Hodgkin lymphoma survivors exposed to doxorubicin or thoracic radiation therapy are at risk for long-term cardiac toxicity. 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. The pathogenesis of injury differs, however, 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:[19,20,21,22]
- Delayed pericarditis.
- Pancarditis, which includes pericardial and myocardial fibrosis, with or without endocardial fibroelastosis.
- Coronary artery disease (CAD).
- Functional valve injury.
- Conduction defects.
In a study of 635 patients treated for childhood Hodgkin lymphoma, the actuarial risk of pericarditis requiring pericardiectomy was 4% at 17 years posttreatment (occurring only in children treated with higher radiation doses). Only 12 patients died of cardiac disease, including seven deaths from acute myocardial infarction; however, these deaths occurred only in children treated with 42 Gy to 45 Gy. Among children treated with 15 Gy to 26 Gy, none developed radiation-associated cardiac problems. Cardiac radiation using sophisticated treatment planning and careful blocking to doses 25 Gy or less is generally safe, and 40 Gy may be administered to small cardiac regions.
In a study of 119 patients with Hodgkin lymphoma diagnosed at a young age (median age 8.3 years) and studied at least 2 years after completion of therapy (median age 20.3 years), 16% of patients had coronary artery abnormalities detected by computed tomography angiography. Mediastinal radiation therapy resulted in a 6.8-fold increase in CAD, with a dose higher than 20 Gy being most harmful. The risk of delayed CAD after lower radiation doses, however, requires additional study of patients followed for longer periods of time to definitively ascertain lifetime risk. Nontherapeutic risk factors for CAD such as family history, obesity, hypertension, smoking, diabetes, and hypercholesterolemia are likely to impact the frequency of disease.
Increased risk of doxorubicin-related cardiomyopathy is associated with female sex, cumulative doses higher than 200 mg/m2 to 300 mg/m2, younger age at time of exposure, and increased time from exposure.[24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39] Prevention or amelioration of anthracycline-induced cardiomyopathy is of utmost importance because the continued usage of anthracyclines is required in cancer therapy. Dexrazoxane (DZR) is a bisdioxopiperazine compound that readily enters cells and is subsequently hydrolyzed to form a chelating agent. Studies to date of cancer survivors treated with anthracyclines have not demonstrated the benefit of enalapril in preventing progressive cardiac toxicity.[40,41] Dexrazoxane has been shown to prevent cardiac toxicity in adults and children treated with anthracyclines,[42,43,44,45,46] however, the use of dexrazoxane in combination with etoposide in treating children with Hodgkin lymphoma remains controversial.[47,48] Studies suggest that dexrazoxane is safe and it does not interfere with chemotherapeutic efficacy. There is a single-study experience suggesting that there could be an increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity; however, at this time, this should not preclude treatment with dexrazoxane.[47,48]