Shrestha, Suman

PURPOSE Radiation-associated cardiac disease is a major cause of morbidity/mortality among childhood cancer survivors. Radiation dose-response relationships for cardiac substructures and cardiac diseases remain unestablished. METHODS Using the 25,481 5-year survivors of childhood cancer treated from 1970 to 1999 in the Childhood Cancer Survivor Study, we evaluated coronary artery disease (CAD), heart failure (HF), valvular disease (VD), and arrhythmia. We reconstructed radiation doses for each survivor to the coronary arteries, chambers, valves, and whole heart. Excess relative rate (ERR) models and piecewise exponential models evaluated dose-response relationships. RESULTS The cumulative incidence 35 years from diagnosis was 3.9% (95% CI, 3.4 to 4.3) for CAD, 3.8% (95% CI, 3.4 to 4.2) for HF, 1.2% (95% CI, 1.0 to 1.5) for VD, and 1.4% (95% CI, 1.1 to 1.6) for arrhythmia. A total of 12,288 survivors (48.2%) were exposed to radiotherapy. Quadratic ERR models improved fit compared with linear ERR models for the dose-response relationship between mean whole heart and CAD, HF, and arrhythmia, suggesting a potential threshold dose; however, such departure from linearity was not observed for most cardiac substructure end point dose-response relationships. Mean doses of 5-9.9 Gy to the whole heart did not increase the risk of any cardiac diseases. Mean doses of 5-9.9 Gy to the right coronary artery (rate ratio [RR], 2.6 [95% CI, 1.6 to 4.1]) and left ventricle (RR, 2.2 [95% CI, 1.3 to 3.7]) increased risk of CAD, and to the tricuspid valve (RR, 5.5 [95% CI, 2.0 to 15.1]) and right ventricle (RR, 8.4 [95% CI, 3.7 to 19.0]) increased risk of VD. CONCLUSION Among children with cancer, there may be no threshold dose below which radiation to the cardiac substructures does not increase the risk of cardiac diseases. This emphasizes their importance in modern treatment planning.

10027 Background: Thoracic radiotherapy (RT) is a risk factor for cardiac disease among survivors of childhood cancer based on studies considering RT doses to the entire heart. Dose to specific cardiac substructures may provide more precise dose-response associations to guide RT planning. We report associations between RT dose to cardiac substructures and risk of specific cardiac outcomes. Methods: We determined the cumulative incidences of CTCAE grade 3 – 5 coronary artery disease (CAD), heart failure (HF), and valvular disease (VD) among 25,481 5-year childhood cancer survivors diagnosed 1970 – 1999 in the CCSS. Median age at diagnosis was 6.1 years (0 – 20 years) and at last follow-up 29.8 years (5.6 – 65.9 years). For the 12,228 individuals receiving RT, fields were reconstructed on an age scaled computational phantom. Mean doses to the entire heart, cardiac chambers, valves, and left main, anterior descending (LAD), circumflex, and right coronary (RCA) arteries were estimated. Adjusted piecewise exponential models (including cumulative anthracycline dose) evaluated associations between mean RT dose to each structure and outcomes. Results: At 30 years from diagnosis, the cumulative incidences of grades 3 – 5 CAD, HF, and VD were 2.3% (95% CI 2.0 – 2.5), 2.6% (95% CI 2.4 – 2.9), and 0.6% (95% CI 0.5 – 0.8) respectively. Low dose RT (mean 5 – 9.9 Gy) to the RCA (relative rate [RR] = 2.6, 95% CI 1.6 – 4.1, p < 0.001), LAD (RR = 1.9, 95% CI 1.1 – 3.3, p = 0.019), and left ventricle (RR = 2.2, 95% CI 1.3 – 3.7, p = 0.002) was associated with increased risk of CAD relative to those not exposed; mean dose of 5 – 9.9 Gy to the entire heart was not (RR = 1.1, 95% CI = 0.8 – 1.6, p = 0.59). Table shows the associated cumulative incidences of CAD for these structures. Mean RT doses of 5 – 9.9 Gy to the aortic valve (RR = 4.6, 95% CI 1.5 – 14.0, p = 0.008) and tricuspid valve (RR = 5.5, 95% CI 2.0 – 15.1, p = 0.001) were associated with risk of VD compared to those with no RT; mean heart dose 5 – 9.9 Gy was not (RR = 0.6, 95% CI = 0.2 – 1.3, p = 0.16). No cardiac structure was significantly associated with an increased risk of HF at a mean dose of 5 – 9.9 Gy. Mean RT doses below 5 Gy were not associated with increased risks of CAD, HF, or VD; doses ≥10 Gy to nearly all substructures and the entire heart were. Conclusions: Low dose RT to the coronary arteries and cardiac valves (5 – 9.9 Gy) from RT is associated with increased risk of CAD and VD, respectively. Sensitivity to low dose RT may vary across the heart and doses to specific structures may be more predictive of late cardiac disease than whole heart dose. These data can guide RT planning to prioritize substructures for avoidance.[Table: see text]