Radiation, chemotherapy, and biologic agents, both independently and in combination, increase the risk of cardiovascular disease in survivors of childhood cancer; in fact, cardiovascular death has been reported to account for 26% of the excess absolute risk of death by 45 or more years from diagnosis in adults who survived childhood cancers, and is the leading cause of noncancer mortality in select cancers such as Hodgkin lymphoma (HL).[1,2] During the 30 years after cancer treatment, survivors are eight times more likely to die from cardiac causes and 15 times more likely to be diagnosed with congestive heart failure (CHF) than the general population.[3,4] Therapeutic exposures conferring the highest risk are the anthracyclines (doxorubicin, daunorubicin, idarubicin, epirubicin, and mitoxantrone) and thoracic radiation. The risks to the heart are related to cumulative anthracycline dose, method of administration, amount of radiation delivered to different depths of the heart, volume and specific areas of the heart irradiated, total and fractional irradiation dose, age at exposure, latency period, and gender.
The effects of thoracic radiation therapy are difficult to separate from those of anthracyclines because few children undergo thoracic radiation therapy without the use of anthracyclines. However, several reports do allow some segregation of the effects of radiation from those of chemotherapy. Of note, the pathogenesis of injury differs, with radiation primarily affecting the fine vasculature of the heart and anthracyclines directly damaging myocytes. Late effects of radiation to the heart include the following:[6,7]
- Delayed pericarditis, which can present abruptly or as a chronic pericardial effusion.
- Pancarditis, which includes pericardial and myocardial fibrosis, with or without endocardial fibroelastosis.
- Myopathy (in the absence of significant pericardial disease).
- Coronary artery disease (CAD), usually involving the left anterior descending artery.
- Functional valve injury, often aortic.
- Conduction defects.
In a recent report from the Children's Cancer Survivors Study (CCSS) cohort, detailed dose-response evaluations for both radiation therapy and anthracycline administration were conducted for the risks (self-reported) of CHF, myocardial infarction (MI), pericardial disease, and valvular abnormalities.
Compared with siblings, survivors of childhood cancer were significantly more likely to report CHF (hazard ratio [HR] = 5.9; 95% confidence interval [CI], 3.4-9.6), MI (HR = 5.0; 95% CI, 2.3-10.4), pericardial disease (HR = 6.3; 95 % CI, 3.3-11.9), or valvular abnormalities (HR = 4.8; 95 % CI, 3.0-7.6). Cardiac radiation exposure of 15 Gy or more increased the risk of CHF, MI, pericardial disease, and valvular abnormalities by twofold to sixfold compared with nonirradiated survivors. There was no evidence for increased risk following doses less than 5 Gy, and slight elevations in risk were not statistically significant following doses between 5 to 15 Gy. The HR for the four self-reported cardiac conditions ranged from 3.6 to 5.5 for cardiac doses greater than 35 Gy. Exposure to 250 mg/m2 or more of anthracyclines also increased the risk of CHF, pericardial disease, and valvular abnormalities by two to five times compared with survivors who had not been exposed to anthracyclines. The cumulative incidence of adverse cardiac outcomes in childhood cancer survivors continued to increase up to 30 years after diagnosis and ranged from about 2% to slightly over 4% overall, but to much higher cumulative percentages for those receiving the highest cardiac radiation doses and the highest cumulative dose of anthracyclines.