Cancer is the leading cause of disease-related mortality in the pediatric age group (1). Thanks to advances in the diagnosis and treatment of childhood cancer, more patients are now surviving to adulthood. However, this improved survival has also brought to light the substantial burden of cardiovascular disease, with increased morbidity and mortality attributed to cardiotoxicity (2, 3).

Childhood cancer survivors (CCS) face a significantly elevated risk of cardiovascular disease as a late effect of cancer therapy. According to data from the Childhood Cancer Survivor Study (CCSS), the risk of developing cardiovascular disease is 5 to 15 times higher in CCS compared to the general population, depending on the specific malignancy and treatment exposure. Moreover, the risk of heart failure is up to 8 times greater in CCS than in their healthy siblings. The spectrum of cardiotoxicity-related complications is broad and includes cancer therapy-related cardiac dysfunction (CTRCD), arrhythmias, valvular disease, and pericardial involvement. Among these, CTRCD is one of the most common and clinically significant. Despite its potential reversibility with early detection and intervention, it often remains undiagnosed in its subclinical stages (4–10).

Cardiotoxicity can manifest in the short, medium, or long term (11). Its etiology and pathogenesis are multifactorial, influenced by both the underlying disease and the treatment received. Moreover, patient-specific risk factors, including individual predisposition and lifestyles, also modulate the development of cardiotoxicity (12).

Currently, the evaluation of cardiovascular function is mostly based on echocardiography and the analysis of serum biomarkers such as Troponin or the N-terminal pro b-type natriuretic peptide (NT-proBNP) (10). Myocardial function is easily assessed using echocardiography. Particularly useful for the quantification of the myocardial function are the left ventricular ejection fraction (LVEF) and the Global Longitudinal Strain (GLS) (13, 14) an echocardiographic measure of myocardial deformation that is more sensitive than LVEF in the detection of subclinical dysfunction or asymptomatic CTRCD (10, 13–15)³. Current guidelines establish a cardiotoxicity risk stratification by measuring of LVEF and GLS, and assessing their decline from baseline.

Follow-up recommendations for pediatric cancer survivors have been recently published by the American Society of Echocardiography (16). According to these guidelines, an LVEF greater than 55% is considered within normal limits, whereas an LVEF below 50% and/or a GLS above –16% (less negative) is classified as abnormal.

This study aimed to perform a comprehensive cardiovascular evaluation in children with cancer at different stages of their disease from diagnosis to the end of treatment.

Our analysis of a large cohort of pediatric oncology patients demonstrates that cardiovascular risk stratification evolves throughout chemotherapy treatment, with a greater proportion of patients presenting subclinical myocardial damage or high cardiovascular risk during therapy. The overall incidence of CTRCD was 2.3%, but 16.5% experienced a ≥10% decrease in LVEF from their baseline, and 34.7% had abnormal GLS values, indicating subclinical dysfunction. ECG abnormalities were observed in 16.2% of patients, primarily QT prolongation and repolarization disturbances, and 7.1% had elevated troponin levels. Interestingly, patients in the early and late treatment groups showed greater cardiac involvement, as evidenced by echocardiographic and biomarker alterations. These findings reinforce the need for continuous cardiac surveillance throughout treatment to detect early cardiotoxicity and prevent irreversible damage.

The incidence of CTRCD related to cardiotoxicity in adulthood is widely reported in the scientific literature. Cardinale et al., described an incidence of cardiotoxicity of 9% in their studied sample (14). However, information in children is scarce and there is great variability depending on the population studied and the diagnostic methods used. Bu-Lock et al. (17), analyzed 125 pediatric patients and reported an incidence of CTRCD of 5% with 19.2% of patients experiencing a significant fall in LVEF. Similarly, Agha et al. (18), in a study including 40 patients, described 5% of CTRCD with 40% of the patients experiencing decrease in LVEF. However, Kocabas et al. (19), was not able to identify CTRCD in 72 patients. In our study, despite only 2.3% of patient having CTRCD, 16.5% had subclinical impairment of the myocardial function.

Traditionally, LV systolic function has been assessed using LVEF and FS, though these measures often fail to detect subtle myocardial changes, as chemotherapy-induced damage tends to be regional and asymmetric (20). More sensitive approaches, such as tissue Doppler imaging (TDI), have been suggested as potential alternatives, particularly for tracking medial S’ velocity declines during chemotherapy (17–19, 21). Although the late treatment group in our study had worse TDI values than the other groups, these differences were not statistically significant.

Systematic measurement of GLS also allows early identification of systolic function abnormalities and has been correlated with the development of long-term cardiotoxicity (22). Thavendiranathan et al., demonstrated that the early fall in GLS was more sensitive than LVEF analysis (21). In this study, a 10-15% decrease in GLS was considered the most useful parameter for predicting long-term cardiovascular disease. However, the SUCCOUR study also questions the usefulness of this parameter, finding no significant difference in patient outcomes when function assessment at follow-up was based on GLS rather than LVEF (23). In our study, GLS was altered in 34.7% of patients, significantly increasing the sensitivity for the detection of cardiovascular risk groups compared to traditional function assessment parameters. However, without longitudinal follow-up, it remains unclear how these early GLS alterations translate into long-term cardiac dysfunction in children surviving from cancer.

Diastolic dysfunction has been explored as an early marker of cardiotoxicity in several studies. To date, there is no scientific evidence to clarify the diagnostic and/or prognostic value of its assessment. Furthermore, in the pediatric age group, changes in diastolic function seem to occur later and have great variability according to age, making their use difficult (17, 24).

Right ventricular function assessment in pediatric oncology patients presents similar challenges, as classical indices such as TAPSE and RV fractional area change have limited sensitivity in detecting subtle RV dysfunction (25). In this study, no significant alterations in RV function or pulmonary hypertension were detected, suggesting that RV involvement may be less prominent in early chemotherapy exposure.

While echocardiographic parameters provide valuable insights, ECG abnormalities have also been reported in pediatric patients undergoing chemotherapy. Previous studies have described conduction disturbances, repolarization abnormalities, and QT prolongation in up to 25% of patients (18, 26). In this study, 16.2% of patients had ECG alterations, most commonly QT prolongation and repolarization disturbances, findings that were particularly pronounced in patients undergoing active chemotherapy. These results suggest that ECG monitoring could be useful for tracking transient electrophysiological changes during treatment, though the long-term significance of these findings remains to be determined.

Biomarkers such as troponin and NT-proBNP remain the most widely used markers for detecting chemotherapy-induced myocardial injury, though interest is growing in newer biomarkers such as microRNAs, and proteomics (27). Troponins, particularly troponin I and troponin T, are the gold standard for detecting myocardial necrosis. In this study, troponin elevations were found in 7.1% of patients, with the highest values observed in those currently undergoing treatment, reinforcing its role as a potential early indicator of myocardial damage (28). NT-proBNP, a well-established marker in heart failure, has also been associated with chemotherapy-induced cardiotoxicity, with levels above 100 ng/L linked to an increased risk of cardiac events (29, 30). In pediatric patients, elevated NT-proBNP levels have been correlated with CTRCD compared to healthy controls (31). Interestingly, in our study, the highest values of NT-proBNP were found in the baseline group, while the lowest levels found in those of the end-of-treatment group suggesting than other factors, such as, inflammation, fluid management, might play a role.

The International Late Effects of Childhood Cancer Guideline Harmonization Group has developed evidence-based recommendations for long-term cardiovascular monitoring in childhood cancer survivors (32). Risk stratification is primarily based on cumulative anthracycline exposure and chest radiotherapy, which determine follow-up intervals. Interestingly, when applying adult guideline criteria, a higher percentage of patients in the early (23.7%) and late (26.4%) treatment groups were classified as having subclinical myocardial dysfunction or high cardiovascular risk. These same groups also had the highest prevalence of ECG abnormalities, reinforcing the need for continuous cardiovascular monitoring throughout treatment. The findings from this study suggest that pediatric oncology patients should undergo dynamic cardiovascular risk stratification at each stage of treatment, allowing for early interventions that may help mitigate long-term cardiovascular complications.

Cardiovascular function in children with cancer changes dynamically throughout chemotherapy, with significant alterations occurring during active treatment phases. Frequent cardiovascular assessments are essential for early detection of myocardial dysfunction, allowing for timely interventions to prevent irreversible cardiac damage. GLS and ECG abnormalities appear to improve sensitivity in detecting subclinical cardiotoxicity, though long-term studies are needed to confirm their prognostic value in children. Pediatric oncology patients require individualized, stage-specific cardiovascular risk stratification to optimize long-term cardiac outcomes. Future studies with larger cohorts and longitudinal follow-up are necessary to refine screening protocols and risk stratification models in pediatric cardio-oncology.