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.

Cancer treatment and survivorship statistics, 2019

“…Among childhood cancer survivors diagnosed and treated between 1962 and 2001, 65% of those who were exposed to toxic pulmonary treatments experienced pulmonary dysfunction, and 57% of those exposed to potentially cardiotoxic therapies experienced cardiac abnormalities. A recent study showed that even childhood cancer survivors exposed to low doses of radiation treatment had a 1.6‐fold risk of developing cardiac disease over the next 30 years if the area of exposure included more than one‐half of the heart …”

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

“…A small number of clinical studies has addressed potential differences in the sensitivity to develop normal tissue radiation injury between male and female patients, including in the cardiopulmonary system [162][163][164][165]. Interestingly, as also described for preclinical animal models, an increased pulmonary radiation toxicity in women compared to men may be at least in part related to a smaller total lung volume in women and therefore a relatively larger percent volume of the female lung exposed to radiation [166,167].…”

Acquired Immunity Is Not Essential for Radiation-Induced Heart Dysfunction but Exerts a Complex Impact on Injury

“…Other than-or in addition to-these differences, there may also be differences in the response to cardiac RT exposure between males and females. Bates et al analyzed the risk for late-onset cardiac diseases in survivors of childhood cancer given RT and/or anthracyclines and reported that female survivors were at greater risk of heart failure, most likely due to anthracycline-related heart failure, and male survivors had a slightly increased risk of coronary artery disease, with an unclear explanation for these observed sex differences [58]. Mulrooney et al found that, in childhood cancer survivors, on multivariate analysis adjusting for cardiac radiation doses, anthracycline doses, and other factors, females were more likely to experience heart failure after cancer treatment [59].…”