2025 AHA科学声明：儿童时期癌症治疗患者的心血管毒性

其他心血管内科· 心脏康复与其他 · 2025

Authors

Abstract

The field of cardio-oncology has expanded over the past 2 decades to address the ever-increasing issues related to cardiovascular disease in patients with cancer and survivors. There is increasing recognition that nearly all cancer treatments pose some short-or long-term risk for development of cardiovascular disease and that pediatric patients with cancer may be especially vulnerable to cardiovascular disease because of young age at treatment and expected long life span afterward. Anthracycline chemotherapy and chest-directed radiotherapy are the most well-studied cardiotoxic therapies, and dose reduction, use of cardioprotection for anthracyclines, and modern radiotherapy approaches have contributed to improved cardiovascular outcomes for survivors. Newer treatments such as small-molecule inhibitors, antibody-based cytotoxic therapy, and immunotherapy have expanded options for previously difficult-to-treat cancers but have also revealed new cardiotoxic profiles. Application of effective surveillance strategies in patients with cancer and survivors has been a focus of practitioners and researchers, whereas the prevention and treatment of extant cardiovascular disease is still developing. Incorporation of new strategies in an equitable manner and appropriate transition from pediatric to adult care will greatly influence long-term health-related outcomes in the growing population of childhood cancer survivors at risk for cardiovascular disease.

T he field of cardio-oncology, also referred to as oncocardiology, has grown over the past 2 decades to address the ever-increasing cardiovascular issues of patients with cancer and survivors. With > 18 million cancer survivors in the United States alone, 1 much of the focus of cardio-oncology has been on adults. Although children represent ≈5% of new cancer diagnoses each year, the high 5-year survival rate ( > 85%) in this age group equates to nearly 500 000 survivors of pediatric cancer, which, when coupled with decades of life expectancy after cancer treatment, results in a growing and aging population at risk for therapy-related cardiovascular disease (CVD). 2 Although the first evidence for cancer treatmentrelated cardiotoxicity (CTRC) emerged shortly after the introduction of chest-directed radiotherapy and anthracy-cline chemotherapy in the late 1960s and 1970s, 3, 4 there has since been an increasing recognition that many chemotherapeutic agents pose some short-or longer-term CVD risk. ] [7] This document, focused on current data in pediatric patients and survivors of pediatric cancer, builds on the prior American Heart Association scientific statement 6 and provides updates on emerging concepts related to established cardiotoxic therapies while also expanding to include consideration of novel agents. In addition, we focus on issues related to transition of care after cancer treatment, examine the role for cardiovascular risk factors and exercise, and provide an update on the clinical cardiac size and function may progress. 48 9] [50] High-dose (≥250 mg/m 2 ) doxorubicin equivalent exposure is associated with a 7.2% 30-year cumulative incidence of heart failure, which is a 7-fold higher rate than in survivors who did not receive anthracycline therapy. 51 In comparison, siblings of survivors have an estimated heart failure incidence of only 0.3% by 45 years of age. 50 Recent data suggest that some long-term survivors may develop an alternative remodeling phenotype that includes reduced LV cavity size with preserved or increased relative wall thickness, although this phenotype may be driven more by radiotherapy than chemotherapy. 52 However, the clinical implications of these findings, including response to standard "heart failure" therapies, have not been established. In addition, a growing body of literature has sought to elucidate the interindividual variability in heart failure risk and cardiac remodeling patterns that is not explained exclusively by cumulative anthracycline dose exposure. 53 ] [56] [57] [58] [59] [60] Various strategies have been explored to mitigate the cardiotoxic effect of anthracyclines in children. Although beneficial in adults, prolonged infusion of doxorubicin to decrease peak plasma concentration did not demonstrate a reduction in the risk of developing cardiomyopathy in children with acute leukemia. 61 62, 63 The cardioprotective effect of dexrazoxane is mediated through its inhibition of the binding of anthracycline to topoisomerase IIb. 64 oncerns for higher rates of second malignant neoplasms in dexrazoxane-treated patients initially limited its use, although more recent studies with longer followup have confirmed its safety and efficacy. 65 As a result, recent international consensus guidelines recommend administration of dexrazoxane in children expected to receive ≥250 mg/m 2 of cumulative doxorubicin equivalents. 63 Liposomal encapsulation of doxorubicin has been investigated as an alternative cardioprotective strategy because it provides reduced drug penetrance into cardiac tissue. 66 Adult studies have demonstrated lower cardiomyopathy/heart failure risk with liposomal compared with standard anthracyclines, although definitive data in pediatrics are lacking. 67, 68 Recent preclinical and early clinical studies of the anthracycline derivatives aclarubicin and diMe-doxorubicin demonstrate how selection of anthracyclines with a more narrow mechanism of action specific to chromatin damage, without the characteristic topoisomerase II-mediated DNA damage, may achieve comparable antitumor efficacy without cardiotoxicity, making this a promising approach for future study. 69

# RADIOTHERAPY CARDIOTOXICITY

RADIOTHERAPY CARDIOTOXICITY

Chest-directed radiotherapy is a well-established risk factor for late CVD in childhood cancer survivors (Figure 1 and Table ). 70 This includes heart failure, CAD, valvular disease, arrhythmia, and pericardial disease. 51, 71, 72 Initial studies linking radiotherapy exposures to CVD typically used prescribed dose or calculated mean dose to the entire heart. 73, 74 Adult data suggest that among breast cancer and Hodgkin lymphoma survivors, there is no threshold dose below which the risk of cardiac disease is absent. 75, 76 milar findings have not been replicated in children, with multiple studies suggesting that mean whole-heart doses of < 5 to 10 Gy do not appear to significantly increase the risk of late cardiac disease. 51, 72 However, it is noteworthy that in current studies of even long-term survivors of childhood cancer, the majority are only in their fourth or fifth decade of life, a time before which cardiac disease becomes prevalent in the general population.

More recently, calculation of mean radiotherapy doses to cardiac substructures, including coronary arteries, cardiac valves, and the 4 chambers of the heart, has allowed improved prediction of late CVD risk in childhood cancer survivors, demonstrating no threshold radiotherapy dose below which there is no increase in late cardiac risk. This is most pronounced in investigations into the relationship between mean radiotherapy dose and risk of CAD: For each 1-Gy increase in mean dose to the right coronary artery, there was a 28.7% increase in the risk of CAD. 77 his is an important finding given that modern radiotherapy techniques such as intensity-modulated radiotherapy or proton therapy are much more conformal than classic 2-or 3-dimensional approaches on which the vast majority of currently available literature focuses. 78, 79 Modern techniques are better able to spare the heart and potentially preferentially spare specifically vulnerable substructures. How these more conformal techniques will affect the burden of CVD in the next generation of childhood cancer survivors remains to be seen because they have been widely used for only 10 to 20 years.

Beyond cardiac disease, radiation also increases the risk for cerebrovascular disease. Data from adult patients

Nonpharmacological Radiotherapy Multiple X X X X* X X* X

Presence of an X indicates reported cardiotoxic effect. ALK dicates anaplastic lymphoma kinase; BCL2, B-cell lymphoma 2; BRAF, B-Raf proto-oncogene, serine/threonine kinase; CAD, coronary artery disease; CNS, central nervous system; EGFR, epidermal growth factor receptor; FLT3, fms-like tyrosine kinase 3; GVHD, graft-vs-host disease; LV, left ventricular; MEK, mitogenactivated protein kinase kinase; mTOR, mammalian target of rapamycin; RET, rearranged drug transfection; TKI, tyrosine kinase inhibitor; and VEGF, vascular endothelial growth factor.

*Data based largely on adult patients with cancer.

Table. Continued

treated for Hodgkin lymphoma and for head and neck cancers show that long-term survivors are at a markedly increased risk of stroke, especially those who received radiotherapy to the mediastinum and neck. 80, 81 Analysis of survivors of childhood cancer showed that radiotherapy increased endothelial dysfunction, which likely mediates this risk. 82

NOVEL THERAPIES

Although small-molecule and immunological cancer therapies generally offer a more tolerable toxicity profile, their on-and off-target effects result in various potential cardiovascular complications (Figure 1 and Table ). Small-molecule kinase inhibitors modulate a range of dysregulated signaling pathways that drive malignant transformation and progression across cancer subtypes in both children and adults. 83 BCR-ABL-targeting tyrosine kinase inhibitors, used in the treatment of Philadelphia (Ph+) chromosome-positive or Ph-like leukemias, are associated with off-target cardiovascular effects, which vary depending on the spectrum of non-ABL kinases inhibited by each agent. 84 Tc prolongation is specific to second-generation tyrosine kinase inhibitors (eg, dasatinib, nilotinib), whereas vascular toxicities are most common with nilotinib and ponatinib. 84 FMS-like tyrosine kinase 3 inhibitors (eg, midostaurin, gilteritinib), effective in the treatment of FMS-like tyrosine kinase 3 inhibitor-mutant acute myeloid leukemia, are most commonly associated with QTc prolongation (incidence, 5%-10%). 85 Vascular endothelial growth factor-targeting kinases or antibody drug conjugates lead to an array of cardiovascular complications, including hypertension (high grade, 6%), 86 heart failure (3%), 87 QTc prolongation, and, less commonly, acute vascular events. Fibrosarcoma B-type and mitogen-activated extracellular kinase inhibitors are indicated for the treatment of low-grade glioma, thyroid cancer, and Langerhans cell histiocytosis. 26 9] [90] Although LV dysfunction is generally reversible in patients who receive these agents, the long-term cardiovascular effects of targeting these pathways remains unknown. Selectively rearranged during transfection receptor tyrosine kinase inhibitors are indicated for the treatment of thyroid cancer and recurrent pediatric solid tumors with an activated mutation or fusion in this proto-oncogene. The main cardiovascular effects of these agents are hypertension and prolongation of the QTc interval. 11 number of immunotherapies have received US Food and Drug Administration approval for pediatric malignancies over the past decade (Figure 1 and Table ). 91 In adult cohorts, immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 and programmed death-1/programmed death-ligand 1 are associated with arrhythmia and, rarely, fatal myocarditis, with the incidence of the latter in pediatrics unknown. [92] [93] [94] For chimeric antigen receptor T-cell therapies, cardiotoxicity (eg, cardiomyopathy, arrhythmia, hypotension/shock, and cardiac arrest) can occur in up to one-third of pediatric, young adult, and adult patients, associated primarily with cytokine release syndrome. 18, [95] [96] [97]

SURVEILLANCE AND SURVIVORSHIP

Early recognition of CVD is integral to optimizing the health of young patients from diagnosis through survivorship (Figure 2 ). This is of particular importance given that data from the Childhood Cancer Survivor Study show that adult survivors of childhood cancer have a higher risk of mortality after major cardiovascular events (heart failure, CAD, and stroke). 98 Risk-based cancer care delivery allows primary CVD prevention (eg, avoidance of cardiotoxic therapy, use of cardioprotectants) and secondary prevention (eg, cardiovascular imaging and blood biomarker-based surveillance/intervention, reduction of cardiovascular risk factors). These considerations differ across the continuum of treatment into survivorship.

During and Shortly After Cancer Treatment

Cardiac Imaging Pediatric-specific, consensus-based guidelines and modern cooperative group clinical trials recommend echocardiographic monitoring for patients receiving anthracyclines, starting before treatment, repeated every 1 to 2 cycles, and at end of therapy (Figure 2 ). 99, 100 The American Society of Echocardiography recommends the use of 2-dimensional echocardiography to estimate LVEF by the biplane Simpson method or 5/6 area-length method to assess LV function both during pediatric cancer therapy and in survivorship. 101, 102 When feasible, 3-dimensional echocardiography may be a superior method to assess LVEF in adolescents and young adults, although its utility has not been established in younger children. 103, 104 6] [107] [108] Although cardioprotective strategies based on decline in global longitudinal strain during cancer therapy did not demonstrate efficacy in adults at 1 year, 3-year follow-up has demonstrated superiority over ejection fraction-based interventions. 109, 110 This finding is supported by similar studies of strain by cardiac magnetic resonance imaging. 111 Pediatric-specific strain data continue to be lacking; thus, initiation of cardioprotective strategies based on global longitudinal strain alone during cancer treatment in children is not currently supported.

Cardiac magnetic resonance imaging, considered the gold standard for assessing LV function, 103 has improved accuracy and reproducibility compared to echocardiography, and may be used to confirm echocardiogramderived borderline LVEF or when there are poor acoustic windows. 102, 112 When performed with gadolinium-based contrast, T1 mapping-derived extracellular volume may provide an additional marker of cardiotoxicity, although clinical utility has not been established. 113, 114 In addition, it more accurately measures cardiac mass, which is a predictor of outcome in adult cancer populations, 115 and is the gold standard to echocardiography in assessing right ventricular function, which can also be affected by anticancer therapy. The primary limitations of cardiac magnetic resonance imaging include lack of widespread availability and the need for sedation in younger children. As an alternative, contrast echocardiography can assess LV volumes and function in the setting of poor echocardiographic windows. 116, 117 rdiac Biomarkers Adult cardio-oncology guidelines recommend troponin and natriuretic peptide monitoring throughout cancer therapy (at baseline, during therapy, and in early followup) for cardiac risk assessment; this recommendation may not be applicable to children. 84 A meta-analysis of 27 studies including 1651 children found an association between anthracycline-induced natriuretic peptide elevations after anthracycline exposure and LV dysfunction (odds ratio, 7.1; P=0.003), but the sensitivity of this biomarker was limited. 118 Although not associated with cardiac dysfunction in this analysis, troponin elevations have been observed early in anthracycline therapy and have been associated with echocardiographic markers of adverse cardiac remodeling in children with acute lymphoblastic leukemia. 119 Other novel biomarkers such as myeloperoxidase, galectin-3, growth differentiation factor-15, and microRNAs have been explored for cardiotoxicity risk assessment 120, 121 ; however, existing data are limited.

Integration of Cardiotoxicity Monitoring Into Clinical Decision-Making

Interruptions and dose modifications in anthracycline delivery, based on the detection of subclinical cardiotoxicity by imaging and blood biomarkers, should be pursued with caution given the potential to compromise cancer outcomes. 122 The threshold for anthracycline dose modifications is controversial and should be informed by the efficacy of alternative regimens and individualized, interdisciplinary decision-making aimed to maintain cancer therapy effectiveness while limiting short-and long-term cardiac deterioration. Early implementation of neurohormonal antagonist medications may improve long-term cardiac function in adult patients with cancer, 123 but there are limited data in pediatrics.

Considerations During Survivorship

The latency and heterogeneity of CVD in long-term childhood cancer survivors pose challenges to the development of comprehensive evidence-based surveillance guidelines. However, since the publication of the last American Heart Association scientific statement, 6 investigations have helped refine screening recommendations for cardiac dysfunction and included guidelines for CAD and valvular disease.

Using microsimulation modeling, Ehrhardt and colleagues 124 estimated the benefits and cost-effectiveness of screening recommendations proposed by the International Guideline Harmonization (IGHG) group. 125 nvestigators classified the risk for developing heart failure, based on treatment exposure, as low (anthracycline 1-99 mg/m 2 or radiotherapy < 15 Gy, or both), moderate (anthracycline 100 to < 250 mg/m 2 or radiotherapy 15 to < 35 Gy), and high (anthracycline ≥250 mg/m 2 or radiotherapy ≥35 Gy, or both anthracycline ≥100 mg/m 2 and radiotherapy ≥15 Gy). 126 The lifetime risk of heart failure in each group was 16.9% (95% CI, 11.2%-23.8%), 24.7% (95% CI, 17.3%-33.5%), and 36.7% (95% CI, 28.7%-43.9%), respectively. 124 Screening was determined to be cost-effective for high-and moderate-risk survivors at 2-and 5-year intervals from completion of cancer treatment, respectively. However, no screening interval was found to be cost-effective for survivors in the low-risk category. On the basis of this and other emerging studies, both an IGHG expert panel and the Children's Oncology Group (COG) recommended a screening frequency of every 2 years for high-risk survivors and every 5 years for moderate-risk survivors. No recommendations for routine screening could be made for low-risk survivors, representing ≈40% of survivors who would have otherwise undergone routine echocardiographic surveillance. This does not, however, equate to a lack of risk, and individualized screening based on clinical signs/symptoms, modifiable cardiovascular risk factors, and medical judgement is recommended. 126 wo-dimensional echocardiography remains the preferred imaging modality, and its use is recommended by the American Society of Echocardiography for cardiotoxicity surveillance in children. The sensitivity and specificity of blood biomarkers for the detection of asymptomatic cardiac dysfunction during long-term survivorship are mixed. 108, 127 Emerging studies suggest that these biomarkers may have a role when they are used in conjunction with advanced cardiac imaging measures such as global longitudinal strain, 108, 128 when standard 2-dimensional echocardiographic imaging results are borderline, or when suspicion is high for ventricular dysfunction. The IGHG panel also recommended surveillance before or in the first trimester of pregnancy for women in the moderate-or high-risk group. However, women with a history of cardiac dysfunction that has resolved, regardless of risk group, may be at higher risk for recurrent dysfunction. Therefore, continued surveillance during pregnancy is recommended. 125 Evidence remains limited on optimal screening for survivors treated with cardioprotectants (eg, dexrazoxane), those with germline genetic risk factors or cardiovascular comorbidities, and those treated with newer cardiotoxic therapies or radiotherapy approaches.

Screening recommendations for CAD and valvular disease in survivors of pediatric cancer remain largely understudied. Chow and colleagues 129 developed and validated risk prediction formulas modeling varying radiotherapy doses to the heart. The cumulative incidence of CAD at 50 years ranged from 2.3% (95% CI, 1.5%-3.1%) to nearly 20% (95% CI, 15.0%-24.7%) for the group with the highest calculated risk score. However, a systematic review conducted by the IGHG found insufficient evidence to support routine CAD screening beyond monitoring and management of modifiable cardiovascular risk factors, similar to the general population. 130 The prevalence of valvular disease, strongly associated with radiotherapy exposure, has varied widely due to differences in diagnoses and classification of valve disease. 71, 131, 132 Largely studied among survivors of Hodgkin lymphoma, a direct dose response has been described, with a cumulative 30-year risk of 12.4% for Hodgkin survivors treated with > 40-Gy radiotherapy. 133 Although contemporary therapies typically avoid such high cardiac doses, newer studies that have included dose/volume metrics suggest that low to moderate doses (5-20 Gy) to large volumes ( > 90%) of the heart increase the risk for valve disease (hazard ratio, 3.9 [95% CI, 1.15-13.49]). 51 Having access to mean cardiac exposure is beneficial in stratifying risk but in reality can be difficult in many patients.

Transition of Care and Equitable Access to Health Care

Studies show that ≈60% to 90% of long-term survivors will develop ≥1 chronic health conditions, including cardiovascular, reproductive, and endocrine disorders, with a majority having severe or life-threatening conditions. 134 hese risks do not reach a plateau but rather increase across the age spectrum. Thus, the long-term health of these survivors depends on the successful transition of their care from pediatric to adult settings. Historically, pediatric oncology transition practices have been limited and insufficient; fewer than half of childhood cancer survivors remain engaged in survivorship-focused care. 135 o improve organizational health care transition from early adolescence to young adulthood, the US Center for Health Care Transition (Got Transition) 136 developed and reported a set of core components of health care transition. 137 Subsequently, in 2023, Marchak et al 138 reported a survey on the transition practices for survivors of childhood cancer. With ≈73% of the invited 209 COG institutions responding, two-thirds indicated that in accordance with their institutional policies, they transitioned survivors from pediatric programs to adult-focused cancer survivorship care. Most of the institutions reported introducing the transition plan during survivorship (usually by survivorship care clinicians) rather than during cancer treatment.

A significant obstacle identified to systematic transition programs is the burden placed on underresourced survivorship programs. 2 These findings indicate that there is a lack of uniformity in transitional survivorship care standards among COG institutions and underscore the need to establish best practices to inform the development of transition programs for childhood cancer survivors. Therefore, the American Academy of Pediatrics has made efforts to disseminate recommendations encouraging primary care physicians to incorporate the evidence-based COG long-term follow-up guidelines into their practice for surveillance of cancer survivors 139 and to partner with oncology subspecialists to educate survivors and facilitate a smooth transition to adultfocused care.

Equitable Access to Transition Care

1] [142] Data from the Childhood Cancer Survivor Study detail a higher burden of CVD risk factors in non-Hispanic Black and Hispanic adult survivors of childhood cancer, similar to that found in the general population. 143 Although disparities are increasingly recognized in the field of childhood cancer survivorship, practitioners often struggle to effectively address them. The absence of robust methods to reduce barriers and the fragmented state of current research hinder the development of suitable equity policies across various levels. Some of the proposed strategies to help address these disparities include a strategic focus on communities at greatest risk, access to quality health care, increasing workforce capacity, and support for standardized research to identify and address disparities. 140 In response, a growing area of investigation has emerged to address inequities in survivorship care. Because survivors of childhood cancer often require transition of complex, multidisciplinary care as they enter the adult health care system, educating adult cardiologists on the risks faced by this group may bolster the successful establishment of cardiac surveillance in adulthood.

CARDIOMETABOLIC CONSIDERATIONS

5] [146] A recent large cohort study reported that Hispanic and non-Hispanic Black survivors had a much higher rate of cardiovascular risk factors, particularly diabetes and obesity, compared with non-Hispanic White survivors. 143 These findings are especially concerning given the high rates of underdiagnosis and undertreatment of these risk factors for survivors compared with control subjects without cancer, contributing to greater disparities in care for this population. These comorbidities have significant implications given data showing that anthracycline-treated survivors who develop hypertension and diabetes have a > 35-fold risk of developing clinically significant cardiovascular complications such as heart failure compared with survivors without these risk factors. 50 everal cancer treatments are associated with the development of cardiovascular risk factors. ] [149] [150] [151] [152] [153] [154] The treatments (eg, corticosteroids, calcineurin inhibitors) used for graft-versus-host disease can place stem cell transplantation survivors at a 9-fold risk of hypertension, 5-fold risk of diabetes, and 3-fold risk for dyslipidemia compared with those who are unaffected. 155 ast, acquired endocrine abnormalities such as growth hormone deficiency and hypogonadism contribute to alteration of lipid levels and the metabolic syndrome if left untreated. 156, 157 creening of childhood cancer survivors for CVD risk factors is recommended by the COG long-term followup guidelines (Figure 2 ). 158 Childhood cancer survivors who have been treated with total-body irradiation or abdominal radiotherapy should have a fasting lipid profile and fasting glucose or hemoglobin A1c test every 2 years and blood pressure checked yearly. Height, weight, and body mass index should be evaluated yearly or every 6 months until growth is completed in those noted to have growth hormone deficiency. 158 If a childhood cancer survivor develops any criteria for metabolic syndrome, health care professionals should screen for associated components. Treatment should include lifestyle counseling on maintenance of appropriate weight, consumption of a heart-healthy diet, participation in adequate physical activity (discussed later), and avoidance of smoking. 158 uring the past 4 decades, a growing body of literature has characterized the epidemiology of CVD in patients with cancer and survivors, identified associations between treatment exposures and resultant cardiovascular complications, and highlighted important modifiers of CVD risk. These accomplishments have allowed the development of risk-based screening and intervention recommendations for CVD and cardiovascular risk factors that differ from those established for the general population because risk scores developed for the general population do not take into consideration unique treatment-related exposures in childhood cancer survivors.

Exercise and Cardiac Rehabilitation

Limited randomized trials have evaluated the impact of unsupervised behavioral interventions on improving physical activity and cardiometabolic health in children with cancer and survivors. Most have shown little or no effect on physical activity levels or cardiopulmonary fitness outcomes, 159 suggesting that supervision is required to deliver the appropriate frequency, intensity, and duration to promote sustained movement and to achieve a cardiorespiratory response. Exercise prescription in children during cancer therapy and through survivorship should consider cardiopulmonary fitness and should be adapted to accommodate other cancer treatment-related impairments (eg, amputation, neuropathy, balance disorder), with progression based on response to initial and subsequent exercise stimulus. A traditional cardiac rehabilitation approach 160 delivered by an exercise professional with specific cancer and exercise knowledge 161 is suggested in which exercise testing identifies targets (low muscle mass and weakness, poor respiratory support, suboptimal cardiac responses) for improvement. 162 Recent studies show that individually prescribed aerobic exercise is safe, 163 demonstrates a positive impact on LV function, 164 and improves cardiopulmonary fitness among children during cancer therapy and after exposure to anthracyclines. 165 Supervised interventions also improve muscle strength and daily physical activity in survivors < 18 years of age. 166 Conversely, 12 months of monthly personalized coaching (6 months in person, 6 months by phone) in adult survivors of childhood cancer only decreased composite CVD risk (Z score difference, -0.18) compared with control subjects. Although this difference was statistically significant, there was no effect of the intervention on individual components of the CVD risk score (average Z score of waist circumference, blood pressure, fasting glucose, inverted high-density lipoprotein cholesterol, triglycerides, and inverted cardiorespiratory fitness) and no difference in physical activity levels between the intervention and control groups at study completion, 167 again suggesting that more frequent supervision, perhaps with telehealthbased technology to increase access, 168, 169 is needed to achieve sustained effects in this population. Because exercise decreases cardiovascular events, second malignant neoplasms, and mortality in survivors of childhood cancer, [170] [171] [172] early referral for appropriate exercise training is warranted. On the basis of the overwhelming positive benefits of exercise and activity throughout the continuum of cancer care, the American Cancer Society has promoted the Moving Through Cancer initiative, with the goal to "ensure that all individuals living with and beyond cancer are assessed, advised, referred to, and supported to engage in appropriate exercise and rehabilitation programming. " 173

CLINICAL MANAGEMENT OF CARDIOTOXICITY

5] [176] In the adult realm, studies support the use of angiotensinconverting enzyme inhibitors and β-blockers in the management of CTRC. 177, 178 Conversely, in small pediatric studies, although there was short-term benefit of the use of angiotensin-converting enzyme inhibitors for CTRC, particularly enalapril, 179, 180 the long-term risk-tobenefit ratio has been called into question. 181 This is based, in part, on a potentially unique remodeling profile seen in survivors of pediatric cancer compared with survivors of adult cancer. 182 Similarly, the primary end point, standardized LV wall thickness-dimension ratio Z score, was not significantly different among childhood cancer survivors treated with low-dose carvedilol with the goal of preventing anthracycline-induced LV dysfunction, leading the authors to conclude that the "results do not support the use of carvedilol for secondary heart failure prevention in anthracycline-exposed childhood cancer survivors. " 183 The mineralocorticoid receptor antagonist spironolactone is regularly used in pediatric patients with heart failure, but there are no data specific to pediatric CTRC. Similarly, although the safety of sacubitrilvalsartan has been established in adults with CTRC, 184, 185 it has not been evaluated in children. ] [188] That said, additional studies are needed to evaluate the role of phenotypically informed interventions for the secondary treatment of CTRC in childhood cancer survivors because many of the traditional heart failure management approaches may not be as applicable to this population. 189 vanced Heart Failure Therapy Data in adult patients demonstrate that LV assist devices are a reasonable option to support patients with heart failure not responsive to oral therapies both during chemotherapy and afterward. 190, 191 Use of such devices in children can be limited by the smaller patient size and restrictive ventricular physiology seen more frequently in this group. For pediatric patients in need of support after anthracycline therapy, the only data currently available come from case reports or small case series. 192, 193 In a study of 80 patients < 18 years of age transplanted for end-stage CTRC, long-term graft survival, risk of secondary malignant neoplasms, time to first infection, time to first rejection, and time to coronary graft vasculopathy were similar to those in patients with other dilated cardiomyopathies, suggesting that transplantation may be a viable path for some patients with cancer and survivors with advanced heart failure. 194 The revised 2016 International Society for Heart and Lung Transplant listing criteria now permit individuals with a history of cancer to be considered for heart transplantation, contingent on determination of their risk of tumor recurrence in consultation with oncology experts and after a designated monitoring period. 195

FUTURE DIRECTIONS

During the past 4 decades, a growing body of literature has characterized the epidemiology of CVD in patients with cancer and survivors, identified associations between treatment exposures and resultant cardiovascular complications, and highlighted important modifiers of CVD risk. This has allowed the development of riskbased screening and intervention recommendations for CVD and cardiovascular risk factors that differ from those established for the general population because risk scores developed for the general population do not take into consideration unique treatment-related exposures in childhood cancer survivors. 129, 196, 197 Risk-based screening has facilitated consideration of secondary prevention trials to reduce the burden of CVD. However, these CVD prevention trials have focused largely on broad clinical risk groups (eg, history of transient LV dysfunction, 180 high-dose [≥250 mg/m 2 ] cumulative anthracycline exposure 183 ), providing mixed results to date. Recent studies have highlighted the prognostic role of NT-proBNP (N-terminal pro-B-type natriuretic peptide) in refining heart failure risk determination in asymptomatic survivors, 108, 127 and this may provide the impetus to consider combined clinical and biomarkerbased (imaging, blood) approaches to screen for survivors who may derive the most benefit from future secondary prevention efforts.

There have been parallel efforts to further refine CVD risk before the initiation of cardiotoxic therapy, driven largely by studies focusing on germline genomics. 53 Although these studies initially focused on candidate genes, they have expanded to include customized arrays and genome-wide approaches, providing insights into the pathogenesis of cardiotoxicity associated with chemotherapies such as anthracyclines. 53 There are ongoing efforts to integrate findings from these genomic studies with transcriptomics, proteomics, and metabolomics, which would allow more precise risk determination, facilitate the development novel blood biomarkers, and identify therapeutic targets. 53 Investigators may also need to consider the role of acquired somatic mutations (eg, clonal hematopoiesis of indeterminate potential) associated with CVD in nononcology populations given the higher prevalence of clonal hematopoiesis of indeterminate potential in childhood cancer survivors compared with community control subjects. 198 he success of these efforts will be strengthened by continued transdisciplinary collaborations and a steadfast commitment to bench-to-bedside translation. The emergence of specialized pediatric cardio-oncology clinics 199, 200 may provide the means to translate these findings, allowing optimization of cardiovascular health outcomes across the cancer care delivery continuum.

ARTICLE INFORMATION

The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.

This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on December 17, 2024, and the American Heart Association Executive Committee on January 16, 2025. A copy of the document is available at https://professional.heart.org/statements by using either "Search for Guidelines & Statements" or the "Browse by Topic" area. To purchase additional reprints, call 215-356-2721 or email Meredith.Edelman@wolterskluwer.com

The American Heart Association requests that this document be cited as follows: Ryan TD, Bates This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be "significant" if (a) the person receives $5000 or more during any 12-month period, or 5% or more of the person's gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $5000 or more of the fair market value of the entity. A relationship is considered to be "modest" if it is less than "significant" under the preceding definition.

†Significant. This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be "significant" if (a) the person receives $5000 or more during any 12-month period, or 5% or more of the person's gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $5000 or more of the fair market value of the entity. A relationship is considered to be "modest" if it is less than "significant" under the preceding definition.

Reviewer Disclosures

†Significant.

|Ryan et al||||Cardiotoxicity in Patients Treated for Childhood Cancer||||| |---|---|---|---|---|---|---|---|---|

|Disclosures|||||||||

|Writing Group Disclosures|||||||||

|Writing|||Other|Speakers'|||||

|group|||research|bureau/|Expert|Ownership|Consultant/||

|member|Employment|Research grant|support|honoraria|witness|interest|advisory board Other||

|Ryan|Children's Hospital Medical||||||||

||Center||||||||

|Armenian|Cancer Center||||||||

|Bates|Oncology, Winship Cancer||||||||

||Institute, Emory University||||||||

|Kinahan|Cancer Center of Northwestern||||||||

||University||||||||

|Leger|University of Washington||||||ceuticals †||

|Mulrooney|Hospital||||||||

|Narayan|School of Medicine/Rady Chil-|[PI of this Career Devel-|||||||

||dren's Hospital San Diego|opment Award]) †; St.|||||||

|||Baldrick's Foundation|||||||

|||(TEAM ABBY Gives|||||||

|||Scholar Award [PI of|||||||

|||this Career Development|||||||

|||Award]) †|||||||

|Kirsten Ness St. Jude Children's Research|None|None|None|None|None|None|None||

||Hospital||||||||

|Okwuosa|||||||||

|Rainusso|Department of Pediatrics, Baylor||||||||

||College of Medicine||||||||

|Steinberger|Children's Hospital||||||||

|Circulation. 2025;151:e00-e00. DOI: 10.1161/CIR.0000000000001308|||||TBD TBD, 2025|e11|||

References

引用 / 出处

2025 AHA科学声明：儿童时期癌症治疗患者的心血管毒性. 2025.