Association of Left Ventricular Myocardium Dose Exposure with Heart Failure in Lung Cancer Radiotherapy

Abstract

The volume of left anterior descending (LAD) coronary artery dose receiving 15 Gy (LAD V15 Gy) has been associated with major adverse cardiac events (MACE; a composite endpoint of unstable angina, heart failure hospitalization/urgent visit, myocardial infarction, coronary revascularization, and cardiac death) and mortality in patients with locally advanced non-small cell lung cancer (LA-NSCLC) following radiotherapy (RT). With growing evidence supporting specific cardiac substructure dose exposure with distinct pathophysiologic cardiac endpoints, our objective was to assess whether RT dose to the left ventricular myocardium (LVM) was associated with the specific cardiac endpoints of heart failure (HF) vs. overall MACE. Retrospective analysis of 701 patients with LA-NSCLC treated with RT between 2003 and 2014. LAD was segmented manually, while LVM (excluding blood pool) was segmented using an open-source deep learning-based automated algorithm (TotalSegmentator; Wasserthal et al, 2022) and dosimetric parameters (mean, max, and VX Gy in 5 Gy increments) collected. HF was defined as any grade ≥3 Common Terminology Criteria for Adverse Event (CTCAE) HF or cardiomyopathy. Receiver operating curve and cut-point analyses estimating HF were performed. Fine and Gray and Cox regressions, adjusting for preexisting cardiovascular (CV) risk factors and other prognostic factors, were calculated. Of 701 patients, the median age was 65 years (interquartile range [IQR], 57-73), 51% were men. At a median follow up of 20 months (IQR, 8-45) following RT, there were 64 HF events. The median time to HF was 20 months (IQR, 9-43), with a 2-year cumulative incidence of 5.2%. The optimal cut-point for the LVM dose variable with the highest C-index predicting HF was LVM V10 Gy ≥10% (.58). By LVM V10 Gy cut point ≥10% vs <10%, the 2-year HF cumulative incidence was 7.2% vs 4.0% (p = .005). Adjusting for baseline CV risk, there was an increased risk of HF with LVM V10 Gy ≥10% (vs. <10%) (subdistribution hazard ratio [SHR] 2.81; 95% confidence interval [CI], 1.02-7.70; p = .045), but not LAD V15 Gy ≥10% (p>.3). Conversely, adjusting for baseline CV risk, there was an increased risk of MACE with LAD V15 Gy ≥10% (SHR = 19.70; 95% CI = 2.57-151.35; p = 0.004), but not LVM V10 Gy ≥10% (p>0.3). On all-cause mortality analysis, adjusting for CV and other prognostic factors, LAD V15 Gy ≥10% (HR = 1.4; 95% CI = 1.02-1.80; p = 0.036), but not LVM ≥10% (p>0.5), remained significantly associated with mortality. Left ventricular myocardium V10 ≥10%, is associated with the specific endpoint of HF, but not overall MACE, while LAD V15 ≥10% remained strongly associated with MACE and all-cause mortality, but not HF. These findings underscore the need to study the interaction between RT dose to specific substructures (i.e., myocardium) and pathophysiologically relevant cardiac endpoints (i.e., HF).