Pediatr Blood Cancer 2015;62:502–508

Assessing Anthracycline-Treated Childhood Cancer Survivors With Advanced Stress Echocardiography A. Blythe Ryerson, PhD, MPH,1* William L. Border, MBChB, MPH,2,3 Karen Wasilewski-Masker, MD, MSc,3,4 Michael Goodman, MD, MPH,1 Lillian Meacham, MD,3,4 Harland Austin, DSc,1 and Ann C. Mertens, PhD1,3,4 Background. Surveillance for anthracycline cardiotoxicity in cancer survivors typically utilizes resting M-mode and twodimensional echocardiography, which are insensitive to detection of subtle myocardial changes. We examined childhood cancer survivors treated with anthracyclines during exercise using various echocardiography techniques to investigate if these tools can better detect subclinical cardiac dysfunction. Procedure. We recruited asymptomatic survivors at least five years post treatment. Echocardiography was performed at rest and at termination of exercise utilizing tissue Doppler techniques and strain rate imaging. Results. Eighty participants were characterized by cardiotoxicity risk status (high [12], moderate [23], low [24], no risk [21]) as defined by the Children’s Oncology Group Long Term Follow-Up Guidelines v3.0. The high-risk group had a higher resting heart rate than controls (100 vs. 88 bpm [P for trend ¼ 0.049]). Peak aerobic capacity in all groups

Key words:

anthracyclines; echocardiography; neoplasms; pediatrics; stress; survivors

INTRODUCTION Over the past few decades, there have been significant improvements in overall 5-year survival rates among children with cancer, largely due to the introduction of new therapeutic strategies [1]. However, because of these improvements in survival, an increasing number of childhood cancer survivors are at increased risk for health problems related to their treatment [2]. Numerous studies have reported on the late effects of chemotherapy and radiation in childhood cancer survivors, with both anthracyclines and radiation known to be cardiotoxic [2–5]. Data from a cohort of pediatric cancer survivors demonstrated a 10.8-fold excess in allcause mortality and 8.2-fold excess risk of death related to cardiac events in this population [4]. The serial noninvasive surveillance of anthracycline cardiotoxicity has traditionally focused on assessment of left ventricular (LV) systolic function using M-mode and two-dimensional resting echocardiography [6,7]. By measuring dimensional changes and utilizing volume calculations, ejection phase indices, namely shortening fraction (SF) and ejection fraction (EF), can be calculated. While these measures are frequently used in the cardiac monitoring of childhood cancer survivors treated with anthracyclines, they are subject to a number of limitations. First, these parameters are insensitive to the detection of subtle myocardial changes which occur in early cardiotoxicity because they only detect measurable changes in the global systolic function that take place in the presence of substantially damaged, dysfunctional myocardium [8–16]. At the point when these parameters allow detection of dysfunction, further deterioration proceeds rapidly and is usually irreversible [17–19]. Second, both SF and EF are dependent on ventricular loading conditions [8,9,20–22]. Loading conditions can be affected by a number of underlying health problems including fever, dehydration, anemia and sepsis, and these may mask real changes in cardiac contractility [23].  C

was similar. Compared to controls at rest, the high-risk group had evidence of diastolic dysfunction with lower E/A ratios (1.4 vs. 2.0, P ¼ 0.008) and higher septal early diastolic velocities (E/E’) of 11.7 versus 9.9 (P ¼ 0.165). With exercise, this difference resolved and myocardial contractile reserve was preserved. Conclusions. Asymptomatic, pediatric cancer survivors at high-risk for anthracycline cardiotoxicity have some evidence of diastolic filling abnormalities at rest. With exercise, they augment their systolic and diastolic function to achieve normal maximal aerobic capacity suggesting they are able to compensate for mild cardiac dysfunction in the early years after exposure. Additionally, findings suggest that routine exercise echocardiography may not be a useful surveillance tool to assess anthracycline cardiotoxicity. Pediatr Blood Cancer 2015;62:502– 508. # 2014 Wiley Periodicals, Inc.

Feasibility studies of new cardiac surveillance modalities would be valuable to clinicians treating patients with previous anthracycline exposure [24,25]. The aim of this study is to describe how the heart muscle function measured during exercise using various Tissue Doppler Imaging (TDI) and Strain Rate Imaging (SRI) techniques differs among pediatric cancer survivors treated with varying anthracycline doses and those who did not receive anthracyclines. Although this analysis is exploratory in nature, we hypothesize that by using a variety of imaging techniques during exercise, we will detect subclinical cardiac dysfunction more frequently in patients than when using standard techniques at rest alone. Additionally, we expect that this dysfunction will demonstrate a dose-related response to anthracycline exposure.

METHODS Study Design Childhood cancer survivors followed through the Cancer Survivor Program at Children’s Healthcare of Atlanta (CHOA) were enrolled in this study, which involved exercise echocardiog1 Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia; 2Sibley Heart Center Cardiology, Atlanta, Georgia; 3Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia; 4Aflac Cancer & Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, Georgia

Grant sponsor: Emory-Children’s Research Grant; Grant sponsor: Scott Hudgens Family Foundation Conflict of interest: Nothing to declare.  Correspondence to: A. Blythe Ryerson, Department of Epidemiology, Rollins School of Public Health, Emory University, 4770 Buford Highway, NE, Mail Stop F-76, Atlanta, GA 30341. E-mail: [email protected]

Received 14 April 2014; Accepted 1 October 2014

2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25328 Published online 12 November 2014 in Wiley Online Library (wileyonlinelibrary.com).

Stress Echos and Anthracycline Cardiotoxicity raphy with Doppler imaging at the Sibley Heart Center at CHOA, a health status questionnaire, and a physical exam. Examinations took place between April 2010 and August 2011. The Emory University Institutional Review Board reviewed and approved this study. Eligible participants were children, adolescents and young adults 8–21 years of age that were diagnosed and treated for cancer at CHOA, or if diagnosed and treated elsewhere, currently followed through the CHOA Cancer Survivor Program. All participants had completed cancer treatment at least five years prior to enrollment, and had no evidence of current malignancy, known cardiac symptoms, or cardiomyopathy. To focus our analysis on the effects of anthracyclines, we excluded subjects if they had a history of radiotherapy with potential impact to the heart. All participants, or their legal guardians, provided written informed consent. Because we wanted to obtain a sample balanced on anthracycline cardiotoxicity risk status, we stratified our study group based on their cumulative lifetime anthracycline exposure. Based on the recommended imaging surveillance frequencies in the longterm follow-up guidelines published by the Children’s Oncology Group (COG), all participants were assigned into control (never treated with anthracyclines), low-risk (

Assessing anthracycline-treated childhood cancer survivors with advanced stress echocardiography.

Surveillance for anthracycline cardiotoxicity in cancer survivors typically utilizes resting M-mode and two-dimensional echocardiography, which are in...
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