Author + information
- Received January 2, 2019
- Revision received March 19, 2019
- Accepted March 20, 2019
- Published online June 10, 2019.
- Katelyn M. Atkins, MD, PhDa,
- Bhupendra Rawal, MSb,
- Tafadzwa L. Chaunzwa, BSc,d,
- Nayan Lamba, BAe,
- Danielle S. Bitterman, MDa,
- Christopher L. Williams, PhDd,
- David E. Kozono, MD, PhDd,
- Elizabeth H. Baldini, MD, MPHd,
- Aileen B. Chen, MD, MPPd,
- Paul L. Nguyen, MDd,
- Anthony V. D’Amico, MD, PhDd,
- Anju Nohria, MDf,
- Udo Hoffmann, MDg,
- Hugo J.W.L. Aerts, PhDd,h and
- Raymond H. Mak, MDd,∗ (, )@Dr_RayMak
- aHarvard Radiation Oncology Program, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, Massachusetts
- bDepartment of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
- cYale School of Medicine, New Haven, Connecticut
- dDepartment of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, Massachusetts
- eHarvard Medical School, Boston, Massachusetts
- fDepartment of Cardiovascular Medicine, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, Massachusetts
- gDepartment of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- hDepartment of Radiology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, Massachusetts
- ↵∗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.
Background Radiotherapy-associated cardiac toxicity studies in patients with locally advanced non–small cell lung cancer (NSCLC) have been limited by small sample size and nonvalidated cardiac endpoints.
Objectives The purpose of this analysis was to ascertain whether cardiac radiation dose is a predictor of major adverse cardiac events (MACE) and all-cause mortality (ACM).
Methods This retrospective analysis included 748 consecutive locally advanced NSCLC patients treated with thoracic radiotherapy. Fine and Gray and Cox regressions were used to identify predictors for MACE and ACM, adjusting for lung cancer and cardiovascular prognostic factors, including pre-existing coronary heart disease (CHD).
Results After a median follow-up of 20.4 months, 77 patients developed ≥1 MACE (2-year cumulative incidence, 5.8%; 95% confidence interval [CI]: 4.3% to 7.7%), and 533 died. Mean radiation dose delivered to the heart (mean heart dose) was associated with a significantly increased risk of MACE (adjusted hazard ratio [HR]: 1.05/Gy; 95% CI: 1.02 to 1.08/Gy; p < 0.001) and ACM (adjusted HR: 1.02/Gy; 95% CI: 1.00 to 1.03/Gy; p = 0.007). Mean heart dose (≥10 Gy vs. <10 Gy) was associated with a significantly increased risk of ACM in CHD-negative patients (178 vs. 118 deaths; HR: 1.34; 95% CI: 1.06 to 1.69; p = 0.014) with 2-year estimates of 52.2% (95% CI: 46.1% to 58.5%) versus 40.0% (95% CI: 33.5% to 47.4%); but not among CHD-positive patients (112 vs. 82 deaths; HR: 0.94; 95% CI: 0.70 to 1.25; p = 0.66) with 2-year estimates of 54.6% (95% CI: 46.8% to 62.7%) versus 50.8% (95% CI: 41.5% to 60.9%), respectively (p for interaction = 0.028).
Conclusions Despite the competing risk of cancer-specific death in locally advanced NSCLC patients, cardiac radiation dose exposure is a modifiable cardiac risk factor for MACE and ACM, supporting the need for early recognition and treatment of cardiovascular events and more stringent avoidance of high cardiac radiotherapy dose.
Dr. Williams has received research grants from Varian Medical Systems. Dr. Nguyen has received consulting fees from Blue Earth, Ferring, Janssen, Astellas, Cota, Nanobiotix, Genome DX, Augmenix, Boston Scientific, Dendreon, and Bayer; and has received grants (to institution) from Janssen and Astellas. Dr. Nohria has received a research grant (to institution) from Amgen; and has served as a consultant for Takeda Oncology. Dr. Hoffmann has received research grants (to institution) from Medimmune, Kowa, and HeartFlow Inc. Dr. Aerts has received consulting fees from Sphera and Genospace. Dr. Mak has served on the Scientific Advisory Board of AstraZeneca; and has received an honorarium from NewRT. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received January 2, 2019.
- Revision received March 19, 2019.
- Accepted March 20, 2019.
- 2019 The Authors