Pediatric Cardio-Oncology: An Emerging Sub-Specialty?
Cancer Treatment-Related Cardiotoxicity
There are nearly 14.5 million survivors of cancer in the US.1 With 15,700 newly diagnosed cancer patients < 20 years old annually, and an approximately 80% 5-year survival rate, there are approximately 450,000 new cancer survivors every year.2 Unfortunately, increasing numbers of patients at risk for cancer treatment-related cardiotoxicity (CTC) is an unintended consequence of successful therapy. In these patients, cardiovascular disease (CVD) has emerged as a leading cause of both morbidity and mortality,3 and survivors are five to six times more likely than sibling controls to develop CVD of various etiologies.4
While anthracycline chemotherapy is the most well studied treatment-related risk factor for CTC,5 other therapies, including radiation, also adversely affect the development of CVD.3 To meet the growing needs of cancer survivors , a number of adult cardio-oncology (or onco-cardiology) programs have emerged at tertiary and quaternary hospitals in the US and Europe, with evidence suggesting that these centers provide more intensive monitoring in patients at risk.6 The Cardio-Oncology Member Section of the American College of Cardiology (ACC) was thus recently established to address all facets of this fledgling subspecialty. Despite smaller patient numbers, there is a need for pediatric care providers with specialized knowledge to care for this unique population both during the course of oncologic treatment and afterwards, when these children are deemed cancer survivors.
The Evolution of Comprehensive Cardiac Care in Cancer Treatment
Anthracycline chemotherapy was introduced in the late 1960s. By the 1970s, invasive and non-invasive metrics of cardiac injury and dysfunction due to CTC became evident.7,8 Although management of symptomatic heart failure was the early focus, efforts were eventually directed towards preventing CTC. The current recommended model for comprehensive cardio-oncology care in adult patients has evolved to begin with cancer and cardiovascular screening by the primary care provider before any cancer diagnosis is made, with involvement of the cardio-oncologist at diagnosis of cancer and continuing through long-term survivorship.9
The cardio-oncologist may play a special role once the diagnosis of cancer is made. Helping determine the appropriate treatment regimen for a patient with a pre-existing cardiovascular condition, a known risk factor for CTC, is particularly important. It is essential that other providers understand that end-stage heart failure is not the only CTC of concern, as myocardial infarction, valvular disease, pericardial disease, hypertension, vascular disease, arrhythmias, and obesity are increasingly recognized.5 Guidelines for surveillance and management of CTC in adult patients before, during, and after cancer therapy have been published.10-12
The benefits of early identification of patients with cardiac complications from cancer treatment is best illustrated in those with breast cancer, who show more frequent response to, and improved outcomes with, early recognition of CTC and initiation of appropriate CV therapy.13,14 This model may serve as a blueprint for the management of pediatric cancer patients, as the most comprehensive current guidelines for surveillance in this group focus solely on long-term survivors.15
The Case for Pediatric Cardio-Oncology
Many studies on long-term cancer survival have their roots in the pediatric and adolescent population, who play a key role in defining the course of CTC.5 The Children's Oncology Group (COG) provides guidelines for timing of CTC screening in survivors after anthracycline chemotherapy, with an algorithm based on dose, age at treatment, and concomitant radiation therapy (www.survivorshipguidelines.org). Many chemotherapy protocols also include some level of screening at baseline and during treatment. Currently, however, a cardiologist becomes involved in patient management only when ventricular dysfunction or clinical heart failure is apparent. Furthermore, these guidelines utilize older methodologies such as shortening fraction in lieu of novel imaging modalities and serum biomarkers that have demonstrated utility in pediatric patients.16-22 This current approach may miss the opportunity for cardiologist involvement in risk assessment, treatment planning, or early intervention when CTC is present but not yet readily apparent. The current strategy may in part be explained by the low incidence of existing CVD in children, or the desire to not introduce yet another cause for concern for additional poor outcomes.
Despite the important work of organized survivorship clinics and the clinical and research efforts currently underway, there are still no dedicated cardio-oncology programs within pediatric institutions. This highlights opportunities for formal collaboration between pediatric cardiologists and oncologists that enables the evaluation and management of a patient from the time of cancer diagnosis through treatment and into survivorship. The use of an agent such as dexrazoxane during chemotherapy, which has shown evidence for CTC prevention in children dating back almost two decades, is an example of such an opportunity.5 Despite concerns that cardio-protective agents may decrease chemotherapy efficacy or lead to secondary malignancies, recent studies in patients with leukemia and lymphoma have argued against these claims.23-24 However, universal use of these drugs is currently not advocated, as a meta-analysis suggests that the risk for CTC must be balanced with that of secondary malignancies.25 With the advent of cardio-oncology as a subspecialty, the early identification of patients at high risk for CTC, mitigation of cardiotoxic side effects, utilization of imaging modalities and serum biomarkers to track disease course, and initiation of therapy when indicated, may improve the quality of care for these patients.
Establishing a Dedicated Cardio-Oncology Program
The team approach is key to establishing clinical and research programs for cardio-oncology patients. Essential elements include collaboration between cardiologists and oncologists who work in unison rather than in parallel, institutional support, dedicated clinical staff, and appropriate education of ancillary services including cardiovascular imaging, pharmacy, and the pathology laboratory. Given the much smaller scale of the pediatric patient population, team members dedicated exclusively to this patient population may not be a wise use of resources. In many instances a pediatric cardiologist, often with a broader focus on heart failure and cardiomyopathy, takes an interest in this population and becomes the "go to" person for oncologists on such matters. Other times, a pediatric oncologist involved in survivorship seeks input from various cardiologists to better understand the outcomes of interest. Regardless, either situation would benefit from formal methods for referral, structured evaluation and follow up, and organizational support for activities such as joint journal clubs, travel to specialty conferences, and dedicated nursing coordinator support. Continuous education programs for trainees and hospital staff, patient education and advocacy, and dissemination of information through local, regional, and national forums all contribute to a successful program.26
Strength in Numbers
A common refrain in pediatric clinical care and research is that the number of patients at any given institution is simply too small for meaningful or broadly applicable results. This is another important reason to establish pediatric cardio-oncology as a sub-specialty: strength in numbers. Fostering a community of like-minded practitioners will encourage collaborative research, generate clinical guidelines, and enable sharing of information regarding challenging or rare cases. Studies similar to the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial, where patients undergoing breast cancer treatment were given beta blockers and/or angiotensin converting enzyme inhibitors to obviate the decline in ventricular function, is best accomplished by a multi-institutional effort.27 This may facilitate interactions with adult cardio-oncology colleagues, providing expertise on uncommon pediatric issues (e.g., premature coronary artery disease), and foster patient transition to adult care.
The field of pediatric cardio-oncology is at the cusp of an exciting and potentially productive period. Beyond simply reacting to end-stage heart failure in a long-term survivor, early involvement may help identify previously unrecognized risk factors, begin collaborative research for early prevention strategies, and establish relationships that would ease introduction of a new care team as necessary. A recent ACC member survey that included both adult and pediatric practitioners showed that > 70% of the respondents perceived cancer treatment related CVD very important, and 65% felt that access to specialized consultants would be advantageous. However, 30% reported having to rely on a single provider with expertise or had no cardio-oncology services available for their patients.9 The dynamic nature of this field will be influenced by advances in oncology and cardiology, and ongoing collaboration at the provider, institutional, and professional organization levels will be critical.
- DeSantis CE, Lin CC, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin 2014;64:252-71.
- Ward E, DeSantis C, Robbins A, Kohler B, Jemal A. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 2014;83-103.
- Bloom MW, Hamo CE, Cardinale D, et al. Cancer therapy-related cardiac dysfunction and heart failure: part 1: definitions, pathophysiology, risk factors, and imaging. Circ Heart Fail 2016;9:e002661.
- Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 2009;339:b4606.
- Lipshultz SE, Adams MJ, Colan SD, et al. Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association. Circulation 2013;128:1927-95.
- Gujral DM, Lloyd G, Bhattacharyya S. Provision and clinical utility of cardio-oncology services for detection of cardiac toxicity in cancer patients. J Am Coll Cardiol 2016;67:1499-500.
- Rinehart JJ, Lewis RP, Balcerzak SP. Adriamycin cardiotoxicity in man. Ann Intern Med 1974;81:475-8.
- Bristow MR, Mason JW, Billingham ME, Daniels JR. Doxorubicin cardiomyopathy: evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Ann Intern Med 1978;88:168-75.
- Barac A, Murtagh G, Carver JR, et al. Cardiovascular health of patients with cancer and cancer survivors: a roadmap to the next level. J Am Coll Cardiol 2015;65:2739-46.
- Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2014;27:911-39.
- Iliescu CA, Grines CL, Herrmann J, et al. SCAI expert consensus statement: evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory. Catheter Cardiovasc Interv 2016;87:E202-23.
- Hamo CE, Bloom MW, Cardinale D, et al. Cancer therapy-related cardiac dysfunction and heart failure: part 2: prevention, treatment, guidelines, and future directions. Circ Heart Fail 2016;9:e002843.
- Cardinale D, Colombo A, Lamantia G, et al. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 2010;55:213-20.
- Cardinale D, Colombo A, Bacchiani G, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 2015;131:1981-8.
- Armenian SH, Hudson MM, Mulder RL, et al. Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Gui9deline Harmonization Group. Lancet Oncol 2015;16:e123-36.
- Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 2004;351:145-53.
- Lipshultz SE, Miller TL, Scully RE, et al. Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high-risk acute lymphoblastic leukemia: associations with long-term echocardiographic outcomes. J Clin Oncol 2012;30:1042-9.
- Mavinkurve-Groothuis AM, Marcus KA, Pourier M, et al. Myocardial 2D strain echocardiography and cardiac biomarkers in children during and shortly after anthracycline therapy for acute lymphoblastic leukaemia (ALL): a prospective study. Eur Heart J Cardiovasc Imaging 2013;14:562-9.
- Nawaytou H, Bernstein HS. Biomarkers in pediatric heart disease. Biomark Med 2014;8:943-63.
- Thavendiranathan P, Poulin F, Lim KD, Plana JC, Woo A, Marwick TH. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol 2014;63:2751-68.
- Pignatelli RH, Ghazi P, Reddy SC, et al. Abnormal myocardial strain indices in children receiving anthracycline chemotherapy. Pediatr Cardiol 2015;36:1610-6.
- Toro-Salazar OH, Ferranti J, Lorenzoni R, et al. Feasibility of Echocardiographic techniques to detect subclinical cancer therapeutics-related cardiac dysfunction among high-dose patients when compared with cardiac magnetic resonance imaging. J Am Soc Echocardiogr 2016;29:119-31.
- Chow EJ, Asselin BL, Schwartz CL, et al. Late mortality after dexrazoxane treatment: a report from the Children's Oncology Group. J Clin Oncol 2015;33:2639-45.
- Asselin BL, Devidas M, Chen L, et al. Cardioprotection and safety of dexrazoxane in patients treated for newly diagnosed t-cell acute lymphoblastic leukemia or advanced-stage lymphoblastic non-Hodgkin lymphoma: a report of the Children's Oncology Group randomized trial Pediatric Oncology Group 9404. J Clin Oncol 2016;34:854-62.
- Shaikh F, Dupuis LL, Alexander S, Gupta A, Mertens L, Nathan PC. Cardioprotection and second malignant neoplasms associated with dexrazoxane in children receiving anthracycline chemotherapy: a systematic review and meta-analysis. J Natl Cancer Inst 2015;108.
- Okwuosa TM, Barac A. Burgeoning cardio-oncology programs: challenges and opportunities for early career cardiologists/faculty directors. J Am Coll Cardiol 2015;66:1193-7.
- Gulati G, Heck SL, Ree AH, et al. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 x 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Eur Heart J 2016;37:1671-80.
Keywords: Adrenergic beta-Antagonists, Angiotensin-Converting Enzyme Inhibitors, Anthracyclines, Arrhythmias, Cardiac, Biomarkers, Breast Neoplasms, Cardiomyopathies, Cardiotoxicity, Coronary Artery Disease, Dexrazoxane, Heart Failure, Hypertension, Leukemia, Lymphoma, Myocardial Infarction, Protective Agents, Risk Assessment, Risk Factors, Ventricular Dysfunction, Ventricular Function, Pediatrics, Child
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