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Cardiovascular disease is the leading nonmalignant cause of late deaths in childhood cancer survivors. Cardiovascular disease and cardiac dysfunction can remain asymptomatic for many years, but eventually lead to progressive disease with high morbidity and mortality. Early detection and intervention are therefore crucial to improve outcomes.
In our study, we aim to assess the prevalence of preclinical cardiac dysfunction in adult childhood cancer survivors using conventional and speckle tracking echocardiography; determine the association between cardiac dysfunction and treatment-related risk factors (anthracyclines, alkylating agents, steroids, cardiac radiation) and modifiable cardiovascular risk factors (abdominal obesity, hypertension); investigate the development of cardiac dysfunction longitudinally in a defined cohort; study the association between cardiac dysfunction and other health outcomes like pulmonary disease, endocrine disease, renal disease, quality of life, fatigue, strength and endurance, and physical activity; and gain experience conducting a clinical study of childhood cancer survivors that will be extended to a national, multicenter study of cardiac complications.
For this retrospective cohort study, we will invite ≥5-year childhood cancer survivors who were treated at the University Children's Hospital Bern, Switzerland with any chemotherapy or cardiac radiation since 1976 and who are ≥18 years of age at the time of the study for a cardiac assessment at the University Hospital Bern. This includes 544 childhood cancer survivors, of whom about half were treated with anthracyclines and/or cardiac radiation and half with any other chemotherapy. The standardized cardiac assessment includes a medical history focusing on signs of cardiovascular disease and its risk factors, a physical examination, anthropometry, vital parameters, the 1-minute sit-to-stand test, and echocardiography including 2-dimensional speckle tracking.
We will invite 544 eligible childhood cancer survivors (median age at the time of the study, 32.5 years; median length of time since diagnosis, 25.0 years) for a cardiac assessment. Of these survivors, 300 (55%) are at high risk, and 244 (45%) are at standard risk of cardiac dysfunction.
This study will determine the prevalence of preclinical cardiac dysfunction in Swiss childhood cancer survivors, inform whether speckle tracking echocardiography is more sensitive to cardiac dysfunction than conventional echocardiography, and give a detailed picture of risk factors for cardiac dysfunction. The results will help improve primary treatment and follow-up care of children with cancer.
ClinicalTrials.gov NCT03790943; https://clinicaltrials.gov/ct2/show/NCT03790943
DERR1-10.2196/17724
Survival of childhood cancer has improved, and the number of childhood cancer survivors (CCS) has greatly increased during recent decades [
Studies from North America, Germany, and The Netherlands have assessed survivors exposed to cardiotoxic cancer therapy, in whom a prevalence of subclinical cardiac dysfunction ranging from 6% to 27% was identified via conventional echocardiography [
Most studies have assessed survivors exposed to anthracyclines and cardiac radiation, which are the most important treatment-related risk factors [
The North American Childhood Cancer Survivor Study analyzed self-reported data on cardiovascular risk factors in more than 10,000 adult CCS and showed that hypertension alone and in combination with other modifiable cardiovascular risk factors significantly increased the risk for heart failure, coronary artery disease, valvular disease, and arrhythmia in adult CCS [
The first and primary objective of this study is to assess the prevalence of preclinical cardiac dysfunction in adult CCS using 2-dimensional (2D) and 3-dimensional (3D) conventional and 2D speckle tracking echocardiography. Second, we will determine the association between cardiac dysfunction and the risk related with treatment (anthracyclines, alkylating agents, steroids, and cardiac radiation) as well as the modifiable cardiovascular risk factors abdominal obesity and hypertension. Our third objective is to investigate the development of cardiac dysfunction longitudinally in a defined cohort. Fourth, we will study the association between cardiac dysfunction and other health outcomes like pulmonary, endocrine, and renal diseases; quality of life; fatigue; strength and endurance; and physical activity. Finally, pursuing these objectives will provide experience conducting a clinical study of CCS that could be used for a national, multicenter study of cardiac complications.
The primary outcomes of this study are abnormal 2D and 3D LV ejection fraction (LVEF) measured using conventional echocardiography and abnormal global longitudinal strain (GLS) measured using 2D speckle tracking echocardiography (
Left ventricular (LV) systolic function
2-dimensional (2D) and 3-dimensional (3D) LV ejection fraction (LVEF)
LV diastolic function
Early diastolic LV filling velocity (E)
Late diastolic LV filling velocity (A)
Early to late LV filling velocity (E/A ratio)
Mitral annular early diastolic velocity (e’) (septal and lateral)
Peak mitral flow velocity (E/e’ ratio)
Peak tricuspid regurgitation (TR) velocity
Left atrial (LA) maximum volume index
Right atrium (RA), right ventricle (RV), RV/RA ratio
Valvular dysfunction, respiratory variation, size of the vena cava
LV systolic function
Global longitudinal strain (GLS)
Global circumferential strain (GCS)
Global radial strain (GRS)
Demographic and socioeconomic characteristics
Clinical characteristics
Cardiac symptoms
History of cardiovascular disease
Modifiable cardiovascular risk factors
Chronic conditions
Sleeping habits
Medications
Thoracic surgeries
Family history of cardiovascular disease and risk factors
Pictorial images for perception of weight status
Qualitative questions
Weight and height
Waist and hip circumference
Blood pressure
Auscultation of the heart and lungs
Palpation of pulses
Carotid
Radial
Tibial
Dorsal feet
Signs of heart failure
Jugular vein pressure
Hepato-jugular reflux
Edema of the lower extremities
Size of the liver and spleen
Documentation of thoracic scars
Secondary outcomes are other conventional echocardiographic parameters of abnormal LV diastolic function (early diastolic LV filling velocity [E], late diastolic LV filling velocity [A], early to late LV filling velocity [E/A ratio], mitral annular early diastolic velocity [e’], peak mitral flow velocity [E/e’ ratio], peak tricuspid regurgitation [TR] velocity, left atrial [LA] maximum volume index), right atrium [RA], right ventricle [RV], RV/RA ratio, valvular dysfunction, respiratory variation, and size of the vena cava, and speckle tracking echocardiography–derived parameters of abnormal LV systolic function (global circumferential strain [GCS], global radial strain [GRS]). Other secondary outcomes include impaired quality of life and fatigue.
We also collect information about treatment with anthracyclines, alkylating agents, steroids, and cardiac radiation; modifiable cardiovascular risk factors (abdominal obesity and hypertension); and other health outcomes including pulmonary, endocrine, and renal diseases; strength and endurance; and physical activity.
This retrospective cohort study is part of routine clinical follow-up care and a collaborative and interdisciplinary effort of the Childhood Cancer Registry, Swiss Childhood Cancer Survivor Study, and departments of Pediatric Hematology and Oncology and Pediatric and Adult Cardiology at the University Hospital Bern, Switzerland (
Administrative staff
PhD student
Study nurse
Master students
Head of pediatric hematology and oncology
Cardiologists specialized in echocardiography
Cardiologist specialized in cardio-oncology
Nurse practitioner specialized in cardio-oncology
Administrative staff
Responsible teams in the study of preclinical diagnosis of cardiac dysfunction in childhood cancer survivors.
Current addresses of eligible survivors are obtained from the Childhood Cancer Registry and updated via the Swiss postal service where necessary (
We extract the following data on each survivor from the cancer registry: cancer diagnose(s), relapse(s), age at cancer diagnosis, year of cancer diagnosis, and whether the person had chemotherapy, radiation (if so, the location of radiation), surgery, or hematopoietic stem cell transplantation (
We collect cumulative doses of anthracyclines, steroids, and alkylating agents from medical records (
Cardiac radiation includes different radiation fields [
Anthracyclines with doxorubicin-equivalent doses (mg/m2) [
Doxorubicin x 1.0
Daunorubicin x 0.5
Epirubicin x 0.67
Idarubicin x 5.0
Mitoxantrone x 4.0
Alkylating agents with cyclophosphamide-equivalent doses (mg/m2) [
Cyclophosphamide x 1.0
Ifosfamide x 4.09
Steroids with prednisone-equivalent doses (g/m2) [
Prednisone x 1.0
Dexamethasone x 6.67
Cardiac radiation (gray)
Chest
Abdomen
Whole or thoracic spine
Total body irradiation
Patients with exposure to any cumulative dose of anthracyclines and/or cardiac radiation (chest, abdomen, whole or thoracic spine, total body irradiation) are placed in the high-risk group (
Study design and risk group stratification of childhood cancer survivors.
At the cardiac assessment, we give survivors oral and written information about the clinical study (
Echocardiography is performed by experienced cardiologists from the Department of Cardiology who are blinded with respect to the patient’s cancer treatment and risk group (
We define cardiac dysfunction according to the American Society of Echocardiography and European Association of Cardiovascular Imaging recommendations [
LV systolic dysfunction is defined as 2D/3D LVEF <52% for men and <54% for women [
The LV diastolic dysfunction definition depends on whether a patient has normal or impaired LVEF [
Abnormal strain (GLS, GCS, GRS) is defined as >2 SD below the mean using sex-specific, age-specific, vendor-specific, and software-specific strain values [
We take a comprehensive personal history of survivors' demographic and socioeconomic characteristics: current occupation, employment status, work hours per week, marital status, offspring, and housing situation (
Weight and standing height are measured using standard procedures, while the patient is barefoot and in light clothes (
We perform a thorough physical examination with special emphasis on signs of cardiovascular disease (
We have the patient perform the 1-minute sit-to-stand test (STS), which captures the number of times a person can stand up and sit down on a regular chair in 1 minute (
At the end of the cardiac assessment, a cardiologist specialized in cardio-oncology and who did not perform the echocardiography explains the results of the echocardiography to survivors and counsels them on their cardiac function and the presence (or absence) of modifiable cardiovascular risk factors (
We ask survivors to complete 4 questionnaires after returning home. The Short Form 36 Health Survey assesses health-related quality of life [
All parts of the cardiac assessment are directly entered into a dedicated REDCap (version 8.5.19, Vanderbilt University, Nashville, TN) database to minimize risk of disclosure. Within the database, each survivor has a unique ID. No personal information can be obtained with this number. Data containing survivors’ unique IDs are stored on encrypted devices or secured servers at the University of Bern.
In 2016-2017, we started using standardized echocardiography for cardiac assessment, as already described (
Recruitment of childhood cancer survivors eligible for the study, current as of October 1, 2019.
Since March 2018, we have been collecting all data in a standardized way. Data collection is performed by the study team from the Childhood Cancer Registry, Swiss Childhood Cancer Survivor Study, Department of Pediatric Hematology and Oncology at the University Hospital Bern, and Department of Cardiology at the University Hospital Bern (
We will compare characteristics of responders and nonresponders using chi-square tests and perform univariable and multivariable logistic regression analyses to investigate the association between cardiotoxic treatment exposures (anthracyclines, alkylating agents, steroids, cardiac radiation) and modifiable cardiovascular risk factors (abdominal obesity, hypertension) and cardiac dysfunction adjusting for sex, age at study, and follow-up time.
From our eligible study population of 544 CSS and based on an expected response rate of 65%, we estimate that approximately 354 survivors will attend the cardiac assessment (
We will use STATA software (Version 15.1, Stata Corporation, Austin, TX) for statistical analyses.
On January 1, 2018, the Childhood Cancer Registry included 711 survivors aged ≥18 years who had been diagnosed and treated at the University Children’s Hospital Bern since 1976 and had survived ≥5 years (
Demographic and clinical characteristics of survivors eligible for participation in the cohort study (n=544), as of January 1, 2018.
Demographic and clinical characteristics | n (%) | ||
Male sex | 297 (55) | ||
Age at the time of the study (years)a | 32.5 (25.4-38.5, 18.3-56.0) | ||
|
|
||
|
<20 | 30 (6) | |
|
20-29 | 197 (36) | |
|
30-39 | 207 (38) | |
|
>39 | 110 (20) | |
Age at diagnosis (years)a | 6.7 (3.1-12.5, 0.1-17.5) | ||
|
|
||
|
<5 | 207 (38) | |
|
5-9 | 134 (25) | |
|
10-14 | 149 (27) | |
|
15-19 | 54 (10) | |
Time since diagnosis (years)a | 25.0 (17.9-32.0, 6.2-42.0) | ||
|
|
||
|
5-10 | 31 (6) | |
|
11-20 | 130 (24) | |
|
21-30 | 220 (40) | |
|
31-40 | 147 (27) | |
|
>40 | 16 (3) | |
|
|
||
|
I Leukemia | 218 (40) | |
|
II Lymphoma | 118 (22) | |
|
III CNSc | 35 (6) | |
|
IV Neuroblastoma | 17 (3) | |
|
V Retinoblastoma | 11 (2) | |
|
VI Renal tumor | 38 (7) | |
|
VII Hepatic tumor | 6 (1) | |
|
VIII Bone tumor | 40 (7) | |
|
IX Soft tissue sarcoma | 33 (6) | |
|
X Germ cell tumor | 8 (2) | |
|
XI&XII Other rare tumorsd | 20 (4) | |
|
|
||
|
1976-1985 | 136 (25) | |
|
1986-1995 | 199 (36) | |
|
1996-2005 | 156 (29) | |
|
2006-2012 | 53 (10) | |
|
|
||
|
High-riske | 300 (55) | |
|
Standard-riskf | 244 (45) | |
Any radiation therapy | 213 (39) | ||
Any surgery | 329 (61) | ||
Any chemotherapy | 531 (98) | ||
Hematopoietic stem cell transplantation | 28 (5) |
amedian (IQR, range).
bICCC-3, International Classification of Childhood Cancer third edition.
cCNS, central nervous system.
dincluding Langerhans cell histiocytosis, other malignant epithelial neoplasms, malignant melanomas, and other or unspecified malignant neoplasms.
eanthracyclines and/or cardiac radiation.
fany chemotherapy other than anthracyclines.
This retrospective, single-center cohort study is investigating the prevalence of cardiac dysfunction and its risk factors in adult CCS and comparing conventional and speckle tracking echocardiography.
Few studies are comparable to ours. A single-center study in The Netherlands included 525 adult CCS who had been treated during 1966-1997 with anthracyclines, high-dose cyclophosphamide, high-dose ifosfamide, and/or cardiac radiation [
Conventional and speckle tracking echocardiography have some strengths and weaknesses that need to be addressed. Until now, conventional echocardiography has been the most commonly used noninvasive imaging modality to quantify cardiac function [
First among this study's limitations is that it is currently confined to a single center. However, the 9 centers treating children and adolescents with cancer in Switzerland collaborate closely and use uniform treatment protocols; we therefore expect that results from the University Hospital Bern are representative of all 9 centers in the country. We are also concerned that our study includes a heterogeneous group of CCS with relatively small numbers of patients in each subgroup defined by treatment exposure or type of cancer. We plan to overcome this limitation by expanding this study to a nationwide study that includes all 9 Swiss Pediatric Oncology Group clinics. Also, our study might be affected by survival bias, as the most severely affected childhood cancer patients and survivors have already died. This could underestimate the cardiotoxic effect of anticancer management. We will collect the number of cardiac deaths from the Swiss Mortality Statistics, and this information will be considered in the analysis and interpretation of the results.
Among this study's several strengths is our attempt to include the complete cohort of survivors treated at the University Children’s Hospital Bern since 1976 based on the database of the Childhood Cancer Registry. We repeat our invitation to nonresponders several times and ask about reasons for not participating. This reduces the potential for selection bias. Also, we link the Childhood Cancer Registry with the Swiss Federal Statistical Office to collect cardiac causes of death in ≥5-year survivors. Second, we have access to all treatment exposures based on actual chemotherapy road maps and are able to look into dose-response relationships. Third, we will continuously include new 5-year survivors and therefore gain knowledge about the risk of cardiac dysfunction in younger patients treated more recently. Finally, our study has been set up within routine survivorship follow-up care using the experience of a multidisciplinary and interdisciplinary team with close collaboration between pediatric and adult cardiology, pediatric hematology and oncology, and clinical epidemiology.
The preliminary results from this retrospective, single-center study suggest that a standardized cardiac assessment that is part of routine follow-up care done in collaboration between pediatric and adult specialists is feasible in Switzerland and widely accepted by survivors and health care providers. In the next step, we will include more Swiss centers in the study to provide standardized clinical follow-up care longitudinally to all CCS on a nationwide scale.
Peer review reports, Swiss Cancer League.
2-dimensional
3-dimensional
late diastolic left ventricular filling velocity
childhood cancer survivors
early diastolic left ventricular filling velocity
early to late left ventricle filling velocity
mitral annular early diastolic velocity
peak mitral flow velocity
global circumferential strain
global longitudinal strain
global radial strain
International Classification of Childhood Cancer third edition
left atrial
left ventricular
left ventricular ejection fraction
right atrium
right ventricle
1-minute sit-to-stand test
tricuspid regurgitation
We thank all childhood cancer survivors for participating in our study. We thank Michele Martinelli for performing the clinical assessment. We thank Susanne Suter, Nadine Lötscher, Caleb Leung, Pascale Annaheim, and Annina Elmiger for supporting the study and providing valuable input. We thank the study team of the SCCSS: Fabiën Belle, Carole Dupont, Rahel Kasteler, Rahel Kuonen, Jana Remlinger, Grit Sommer, Maria Otth, and Annette Weiss. We also thank the data managers of the SPOG: Dr. Claudia Althaus, Nadine Assbichler, Pamela Balestra, Heike Baumeler, Nadine Beusch, Sarah Blanc, Dr. Pierluigi Brazzola, Susann Drerup, Janine Garibay, Franziska Hochreutener, Monika Imbach, Friedgard Julmy, Eléna Lemmel, Rodolfo Lo Piccolo, Heike Markiewicz, Dr. Veneranda Mattielo, Annette Reinberg, Dr. Renate Siegenthaler, Astrid Schiltknecht, Beate Schwenke, and Verena Stahel. And we thank the SCCR team of Meltem Altun, Erika Brantschen, Katharina Flandera, Elisabeth Kiraly, Verena Pfeiffer, Shelagh Redmond, Julia Ruppel, and Ursina Roder. For editorial assistance, we thank Christopher Ritter. This study was supported by the Swiss Cancer League (KLS-3886-02-2016), which funds the salary of a PhD student (CS) and study nurse. The Stiftung für krebskranke Kinder, Regio basiliensis (AND-4641-01-2018) gave a travel grant to CS for a research visit to St. Jude Children’s Research Hospital, Memphis, TN, USA. The work of the Childhood Cancer Registry is supported by the Swiss Pediatric Oncology Group (www.spog.ch), Schweizerische Konferenz der kantonalen Gesundheitsdirektorinnen und -direktoren (www.gdk-cds.ch), Swiss Cancer Research (www.krebsforschung.ch), Kinderkrebshilfe Schweiz (www.kinderkrebshilfe.ch), the Federal Office of Public Health (FOPH), and the National Institute of Cancer Epidemiology and Registration (www.nicer.org).
NXvdW, MP, TS, CEK, and CS designed the study and developed the study material. MP, TS, CEK, NXvdW, CS, ESHL, DR, and JR participated in study management and coordination. CS, CEK, and NXvdW drafted the manuscript. All authors commented on and approved the final version.
JR reports personal fees from SOBI, Roche, and Pierre Fabre for advisory board membership, which is independent of the submitted work.