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

      Purpose/Objective(s)

      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).

      Materials/Methods

      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.

      Results

      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).

      Conclusion

      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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