A Lifelong Perspective on the Cardiovascular Toxicity of Cancer Therapy in Children

Long-term cardiovascular toxicity in children, adolescents, or young adults after cancer treatment can be a serious problem for survivors, their families, and their health care providers. Death rates from cardiovascular disease are more than six times higher in childhood cancer survivors than in the general population [1, 2]. Declines in ventricular function caused by anthracyclines, other classes of chemotherapy drugs, or radiotherapy are common. In a Dutch cohort of 514 childhood cancer survivors treated with these modalities, 27% had evidence of asymptomatic cardiac dysfunction at their first echocardiogram more than 5 years after primary cancer treatment [3]. The 30-year cumulative incidence of symptomatic cardiac disease ranged from 0.8% to 4.1%, depending on the type of cardiac disease, and the incidence is considerably higher in survivors exposed to both anthracyclines and cardiac irradiation [4, 5]. The lifetime cumulative incidence of symptomatic cardiac disease in survivors is unknown, but may be progressive. Cardiovascular risk factors are detected in many survivors of cancer treated in childhood and early adult life[6, 7]. The US Childhood Cancer Survivor Study recently reported that more than 10% of 5-year survivors had two or more modifiable risk factors. Furthermore, these risk factors are associated with cardiac events and can potentiate the increased risk caused by cancer treatment [ref Armstrong JCO]. Systemic hypertension in survivors was independently associated with an increased relative risk of cardiac death of 5.6. [6]

The impact of cardiovascular toxicity is also increasing in the general population because the group of childhood and young adult cancer survivors treated with cardiotoxic agents is expanding. With childhood cancer survival rates approaching 80%, and the longer life-expectancy generally associated with youth, the population of survivors at risk for premature cardiovascular morbidity and mortality is aging and expanding. This increased cardiovascular toxicity will also increase the need for resources by public health and health care systems. Several studies have shown that hospitalization rates in survivors of childhood and adolescent cancers are increased 1.5- to 4-fold higher than expected. [8-10]

The number of studies on the cardiovascular toxicity of childhood cancer treatment and its long-term effects is large and has been increasing since the 1980s [11]. However, although our knowledge of cardiovascular disease in cancer survivors is expanding, much is still unknown. Gaps remain in diagnostic strategies and in follow-up interventions to decrease the excess burden of future cardiovascular disease [12]. Long-term epidemiological studies are needed to increase our understanding of cardiotoxic cancer treatment and of optimal care for survivors.

The AHA Scientific Statement entitled “Long-term Cardiovascular Toxicity in Children, Adolescents and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions” is a welcome addition to the literature. It is a comprehensive summary of the pathophysiology, clinical course, monitoring, prevention, management, and needed research in this area. Much of the literature concerns the short- and medium-term effects of a single antineoplastic agent, but this Statement describes the risk factors associated with each therapy and the additive impact of multiple cardiotoxic agents decades after exposure. Many studies have identified younger age at the time of cancer therapy to be a risk factor for late cardiotoxicity, implying that myocardial damage is greatest in the immature heart. In keeping with the finding that these survivors have a lifetime during which they are at higher risk for cardiovascular events, the discussion about the interaction of traditional cardiovascular risk factor sand the late effects of cancer therapy is both relevant and far-sighted.

The American College of Cardiology/American Heart Association classification for diagnosing and managing heart failure in adults may be useful for categorizing what is known about managing heart failure in survivors of childhood cancer. However this is only a starting point. Heart failure survivors may require different management if, for example, restrictive rather than dilated cardiomyopathy is more of an issue over time.

The Statement also identifies several areas in need of research. Evidence-based strategies to detect and monitor late cardiotoxicity are lacking. Echocardiography is the diagnostic and monitoring modality of choice, but the most widely used indices of left ventricular systolic function __fractional shortening and ejection fraction__ are load-dependent and not sensitive to early left ventricular systolic and diastolic dysfunction. The high incidence of subclinical abnormalities in left ventricular function is disconcerting, in the face of a progressive decline in systolic and diastolic ventricular function among survivors exposed to the highest doses of cardiotoxic therapy. Newer echocardiographic techniques (including myocardial velocity and deformation) and other forms of cardiac imaging, such as cardiac magnetic resonance imaging, may have greater utility in assessing myocardial function, but the evidence is not yet sufficient to add these modalities into routine screening algorithms. The authors of the Statement suggest that future epidemiological studies may help develop cost-effective tools with high sensitivity and negative predictive values, and recommend screening guidelines developed by the Children’s Oncology Group in the meantime[13]. However, given their expense, economic valuations are usually reserved for guidelines that are already validated.

Several medical therapies have been evaluated in the hope of minimizing the late cardiotoxicity of cancer therapy. Administering dexrazoxane, an iron-chelating agent, with doxorubicin helps prevent cardiotoxicity[14]. Serum concentrations of both cardiac troponin T and N terminal pro-brain natriuretic peptide are lower in survivors of high-risk acute lymphoblastic leukemia who received dexrazoxane than in those who received doxorubicin alone [15], implying reduced cardiomyocyte stress or death in the survivors treated concomitantly with dexrazoxane. The importance of cardio protection during treatment of childhood cancers is highlighted by the fact that, for childhood cancer survivors with marked cardiac dysfunction, conventional heart failure therapy does not improve long-term outcomes. Also, regardless of their cancer treatment, survivors are at much higher risk for cardiovascular disease as adults and need evidence-based cardiovascular monitoring and preventive interventions throughout their lives.

Finally, the interpretation of emerging data in this field requires a sense of perspective. Although the incidence of clinical heart failure may appear to be low several decades after the completion of therapy, the overall effect on cardiovascular health for each survivor over the course of a lifetime is what needs to be considered. The scarcity of randomized trials in this field and the long duration of follow-up required to determine the effects of cancer therapy on cardiovascular events in adulthood, mandate the funding of such research, including long-standing comprehensive registries, to advance this field.