Left Coronary Artery Dose Exposure Predicts Major Adverse Cardiac Events in Coronary Heart Disease Negative Lung Cancer Patients


      Validated cardiac dose constraints to predict radiotherapy (RT)-associated Major Adverse Cardiac Events (MACE) in patients with non-small cell lung cancer (NSCLC) are lacking. We sought to identify cardiac substructure dose variables predictive of MACE (myocardial infarction, cardiac death, revascularization, heart failure).


      Retrospective analysis of 449 consecutive locally-advanced NSCLC patients treated with thoracic RT and without pre-existing coronary heart disease was performed. Cardiac chambers (left and right atria, ventricles), coronary arteries (left main, left anterior descending [LAD], left circumflex [LCx], right, posterior descending), and whole heart were manually delineated in MIMvista according to published contouring guidelines. Mean (Gy), max (Gy), and volume (%) receiving X Gy dose (VX Gy, in 5 Gy increments to 70 Gy) were obtained for each structure. Receiver operating curve (C-index) and cut-point analyses were performed. Cumulative incidence estimates and Fine and Gray regressions were adjusted for non-cardiac death as a competing risk.


      The median delivered mean heart dose was 12.3 Gy. After a median follow-up of 33 months, 24 patients developed ≥1 MACE (1-year cumulative incidence, 2.5% [95% CI 1.3-4.2]). Baseline Framingham risk was low or moderate in 51% and high in 49%. The best-performing dose parameter (C-index) and cut-point by substructure was LCx V15 Gy (.76) <15%, LAD V15 Gy (.76) <23%, left ventricle V15 Gy (.73) <3%, posterior descending mean (.70) <2 Gy, whole heart V20 Gy (.69) <24%, right ventricle mean (.69) <4 Gy, left main V20 Gy (.69) <82%, while both atria and right coronary artery were ≤.65. Specifically, a LCx V15 Gy ≥15% vs. <15% (sensitivity 83%, specificity 64%) corresponded to an 8-fold increase in 1-year MACE cumulative incidence (5.4% [95% CI 2.6-9.5] vs. 0.7% [95% CI 0.2-2.4], respectively; P<.001). Similarly, a LAD V15 Gy ≥23% vs. <23% (sensitivity 83%, specificity 63%) corresponded to a 14-fold increase in 1-year MACE cumulative incidence (5.7% [95% CI 2.9-9.8] vs. 0.4% [95% CI 0.0-1.9], respectively; P<.001). Adjusting for baseline Framingham risk, both LCx and LAD V15 Gy were associated with a significantly increased risk of MACE (adjusted hazard ratio, AHR [1.02/%, 95% CI 1.01-1.03]; P<.001) and (AHR [1.03/%, 95% CI 1.02-1.04]; P<.001).


      Despite the competing risk of cancer-specific death in NSCLC patients, left circumflex V15 Gy ≥15% and left anterior descending V15 Gy ≥23% confer an 8- and 14-fold increase, respectively (5% absolute for each), in the 1-year cumulative incidence of MACE in patients without baseline coronary heart disease. These newly identified left coronary dose-volume thresholds are worthy of further study for validation as critical cardiac substructure dose constraints for RT planning are currently lacking.


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