• 2019-07
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  • 2019-11
  • 2020-03
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  • br a detailed history and physical


    (36) , a detailed history and physical to assess for signs or symptoms concerning for ischemia and CHD should be performed, and if present or if very poor functional capacity, further workup, including func-tional stress test with imaging, should be considered. The optimal method for risk assessment, monitoring, and risk reductive measures beyond current recom-mended guidelines warrants prospective testing.
    For radiotherapy planning, we suggest a more stringent avoidance of high cardiac radiotherapy dose and reconsideration of stricter cardiac JNJ-42153605 dose constraints than those recently published (MHD <20 Gy) (12) or in national guidelines (MHD <20 Gy in 2019 guidelines but previously #26 Gy) (36). Specifically, 
    we recommend MHD <10 Gy, based on a comparison with recently published dose stratifications (12,13) and our clinical threshold for toxicity, as a cutoff <10 Gy correlated with MACE and grade $3 CTCAE 2-year cumulative incidences of 1% and 14%, respectively, in CHD-negative patients, and 10% and 30%, respectively, in CHD-positive patients, and was conservatively just below cutpoint analysis thresh-olds (13.5 and 11.5 Gy for MACE and grade $3 CTCAE, respectively). If recommended doses must be excee-ded due to tumor location and/or lung dose safety, we advocate for early, frequent cardiology follow-up for primary or secondary prevention with aggressive risk factor management.
    Although we did not observe an association be-tween cardiac dose and risk of MACE/CTCAE/ACM in CHD-positive patients, we suspect this is due to sur-passing an observable dose-response relationship in the setting of elevated baseline cardiac risk with high-dose thoracic RT, rather than cardiac dose not being important in these patients. Indeed, among the 50 CHD-positive patients who received <5 Gy MHD, the 2-year cumulative incidence of MACE was already 10.1% while patients receiving $10 Gy had rates of 12.1%. Furthermore, the absolute increase in the 2-year cumulative incidence of MACE with MHD $10 Gy versus <10 Gy in CHD-negative versus CHD-positive patients was similar (2.4% vs. 2.1%, respectively), which may reflect an effect of cardiac dose being masked in CHD-positive patients who have elevated baseline cardiac event rates, even at MHD <5 Gy. Thus, there may not be a “safe” cardiac dose threshold in this setting, and these patients may warrant dose limits that are significantly lower, although this warrants further investigation.
    STUDY LIMITATIONS. Potential limitations of this study include the heterogeneous treatment regimens and its retrospective nature. Indeed, more than one-third of treatment regimens included surgery, which was associated with reduced risk of ACM and likely a surrogate for better baseline cardiac and performance status. Nonetheless, after accounting for treatment regimens, chemotherapy use, and radiotherapy technique, cardiac dose remained an independent predictor of MACE, CTCAE, and ACM, suggesting that our results may be generalizable to a broad range of locally advanced NSCLC treatment paradigms that include radiotherapy. Importantly, despite MACE and CTCAE events commonly occurring post-radiotherapy in this study, retrospective assessment may in fact underestimate true cardiac risk, particularly in pa-tients with limited follow-up due to competing risks or medical care received locally and incompletely
    captured despite in-depth medical record review. Similarly, although we observed a 36% prevalence of CHD, consistent with studies from others (13,31), this may be an underestimate in the retrospec-tive setting.
    Our study strongly suggests that despite the competing risk of cancer-specific death and short life expectancy of locally advanced NSCLC patients, there is a high risk for MACE within 2-years post-radiotherapy and cardiac radiation dose exposure is an independent predictor of MACE, grade $3 CTCAE, and ACM. The results of this study highlight the importance of early recognition and treatment of cardiovascular events and inform the design of future prospective trials that incorporate baseline cardiac risk stratification with cardiac radiation dose reduc-tion techniques and post-radiotherapy cardiac pre-ventative care. Indeed, as cardiac dose exposure is a modifiable predictor, we suggest more stringent avoidance of high cardiac radiotherapy dose and reconsideration of stricter cardiac radiation dose constraints in national radiotherapy guidelines. 
    ADDRESS FOR CORRESPONDENCE: Dr. Raymond H. Mak, Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, 450 Brookline Avenue, Boston, Massachusetts 02115. E-mail: [email protected] Twitter: @Dr_RayMak.