Two closed Pediatric Oncology Group therapeutic phase III studies for Hodgkin lymphoma (HL) [36,37] measured myocardial toxicity clinically and sequentially over time by echocardiography and electrocardiography, and by determination of levels of cardiac troponin T (cTnT), a protein that is elevated after myocardial damage.[30,38,39,40,41,42] Long-term outcomes for these patients are not yet available.
The angiotensin-converting enzyme inhibitor enalapril has been used in the attempt to ameliorate doxorubicin-induced left ventricular dysfunction. Although a transient improvement in left ventricular function and structure was noted in 18 children, left ventricular wall thinning continued to deteriorate; thus, the intervention with enalapril was not considered successful. For this reason, studies to date in doxorubicin-treated cancer survivors have not demonstrated a benefit of enalapril in preventing progressive cardiac toxicity.[28,29]
A number of studies have examined cardiac function after radiation therapy and doxorubicin exposure using cardiopulmonary exercise stress tests and have found abnormalities in exercise endurance, cardiac output, aerobic capacity, echocardiography during exercise testing, and ectopic rhythms.[43,44,45,46,47] In addition to subclinical abnormalities of systolic function observed by conventional echocardiography, diastolic dysfunction (impaired ventricular relaxation) has also been observed, which may precede impairment of systolic function. Specific abnormalities of cardiac function may progress over time after therapy, as suggested by a report targeting parameters of left ventricular contractility. An increased prevalence of diastolic dysfunction has also been reported in childhood cancer survivors, consistent with the hypothesis of increased vascular and ventricular stiffness associated with precocious cardiovascular aging. It remains unclear whether these abnormalities will have clinical impact. Asymptomatic cardiac toxic effects can be demonstrated in patients who have normal clinical assessments, and abnormalities can be linked to lower self-reported health and New York Heart Association cardiac function scores.[51,52] Clearly, additional studies with long-term follow-up will be necessary to determine optimal screening modalities and frequencies.
Prevalence, Clinical Manifestations, and Risk Factors for Cardiac Toxicity
Children's 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).