Critical Volumetric Threshold of 15 Gy Exposure to Left Coronary Arteries Predicts Major Adverse Cardiac Events and Mortality in Lung Cancer Radiotherapy

Abstract

<h3>Purpose/Objective(s)</h3> Left anterior descending (LAD) coronary artery volume receiving 15 Gy (V15 Gy) ≥10% and left circumflex (LCX) V15 Gy ≥14% are associated with an increased risk of major adverse cardiac events (MACE), while LAD V15 Gy ≥10% can significantly increase the risk of mortality in patients with non-small cell lung cancer (NSCLC). Given that reduction of coronary dose is a modifiable risk factor during RT planning, we identified absolute critical volume (vol) thresholds of left coronary artery (LCA) exposure to 15 Gy that predict for MACE and all-cause mortality (ACM). <h3>Materials/Methods</h3> Retrospective analysis of 701 patients with locally advanced NSCLC treated with RT between 2003 and 2014. Coronary arteries were manually segmented with an 8-mm brush size. The absolute vol (cc) of LAD, LCX, or LCA (combined LAD+LCX) structures receiving ≥15 Gy were calculated. Area under the receiver operating curve (AUC) and cut-point analyses estimating MACE (unstable angina, heart failure, myocardial infarction, coronary revascularization, and cardiac death) were performed. Fine and Gray and Cox regressions were performed, adjusting for pre-existing coronary heart disease (CHD) and other cardiovascular and cancer prognostics factors. <h3>Results</h3> The median age was 65 years (interquartile range, 57-73 years) and 50.8% (n = 356) were men. The optimal cut-point (C-index) for the absolute vol. receiving ≥15 Gy for the LAD, LCX, and LCA was ≥1.1 cc (0.63), ≥1.3 cc (0.65), and ≥2.6 cc (0.64), respectively. Adjusting for baseline CHD and other factors, there was an increased risk of MACE with an LAD V15 Gy vol. ≥1.1 cc (adjusted hazard ratio [AHR], 7.59; 95% confidence interval [CI], 2.24-25.69; P = 0.001), an LCX V15 Gy vol. ≥1.3 cc (AHR, 8.24; 95% CI, 2.84-23.90; P < 0.001), and an LCA V15 Gy vol. ≥2.6 cc (AHR, 9.01; 95% CI, 2.66-30.56; P < 0.001), while only LAD-containing variables (not LCX alone) were associated with an increased risk of ACM as follows; LAD V15 Gy vol. ≥1.1 cc (AHR, 1.44; 95% CI, 1.14-1.81; P = 0.002) and LCA V15 Gy vol. ≥2.6 cc (AHR, 1.31; 95% CI, 1.04-1.64; P = 0.023). There was a significantly increased risk of all-cause mortality in CHD-negative patients with an LAD V15 Gy vol. ≥1.1 (HR, 1.39; 95% CI, 1.10-1.74; P = 0.005) and LCA V15 Gy vol. ≥2.6 (HR, 1.32; 95% CI, 1.05-1.65; P = 0.019); but not among CHD-positive patients, (P > 0.05). Specifically, the 2-year ACM estimates in CHD-negative patients for LAD V15 Gy vol. (≥1.1 vs. < 1.1 cc) was 50.9% vs. 42.3%, and for LCA V15 Gy vol. (≥2.6 vs. < 2.6 cc) was 51.1% vs. 43.0%, respectively (P for interaction ≤.01). <h3>Conclusion</h3> Critical volume thresholds of 15 Gy for the LAD and LCA were independent predictors of MACE and ACM, particularly in patients without CHD. These constraints may help inform RT planning by guiding LCA dose reduction and identify patients who may benefit most from advanced RT techniques to mitigate excess cardiac risk.