br NSCLC br MHD mean heart dose
MHD = mean CVT-12012 dose
MACE = major adverse cardiac
CTCAE = common terminology criteria for adverse event
ACM = all-cause mortality
Cardiac toxicity following radiotherapy has been observed in long-term breast cancer and Hodgkin lymphoma survivors, with a
typical latency period of more than a decade and increased incidence with higher heart dose, younger age at treatment, and pre-existing cardiac risk factors (1–3). However, although these malignancies portend a more favorable prognosis, lung cancer is conversely the leading cause of cancer-related death in the United States (4). Thus, the clinical relevance of radiotherapy-associated cardiac toxicity in locally advanced non–small cell lung cancer (NSCLC) pa-tients has historically been minimized given the competing risk of cancer-specific death and presump-tion of prolonged latency to cardiotoxicity (5,6).
The secondary objective included analyzing cardiac event subgroups using oncology clinical trial common terminology criteria for adverse event (CTCAE) scales (20). This study provides a deeper understanding of the rela-tionship between CHD and the incremental risk of cardiac radiation dose exposure as a potentially modifiable risk factor, thereby substantially affecting national guidelines on radiotherapy planning and providing a shared framework among radiation oncolo-gists, primary care physicians, and cardiolo-gists to increase recognition and treatment of
cardiovascular events and inform post-radiotherapy cardiac risk prevention strategies.
coronary heart disease
non–small cell lung
However, recent multicenter trials have reported improved 5-year survival rates of 15% to 20% and median survival times >2 years (7,8), while encour-aging results have been observed with lung cancer screening in high-risk populations, molecularly tar-geted therapies in advanced disease, and con-solidative immunotherapy for locally advanced disease (9–11). Moreover, recent studies have re-ported that cardiac events in NSCLC patients treated with radiotherapy are common, associated with car-diac radiation dose and baseline cardiac risk (12,13), and predict for mortality (7,14). However, these studies were limited by small sample size, inconsis-tent endpoints, and variable baseline cardiac risk assessment (5–7,12,13,15,16). To the best of our knowledge, no prior NSCLC studies have utilized American Heart Association (AHA)/American College of Cardiology (ACC)–defined endpoints (17), thus precluding rational extrapolation to baseline Fra-mingham risk (18) and guideline-based cardiovascu-lar risk prevention interventions (19). Therefore, given improving NSCLC outcomes together with clinically significant cardiac events post-radiotherapy, there remains an urgent need for improved cardiac risk assessment using validated cardiac endpoints, identification of predictive factors, and maximized risk reduction strategies with opti-mized radiotherapy approaches.
The primary objective of the current study was to determine whether cardiac radiation dose exposure was associated with an increased risk of AHA/ACC-defined major adverse cardiac events (MACE) (17) and all-cause mortality (ACM) in a large cohort of locally advanced NSCLC patients treated with thoracic radiotherapy, adjusting for traditional lung cancer and cardiovascular prognostic factors, including pre-existing coronary heart disease (CHD).
PATIENT POPULATION. Single-institution retrospec-tive cohort study of 748 consecutive locally advanced NSCLC patients treated between November 30, 1998, and January 27, 2014, at Dana-Farber Cancer Insti-tute, Brigham and Women’s Hospital, and Dana-Farber Cancer Institute/Brigham and Women’s Hospital at Milford Regional Medical Center. Eligible patients had 2010 American Joint Commission on Cancer clinical stage II (medically inoperable or unresectable) or III NSCLC treated with thoracic radiotherapy using conventional (3-dimensional conformal radiotherapy) or intensity-modulated radiotherapy techniques. Patients treated with ste-reotactic body radiotherapy were excluded. This study was approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board.
TREATMENT. Patients were treated with definitive concurrent chemoradiotherapy (without surgery), neoadjuvant radiotherapy or chemoradiotherapy (prior to surgical resection), or adjuvant radiotherapy or chemoradiotherapy (following surgical resection). Chemotherapy was typically administered as a plat-inum doublet, including cisplatin or carboplatin plus a cytotoxic agent (pemetrexed, docetaxel, paclitaxel, gemcitabine, or vinorelbine). A 3-dimensional or 4-dimensional computed tomography (CT) scan was obtained for radiotherapy planning, and when avail-able, diagnostic CT and/or positron emission tomog-raphy scans were coregistered to the planning CT to aid delineation of tumor and normal anatomy struc-tures. Radiation was targeted to the gross tumor and/or areas most at risk for microscopic tumor and was typically delivered in daily fractions (treatments) of 1.8 to 2.0 Gy (range 1.8 to 4.0 Gy; 99.2% [742 of 748] received 1.8-2.0 Gy fractions) to cumulative doses of 50 to 66 Gy. Radiotherapy was planned using Varian