Therapy-Related Cardiac Risk in Childhood Cancer Survivors: An Analysis of the Childhood Cancer Survivor Study

Abstract

Purpose: The impacts of radiotherapy dose and exposed cardiac volume, select chemotherapeutic agents, and age at exposure on risk for late-onset cardiac disease in survivors of childhood cancer remain unresolved.

Patients and methods: We determined the rates of severe to fatal cardiac disease in 24,214 5-year survivors in the Childhood Cancer Survivor Study diagnosed between 1970 and 1999 at a median age of 7.0 years (range, 0 to 20.9 years), with a median attained age of 27.5 years (range, 5.6 to 58.9 years). Using piecewise exponential models, we evaluated the association between cardiac disease rates and demographic and treatment characteristics.

Results: The cumulative incidence of cardiac disease 30 years from diagnosis was 4.8% (95% CI, 4.3 to 5.2). Low to moderate radiotherapy doses (5.0 to 19.9 Gy) to large cardiac volumes (≥ 50% of heart) were associated with an increased rate of cardiac disease (relative rate, 1.6; 95% CI, 1.1 to 2.3) compared with survivors without cardiac radiotherapy exposure. Similarly, high doses (≥ 20 Gy) to small cardiac volumes (0.1% to 29.9%) were associated with an elevated rate (relative rate, 2.4; 95% CI, 1.4 to 4.2). A dose-response relationship was observed between anthracycline chemotherapy and heart failure with younger children (age ≤ 13 years) at the greatest risk for heart failure after comparable dosing.

Conclusion: These observations support advances in radiation field design and delivery technology to reduce cardiac dose/volume and should guide future treatment protocols. They also inform clinical practice guidelines for post-therapy surveillance and risk-reducing strategies.

FIG 1.

Cumulative incidence, based on (A-C) mean heart dose, (D-F) volume of heart (%) receiving radiotherapy (RT) greater than or equal to 20 Gy, and (G-I) voulme of heart (%) receiving RT greater than or equal to 5 Gy when maximum heart dose is less than 20 Gy. (J-L) Cumulative anthracycline dose. (*) 0% maximum radiation dose to the heart = 0.1 to 19.9 Gy. (†) 0% maximum radiation dose to the heart = 0.1 to 4.9 Gy.