Cardiac Events After Radiation Therapy: Combined Analysis of Prospective Multicenter Trials for Locally Advanced Non-Small-Cell Lung Cancer

Abstract

Purpose Radiation therapy is a critical component in the care of patients with non-small-cell lung cancer (NSCLC), yet cardiac injury after treatment is a significant concern. Therefore, we wished to elucidate the incidence of cardiac events and their relationship to radiation dose to the heart. Patients and Materials Study eligibility criteria included patients with stage II to III NSCLC treated on one of four prospective radiation therapy trials at two centers from 2004 to 2013. All cardiac events were reviewed and graded per Common Terminology Criteria for Adverse Events (v4.03). The primary end point was the development of a grade ≥ 3 cardiac event. Results In all, 125 patients met eligibility criteria; median follow-up was 51 months for surviving patients. Median prescription dose was 70 Gy, 84% received concurrent chemotherapy, and 27% had pre-existing cardiac disease. Nineteen patients had a grade ≥ 3 cardiac event at a median of 11 months (interquartile range, 6 to 24 months), and 24-month cumulative incidence was 11% (95% CI, 5% to 16%). On multivariable analysis (MVA), pre-existing cardiac disease (hazard ratio [HR], 2.96; 95% CI, 1.07 to 8.21; P = .04) and mean heart dose (HR, 1.07/Gy; 95% CI, 1.02 to 1.13/Gy; P = .01) were significantly associated with grade ≥ 3 cardiac events. Analyzed as time-dependent variables on MVA analysis, both disease progression (HR, 2.15; 95% CI, 1.54 to 3.00) and grade ≥ 3 cardiac events (HR, 1.76; 95% CI, 1.04 to 2.99) were associated with decreased overall survival. However, disease progression (n = 71) was more common than grade ≥ 3 cardiac events (n = 19). Conclusion The 24-month cumulative incidence of grade ≥ 3 cardiac events exceeded 10% among patients with locally advanced NSCLC treated with definitive radiation. Pre-existing cardiac disease and higher mean heart dose were significantly associated with higher cardiac event rates. Caution should be used with cardiac dose to minimize risk of radiation-associated injury. However, cardiac risks should be balanced against tumor control, given the unfavorable prognosis associated with disease progression.

Fig 1.

Cumulative incidence of grade ≥ 3 cardiac events. (A) Actual cumulative incidence of grade ≥ 3 cardiac events (with noncardiac death as competing risk) for the total cohort, (B) for those with and without pre-existing cardiac disease, and (C) for those with greater than or less than the median mean heart dose of 11 Gy.

Fig 2.

Model-predicted cumulative incidence of a grade ≥ 3 cardiac event within 24 months of treatment by increasing mean heart dose (A) for those with and without pre-existing cardiac disease and (B) for the subpopulation of only those without baseline cardiac disease. Representative patient Framingham risk scores of 10 and 20 are shown.

Fig A1.

The cardiac dose correlation (Corr.) matrix demonstrates the correlation between mean heart dose and volume receiving 5 Gy (V5_Gy) to V50_Gy (%). The distribution of each variable is shown on the diagonal.

Fig A2.

Cumulative incidence of grade ≥ 3 cardiac events (volume receiving 5 Gy [V5_Gy] and V30_Gy). Actual cumulative incidence of grade ≥ 3 cardiac events (with noncardiac death as competing risk) (A) for those greater than or less than the median V5_Gy of 40% (P < .01) and (B) for those greater than or less than the median V30_Gy of 12% (P < .01).

Fig A3.

Predicted probability of grade ≥ 3 cardiac events within 24 months. Model-predicted cumulative incidence of a grade ≥ 3 cardiac event within 24 months of treatment for those with and without pre-existing cardiac disease with increasing (A) V5_Gy and (B) V30_Gy.

Fig A4.

K-M estimated for (A) overall survival and (B) progression-free survival.