Introduction
The past 5 decades have seen significant improvements in outcomes for pediatric patients with cancer. Unfortunately, children and adolescents who have been treated for cancer are more likely to develop cardiovascular disease as a result of their therapies. With greater than 15,000 cancers diagnosed each year in patients under the age of 19 years old,¹ the progress in treatment has resulted in approximately 450,000 survivors of pediatric cancer in the United States.² Thus, the long-term effects of cancer therapy have become increasingly important in this group.

Some treatment modalities are implicated in the development of cardiotoxicity in pediatric and adult populations, including anthracyclines, radiation therapy, alkylating agents, targeted cancer therapies (small molecules and antibody therapies), antimetabolites, antimicrotubule agents, immunotherapy, interleukins, and chimeric antigen receptor T-cells.³ For some therapies, such as anthracyclines, the mechanism of injury is elucidated, but for many others it is not. A few primary protective strategies exist, but in many cases observation and close monitoring is the only defense against developing end-stage cardiovascular disease (i.e., secondary prevention). When disease is identified, any of a number of therapies may be appropriate; however, in the pediatric and adolescent population, supportive data are limited.

Risk Stratification
According to the National Comprehensive Cancer Network, those individuals who have undergone treatment for cancer should be considered American College of Cardiology/American Heart Association Stage A heart failure at a minimum.⁴ For survivors of pediatric cancers, The Childhood Cancer Survivor Study has been a wealth of information in this regard. This cohort study compared patients to sibling controls and demonstrated an increased incidence of heart failure, valvular disease, pericardial disease, and coronary artery disease.⁵ Data from this cohort have also demonstrated the importance of modifiable risk factors, such as hypertension, obesity, and dyslipidemia on cardiovascular outcomes.⁶ Using these data, an online risk calculator is available to predict risk of heart failure, ischemic heart disease, and stroke by age 50 in survivors of childhood cancer.^7,8 This calculator focuses primarily on anthracycline and radiation therapies and is not used in making specific surveillance recommendations. Although there is a general understanding of the importance of cardiovascular care for pediatric patients during and after cancer therapy, there is often a lack of operationalized care.⁹ This is not to mention that, unlike many adult centers, involvement of a cardiovascular specialist for pre-treatment risk evaluation is the exception rather than the rule. As this population expands, more pediatric centers are developing cardio-oncology programs with the goal of better serving the needs of these patients, but general cardiologists will still be at the front line in many institutions.

Available Guidelines and Timing of Therapy
A number of medical societies and organizations have produced guidelines, consensus statements, or position papers on the care of patients who have undergone therapy for cancer. Many resources are intended for adult patients (Table 1),^4,10-14 and a handful have specifically focused on pediatric and/or adult survivors of pediatric cancers (Table 2).^15-18 Recent efforts have been made to consolidate the various guidelines for survivors of pediatric cancers, including specific direction on surveillance modality and strength of recommendation.¹⁶

Table 1: Recommendations for Care of the Adult Patient Status Post-Therapy for Cancer Based on Leading Resources

Discussion or Recommendations	European Society for Medical Oncology Clinical Practice Guidelines (2012)11	American Society of Echocardiography and European Association of Cardiovascular Imaging Expert Consensus for Multimodality Imaging (2014)12	European Society of Cardiology Position Paper (2016)13	Canadian Cardiovascular Society Guidelines (2016)14	American Society of Clinical Oncology Clinical Practice Guideline (2017)15	National Comprehensive Cancer Network (US) Clinical Practice Guidelines (2018)4
Anthracycline/Radiation Exposure/Risks	Yes	Yes	Yes	Yes	Yes	Yes
Other Chemotherapy Agents Exposure/Risks	Yes	Yes	Yes	Yes	No	Yes
Left Ventricular Ejection Fraction Assessment by Imaging Modalities	Yes	Yes	Yes	Yes	Yes	Yes
Use of Circulating Biomarkers	Yes	Yes	Yes	Yes	Yes	Yes
Assessment/Diagnosis of Other CV Disease*	Yes	Yes	Yes	Yes	No	No
Treatment for Ventricular Dysfunction or Heart Failure	Yes	No	Yes	Yes	Yes	No
Treatment for Other CV Disease	Yes	No	Yes	Yes	No	No
Survivors of Pediatric Cancers	No	No	Per International Late Effects of Childhood Cancer Guideline Harmonization Group16	Per Children's Oncology Group	No	Per Children's Oncology Group
* For example, hypertension, ischemia, QT-prolongation, thrombosis, valvular disease, pericardial disease.

Table 2: Resources Providing Information and/or Guidance for CV Care of Survivors of Pediatric Cancers

American Heart Association Scientific Statement on Pediatric, Adolescent, and Young Adult Long-Term Survivors15

Children's Oncology Group

Dutch Childhood Oncology Group18

Scottish Intercollegiate Guidelines Network

UK Children's Cancer and Leukaemia Group

International Late Effects of Childhood Cancer Guideline Harmonization Group16

Primary prevention of cardiotoxicity is the ultimate goal in patient management. Strategies range from modified dosing to alternative anthracycline formulations to use of medications thought to prevent myocardial damage (e.g., dexrazoxane). However, there are still limited resources regarding treatment once cardiovascular toxicity develops. Existing adult heart failure guidelines are supplemented by cardio-oncology-specific recommendations that include guidance for therapy in response to changes in imaging and serum biomarkers and symptomatic heart failure and directed by specific chemotherapy exposures. Although there are several studies reviewing treatment strategies for cardiotoxicity in adult survivors of pediatric cancers, those for patients still in the pediatric age range are limited.^19,20 Therefore, management of cardiotoxicity in children is largely based on adult experience.

Recent data suggest that angiotensin-converting enzyme inhibitors can reproducibly improve markers of subclinical cardiac dysfunction in young patients.²¹ Additionally, a small retrospective study in survivors of pediatric cancer demonstrated improvements in left ventricular dimensions, mass, afterload, and systolic function with angiotensin-converting enzyme inhibitor therapy. However, these benefits were not sustained, with subsequent deterioration after 6 years on therapy.²² In one small single-center study, pre-treatment with a beta blocker provided a potential protective effect for children with acute lymphoblastic leukemia, improving echocardiographic indices and inhibiting troponin leak following anthracycline administration.²³ Importantly, there is an ongoing randomized controlled trial to assess the efficacy of carvedilol in preventing the development of left ventricular dysfunction in survivors of childhood cancer.²⁴ However, for most patients who develop ventricular dysfunction or other toxicities, application of more general pediatric heart failure treatment guidelines is the only option.²⁵

The optimal timing and strategy for cardiovascular therapy initiation is unclear given the lack of available data. Practitioners generally do not initiate heart failure therapies in the absence of objective changes in ventricular performance, but there is increasing evidence to suggest that assessment of ejection fraction and/or shortening fraction are inadequate to detect subclinical myocardial dysfunction.^21,26 There may be a number of pediatric patients with subclinical myocardial changes but normal ventricular function based on conventional measures. As cardiac imaging techniques evolve, the threshold to detect and initiate heart failure therapies may change. Of note, although the benefits of early initiation of therapy are described in adult cancer survivors,²⁷ they remain unproven in the pediatric population.

Areas of Need
Regarding monitoring and therapy for cardiotoxicity in pediatric cancer, three primary areas of need arise. First is the need for risk stratification that incorporates not only patient and treatment risk factors going into therapy, but also use of factors that take into account advanced imaging, serum biomarkers, exercise testing, and other modalities increasingly shown to be sensitive in detecting subclinical ventricular dysfunction post-therapy. Further, a better understanding of how traditional cardiovascular risk factors affect outcomes both in short-term and late-term survivors is of clear import.

The second area of need is the development of treatment guidelines that take into consideration high-quality data specific to pediatric patients exposed to cancer therapies. Given the smaller population of patients for study compared with adult cancer populations, this is not a simple fix. However, with continued cooperation between cardiology and oncology, multicenter trials such as those currently underway for the effects of carvedilol in preventing development of cardiotoxicity,²³ will provide powerful data to direct recommendations and possibly guidelines.

Third, provider education on issues important to the cardiovascular health and follow-up in patients who have undergone cancer therapy is of critical importance. Recent surveys of cardiology program directors showed that fewer than 10% of programs had cardio-oncology-specific training opportunities.²⁸ More importantly, there was no reported formalized training for pediatric cardio-oncology.²⁹ Systematic integration of cardio-oncology into fellowship training would likely improve the knowledge base and practice among all new pediatric cardiology physicians. But limiting education to cardiology is not enough; ensuring that oncologists also have a good understanding of the issues if of equal importance to ensure proper surveillance is followed as well as integration of cardiology into care pathways when indicated.

Finally, the most difficult need to fill is that of providing guidance regarding new and emerging cancer therapies. Modalities such as small molecule inhibitors, immune checkpoint inhibitors, and cancer immunotherapy are regularly finding a foothold in pediatric cancer therapies, often to great effect. Meeting this need will never be "one and done," but there needs to be a commitment to regular updating and reporting of data pertaining to the cardiovascular effects of these therapies. Additionally, multicenter collaborations are more important in this area than any other given the often-limited experience with such agents.

Summary
The field of cardio-oncology, both pediatric and adult, will continue to evolve as novel pediatric cancer therapies emerge and the population of childhood cancer survivors increases. As this occurs, incorporating new, potentially cardiotoxic therapies and standardizing the approach to cardiology involvement in the care of this complex group of patients is critically important. A coordinated effort among pediatric cardiology and oncology programs will help to advance multicenter research efforts, better define best practices, and help to further define the role of the cardiologist in the care of survivors of childhood cancer.

References

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Keywords: American Heart Association, Anthracyclines, Risk Factors, Cardiotoxicity, Coronary Artery Disease, Cohort Studies, Secondary Prevention, Antimetabolites, Alkylating Agents, Neoplasms, Heart Failure, Societies, Medical, Dyslipidemias, Hypertension, Immunotherapy, Stroke, Obesity, Interleukins, Receptors, Antigen, T-Lymphocytes, Dexrazoxane, Angiotensin-Converting Enzyme Inhibitors, Peptidyl-Dipeptidase A, Risk Factors, Troponin, Retrospective Studies, Stroke Volume, Adrenergic beta-Antagonists, Ventricular Dysfunction, Left, Echocardiography, Cardiac Imaging Techniques, Ventricular Function, Primary Prevention, Immunotherapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Cardio-oncology

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