The EARLY study: Early detection of acute and early-onset cARdiovascuLar toxicitY in children with cancer using a multiparametric approach.

Early detection of (subclinical) cardiotoxicity is crucial, to allow for timely
intervention and prevention of further progression of cardiac disease.
Anthracyclines and radiotherapy of the chest and mediastinum including the
heart are both cornerstones in the treatment of children with cancer (CC),
including Hodgkin Lymphoma (HL), osteosarcoma (OS), Ewing sarcoma (ES) and soft
tissue sarcoma (STS). Irradiated patients are also prone to develop accelerated
coronary artery disease, valvular and pericardial disease, conduction
abnormalities and arrhythmias, especially if treated with high-dose thoracic
radiotherapy. In CC patients treated with an anthracycline-based chemotherapy,
approximately 10% develop overt congestive heart failure 40 years after
treatment, as a result of anthracycline exposure. Prospective information on
the incidence, the extent and prognostic value of subclinical cardiotoxicity in
children during treatment for CC is scarce. Echocardiography is the current
tool for detecting cardiac disease related to
cardiotoxicity - given its low costs, widespread availability, and
reproducibility - but was limited in the past to detection of only overt
systolic dysfunction. Recently introduced advanced echocardiography techniques
using strain measurements by myocardial deformation analysis, have demonstrated
the potential to detect subclinical cardiac dysfunction, even before systolic
dysfunction becomes apparent. In addition, cardiac MRI has recently emerged as
an important non-invasive imaging tool for myocardial tissue characterization.
Myocardial tissue mapping by MRI allows for quantification of myocardial
fibrosis and scar tissue as a response to cardiac damage by cardiotoxicity,
while myocardial deformation analysis provides subtle functional assessment of
the heart, with delineation of the maladaptive changes in response to myocyte
injury. Cardiac biomarkers and ECG analysis can provide complementary
information about the cardiac disease status, while genetic testing may help
with prediction of potentially increased susceptibility for the development of
cardiotoxicity of the individual patient. Therefore, a multimodality approach
using advanced echocardiography and MRI, together ECG, will allow for a
comprehensive assessment of potential risk factors and disease course of early
cardiac disease in CC patients, and will hopefully provide insights for early
detection and early start of treatment in CC treated with anthracyclines and/or
radiotherapy in the cardiac region.

1. To investigate the feasibility to perform advanced echocardiographic
measurements
2. To describe the incidence and variation of cardiac damage during and shortly
after treatment using detailed advanced echocardiographic measurements and ECG
at different time points
3. To assess the association between abnormalities measured in objective 1 with
anthracycline dose, chest irradiation dose, disease profile, age at diagnosis,
and gender.
4. To collect blood for future assessment of biomarkers and
pharmacogenetics.Subgroup of 30 children with cancer with anthracyclines
5. To investigate the feasibility to perform cardiac MRI during MRI*s that are
planned for tumor response evaluation.
6. To describe the incidence and variation of cardiac damage during and shortly
after treatment using MRI markers of myocardial fibrosis at different time
points, and the association with anthracycline dose, chest irradiation dose,
disease profile, age at diagnosis, and gender.
7. To investigate the association between MRI abnormalities and echo
parameters.

Prospective follow-up pilot-study in children with cancer from diagnosis to 1
year post diagnosis.

Patient burden
Cardiac evaluation for this study will be closely intertwined with the routine
oncological evaluation documented in the international cancer treatment
protocols, to minimize the burden on the study participants. Echocardiography,
MRI and ECG are routinely obtained for the first time point of the study (at
baseline). The supportive care guidelines state that an echocardiogram should
be performed when a cumulative dose of anthracyclines (doxorubicine and
daunorubicine 240 mg/m2; epirubicine 400 mg/m2; idarubicine and mitoxantrone 60
mg/m2) is reached. The cardiac MRI evaluation will be incorporated in the
routine MRI for oncological evaluation (extra duration 15-20 minutes of cardiac
scanning), which implies only a limited burden on the study participants. MRI
at time points 3-4 months and 1 year after treatment are for research purposes.
Echocardiography and ECG will be done simultaneously and will approximately
take one hour. Blood samples for future use for cardiac biomarkers and genetic
testing will be drawn at the same time when the patient will need blood sample
collection routinely for treatment evaluation. All CC patients included into
this study will have a central venous access.