Advancements in treatment and supportive care for childhood cancer have led to a dramatic increase in the overall survival such that >80% of newly diagnosed children will become long-term survivors.¹ In response to this emerging population, a number of cohorts have been established to facilitate investigation of the long-term health impacts of cancer therapy.^2-5 These and other similar initiatives have contributed to the recognition of the many potential chronic and late-occurring health conditions that survivors may experience, among which are myriad cardiovascular (CV) complications.^6-12

We now recognize that childhood cancer survivors are seven times more likely than their siblings to die from a CV etiology, establishing CV conditions as the leading cause of noncancer-related mortality in this population.¹³ The risks for and spectrum of CV conditions in survivors are notable. In the largest investigation to date, investigators from The Childhood Cancer Survivor Study reported a fivefold-or-greater risk for congestive heart failure (HF), myocardial infarction, pericardial disease, and valvular abnormalities among nearly 15,000 childhood cancer survivors compared with siblings.¹⁰ Cardiomyopathy, the most widely investigated of these outcomes, is largely attributable to age- and dose-dependent exposures to the anthracycline (e.g., doxorubicin, daunorubicin, idarubicin, and epirubicin) and anthraquinone (e.g., mitoxantrone) classes of chemotherapy and cardiac-directed radiation. Myocardial dysfunction can be seen following nearly any cumulative anthracycline/anthraquinone exposure,^14,15 but those patients who receive a doxorubicin-equivalent dose of ≥250 mg/m2 seem to be at highest lifetime risk.^16,17 In addition to the risks for cardiomyopathy, chest radiation has also been associated with increased risk for valvular disease,^10,17,18 pericarditis,¹⁰ coronary artery disease,^10,17 and conduction disorders.¹⁷

Not all CV conditions experienced by survivors, however, can be solely attributed to direct cardiotoxic exposures. For example, the constellation of CV risk factors known as the metabolic syndrome occurs more frequently in survivors of acute lymphoblastic leukemia previously exposed to cranial radiation compared with those who were not.^19-21 The occurrence of these risk factors is particularly concerning given reports that the presence of any one of hypertension, dyslipidemia, obesity, or diabetes conveys multiplicative, rather than additive, increases in risk for coronary artery disease, HF, valvular disease, and arrhythmia in long-term childhood cancer survivors.²² Similar findings are reported in survivors previously treated with hematopoietic stem cell transplant, where those who develop CV risk factors (hypertension, diabetes, and/or dyslipidemia) are at greater risk for CV disease than those who do not.^23,24 Although the underlying mechanisms remain unestablished, the strength of association with these potentially modifiable risk factors supports future investigations seeking to establish pathophysiologic targets for subsequent intervention.

As knowledge of late toxicities of cancer therapies has grown, frontline treatment regimens for many childhood cancers have reduced, and in some cases eliminated, cardiotoxic exposures.^25,26 For example, many Hodgkin lymphoma consortia have successfully incorporated alternative treatment agents in order to permit reduced exposures to anthracyclines and cardiac radiation.²⁷ Reassuringly, a similar evolution in therapy across the broader spectrum of pediatric oncology has contributed to a fivefold reduction in the incidence of cardiac-related causes of death since the 1970s.²⁸ Although this progress is encouraging, there are a number of childhood cancers for which cardiotoxic therapy reductions are not yet feasible without consequence to overall survival rates; therefore, many newly diagnosed individuals continue to incur risk for subsequent CV disease.

To address these needs, investigators have studied the use of alternative preventative strategies. Liposomal doxorubicin preparations, for example, have shown promise in adults with cancer largely due to reduced capillary penetration of cardiac (compared with tumor) tissue, thereby aiming to reduce cardiotoxicity without negative consequence to overall treatment efficacy.^29,30 Pediatric investigators have utilized liposomal doxorubicin in frontline pediatric treatment with encouraging early success; however, long-term follow-up studies are needed to determine potential CV benefits.^30,31 Another strategy has been the use of dexrazoxane, shown to attenuate anthracycline-mediated cardiotoxicity through what is believed to be the chelation of anthracycline-iron complexes, resulting in a reduction of iron-dependent free radical damage to cardiac myocytes.³² Its efficacy has gained approval by the United States Food and Drug Administration for use in women with metastatic breast cancer exposed to higher doses of doxorubicin, and its off-label use has shown promise in a number of pediatric oncology studies.³³ As a historical note, initial results from a large Children's Oncology Group (COG) investigation in children diagnosed with Hodgkin lymphoma in the late 1990s suggested a non-statistically significant but concerning increase in the 4-year cumulative incidence of subsequent neoplasms in those who received dexrazoxane versus those who did not (3.43 vs. 0.6%, respectively; p = 0.060).³⁴ The results from a second COG clinical trial performed during the same era were recently reported by Asselin and colleagues. In this study, children with T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma were randomized whether to receive dexrazoxane. In contrast to the report from the Hodgkin studies, there was no statistically significant or suggested difference in the rates of subsequent neoplasms between groups (0.8 vs. 0.7%, respectively; p = 0.17).³⁵ To address the concerns raised by the Hodgkin study, Chow and colleagues extended follow-up for the participants in both of these COG investigations.³⁶ At a median of 12.6 years (range of 0-15.5 years) follow-up, dexrazoxane was not significantly associated with increased mortality (hazard ratio 1.03, 95% confidence interval, 0.73-1.45) or occurrence of second cancers (hazard ratio 1.24, 95% confidence interval, 0.49-3.15). These findings are reassuring as to the safety of anthracycline use in children with cancer. Providers should therefore consider the use of this agent for individuals likely to receive significant exposures to anthracycline chemotherapies.

The aforementioned risks for CV disease have prompted leading survivorship organizations to put forth recommendations for surveillance in individuals exposed to established cardiotoxic cancer treatments.^37-41 A major focus within these guidelines has been that of cardiomyopathy screening, inherently due to the ready availability of effective surveillance mechanisms.^42,43 Although a number of mechanisms exist by which to detect subclinical cardiac dysfunction, 2-dimensional echocardiography remains most frequently utilized due to its widespread availability.^43,44 Current screening strategies comprise risk-stratified surveillance with 2-dimensional echocardiography, based upon age at exposure to cumulative doses of anthracyclines and radiation. However, the prolonged latency of cardiomyopathy onset has limited the ability to determine treatment efficacy in this unique population, thereby limiting optimal refinement of surveillance strategies. To overcome these limitations, recent simulation models have informed the development of more cost-effective screening approaches.^45,46

Paramount to the young but growing field of pediatric cardio-oncology is the need to develop effective intervention strategies for individuals with cancer treatment-related cardiac dysfunction. Promising results from studies of adults treated for cancer indicate reduced rates of early anthracycline-induced cardiac dysfunction through the use of the angiotensin-converting enzyme inhibitor enalapril, with or without the addition of the beta-blocker carvedilol.^47,48 However, when enalapril was given to childhood cancer survivors who had already developed left ventricular dysfunction, improved function was transient, suggesting that conventional treatments are likely ineffective following the onset of measurable cardiac dysfunction.⁴⁹ Therefore, interventions that prevent the progression to clinically detectable HF are needed. A randomized, placebo-controlled trial investigating the impact of carvedilol for primary prevention of cardiomyopathy in childhood cancer survivors exposed to high cumulative doses of anthracyclines but with no current cardiac dysfunction is ongoing (PREVENT-HF [Carvedilol in Preventing Heart Failure in Childhood Cancer Survivors]). Despite the limitations of existing data, the American College of Cardiology and the American Heart Association recommend initiation of angiotensin-converting enzyme inhibitors or beta-blockers for subclinical cardiomyopathy regardless of etiology.^50,51 As such, consensus statements from leaders in the field of cardio-oncology endorse the same practices in childhood cancer survivors.⁷ The same experts endorse consideration of screening for other CV late effects on a case-by-case basis because highly sensitive and specific screening modalities have not yet reached routine practice.

Given the paucity of data to guide secondary and tertiary preventative strategies for cardiomyopathy and other CV late effects, one approach has been to address other, modifiable CV risk factors, such as those aforementioned germane to the metabolic syndrome. A number of studies support the safety and modest benefits of exercise in cancer survivors.^52-55 Although these results do not address the uncertain impact of intervention on the disease trajectory of these CV comorbidities in survivors, early and aggressive management has been endorsed by leading organizations.⁷

Many cancer treatments undoubtedly increase the risk for CV events in long-term childhood cancer survivors. Yet modifications to treatment intensity and advances in supportive care have reassuringly coincided with a reduction in CV mortality in survivors. This emerging group of aging survivors is uniquely suited for a multidisciplinary, cardio-oncology approach to care centered on early detection, risk reduction, and intervention in order to limit these late-occurring sequelae. Future efforts are needed to better understand underlying disease mechanisms and to subsequently optimize interventions in those for whom risk-reduction strategies are ineffective.

References

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Keywords: Angiotensin-Converting Enzyme Inhibitors, Anthracyclines, Arrhythmias, Cardiac, Breast Neoplasms, Cardiomyopathies, Cardiotoxicity, Comorbidity, Coronary Artery Disease, Diabetes Mellitus, Dyslipidemias, Echocardiography, Heart Conduction System, Heart Failure, Hematopoietic Stem Cell Transplantation, Hypertension, Metabolic Syndrome, Myocardial Infarction, Myocytes, Cardiac, Obesity, Pericarditis, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Primary Prevention, Risk Factors, Risk Reduction Behavior, Ventricular Dysfunction, Left, Pediatrics

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