Cardiac Radiation Dose and Patient Risk Factors for Predicting Major Adverse Cardiac Events in Lung Cancer Patients

Abstract

<h3>Purpose/Objective(s)</h3> Thoracic radiotherapy (TRT) is a mainstay treatment for locally advanced non-small cell lung cancer (LA-NSCLC). Mean heart dose (MHD) and left anterior descending (LAD) receiving ≥15 Gy (LADV15) was shown to predict major adverse cardiac events (MACE) in LA-NSCLC patients receiving TRT. We aim to develop a clinically applicable MACE risk prediction score model, including both cardiac dosimetric and baseline risk factors. <h3>Materials/Methods</h3> Retrospective data from 748 consecutive patients with LA-NSCLC treated with curative intent between November 1998 to December 2013 were included. The data was split based on diagnosis dates to allow external validation. Model development was performed on 500 consecutive patients diagnosed before December 2010 using multivariable Cox-proportional hazard model; backward elimination scheme (α = 0.05) was used to select the predictors for the final model. Potential predictors were selected <b>a priori</b> based on prior literature: age, pre-existing coronary heart disease (CHD), Framingham Risk, hypertension (HTN), MHD, LADV15, intensity modulated RT (IMRT) use, and interaction between CHD and LADV15 (CHD:LADV15). Model performance was assessed by the Harrell's c-index and internally validated using leave-one out cross validation (LOOCV). The model was applied to the remaining 248 consecutive patients from the initial cohort as the external validation "test" dataset. <h3>Results</h3> The development and test cohorts had median age 64 vs 66 years (<i>P</i> = 0.02), 51.0 vs. 50.4% females (<i>P</i> = 0.88), and 89.4 vs 89.1% stage III cancer (<i>P</i> = 0.91). The final model incorporated CHD, HTN, LADV15, and CHD:LADV15 (β coefficients: 2.703, 1.129, 0.043, -0.047; all <i>P</i> < 0.001; c-index 0.773). LOOCV Pseudo R² = 0.0195. The c-index on the external test dataset was 0.727. Actuarial 3-year MACE rates were 10.7% for development cohort and 15.4% for test cohort. Stratifying development cohort patients into terciles based on MACE risk prediction scores yielded 3-year MACE rates of 0%, 5.7%, and 25.6% for lowest to highest risk-terciles, respectively; among test cohort, the 3-year MACE rates were 4.9%, 10.5%, and 31.9%. Respectively, the 3-year overall survival rates for lowest to highest MACE risk-terciles were 47.3%, 35.2%, and 32.8% among development cohort, and 52.3%, 43.9% and 30.6% within test cohort (both Log-rank <i>P</i> < 0.05). <h3>Conclusion</h3> The 3-year MACE rates spans 5% to 32% from lowest to highest risk groups. Both LADV15 and pre-existing cardiac risk factors are important in predicting MACE risk post-TRT. MACE risk score was associated with survival. This tool has the potential to estimate personalized LADV15 constraints based on patient risk factors and acceptable MACE risk thresholds (e.g., 5-10%), thus may help identify patients who may benefit most from the application of advanced RT techniques to further reduce LAD dose as a modifiable risk factor during RT planning.