers with cardiac substructure dose has not been studied for prediction of MACE. We sought to develop an integrated model for cardiac substructure dose and baseline coronary artery calcium (CAC) scoring and establish its relationship to MACE. A retrospective cohort analysis was performed of consecutive patients with locally advanced non-small cell lung cancer (NSCLC) treated with definitive RT from 2006-2018 at a single institution. Demographics, medical history, cardiac events, and treatments received were recorded. Cardiac substructures were contoured, including the left descending artery (LAD), left main coronary artery (LMCA), left circumflex (LCX), right coronary artery (RCA), TotalLeft (LAD+LMCA+LCX), and TotalCor (TotalLeft+RCA). Doses were measured in 2 Gy equivalent dose. CAC was scored by visual assessment and compared to established automated Agatston scoring. Primary endpoint was MACE incidence. Receiver operating characteristic (ROC) curves assessed dose and CAC metric model performance. Threshold modeling was conducted using the log rank statistic with 95% confidence intervals measured using bootstrap resampling with 1000 iterations. Competing risk models adjusted for death were used to measure cumulative incidence of MACE as well as in univariable and multivariable risk regression modeling. Pearson correlations were used to validate CAC scoring. P-values were two tailed and considered significant at P≤0.05. Of 233 eligible patients, 61.4% were male with a 68.1 years (range 34.9-90.7) median age. Median follow-up was 73.7 months (range 1.6-153.9). Median overall survival was 34.8 months. Following RT, 22.3% experienced at least one cardiac event at a median time of 21.5 months (range 1.7-118.9). Visual CAC scoring showed significant correlation with automated Agatston scoring (r = 0.72, P=1e-5). While left sided coronary arteries (TotalLeft), mean heart dose (MHD) and CAC scores individually predicted for MACE (AUC = 0.56-0.59), a multivariable model of TotalLeft CAC had the highest ROC analysis performance (AUC = 0.69). On univariable and multivariable competing risk regression analyses, TotalLeft V15 Gy >2.53 cc and CAC score >5 independently associated with MACE (P<0.05). A model incorporating age, TotalLeft CAC>5 and V15>2.53cc, showed incrementally higher MACE incidences for low (9.3%), intermediate (18.4%), and high-risk groups (27.7%) (P<0.01). RT-induced MACE occurs in >20% of those undergoing thoracic RT in a median time of <2 years. We validate significant associations between TotalLeft RT dose and MACE and establish CAC as a predictive risk factor. These findings may serve to inform personalized RT and future cardiac risk in locally advanced NSCLC.