Cardiovascular Complications Associated With Cancer Treatment in Children

The treatment of several childhood cancers increases the risk of developing cardiovascular disease. These complications may arise during cancer therapy or years after treatment has been completed. Pediatricians should recognize the risk factors associated with cardiovascular disease in childhood cancer survivors. The establishment of pediatric cardio-oncology programs is essential to ensure adequate assessment, monitoring, and treatment of cardiovascular complications related to cancer therapy.Recognize that cardiovascular toxicity from cancer treatment can affect more than just the heart.Identify risk factors associated with the development of cardiovascular disease in children with cancer.Describe the recommended initial and surveillance cardiovascular evaluations for pediatric cancer survivors.There are approximately 15 700 new cases of cancer in children in the United States each year. The current 5-year survival rate is around 80%, resulting in a growing population of approximately 500 000 pediatric cancer survivors. Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in this population, with survivors having a 6-fold increased risk of developing CVD compared with their siblings.1 While anthracyclines and radiation therapy are well-known for causing cardiotoxicity during and after cancer treatment, many other anticancer agents, including immunotherapies and multi–tyrosine kinase inhibitors (multi-TKIs), can also significantly impact the cardiovascular system. Additionally, pediatric cancer survivors are at increased risk for comorbidities such as obesity and reduced exercise tolerance, which can further exacerbate cancer treatment–related cardiotoxicity (CTRC).2,3 Pediatric cardio-oncology, also referred to as oncocardiology, has emerged as a subspecialty focused on evaluating, treating, and preventing cardiovascular complications associated with cancer therapy in children. Multidisciplinary cardio-oncology programs are increasingly being established to address the complex, immediate, and long-term cardiovascular and oncological needs of this patient population. This review summarizes our current understanding of the cardiovascular complications that may occur during cancer treatment in children, as well as the long-term cardiovascular effects observed in survivors. General pediatricians should become familiar with this topic to recognize potential complications early and refer patients promptly to specialized cancer care centers.The risk of developing CVD in children during cancer treatment and in pediatric cancer survivors is multifactorial and depends on the type of cancer, the treatment modalities used, and individual patient characteristics, including genetic predisposition and the presence of comorbidities. Understanding these risk factors is essential for early diagnosis, targeted prevention, and timely intervention in children at risk for CTRC.Pediatric cancers associated with an increased risk of developing CTRC, in no particular order of prevalence, include acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), Hodgkin lymphoma, bone tumors, and nonrhabdomyoma soft tissue sarcomas. The primary contributor to CTRC in these groups is exposure to high cumulative anthracycline-equivalent doses, typically ranging from 300 mg/m2 to 600 mg/m2. In addition, radiation therapy for sarcomas located in the chest or for bulky mediastinal Hodgkin lymphomas can significantly impact cardiac function.Although current treatment regimens for ALL generally involve lower cumulative anthracycline exposure, patients may still require hematopoietic stem cell transplantation in the setting of relapse. Conditioning regimens for hematopoietic stem cell transplantation often include cardiotoxic chemotherapeutic agents and total body irradiation, both of which increase the risk of developing CVD. Furthermore, the development of metabolic syndrome in patients with ALL, as well as poor mobility and limited exercise tolerance (sedentary behavior) in many patients with bone tumors, contributes to an elevated risk of cardiovascular comorbidities.4Anthracyclines are chemotherapy agents that disrupt the function of the enzyme topoisomerase II, leading to DNA damage. These agents, including doxorubicin, daunorubicin, and mitoxantrone, are commonly used to treat acute leukemias and solid tumors in children. The cardiotoxic effects of anthracyclines have been recognized for more than 50 years. All anthracyclines damage the myocardium through several mechanisms, including oxidative stress, DNA damage, calcium dysregulation, mitochondrial dysfunction, and inflammation, which can result in left ventricular (LV) dysfunction and heart failure.5,6The risk of developing heart failure varies depending on the type of anthracycline used to treat a particular cancer. For example, when compared at equivalent doses to doxorubicin (the standard reference for anthracycline cardiotoxicity), daunorubicin carries approximately half the risk of heart failure, whereas mitoxantrone is associated with a 10-fold higher risk.7 The likelihood of developing LV dysfunction is also dose-dependent. The estimated long-term risk of heart failure following anthracycline exposure is approximately 3%, 5%, and 8% for cumulative doxorubicin-equivalent doses of less than 250 mg/m2, 250–450 mg/m2, and more than 450 mg/m2, respectively.8 Although heart failure may develop years after the completion of cancer therapy, a recent clinical trial in pediatric AML reported a greater than 20% incidence of significant LV dysfunction during or shortly after treatment. Notably, this dysfunction was associated with decreased survival in affected patients.9In addition to anthracyclines, several other chemotherapy agents, such as arsenic trioxide, alkylating agents (eg, cyclophosphamide), and antimetabolites (eg, cytarabine), as well as supportive medications like ondansetron (for nausea) and methadone (for chronic pain), can cause QTc prolongation and arrhythmias.10 Although these arrhythmias typically occur during active cancer treatment, they may also appear later in life, particularly in the context of other forms of CTRC such as cardiomyopathy or heart failure.The identification of specific genomic alterations in certain pediatric cancers, along with growing insights into the role of the immune system in cancer control, has led to the development of novel therapeutic approaches for children with cancer. Multi-TKIs such as dasatinib, cabozantinib, and trametinib have been incorporated into the treatment of both newly diagnosed and recurrent pediatric cancers. The most common cardiovascular side effects associated with these agents include QTc interval prolongation and hypertension, which are generally reversible with dose reduction or discontinuation of therapy. In addition, the combination of fibrosarcoma B-type and mitogen-activated extracellular kinase inhibitors has been associated with LV dysfunction, which is also typically reversible after discontinuation. However, the long-term cardiovascular consequences of targeting these molecular pathways in children remain largely unknown.11,12The use of a patient’s own immune system to treat cancer has revolutionized therapy over the past decade. Immune checkpoint inhibitors have been introduced in the treatment of refractory or recurrent pediatric cancers. These agents have been associated with arrhythmias in both adults and children and with life-threatening myocarditis in adults, although the incidence in children is not yet well defined. Chimeric antigen receptor T-cell therapy has been used in the treatment of leukemia and lymphomas and is being explored for pediatric solid tumors. Cardiotoxicity in this setting most commonly manifests as cytokine release syndrome (CRS), which may involve hypotension, arrhythmias, and heart failure but is generally reversible with intensive supportive care. Similarly, the monoclonal antibody, dinutuximab, used in the treatment of neuroblastoma, can lead to comparable cardiovascular symptoms.13Blinatumomab is a bispecific T-cell engager immunotherapy that binds to CD19, a protein expressed on leukemia cells, and CD3 on T cells, thereby enabling T-cell–mediated killing of malignant cells. It has been recently incorporated into the standard treatment of both newly diagnosed and refractory ALL. Cardiovascular toxicities associated with blinatumomab include arrhythmias, CRS, and hypertensive crises.14Radiation therapy to the chest is a well-established risk factor for CVD in pediatric cancer survivors. In addition to heart failure and arrhythmias, which may also result from chemotherapy, radiation can lead to valvular disease, coronary artery disease, and pericardial disease. The risk of developing CVD is dose-dependent, and there is no “safe” radiotherapy dose below which the risk of late cardiac complications, particularly coronary artery disease, is entirely eliminated. Efforts to reduce long-term cardiovascular toxicity include de-escalation of radiotherapy based on a patient’s initial response to chemotherapy, as well as the use of advanced techniques such as proton therapy and intensity-modulated radiation therapy (IMRT). These approaches have the potential to minimize cardiac exposure and mitigate the long-term cardiovascular effects of radiation.15Several individual risk factors have been identified that increase the likelihood of developing CTRC, although variability across studies makes generalization challenging. These risk factors include young age (patients younger than 13 years), female sex, Black race, previous diagnosis of congenital heart disease, and concurrent comorbidities such as hypertension, dyslipidemia, and diabetes. Additionally, genetic polymorphisms in genes involved in intracellular drug transport and drug metabolism, including ABCC2, CYP3A5, NQO1, SLC22A6, and SLC28A3, may modulate an individual’s susceptibility to anthracycline-induced cardiotoxicity. International cardio-oncology societies have established 4 risk categories for CTRC. This risk stratification only considers the age of the patient (children/adolescents vs adults), the total cumulative dose of doxorubicin, and the radiation therapy dose received by the heart (Table 1), and it does not currently incorporate the individual risk factors listed above. The incorporation of novel therapies and individual risk factors in the risk stratification of CTRC for pediatric cancer survivors is the focus of research in pediatric cardio-oncology.16,17The unintended cardiovascular effects associated with cancer treatment in children extend beyond LV dysfunction caused by anthracyclines. Several cytotoxic agents, multi-TKIs, radiation therapy, and immunotherapy can lead to a wide spectrum of cardiovascular complications, including cardiomyopathy, arrhythmias, coronary artery disease, valvular abnormalities, and hypertension. In addition, many pediatric cancer survivors are at increased risk for developing metabolic syndrome (MetS) (Table 2). These complications may arise during cancer treatment, immediately afterward, or even years later. Cardiovascular disease is a leading cause of morbidity and mortality among pediatric cancer survivors, significantly impacting long-term quality of life. Cardiomyopathy and heart failure are among the most serious cardiovascular complications of pediatric cancer treatment. Anthracycline-induced cardiomyopathy is dose-dependent and may present during therapy, a few months after treatment, or many years later. Although medical management is available, symptoms of LV dysfunction can rapidly progress and become irreversible, potentially requiring a ventricular assist device or heart transplantation.2Arrhythmias may result not only from cancer-specific therapies such as chemotherapy and radiation, but also from commonly used supportive care medications, including antiemetics, antimicrobials, and opioids, that can prolong the corrected QT interval. Medical providers should be cautious about prescribing multiple QT-prolonging medications simultaneously and should consider alternative agents whenever possible. Pediatric cancer survivors are at increased risk for atrial fibrillation, supraventricular premature complexes, supraventricular tachycardia, and ventricular tachycardia. Long-term monitoring and, in some cases, antiarrhythmic medications or implanted cardiac devices may be necessary. Radiation therapy can lead to late-onset valvular disease, such as mitral regurgitation, aortic stenosis, and coronary artery disease. However, advances in modern radiation techniques allow greater cardiac sparing, which may reduce the incidence of these complications.15,18Hypertension is likely the most common cardiovascular side effect associated with cancer therapy. It may be transient but often requires medical treatment. Hypertension is frequently observed in patients receiving corticosteroids during induction therapy for ALL, at diagnosis in patients with renal tumors or pheochromocytomas, and in those treated with multi-TKIs. Persistent hypertension increases the risk for stroke, kidney disease, and other cardiovascular complications, underscoring the importance of regular monitoring and management.19 MetS refers to a cluster of conditions, including obesity, glucose intolerance, dyslipidemia, and hypertension, that elevate the risk of CVD and type 2 diabetes. Although the definition of MetS in pediatrics remains unsettled, clinicians are encouraged to screen for and manage these risk factors. Pediatric cancer survivors, particularly those treated for ALL or who underwent hematopoietic stem cell transplantation, are at heightened risk for developing MetS. These comorbidities can further exacerbate existing cardiomyopathy caused by cancer treatment.20 Finally, chemotherapy has been associated with the development of clonal hematopoiesis of indeterminate potential (CHIP). Although most abnormal clones do not progress to leukemia, CHIP has been linked to increased risks of heart failure and coronary artery disease in adults.21 Its relevance in the development of CVD in children and survivors of childhood cancer is currently under investigation.The evaluation of cardiovascular effects associated with cancer treatment relies heavily on serial echocardiograms. The American Society of Echocardiography recommends assessing left ventricular ejection fraction (LVEF) using 2-dimensional echocardiography, with the Simpson method being the preferred technique in younger patients. When it is available, 3-dimensional echocardiography is the preferred method to evaluate LVEF in adolescents. A normal ejection fraction (EF) is defined as equal to or greater than 55%. An EF between 51% and 54% is considered borderline and should be confirmed by a repeat echocardiogram within 1–2 weeks for patients actively receiving chemotherapy, or within 6 months for pediatric cancer survivors. An EF below 50% is considered abnormal and warrants prompt evaluation by a pediatric cardiologist.22Two-dimensional echocardiography is recommended before initiating anthracycline-based chemotherapy, every 2 cycles during treatment, and at the end of therapy. In pediatric cancer survivors, the frequency of echocardiograms is guided by the cumulative dose of anthracyclines and the dose of radiation therapy involving the heart. The use of shortening fraction (SF) to assess LV function, a historic parameter to evaluate LV function, is currently discouraged due to its high variability and limited accuracy. Global longitudinal strain (GLS), which measures the percentage of segmental myocardial shortening, has demonstrated early diagnostic and prognostic value in adults with cancer during therapy. In adult guidelines, GLS has been considered the optimal parameter of deformation for the early detection of subclinical LV dysfunction for more than a decade.23 However, more data are required for the better understating of myocardial deformation parameters in the risk stratification of children with cancer and prediction of development of cardiomyopathy among long-term childhood cancer survivors. Despite this, GLS should be included as part of the echocardiographic evaluation in children with cancer and pediatric cancer survivors. Patients with abnormal GLS but normal EF (≥55%) may require more frequent follow-up. Figure 1 summarizes the differences among the echocardiographic parameters discussed. Cardiac magnetic resonance (CMR) imaging is considered the gold standard for evaluating LV function. It also provides detailed information on cardiac mass, tissue characterization, and right ventricular function. CMR is typically reserved for patients with borderline EF, technical limitations in echocardiographic imaging, suspected myocarditis, or cardiac tumors. The main limitations of CMR are limited availability, expensive cost, and the frequent need for sedation in young children.22,24 Although serial monitoring of troponin and natriuretic peptides is recommended in adult cancer patients to assess cardiotoxicity, this practice is not currently recommended in children and remains an active area of research. Periodic assessment of body mass index, blood pressure (including 24-hour ambulatory blood pressure monitoring), glucose and hemoglobin A1c levels, and lipid profile, as well as obtaining serial electrocardiograms, are recommended based on prior exposure to particular chemotherapy drugs and radiation therapy.20Several efforts have been made to mitigate the cardiovascular effects of cancer therapy in children and adolescents, including individual risk–adjusted treatment plans.25 Novel technologies, such as IMRT and proton radiotherapy, allow the delivery of radiation to tumors while sparing normal tissues, including the heart and great vessels. Additionally, modern treatment protocols have de-escalated radiation exposure by reducing treatment volumes or omitting radiation altogether following an excellent response to neoadjuvant chemotherapy in patients with Hodgkin lymphoma.The cardiotoxic effects of anthracyclines can be significantly reduced through the concomitant administration of dexrazoxane during chemotherapy. Dexrazoxane acts by decreasing the formation of reactive oxygen species and inhibiting the binding of anthracyclines to topoisomerase IIβ in the myocardium. Its cardioprotective effect helps preserve normal LV function, especially in patients receiving a cumulative doxorubicin dose greater than 250 mg/m2, both during treatment and for several decades afterward. Initial concerns about an increased risk of secondary malignancies or reduced cancer treatment efficacy associated with dexrazoxane have been disproven. Consequently, international consensus guidelines now recommend the use of dexrazoxane in children with cancer who are expected to receive a cumulative doxorubicin-equivalent dose of ≥250 mg/m2. Other strategies, such as prolonged infusion of doxorubicin, have not demonstrated consistent benefit in reducing anthracycline-related cardiomyopathy.26,27International cardio-oncology groups and societies recommend heart failure therapy for both children and pediatric cancer survivors diagnosed with CTRC. These patients should receive treatment similar to that of children without a history of cancer, following a guideline-directed medical approach. This includes the use of agents such as angiotensin-converting enzyme inhibitors, angiotensin receptor-neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and more recently sodium-glucose cotransporter 2 (SGLT2) inhibitors. The specific indications for these therapies are beyond the scope of this review and should be determined by practitioners with experience in pediatric heart failure. Additionally, pediatric cancer survivors with advanced heart failure may be candidates for advanced therapies, including ventricular assist devices and heart transplantation, depending on their comorbidities and risk of cancer recurrence.28,29Pediatric cancer survivors are at increased risk for developing hypertension, dyslipidemia, and diabetes. The prevalence of diabetes and obesity is higher among Hispanic and non-Hispanic Black survivors compared with non-Hispanic White survivors. The Children’s Oncology Group provides guidelines for the surveillance of CVD risk factors in pediatric cancer survivors. These recommendations include periodic assessment of blood pressure, height, weight, body mass index, as well as fasting lipid profiles and glucose or hemoglobin A1c levels a pediatric cancer for to a often a pediatric is recommended for further evaluation and cancer survivors are also encouraged to in regular However, in have been observed when exercise is the impact of including in cardiovascular secondary and the American Society has the to ensure that affected by cancer are and in exercise and better understanding of CTRC has led to the development of and intervention for pediatric cancer survivors over the past decade. such as CHIP and established imaging may more risk assessment and management for pediatric cancer patients. Despite these the of therapies to to heart failure in patients with LV dysfunction following cancer treatment the need for research. 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