br TABLE Continued br Total CHD
TABLE 1 Continued
Total CHD Negative CHD Positive
Prescribed RT dose, Gy
Heart mean, Gy
Values are median (interquartile range), n (%), or n. *Based on dose plan information available for n ¼ 701 total patients. The distributions of continuous variables were compared using the Wilcoxon rank sum test, while categorical covariates were compared using the Fisher exact test.
3D-CRT ¼ 3-dimensional conformal radiation therapy; CAD ¼ coronary artery disease; CHD ¼ coronary heart disease; CHF ¼ congestive heart failure; CRT ¼ chemoradiotherapy; DVT ¼ deep venous thrombosis; ECOG ¼ Eastern Cooperative Oncology Group; Gy ¼ Gray; IMRT ¼ intensity modulated radiation therapy; MI ¼ myocardial infarction; NSCLC ¼ non-small cell lung cancer; PAD ¼ peripheral artery disease; PE ¼ pulmonary embolism; PS ¼ performance status; PY ¼ pack-years; RT ¼ radiation therapy; SCC ¼ squamous cell carcinoma.
adjusting for lung cancer and cardiovascular prog-nostic and treatment factors. For the models, time 0 was the start date of radiotherapy and concluded by the date of first MACE/CTCAE (or death for ACM) or last observation, whichever came first. Unadjusted hazard ratios (HRs) and adjusted hazard ratios (AHRs) with 95% confidence intervals (CIs) were calculated. Multivariable models included covariables with p # 0.05 on univariable analysis and MHD and CHD (regardless of p value). The interaction between MHD (continuous variable) and pre-existing CHD (categor-ical variable) was tested. A 2-sided p # 0.05 was considered statistically significant except in the case of multiple testing, where p # 0.025 (0.05/2) was considered significant. Stata version 15.1 (StataCorp LLC, College Station, Texas) and SAS version 9.4 (SAS Institute Inc, Cary, North Carolina) statistical soft-ware were used for all analyses.
TABLE 2 Cumulative Incidences at 2 Years of Cardiac Event Subgroups by Pre-Existing CHD Status
Grade $3 CTCAE
*Patients requiring pericardiocentesis with WY 14643 showing no evidence of malignant cells. Estimates were compared using a 2-sided Gray’s p value.
ACC ¼ American College of Cardiology; AHA ¼ American Heart Association; CM ¼ cardiomyopathy; CTCAE ¼ common terminology criteria for adverse event; CV ¼ cardiovascular; cyto. ¼ cytology; MACE ¼ major adverse cardiac event; other abbreviations as in Table 1.
Despite the competing risk of cancer-specific death and short life expectancy of locally advanced NSCLC patients, we observed a high risk for MACE within 2 years post-radiotherapy, and cardiac radiation dose exposure was an independent predictor of MACE, grade $3 CTCAE, and ACM. As cardiac radiation dose is modifiable during the radiotherapy planning pro-cess, these results underscore the importance of more stringent avoidance of high cardiac radiotherapy dose, highlight the importance of early recognition and treatment of cardiovascular events, as well as inform the design of prospective trials incorporating baseline cardiac risk stratification with cardiac radiation dose reduction techniques and post-radiotherapy cardiac preventative care.
Strengths of this study include cardiac radiation dose analysis in one of the largest locally advanced NSCLC cohorts that expands substantially on recent smaller reports, the first application of AHA/ACC-defined MACE as a primary endpoint in this patient population, and comprehensive detailing of cardiac risk factors and validated cardiac endpoints to provide a shared framework between radiation on-cologists, primary care physicians, and cardiologists to identify high-risk patients and inform post-radiotherapy cardiac risk prevention strategies.
Several points require further discussion. First, our observed MACE rates among CHD-negative patients (harboring moderate median Framingham risk) exceed rates in high-risk Framingham Heart Study participants, even within a narrow time frame post-radiotherapy (29,30). For example, the 1-year rate of atherosclerotic CVD and CV death/nonfatal MI was approximately 0.6% in Framingham participants eligible for lung cancer screening (29) or with high-risk Agatston coronary calcium scores (30). By contrast, we observed a 1-year cumulative incidence of CV death/nonfatal MI and total MACE of 1.7% and 2.5%, respectively (Table 2). Such rates surpass guideline thresholds for recommending aggressive risk reduction (19). Moreover, large database and epidemiological studies estimate that >40% of pa-tients with lung cancer have pre-existing CVD, and shared risk profiles exist between CVD and cancer-related mortality (31,32) with higher cancer-related mortality in individuals meeting guideline-based statin eligibility (33). However, less than one-half of these patients are treated with guideline-directed
CENTRAL ILLUSTRATION Cardiac Radiation Dose and Lung Cancer Mortality