title: Cardiac Toxicity After Radiotherapy for Stage III Non-Small-Cell Lung Cancer: Pooled Analysis of Dose-Escalation Trials Delivering 70 to 90 Gy.
abstract: Purpose The significance of radiotherapy (RT) -associated cardiac injury for stage III non-small-cell lung cancer (NSCLC) is unclear, but higher heart doses were associated with worse overall survival in the Radiation Therapy Oncology Group (RTOG) 0617 study. We assessed the impact of heart dose in patients treated at our institution on several prospective dose-escalation trials. Patients and Methods From 1996 to 2009, 127 patients with stage III NSCLC (Eastern Cooperative Oncology Group performance status, 0 to 1) received dose-escalated RT to 70 to 90 Gy (median, 74 Gy) in six trials. RT plans and cardiac doses were reviewed. Records were reviewed for the primary end point: symptomatic cardiac events (symptomatic pericardial effusion, acute coronary syndrome, pericarditis, significant arrhythmia, and heart failure). Cardiac risk was assessed by noting baseline coronary artery disease and calculating the WHO/International Society of Hypertension score. Competing risks analysis was used. Results In all, 112 patients were analyzed. Median follow-up for surviving patients was 8.8 years. Twenty-six patients (23%) had one or more events at a median of 26 months to first event (effusion [n = 7], myocardial infarction [n = 5], unstable angina [n = 3], pericarditis [n = 2], arrhythmia [n = 12], and heart failure [n = 1]). Heart doses (eg, heart mean dose; hazard ratio, 1.03/Gy; P = .002,), coronary artery disease ( P < .001), and WHO/International Society of Hypertension score ( P = .04) were associated with events on univariable analysis. Heart doses remained significant on multivariable analysis that accounted for baseline risk. Two-year competing risk-adjusted event rates for patients with heart mean dose < 10 Gy, 10 to 20 Gy, or ≥ 20 Gy were 4%, 7%, and 21%, respectively. Heart doses were not associated with overall survival. Conclusion Cardiac events were relatively common after high-dose thoracic RT and were independently associated with both heart dose and baseline cardiac risk. RT-associated cardiac toxicity after treatment of stage III NSCLC may occur earlier than historically understood, and heart doses should be minimized.
authors.affiliation: Kyle Wang, Michael J. Eblan, Matthew Lipner, Timothy M. Zagar, Panayiotis Mavroidis, Carrie B. Lee, Brian C. Jensen, Julian G. Rosenman, and Lawrence B. Marks, University of North Carolina Hospitals; Allison M. Deal and Yue Wang, Lineberger Comprehensive Cancer Center Biostatistics Core, University of North Carolina Hospitals, Chapel Hill; Thomas E. Stinchcombe, Duke University Hospitals, Durham, NC; and Mark A. Socinski, Florida Hospital Cancer Institute, Orlando, FL.
authors.forename: Kyle
authors.initials: K
authors.lastname: Wang
authors.affiliation: Kyle Wang, Michael J. Eblan, Matthew Lipner, Timothy M. Zagar, Panayiotis Mavroidis, Carrie B. Lee, Brian C. Jensen, Julian G. Rosenman, and Lawrence B. Marks, University of North Carolina Hospitals; Allison M. Deal and Yue Wang, Lineberger Comprehensive Cancer Center Biostatistics Core, University of North Carolina Hospitals, Chapel Hill; Thomas E. Stinchcombe, Duke University Hospitals, Durham, NC; and Mark A. Socinski, Florida Hospital Cancer Institute, Orlando, FL.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eblan
authors.affiliation: Kyle Wang, Michael J. Eblan, Matthew Lipner, Timothy M. Zagar, Panayiotis Mavroidis, Carrie B. Lee, Brian C. Jensen, Julian G. Rosenman, and Lawrence B. Marks, University of North Carolina Hospitals; Allison M. Deal and Yue Wang, Lineberger Comprehensive Cancer Center Biostatistics Core, University of North Carolina Hospitals, Chapel Hill; Thomas E. Stinchcombe, Duke University Hospitals, Durham, NC; and Mark A. Socinski, Florida Hospital Cancer Institute, Orlando, FL.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Deal
authors.affiliation: Kyle Wang, Michael J. Eblan, Matthew Lipner, Timothy M. Zagar, Panayiotis Mavroidis, Carrie B. Lee, Brian C. Jensen, Julian G. Rosenman, and Lawrence B. Marks, University of North Carolina Hospitals; Allison M. Deal and Yue Wang, Lineberger Comprehensive Cancer Center Biostatistics Core, University of North Carolina Hospitals, Chapel Hill; Thomas E. Stinchcombe, Duke University Hospitals, Durham, NC; and Mark A. Socinski, Florida Hospital Cancer Institute, Orlando, FL.
authors.forename: Matthew
authors.initials: M
authors.lastname: Lipner
authors.affiliation: Kyle Wang, Michael J. Eblan, Matthew Lipner, Timothy M. Zagar, Panayiotis Mavroidis, Carrie B. Lee, Brian C. Jensen, Julian G. Rosenman, and Lawrence B. Marks, University of North Carolina Hospitals; Allison M. Deal and Yue Wang, Lineberger Comprehensive Cancer Center Biostatistics Core, University of North Carolina Hospitals, Chapel Hill; Thomas E. Stinchcombe, Duke University Hospitals, Durham, NC; and Mark A. Socinski, Florida Hospital Cancer Institute, Orlando, FL.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Zagar
authors.affiliation: Kyle Wang, Michael J. Eblan, Matthew Lipner, Timothy M. Zagar, Panayiotis Mavroidis, Carrie B. Lee, Brian C. Jensen, Julian G. Rosenman, and Lawrence B. Marks, University of North Carolina Hospitals; Allison M. Deal and Yue Wang, Lineberger Comprehensive Cancer Center Biostatistics Core, University of North Carolina Hospitals, Chapel Hill; Thomas E. Stinchcombe, Duke University Hospitals, Durham, NC; and Mark A. Socinski, Florida Hospital Cancer Institute, Orlando, FL.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Kyle Wang, Michael J. Eblan, Matthew Lipner, Timothy M. Zagar, Panayiotis Mavroidis, Carrie B. Lee, Brian C. Jensen, Julian G. Rosenman, and Lawrence B. Marks, University of North Carolina Hospitals; Allison M. Deal and Yue Wang, Lineberger Comprehensive Cancer Center Biostatistics Core, University of North Carolina Hospitals, Chapel Hill; Thomas E. Stinchcombe, Duke University Hospitals, Durham, NC; and Mark A. Socinski, Florida Hospital Cancer Institute, Orlando, FL.
authors.forename: Panayiotis
authors.initials: P
authors.lastname: Mavroidis
authors.affiliation: Kyle Wang, Michael J. Eblan, Matthew Lipner, Timothy M. Zagar, Panayiotis Mavroidis, Carrie B. Lee, Brian C. Jensen, Julian G. Rosenman, and Lawrence B. Marks, University of North Carolina Hospitals; Allison M. Deal and Yue Wang, Lineberger Comprehensive Cancer Center Biostatistics Core, University of North Carolina Hospitals, Chapel Hill; Thomas E. Stinchcombe, Duke University Hospitals, Durham, NC; and Mark A. Socinski, Florida Hospital Cancer Institute, Orlando, FL.
authors.forename: Carrie B
authors.initials: CB
authors.lastname: Lee
authors.affiliation: Kyle Wang, Michael J. Eblan, Matthew Lipner, Timothy M. Zagar, Panayiotis Mavroidis, Carrie B. Lee, Brian C. Jensen, Julian G. Rosenman, and Lawrence B. Marks, University of North Carolina Hospitals; Allison M. Deal and Yue Wang, Lineberger Comprehensive Cancer Center Biostatistics Core, University of North Carolina Hospitals, Chapel Hill; Thomas E. Stinchcombe, Duke University Hospitals, Durham, NC; and Mark A. Socinski, Florida Hospital Cancer Institute, Orlando, FL.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Jensen
authors.affiliation: Kyle Wang, Michael J. Eblan, Matthew Lipner, Timothy M. Zagar, Panayiotis Mavroidis, Carrie B. Lee, Brian C. Jensen, Julian G. Rosenman, and Lawrence B. Marks, University of North Carolina Hospitals; Allison M. Deal and Yue Wang, Lineberger Comprehensive Cancer Center Biostatistics Core, University of North Carolina Hospitals, Chapel Hill; Thomas E. Stinchcombe, Duke University Hospitals, Durham, NC; and Mark A. Socinski, Florida Hospital Cancer Institute, Orlando, FL.
authors.forename: Julian G
authors.initials: JG
authors.lastname: Rosenman
authors.affiliation: Kyle Wang, Michael J. Eblan, Matthew Lipner, Timothy M. Zagar, Panayiotis Mavroidis, Carrie B. Lee, Brian C. Jensen, Julian G. Rosenman, and Lawrence B. Marks, University of North Carolina Hospitals; Allison M. Deal and Yue Wang, Lineberger Comprehensive Cancer Center Biostatistics Core, University of North Carolina Hospitals, Chapel Hill; Thomas E. Stinchcombe, Duke University Hospitals, Durham, NC; and Mark A. Socinski, Florida Hospital Cancer Institute, Orlando, FL.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Socinski
authors.affiliation: Kyle Wang, Michael J. Eblan, Matthew Lipner, Timothy M. Zagar, Panayiotis Mavroidis, Carrie B. Lee, Brian C. Jensen, Julian G. Rosenman, and Lawrence B. Marks, University of North Carolina Hospitals; Allison M. Deal and Yue Wang, Lineberger Comprehensive Cancer Center Biostatistics Core, University of North Carolina Hospitals, Chapel Hill; Thomas E. Stinchcombe, Duke University Hospitals, Durham, NC; and Mark A. Socinski, Florida Hospital Cancer Institute, Orlando, FL.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Stinchcombe
authors.affiliation: Kyle Wang, Michael J. Eblan, Matthew Lipner, Timothy M. Zagar, Panayiotis Mavroidis, Carrie B. Lee, Brian C. Jensen, Julian G. Rosenman, and Lawrence B. Marks, University of North Carolina Hospitals; Allison M. Deal and Yue Wang, Lineberger Comprehensive Cancer Center Biostatistics Core, University of North Carolina Hospitals, Chapel Hill; Thomas E. Stinchcombe, Duke University Hospitals, Durham, NC; and Mark A. Socinski, Florida Hospital Cancer Institute, Orlando, FL.
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Marks
mesh_terms: D000293:Adolescent; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000532:radiotherapy*; D066126:Cardiotoxicity / Q000209:etiology*; D002648:Child; D002675:Child, Preschool; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D009367:Neoplasm Staging; D011446:Prospective Studies; D011832:Radiation Injuries / Q000209:etiology*; D011878:Radiotherapy / Q000009:adverse effects