**2. Cardiac toxicity**

Cardiotoxicity, specifically congestive heart failure (CHF) is a leading cause of morbidity and mortality in long-term survivors of Wilms tumor [2, 3]. Anthracyclines have preferential myocytic toxicity that results in a reduction of myocardial mass, myofibril dysfunction, decrease in contractility, and cardiomyopathy [6]. The most important risk factor is cumulative anthracycline dose, although all dose levels have been associated with myocyte injury [7]. Asymptomatic echocardiographic abnormalities such as increased end-systolic wall stress or decreased contractility can be found in survivors [8, 9]. Further, cardiac damage from therapy is progressive with an increasing lifelong risk of developing cardiac dysfunction that may necessitate cardiac transplant in some survivors [10, 11]. The severity of late cardiac effects will depend on factors including the age and sex of the child at time of treatment, cumulative anthracycline dose, cardiac radiation exposure, and presence of independent risk factors for cardiovascular disease not related to therapy.

Cardiac irradiation may result in scarring and stiffening of heart tissues resulting in arrhythmias, cardiomyopathy, valvular stenosis or insufficiency, coronary artery disease, and pericarditis or pericardial fibrosis [12]. Risk factors for cardiac morbidity include patient age at time of RT, RT dose and fractionation, irradiated cardiac volume, exposure to chemotherapeutic agents, and presence of cardiovascular risk factors.

The 20-year cumulative frequency of CHF among patients on NWTS-1 to NWTS-4 studies was 4.4% in patients initially treated with doxorubicin and 17.4%

### *Long-Term Toxicities among Wilms Tumor Survivors DOI: http://dx.doi.org/10.5772/intechopen.110130*

in patients treated with doxorubicin for first or subsequent relapse [13]. The relative risk (RR) of CHF was increased with female sex (relative risk RR 4.5) and cumulative doxorubicin dose (RR 3.2/100 mg/m2), and left abdominal RT (RR 1.8/10 Gy). In an analysis of patients enrolled on the NWTS-3 and NWTS-4 studies, the 20-year risk of CHF after primary treatment with doxorubicin was 1.2% [14]. In a report from the CCSS, after 25 years of follow up, the HRs were 23.6 for CHF, 50.7 for renal failure, and 8.2 for hypertension (HTN), compared to the sibling group. Exposure to doxorubicin, in the absence of cardiac RT, did not show a clear association with an increased risk of CHF (≤ 250 mg/m2, HR 4.8). Cardiac RT was associated with an elevated risk of developing CHF. In the absence of doxorubicin, cardiac RT was associated with a HR of 6.6 for CHF. The HR for CHF was increased among those who received both cardiac RT and doxorubicin (≤ 250 mg/m2, HR 13.0, > 250 mg/ m2, HR 18.3) [3].

The first study to corelate mean cardiac dose with late cardiac morbidity was a study of 4122 five-year French and British childhood survivors (mean follow-up, 27 years). The risk of cardiac death was higher in patients who received a mean cardiac RT dose of >5 Gy (5–14.9 Gy RR 12.5; >15 Gy RR, 25.1) and cumulative anthracycline dose of >360 mg/m2 (RR 4.4). There was a linear relationship between the mean cardiac RT dose and the risk of cardiac death (adjusted RR at 1 Gy, 60%) [15]. In another report of 229 childhood cancer survivors at the Institute Gustave Roussy 15 years or more after doxorubicin therapy, patients who received a mean cardiac RT dose between 5 and 20 Gy had a RR of CHF of 2.52 and those who received ≥20 Gy had a RR 5.65. The 25-year risk of cardiac failure was estimated at 34% in the 34 patients who received ≥250 mg/m2 of doxorubicin and mean cardiac RT dose of ≥5 Gy [16]. A report from the CCSS showed a dose-response relationship between mean cardiac RT dose and any cardiac disease, coronary artery disease and heart failure at mean doses ≥10 Gy. Exposure of low- to moderate-dose RT (5 to 19 Gy) to a large volume of the heart (≥ 50%) had a 1.6-fold increased risk of cardiac disease and exposure of any volume of the heart to RT doses of ≥20 Gy conferred an increased risk of cardiac disease [17].
