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. 2021 Feb 1;7(2):206-219.
doi: 10.1001/jamaoncol.2020.6332.

Association of Left Anterior Descending Coronary Artery Radiation Dose With Major Adverse Cardiac Events and Mortality in Patients With Non-Small Cell Lung Cancer

Katelyn M Atkins  1   2 , Tafadzwa L Chaunzwa  2 , Nayan Lamba  2 , Danielle S Bitterman  2 , Bhupendra Rawal  3 , Jeremy Bredfeldt  2 , Christopher L Williams  2 , David E Kozono  2 , Elizabeth H Baldini  2 , Anju Nohria  4 , Udo Hoffmann  5 , Hugo J W L Aerts  2   6 , Raymond H Mak  2
Affiliations

Association of Left Anterior Descending Coronary Artery Radiation Dose With Major Adverse Cardiac Events and Mortality in Patients With Non-Small Cell Lung Cancer

Katelyn M Atkins et al. JAMA Oncol. .

Abstract

Importance: Radiotherapy accelerates coronary heart disease (CHD), but the dose to critical cardiac substructures has not been systematically studied in lung cancer.

Objective: To examine independent cardiac substructure radiotherapy factors for major adverse cardiac events (MACE) and all-cause mortality in patients with locally advanced non-small cell lung cancer (NSCLC).

Design, setting, and participants: A retrospective cohort analysis of 701 patients with locally advanced NSCLC treated with thoracic radiotherapy at Harvard University-affiliated hospitals between December 1, 2003, and January 27, 2014, was performed. Data analysis was conducted between January 12, 2019, and July 22, 2020. Cardiac substructures were manually delineated. Radiotherapy dose parameters (mean, maximum, and the volume [V, percentage] receiving a specific Gray [Gy] dose in 5-Gy increments) were calculated. Receiver operating curve and cut-point analyses estimating MACE (unstable angina, heart failure hospitalization or urgent visit, myocardial infarction, coronary revascularization, and cardiac death) were performed. Fine and Gray and Cox regressions were adjusted for preexisting CHD and other prognostic factors.

Main outcomes and measures: MACE and all-cause mortality.

Results: Of the 701 patients included in the analysis, 356 were men (50.8%). The median age was 65 years (interquartile range, 57-73 years). The optimal cut points for substructure and radiotherapy doses (highest C-index value) were left anterior descending (LAD) coronary artery V15 Gy greater than or equal to 10% (0.64), left circumflex coronary artery V15 Gy greater than or equal to 14% (0.64), left ventricle V15 Gy greater than or equal to 1% (0.64), and mean total coronary artery dose greater than or equal to 7 Gy (0.62). Adjusting for baseline CHD status and other prognostic factors, an LAD coronary artery V15 Gy greater than or equal to 10% was associated with increased risk of MACE (adjusted hazard ratio, 13.90; 95% CI, 1.23-157.21; P = .03) and all-cause mortality (adjusted hazard ratio, 1.58; 95% CI, 1.09-2.29; P = .02). Among patients without CHD, associations with increased 1-year MACE were noted for LAD coronary artery V15 Gy greater than or equal to 10% (4.9% vs 0%), left circumflex coronary artery V15 Gy greater than or equal to 14% (5.2% vs 0.7%), left ventricle V15 Gy greater than or equal to 1% (5.0% vs 0.4%), and mean total coronary artery dose greater than or equal to 7 Gy (4.8% vs 0%) (all P ≤ .001), but only a left ventricle V15 Gy greater than or equal to 1% increased the risk among patients with CHD (8.4% vs 4.1%; P = .046). Among patients without CHD, 2-year all-cause mortality was increased with an LAD coronary artery V15 Gy greater than or equal to 10% (51.2% vs 42.2%; P = .009) and mean total coronary artery dose greater than or equal to 7 Gy (53.2% vs 40.0%; P = .01).

Conclusions and relevance: The findings of this cohort study suggest that optimal cardiac dose constraints may differ based on preexisting CHD. Although the LAD coronary artery V15 Gy greater than or equal to 10% appeared to be an independent estimator of the probability of MACE and all-cause mortality, particularly in patients without CHD, left ventricle V15 Gy greater than or equal to 1% appeared to confer an increased risk of MACE among patients with CHD. These constraints are worthy of further study because there is a need for improved cardiac risk stratification and aggressive risk mitigation strategies.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Bitterman reported receiving personal fees from Agios Pharmaceuticals outside the submitted work. Dr Williams reported receiving grants from ViewRay Medical Systems outside the submitted work. Dr Nohria reported receiving grants from Amgen Inc and personal fees from Takeda Oncology outside the submitted work. Dr Hoffmann reported receiving consulting fees from Abbott, Duke University (National Institutes of Health [NIH]), Recor Medical and grants on behalf of Kowa Company, MedImmune, HeartFlow, Duke University (Abbott), Oregon Health & Science University (American Hospital Association 13FTF16450001), Columbia University (NIH, 5R01-HL109711), NIH/National Heart, Lung, and Blood Institute [NHLBI] 5K24HL113128, NIH/NHLBI 5T32HL076136, and NIH/NHLBI 5U01HL123339 outside the submitted work. Dr Aerts reported receiving personal fees from Sphera & Genospace and Onc.AI Inc outside the submitted work. Dr Mak reported receiving personal fees from AstraZeneca, grants and personal fees from ViewRay Inc, and personal fees from NewRT outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Cumulative Incidence of Major Adverse Cardiac Events (MACE) Stratified by Left Anterior Descending (LAD) Coronary Artery Volume (V)15 Gy Less Than 10% or Greater Than or Equal to 10%
Cumulative incidence of MACE in the total population (P < .001) (A), patients without preexisting coronary heart disease (CHD) (P = .001) (B), or patients with preexisting CHD (P = .25) (C). RT indicates radiotherapy.
Figure 2.
Figure 2.. All-Cause Mortality Stratified by Left Anterior Descending (LAD) Coronary Artery Volume (V)15 Gy Less Than 10% or Greater Than or Equal to 10%
All-cause mortality in the total population (log-rank P = .09) (A), patients without preexisting CHD (log-rank P = .009) (B), or patients with preexisting CHD (log-rank P = .12) (C). RT indicates radiotherapy.
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