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  • br A Total Population br Percent Major Adverse br

    2020-08-28


    A Total Population
    Percent Major Adverse
    Cardiac Events 20
    Time (Years) Following Radiation Therapy Start
    No Pre-Existing CHD
    Pre-Existing CHD
    B No Pre-Existing Coronary Heart Disease
    PercentMajorAdverseCardiacEvents 30
    Time (Years) 1254977-87-1 Following Radiation Therapy Start
    C Pre-Existing Coronary Heart Disease
    Cardiac Events Percent Major Adverse 
    Time (Years) Following Radiation Therapy Start
    (C) patients with pre-existing CHD (Gray’s p ¼ 0.98). CHD ¼ coronary 1254977-87-1 disease; MACE ¼ major adverse cardiac events; MHD ¼ mean heart dose.
    TABLE 3 Competing Risks and Cox Regression Analyses for Major Adverse Cardiac Events and All-Cause Mortality
    Major Adverse Cardiac Events
    All-Cause Mortality
    Univariable
    Multivariable
    Univariable
    Multivariable
    Lung cancer factors
    Sex*
    ECOG PS
    Smoking*
    Weight loss*
    Stage
    Tumor laterality
    Histology
    Baseline cardiac factors
    CHD
    Arrhythmia
    Treatment factors
    RT/surgery sequence
    RT/CRT
    Chemo (any)
    RT technique
    RT year
    Interaction
    *Both a lung cancer and cardiac prognostic factor. †Interaction term between heart dose (continuous variable) and pre-existing CHD (categorical variable).
    ACD ¼ all-cause death; adeno ¼ adenocarcinoma; AHR ¼ adjusted hazard ratio; chemo ¼ chemotherapy; ECOG ¼ Eastern Cooperative Oncology Group; HR ¼ hazard ratio; other abbreviations as in Tables 1 and 2.
    FIGURE 1 All-Cause Mortality Estimates Stratified by Pre-Existing CHD and MHD
    A
    Percent All-Cause Mortality 
    Total Population
    Time (Years) Following RT Start
    No Pre-Existing CHD
    Pre-Existing CHD
    B
    Percent All-Cause Mortality 
    No Pre-Existing CHD
    Time (Years) Following RT Start
    C
    Percent All-Cause Mortality 
    Pre-Existing CHD
    Time (Years) Following RT Start
    medical therapy and/or are medically optimized according to AHA/ACC recommendations (31,34). Together, these findings illustrate that patients with locally advanced NSCLC represent a distinctly high cardiovascular-risk population both at baseline and due to radiation exposure with an unmet need for optimized cardiac risk reduction.
    Second, utilization of MACE endpoints (17) allows comparison to comprehensive radiotherapy-associated cardiotoxicity studies in breast cancer and Hodgkin lymphoma (1–3). Indeed, Darby et al. (3) reported that major coronary event (MI, 
    revascularization, CV death) rates increased linearly with MHD by 7.4% per Gy, beginning within 5 years post-radiotherapy (3), and Van Nimwegen et al. (1,2) similarly showed 7.4% per Gy excess relative risk of CHD with a median interval to CHD of >18 years. Although we observed a similar absolute risk of MACE (HR: 1.05/Gy) in NSCLC patients with no apparent threshold below which the risk was decreased (Online Figure 1), these events occurred over a considerably more contracted timeframe (1 to 2 years) in patients with high baseline cardiac risk and a significant competing risk of lung cancer mortality. Together,
    these results suggest that cardiac events may be under-measured after high-dose thoracic radio-therapy and may impart an even greater clinical effect as competing risks decrease with improved NSCLC outcomes (7–11), thereby further illustrating the importance of cardiac dose reduction.
    Third, our observed cumulative incidence of grade $3 CTCAE (23% at 2 years) was higher than recent studies reporting 2-year rates of 10% and 11% for “symptomatic cardiac events” or grade $3 CTCAE, respectively (12,13). These differences may be due, in part, to a higher proportion of CHD-positive patients in our cohort (36% vs. 14% to 27%), as MHD was similar (12,13). Notably, our study included 748 pa-tients, perhaps providing more robust estimates of cardiac events and baseline risk compared with smaller cohorts (n ¼ 112 [12] or n ¼ 125 [13]), which may be reflected by the interaction between CHD and MHD observed in our study compared with Dess et al.
    Given the global burden of NSCLC and improving outcomes in the era of immunomodulatory and molecularly targeted therapies (9,11), post-radiotherapy cardiac events present a formidable health problem for which aggressive risk mitigation strategies are imminently needed and adequate practice guidelines are lacking. Indeed, American Society of Clinical Oncology recommendations focus on anthracycline and anti-HER2–associated car-diotoxicity with echocardiogram-based monitoring
    (35) , but are insufficient for radiotherapy-based risk assessment, particularly in high cardiac-risk NSCLC patients. Accordingly, we recommend that all NSCLC patients undergo age appropriate screening for car-diac risk factors with estimation of 10-year cardio-vascular risk using either Framingham or AHA/ACC risk scores. Cardiac risk factors (i.e., blood pressure, cholesterol, and hemoglobin A1c) should be opti-mized per current guideline recommendations. Given the increased prevalence of CVD in this population