Cardiac Events after Radiation Therapy (RT) for Stage II-III Non-Small Cell Lung Cancer (NSCLC): Analysis of 748 Patients

Abstract

Radiation therapy-associated cardiac toxicity in patients with NSCLC arises sooner and is of greater clinical significance than historically appreciated. Recent studies have been limited by inconsistent definitions and small size. This study reports major cardiac events after RT in a large cohort of patients with NSCLC using comprehensive, validated cardiac toxicity criteria and dose-volume data. Retrospective study of 748 patients with Stage II (9%) to III (91%) NSCLC treated with 3D-conformal (77%) or intensity-modulated (22%) RT (median dose, 64 Gy) and chemotherapy (61%), chemotherapy and surgery (33%), or RT alone (4%) between 1998–2014 at one institution. Hearts were re-contoured per cardiac atlas definitions. Patients without baseline coronary heart disease (CHD) or CHD risk equivalent were stratified by Framingham risk. Primary endpoint was major cardiac events, defined as any grade ≥3 Common Terminology Criteria for Adverse Events (CTCAE, v4.03) or Major Adverse Cardiac Events (MACE). Estimates of Kaplan-Meier overall survival (OS) and cumulative incidence of cardiac events (non-cardiac death as a competing risk) were calculated. Fine and Gray and Cox regressions were performed. Median follow up from RT was 1.9 years. Median mean heart dose was 12.3 Gy. Two-year OS stratified by low, moderate, or high Framingham risk group or known CHD was 62.7%, 56.0%, 47.0%, and 46.8%, respectively (P=.001). Median time to first major cardiac event was 10.4 months; cumulative incidence at 1, 2, and 5-years was 18.2%, 23.5%, and 32.4%, respectively. Two-year cumulative incidence of major cardiac events (conduction, 12.0%; heart failure, 5.7%; MACE, 4.8%; pericardial [all], 4.7%; pericardial [effusion, cytology benign], 1.8%; coronary/ischemic, 2.5%; valvular, 1.1%; and cardiopulmonary/other, 5.4%) was increased in patients with vs without baseline CHD (31.2% vs 18.9%; P<.0001) and those with mean heart dose >12 Gy vs ≤12 Gy (26.7% vs 19.3%; P=.009), respectively. On multivariable analysis (MVA), baseline CHD (hazard ratio [HR] 1.75, 95% CI 1.35–2.28; P<.0001) and mean heart dose (HR 1.09/5 Gy, 95% CI 1.02–1.16; P=.013) were significantly associated with major cardiac events. On MVA accounting for baseline CHD and known lung cancer prognostic factors, major cardiac events were significantly associated with decreased OS (HR 2.91, 95% CI 2.39–3.55; P<.0001), while mean heart dose was not (HR 1.04/5 Gy, 95% CI 0.99–1.09; P=.107). In this large cohort of patients with NSCLC, major cardiac events were common, occurred sooner than previously reported, and were associated with baseline CHD and heart dose. These results build upon recent reports, support efforts to minimize heart irradiation, and highlight the importance of pre-treatment cardiac risk assessment and development of risk mitigation strategies for high risk patients.