Assessment of Coronary Artery Calcification Burden as a Risk Factor for Cardiac Toxicity in Patients Treated on Radiation Dose-escalation Trials for Stage III Non-small-cell Lung Cancer

Abstract

We recently determined that while mean heart dose (MHD) over 10 Gy can significantly increase the risk of major adverse cardiac events (MACE) and mortality in patients with non-small cell lung cancer (NSCLC), left coronary (left anterior descending [LAD] and left circumflex [LCx]) V15 Gy is most predictive of MACE compared to whole heart and other cardiac substructure dose parameters. In some cases, MHD may be discordant with left coronary dose exposure, and we sought to determine whether classification based on low or high MHD with low or high left coronary dose exposure could improve cardiac risk stratification. Materials/Methods: Retrospective analysis of 701 locally advanced NSCLC patients treated with thoracic radiotherapy. Cardiac anatomy was manually delineated. Four dosimetric groups were determined based on high or low MHD (10 Gy vs. <10 Gy) and left coronary artery (LCA) dose (LAD V15 Gy 10% vs. <10% and LCx V15 Gy 14% vs <14%), and defined as: MHD high /LCA low , MHD high /LCA high , MHD low /LCA low , and MHD low /LCA high. MACE (unstable angina, heart failure, myocardial infarction, coronary revascularization, and cardiac death) cumulative incidence was estimated and Fine and Gray regressions performed, adjusting for pre-existing CHD and other prognostic factors. Results: The median follow-up was 20.4 months overall and 47.8 months in patients alive. There was discordance between MHD and LCA in 15.1% (n Z 106) of cases: by group, 12.1% (n Z 85) were MHD high /LCA low , 3.0% (n Z 21) were MHD low /LCA high , 35.4% (n Z 248) were MHD high /LCA high , and 32.3% (n Z 227) were MHD low /LCA low. The 2-year MACE cumulative incidence was 5.7% (95% CI: 4.1-7.5) overall and by MHD/LCA subgroup as follows: MHD low /LCA high 19.7% (95% CI: 6.1-38.9), MHD high /LCA high 8.2% (95% CI: 5.2-12.1), MHD low /LCA low 1.8% (95% CI: 0.6-4.2), and MHD high /LCA low , 1.2% (95% CI: 0.1-5.7). Adjusting for age, intensity modulated radiation therapy (IMRT) use, and baseline CHD, only combinations with low left coronary artery dose were associated with significantly reduced risk of MACE, specifically MHD high /LCA low (subdistribution hazard ratio, SHR[0.19, 95% CI: 0.04-0.84]; P Z .029) and MHD low /LCA low (SHR [0.36, 95% CI: 0.17-0.77]; P Z .008). Conclusion: When mean heart and left coronary dose exposure is discordant, isolated low left coronary artery dose exposure, but not isolated low MHD, significantly reduces the risk of MACE in patients with locally advanced NSCLC following radiotherapy. Given the limitations of MHD and emerging data determining optimal cardiac substructure (left coronary and left ventricle) dose constraints, the utility and clinical significance of national guidelines for MHD and whole heart metrics should be re-evaluated.