Association of Cardiac Sub-Structure Radiation Dose with Bradyarrhythmias and Tachyarrhythmias after Lung Cancer Radiotherapy

Abstract

<h3>Purpose/Objective(s)</h3> Arrhythmias are the most common cardiac events following radiotherapy (RT) for non-small cell lung cancer (NSCLC). However, data detailing types of arrhythmias and associated cardiac sub-structure dose-volume predictors is limited. <h3>Materials/Methods</h3> Retrospective analysis of 748 patients with locally advanced NSCLC treated with RT. Cardiac chambers and coronary arteries were manually segmented and dose-volume histogram (DVH) parameters (mean, max, and volume [V] receiving X Gy [in 5 Gy increments]) were calculated. 15 Common Terminology Criteria for Adverse Events (CTCAE) arrhythmia types were assessed. Receiver operating curve and cut-point analyses estimating grade ≥3 bradyarrhythmias, atrial flutter/fibrillation (AF), non-AF supraventricular tachyarrhythmias (other SVT), and ventricular tachyarrhythmias (VT) were performed. Cox and Fine and Gray regressions were performed (non-cardiac death as a competing risk). <h3>Results</h3> The median age was 65 years, 128/748 patients experienced ≥1 Grade ≥3 CTCAE arrhythmia (median onset, 1.6 years). The 2-year cumulative incidences were: 11.9% overall, 9.0% AF, 1.8% other SVT, 1.0% VT, 1.7% bradyarrhythmias. DVH parameters with highest AUC predicting each arrhythmia group are in Table 1. Adjusting for pre-existing arrhythmia and coronary heart disease: 1) left atrium (LA) V5 Gy ≥60 cc was associated with an increased risk of AF (subdistribution hazard ratio [SHR] 2.06, 95% CI 1.29-3.28; p=.002); 2) right atrium (RA) V60 Gy ≥0.03 cc was associated with an increased risk of other SVT (SHR 4.72, 95% CI 1.65-13.50; p=.004); 3) left main (LM) coronary artery V5 Gy ≥1 cc was associated with an increased risk of VT (SHR 7.4, 95% CI 1.72-31.71; p=.007); and 4) LM V10 Gy ≥1 cc was associated with an increased risk of bradyarrhythmias (SHR 2.27, 95% CI 1.04-4.96; p=.04). The 2-year estimates of AF for LA V5 Gy ≥ 60 cc vs. <60cc were 14.1% vs 5.5% (p<.001), respectively. On all-cause mortality (ACM) analysis, adjusting for lung cancer and cardiac prognostic factors, LA V5 Gy ≥60 cc was associated with an increased risk of ACM (HR 1.22, 95% CI 1.00-1.49; p=.046), while the other DVH variables were not (P>0.05). The 2-year ACM for LA V5Gy ≥60 cc vs <60 cc was 54% vs 46% (p=.010), respectively. <h3>Conclusion</h3> To our knowledge, this is the first report describing functionally distinct arrhythmia classes being associated with RT dose to discrete atrial and coronary sub-structures. Specifically, LA V5 Gy ≥60 cc is associated with an increased risk of AF and mortality. These observations build on our growing knowledge of sub-structure dose leading to localized cardiac dysfunction and guide potential mitigation approaches.