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    Late Effects of Treatment for Childhood Cancer (PDQ®): Treatment - Health Professional Information [NCI] - Late Effects of the Cardiovascular System


    Prevalence, Clinical Manifestations, and Risk Factors for Cardiac Toxicity

    Several investigations have described cardiac outcomes in adults treated for cancer during childhood. The methods used to assess cardiac outcomes in these studies range from self-report of clinically manifested cardiac disease to prospective medical assessment of cardiac function. Collectively, study results support dose-relationships of cardiac toxicity associated with anthracycline usage and radiation therapy impacting cardiac structures. However, these data may not reflect outcomes after contemporary approaches using lower cumulative doses of cardiac toxic treatment modalities and radiation technologies that facilitate protection of normal tissues.

    • Childhood Cancer Survivors Study (CCSS) investigators detailed dose-response evaluations for both radiation therapy and anthracycline administration to analyze risks (self-reported) of CHF, myocardial infarction (MI), pericardial disease, and valvular abnormalities (see Figure 2).[55] 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.[55] 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 the risk in 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.[55]

    Figure 2. Cumulative incidence of cardiac disorders among childhood cancer survivors by average cardiac radiation dose. BMJ 2009; 339:b4606. © 2009 by British Medical Journal Publishing Group.

    • A study of 4,122 5-year survivors of childhood cancer diagnosed before 1986 in France and the United Kingdom also demonstrated an association between radiation dose and risk of cardiovascular mortality.[56] The risk of dying from cardiac diseases was significantly higher in individuals who had received a cumulative dose of anthracyclines greater than 360 mg/m2 (relative risk [RR], 4.4; 95% confidence interval [CI], 1.3-15.3) and after an average radiation dose exceeding 5 Gy (RR, 12.5 for 5-14.9 Gy and RR, 25.1 for >15 Gy) to the heart. A linear relationship was found between the average dose of radiation to the heart and the risk of cardiac mortality (excess RR at 1 Gy, 60%).
    • Dutch investigators evaluated subclinical cardiac function of adult 5-year childhood cancer survivors. Among 601 eligible survivors, 514 were evaluable for assessment of the left ventricular shortening fraction (LVSF).[20] Subclinical cardiac dysfunction (LVSF <30%) was associated with younger age at diagnosis, higher cumulative anthracycline dose, and radiation to the thorax. High-dose cyclophosphamide and ifosfamide were not associated with a reduction of LVSF.
    • In a Dutch hospital-based cohort of 1,362 5-year childhood cancer survivors diagnosed between 1966 and 1996 (median attained age, 29.1 years; median follow-up time from diagnosis, 22.2 years), the 30-year cause-specific cumulative incidence of symptomatic cardiac events was significantly increased after treatment with both anthracyclines and cardiac irradiation (12.6%; 95% CI, 4.3-10.3), after anthracyclines (7.3%; 95% CI, 3.8-10.7), and after cardiac irradiation (4.0%; 95% CI, 0.5-7.4) compared with other treatments.[25] Study results indicate an exponential relationship between cumulative anthracycline dose, cardiac irradiation dose, and risk of cardiac event.
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