Subclinical Cardiac Dysfunction in Childhood Cancer Survivors on 10-Years Follow-Up Correlates With Cumulative Anthracycline Dose and Is Best Detected by Cardiopulmonary Exercise Testing, Circulating Serum Biomarker, Speckle Tracking Echocardiography, and Tissue Doppler Imaging.

Cordula Maria Wolf,Jochen Weil,Christian Meierhofer,Irene Schmid,Renate Oberhoffer,Alfred Hager,Jan Müller,Peter Ewert,Barbara Reiner,Andreas Kühn

doi:10.3389/fped.2020.00123

Abstract

Background: Survivors of childhood cancer are at risk for anthracycline- and/or radiotherapy-induced cardiotoxicity.Aims: The aim of this study was to assess clinical, laboratory, and imaging parameters of subclinical cardiovascular disease in childhood cancer survivors.Methods: Patients underwent cardiopulmonary exercise test (CPET), laboratory testing, transthoracic echocardiography (TTE) with tissue doppler imaging (TDI) and speckle tracking. A subset of patients also underwent cardiovascular magnetic resonance imaging (CMR). Findings were correlated to cumulative anthracycline and exposure to mediastinal irradiation during cancer treatment. In a subgroup analysis, TTE and CMR findings were compared to data from 40 gender- and age-matched patients with childhood onset hypertrophic cardiomyopathy (HCM).Results: Cardiac evaluation was performed in 79 patients (43 males) at 11.2 ± 4.5 years after cancer treatment. Oncologic diagnosis at a median age of 12.0 years was Hodgkin lymphoma in 20, sarcoma in 17, acute leukemia in 24, relapse leukemia in 10, and others in 8 patients. Cumulative anthracycline dose exceeded 300 mg/m2 in 28 patients. Twenty six patients also received mediastinal irradiation. Decreased peak respiratory oxygen uptake in % predicted on CPET, increased levels of N-terminal pro-brain natriuretic peptide (NTproBNP), increased global longitudinal strain on TTE speckle tracking, and diastolic dysfunction on TDI were the most prominent findings on detailed cardiology follow-up. In contrast to HCM patients, childhood cancer survivors did not show left ventricular hypertrophy (LVPWd z-score median 0.9 vs. 2.8, p < 0.001), hyperdynamic systolic function on TTE (Ejection fraction 62 ± 7 vs. 72 ± 12%, p = 0.001), or fibrotic myocardial changes on CMR (Late gadolinium positive 0/13 vs. 13/36, p = 0.001; extracellular volume fraction 22 ± 2 vs. 28 ± 3, p < 0.001) at time of follow-up. There was no correlation between chest radiation exposure and abnormal cardiac findings. Cumulative anthracycline dose was the only significant independent predictor on multivariate analysis for any cardiovascular abnormality on follow-up (p = 0.036).Conclusion: Increasing cumulative anthracycline dose during cancer treatment correlates with subclinical cardiac dysfunction in childhood cancer survivors best detected by elevated cardiac serum biomarkers, decreased exercise capacity on CPET, and abnormalities on echocardiographic speckle tracking and TDI.

Highlights

Due to advancements in treatment, survival rates for childhood cancer have substantially improved during the past decades with an overall 5-year survival rate of over 80% today [1,2,3]
The diagnosis of hypertrophic cardiomyopathy (HCM) was based on clinical evaluation and cardiac catheterization or Transthoracic echocardiography (TTE) detecting myocardial hypertrophy in the absence of another cardiac or systemic disease causing the degree of left ventricular hypertrophy identified [42, 43]
There was no significant correlation between cumulative anthracycline dose and decreased systolic echocardiographic function as shown by TTE ejection fraction (EF) on follow-up

Summary

Introduction

Due to advancements in treatment, survival rates for childhood cancer have substantially improved during the past decades with an overall 5-year survival rate of over 80% today [1,2,3]. More than half of childhood cancer patients receive anthracyclines as part of their cancer therapy [4] and anthracycline-mediated cardiovascular complications contribute to morbidity and mortality in the growing population of childhood cancer survivors [reviewed in Franco et al, [5], Raj et al, [6], Todaro et al, [7], Van Der Pal et al, [8] and [9]] Anthracyclines express their antiproliferation of cancer cell effects through inhibition of DNA replication, RNA replication, DNA cross-linking, and topoisomerases [10]. Survivors of childhood cancer are at risk for anthracycline- and/or radiotherapy-induced cardiotoxicity

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Discussion

Conclusion