Early Detection of Cardiovascular Changes After Radiotherapy for Breast Cancer (EARLY HEART Study) in the Frame of the Implications of MEDIcal Low Dose RADiation Exposure (MEDIRAD) European Project
Phase: NA
Conditions: Breast Cancer Female
Sponsor: Institut de Radioprotection et de Surete Nucleaire

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European Commission Horizon 2020 
Topic: NFRP-9 Impacts of low dose radiation exposure 
 
MEDIRAD project 
Implications of MEDIcal low dose RADiation exposure 
Agreement 755523 
 
 
 
Clinical study protocol: 
 
EARLY-HEART 
EARLY detection of cardiovascular changes (HEART) 
after radiotherapy for breast cancer 
 
 
 
 
 
 
 
 
 
Version number/date:  
1.2, 05-07-2017 
 
 
 
 

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Investigators and collaborators 
 
Work package 4.1 Clinical and molecular epidemiology studies on low dose radiation-
induced early cardiovascular changes after breast cancer radiotherapy 
Leader: 
 
 
 
 
 
Prof.Dr. J.A. Langendijk 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
UMCG 
 
 
 
 
Hanzeplein 1 
 
 
 
 
9713 GZ Groningen 
 
 
 
 
The Netherlands 
 
 
 
 
j.a.langendijk@umcg.nl 
 
 
 
 
+31-503615532 
 
Work package task 4.1.1 MEDIRAD EARLY-HEART: early detection of cardiovascular 
changes after RT for breast cancer 
 
Coordinator and local investigators IRSN: 
 
 
 
 
Coordinator: 
S. Jacob, PhD  
 Laboratory of Radiation Epidemiology 
 IRSN 
 BP 17 
 92260 Fontenay aux Roses 
 France 
 sophie.jacob@irsn.fr 
 
 G Jimenez, MD 
Clinique Pasteur 
Radiothérapie (Oncorad) / Atrium 
1 rue de la Petite Vitesse 
31300 Toulouse 
France 
gjimenez@clinique-pasteur.com 
 
A. Pathak, MD, PhD 
 Clinique Pasteur 
Cardiology Department 
 45 ave de Lombez 
 31300 Toulouse 
 France 
 apathak@clinique-pasteur.com 
 
 
Local investigators UMCG:  
 
 
 
 
A.P.G. Crijns, MD PhD  
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
UMCG 
 
 
 
 
Hanzeplein 1 
 
 
 
 
9713 GZ Groningen 
 
 
 
 
The Netherlands 
 
 
 
 
a.p.g.crijns@umcg.nl 
 
 
 
 
+31-652724432 
 
Prof.Dr. R. Vliegenthart 
 
 
 
 
Department of Radiology 
 
 
 
 
UMCG 

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Hanzeplein 1 
 
 
 
 
9713 GZ Groningen 
 
 
 
 
The Netherlands 
 
 
 
 
r.vliegenthart@umcg.nl 
 
 
 
 
+31-652724432 
 
 
Local investigators TUM-MED: 
 
 
 
 
Prof.Dr. S. Combs  
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
TUM-MED 
 
 
 
 
Ismanninger Strasse 
 
 
 
 
81675 München 
 
 
 
 
Germany 
 
 
 
 
stephanie.combs@tum.de 
 
 
 
 
 
 
D. Schilling, PhD  
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
TUM-MED 
 
 
 
 
Ismanninger Strasse 
 
 
 
 
81675 München 
 
 
 
 
Germany 
 
 
 
 
daniela.schilling@tum.de 
 
 
 
 
 
M. Mayinger, MD  
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
TUM-MED 
 
 
 
 
Ismanninger Strasse 
 
 
 
 
81675 München 
 
 
 
 
Germany 
 
 
 
 
michael.mayinger@tum.de 
 
Local investigators ICO: 
A. Eraso, MD PhD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
ICO 
 
 
 
 
Av. França s/n 
 
 
 
 
Girona 
 
 
 
 
Spain 
 
 
 
 
aeraso@iconcologia.net 
 
F. Guedea, MD PhD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
ICO 
 
 
 
 
Av Gran via de l’hospilalet 199-203 
 
 
 
 
L’Hospitalet del llobregat 
 
 
 
 
Spain 
 
 
 
 
fguedea@iconcologia.net 
 
E. Oliva, MD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
ICO 
 
 
 
 
Av. França s/n 
 
 
 
 
Girona 
 
 
 
 
Spain 
 
 
 
 
eoliva@iconcologia.net 
 

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E. Canals, MD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
ICO 
 
 
 
 
Av. França s/n 
 
 
 
 
Girona 
 
 
 
 
Spain 
 
 
 
 
ecanals@iconcologia.net 
 
 
Local investigators CCUL: 
M. Fiuza,  MD PhD 
 
 
 
 
Department of Cardiology 
 
 
 
 
CCUL 
 
 
 
 
Av Prof Egas Moniz 
 
 
 
 
1649-028 Lisbon 
 
 
 
 
Portugal 
 
 
 
 
manuela.fiuza@gmail.com 
 
S. Constantino,  PhD 
 
 
 
 
Laboratory of Angiogenesis 
 
 
 
 
CCUL 
 
 
 
 
Av Prof Egas Moniz 
 
 
 
 
1649-028 Lisbon 
 
 
 
 
Portugal 
 
 
 
 
sconstantino@medicina.ulisboa.pt 
 
F. Pina, MD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
Hospital Santa Maria 
 
 
 
 
Av Prof Egas Moniz 
 
 
 
 
1649-028 Lisbon 
 
 
 
 
Portugal 
 
 
 
 
filomena.pina@chln.min-saude.pt 
 
 
Local investigators Université Paris Descartes: Core center for reading Cardiac CT and 
Cardiac MR. 
Elie Mousseaux 
 
 
 
 
Department of Radiology 
 
 
 
 
Hopital Européen Georges Pompidou 
 
 
 
 
20 rue Leblanc, 75908 Paris Cedex 15 
 
 
 
 
Elie.mousseaux@aphp.fr 
 
 
 
 

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Other collaborators: 
 
 
Work package task 4.2.2: Preclinical and clinical identification of standard and innovative 
biomarkers of radiation-induced cardiovascular toxicity  
Leader 
Constanza Emanueli, PhD 
Bristol Heart Institute, School of Clinical Sciences,  
University of Bristol 
Bristol Royal Infirmary, Upper Maudlin Street  
BS2 8HW 
Bristol 
United Kingdom 
costanza.emanueli@bristol.ac.uk 
 
 
Work package 4.3 Cardiovascular risk modelling 
Leader: 
Christian Kaiser, PhD 
Helmholtz Zentrum München 
German Research Center for Environmental Health 
Institute of Radiation Protection 
85764 Oberschleissheim, Germany 
christian.kaiser@helmholtz-muenchen.de 
 
Work package 2.4.1 Imaging and radiation dose repository 
Leader 
Professor Osman Ratib 
Institute of Translational Molecular Imaging 
Rue Gabrielle-Perret-Gentil, 4 
Geneve, Switzerland 
osman.ratib@unige.ch 
 
 
 
Sponsors: 
UMCG for Netherlands, IRSN for France, TUM-MED for Germany, ICO for Spain 
and CCUL for Portugal 
 
 
Central data management: Data management of IRSN, Institut de radioprotection et Sûreté 
Nucléaire 
 
 
 
 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Coordinator IRSN: 
Sophie Jacob, PhD 
 
July 6, 2017 
Work package leader co-local 
investigator UMCG: 
Johannes A. Langendijk 
 
July 7, 2017 
Local principal investigator UMCG: 
A.P.G. Crijns, MD PhD 
 
July 7, 2017 
Local principal investigator TUM-MED: 
Prof.Dr. S. Combs 
 
July 10, 2017 
Local principal investigator ICO: 
A. Eraso, MD PhD 
 
July 7, 2017 
Local principal investigator CCUL: 
M. Fiuza, MD PhD 
 
July 6, 2017 
Local principal investigator Université 
Paris Descartes:  
Elie Mousseaux, MD PhD 
 
July 7, 2017 
  
 
 

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TABLE OF CONTENTS 
 
1. 
TWO-PAGE OUTLINE OF THE PROTOCOL ......................................................................................... 10 
2. 
BACKGROUND AND INTRODUCTION ................................................................................................. 12 
2.1. 
INTRODUCTION .................................................................................................................................... 12 
2.2. 
SUMMARY AND PROPOSED STUDY ........................................................................................................ 14 
3. 
OBJECTIVES OF THE TRIAL ................................................................................................................ 15 
3.1. 
GENERAL OBJECTIVES ........................................................................................................................ 15 
3.2. 
ENDPOINTS ......................................................................................................................................... 16 
3.2.1. 
PRIMARY ENDPOINTS ...................................................................................................................... 16 
3.2.2. 
SECONDARY ENPOINTS ................................................................................................................... 16 
4. 
PATIENT SELECTION CRITERIA .......................................................................................................... 17 
5. 
TRIAL DESIGN ........................................................................................................................................ 18 
6. 
THERAPEUTIC REGIMENS, EXPECTED TOXICITY, DOSE MODIFICATION .................................... 18 
6.1. 
RADIOTHERAPY .................................................................................................................................. 18 
6.2. 
PATIENT POSITIONING ......................................................................................................................... 18 
6.3. 
PLANNING CT SCAN ACQUISITION ........................................................................................................ 18 
6.4. 
TARGET VOLUMES AND ORGANS AT RISK ............................................................................................. 19 
6.5. 
TREATMENT PLANNING ........................................................................................................................ 19 
7. 
CLINICAL EVALUATION, LABORATORY TESTS AND FOLLOW-UP ................................................ 20 
7.1. 
BEFORE INCLUSION ............................................................................................................................. 20 
7.2. 
BEFORE START OF TREATMENT PROTOCOL .......................................................................................... 20 
7.3. 
DURING TREATMENT ........................................................................................................................... 21 
7.4. 
SUBSEQUENT FOLLOW-UP ................................................................................................................... 21 
7.5. 
BLOOD SAMPLES FOR BIOMARKERS ANALYSIS ..................................................................................... 21 
8. 
FLOWCHART .......................................................................................................................................... 22 
9. 
STATISTICAL CONSIDERATIONS ........................................................................................................ 22 
9.1. 
STUDY DESIGN ................................................................................................................................... 22 
9.2. 
SAMPLE SIZE ...................................................................................................................................... 22 
9.3. 
ANALYSIS PLAN .................................................................................................................................. 23 
10. 
REPORTING ADVERSE EVENTS ...................................................................................................... 25 
11. 
ETHICAL CONSIDERATIONS ............................................................................................................ 26 
11.1. 
REGULATION STATEMENT ................................................................................................................ 26 
11.2. 
RECRUITMENT AND CONSENT .......................................................................................................... 26 
11.3. 
OBJECTION BY MINORS OR INCAPACITATED SUBJECTS ..................................................................... 27 
11.4. 
BENEFITS AND RISKS ASSESSMENTS, GROUP RELATEDNESS ............................................................. 27 
11.5. 
COMPENSATION FOR INJURY ........................................................................................................... 27 
12. 
DATA COLLECTION, DATA MANAGEMENT, MONITORING AND PUBLICATION ........................ 27 
12.1. 
DATA MANAGEMENT ........................................................................................................................ 27 
12.2. 
ECRF ............................................................................................................................................. 29 
12.3. 
DOSE DATA REPOSITORY; STORAGE OF DICOM DATA ...................................................................... 29 
12.4. 
MONITORING AND QUALITY ASSURANCE ........................................................................................... 30 
12.5. 
QUALITY ASSURANCE ...................................................................................................................... 32 
12.6. 
ANONYMIZATION OF DATA ............................................................................................................... 32 
12.7. 
RETENTION OF RECORDS ................................................................................................................. 32 
12.8. 
AMENDEMENTS ............................................................................................................................... 33 
12.9. 
ANNUAL PROGRESS REPORT ........................................................................................................... 33 
12.10. 
TEMPORARY HALT AND (PREMATURELY) END OF STUDY REPORT ....................................................... 33 
13. 
TRIAL INSURANCE ............................................................................................................................. 33 

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14. 
PUBLICATION POLICY ....................................................................................................................... 34 
15. 
REFERENCES ..................................................................................................................................... 34 
16. 
APPENDICES ...................................................................................................................................... 37 
DECLARATION OF HELSINKI ............................................................................................................................. 37 
INFORMED CONSENT FORM ............................................................................................................................. 40 
CRF ELIGIBILITY ......................................................................................................................................... 45 
CRF CANCER .............................................................................................................................................. 46 
CRF PLANNED RT .......................................................................................................................................... 48 
CRF RT TOXICITY ....................................................................................................................................... 49 
CRF CARDIOLOGY ..................................................................................................................................... 50 
LOCAL CRF ECHO-ST ................................................................................................................................ 52 
CTCA  PROTOCOL  AND LOCAL CRF AT TIME OF ACQUISITION ...................................................................... 53 
CARDIAC MRI PROTOCOL  AND LOCAL CRF AT TIME OF ACQUISITION ............................................................ 56 
BLOOD SAMPLE PROTOCOL .................................................................................................................... 59 
 
 
 
 
 

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List of abbreviations and relevant definitions 
 
 
AE 
ASE/EAE  
Adverse Event 
American Society of Echography / European Association of Echography 
BC 
BLOOD 
Breast Cancer 
Circulating biomarkers  
CAC 
3D CRT 
CT 
CTCA 
CRF 
CTCAE 
CTV 
DCIS 
DICOM 
DVH 
ECHO-ST-ST 
ENACT 
GLS/GLSR 
Gy 
Calcium artery calcium  
Three Dimensional Conformal Radiation Therapy 
Cardiac Computed tomography  
Computed tomography coronary angiography 
Case Repot Form 
Common Terminology Criteria for Adverse Events 
Clinical Target Volume 
Ductal Carcinoma In Situ 
Digital imaging and communications in medicine, 
Dose Volume Histogram 
2D-speckle-tracking echocardiography  
Enabling Communication Technology  
Global and Segmental Longitudinal Strain and Strain Rate 
Gray 
IC 
IHD 
IMRT 
Informed Consent 
ischemic heart disease 
Intensity modulated radiotherapy  
MREC  
Medical research ethics committee (MREC) 
LVEF 
MAPSE 
MRI 
NTCP 
OAR 
Left Ventricular Ejection Fraction 
Mitral annular plane systolic excursion  
Cardiac magnetic resonance imaging 
Normal Tissue Complication Probability 
Organ At Risk 
PTV 
RT 
Sponsor 
Planning target volume 
Radiotherapy 
The sponsor is the party that commissions the organisation or performance of the 
research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A party that 
provides funding for a study but does not commission it is not regarded as the 
sponsor, but referred to as a subsidising party. 
Sv 
TAPSE 
VMAT 
Sievert 
Tricuspid annular plane systolic excursion 
volumetric modulated arc therapy 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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1. TWO-PAGE OUTLINE OF THE PROTOCOL 
 
1.1. Background: Breast cancer (BC) radiotherapy (RT) leads to coincidental radiation of the 
heart, resulting in increased risk of a variety of heart diseases. The prevalence of BC survivors 
at risk of cardiac complications will gradually increase, as the incidence of BC in Europe is still 
rising while prognosis significantly improved over the last decades. These late cardiac 
complications have a major impact on quality of life and lead to subsequent morbidity and 
increased mortality. Therefore, identifying BC patients with the highest-risk of radiation-induced 
cardiac complications is crucial for developing strategies for primary and secondary prevention, 
which may contribute to healthy ageing. So far, little has been done on the relationship 
between dose distribution to different anatomical cardiac structures during RT and early 
cardiovascular changes that may lead to cardiac complications. 
 
1.2. Main study objective: The main objective is to identify and validate the most important 
cardiac imaging (ECHO-ST, CTCA and MRI) and circulating biomarkers of radiation-induced 
cardiovascular changes arising in the first 2 years after breast cancer radiotherapy. 
 
1.3. Study design: An international multicenter prospective cohort study 
 
1.4. Endpoints: The primary endpoint is defined as a mean decrease in Global and Segmental 
Longitudinal Strain and Strain Rate (GLS/GLSR) of at least 2.5% assessed by cardiac 
ultrasound 6 to 24 months after RT compared to baseline.  
The secondary endpoints are: 
 
Changes in myocardial function assessed by cardiac ultrasound 6 to 24 months after RT 
compared to baseline.  
 
Anatomical changes in coronary artery atherosclerosis (number of coronary segments 
containing any plaque/stenosis, and calcium score) by cardiac CT 24 months after RT 
compared with baseline. The endpoint is defined as 15% or greater changes. 
 
Myocardial changes by MRI 6 to 24 months after RT compared with baseline (morphology, 
function, tissue characterization by delayed enhancement and pre-/post-contrast T1 mapping). 
The endpoint is defined as in increase of the mean T1 mapping value of at least 7%. 
 
Temporal changes in circulating biomarkers at the end of RT and 6 to 24 months after RT 
compared with baseline. The endpoint is defined as a significant increase or decrease in each 
biomarker between time points. 
 
1.5. Selection criteria: Female unilateral BC patients aged 40-75 years treated with primary 
breast conserving surgery and postoperative radiotherapy using modern planning-CT based 
RT technologies. 

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1.6. Interventions:  
• 
Cardiac imaging: 
o Electrocardiogram to detect any arrhythmia followed by Automated 2D-speckle-tracking 
echocardiography (ECHO-ST), the most commonly used modality to evaluate 
myocardial dysfunction and a new technique of assessing myocardial deformation 
o Computed tomography (CT) to evaluate coronary artery lesions by assessing plaques 
(calcified and non-calcified) and stenosis of the coronary arteries, and determination of 
coronary artery calcium score 
o Cardiac magnetic resonance imaging (MRI) for the evaluation of the myocardium 
(including tissue abnormalities, cardiac morphology and function).  
• 
Circulating biomarkers (BLOOD) will be based on a panel of circulating classical and novel 
blood-based biomarkers. 
Imaging and circulating biomarkers will be assessed at baseline before RT (ECHO-ST, CT, 
MRI, BLOOD); at the end of RT (BLOOD); 6 months after RT (ECHO-ST, MRI, BLOOD) 
and 24 months after RT (ECHO-ST, CT, MRI, BLOOD). 
 
1.7. Statistical considerations: 
With 250 women, the study will have 80% power, with an α=0.05 to find a mean decrease in 
GLS/GLSR of at least 2.5%. 
The analysis plan is divided into three parts. In the first part a descriptive analysis of the data 
is done. Differences in biomarkers between unexposed and paired exposed groups (e.g. right 
vs. left-sided breast RT) at different time points are analysed to generate preliminary 
hypotheses on effects of RT on the heart. To investigate the time course of continuous 
variables extracted from ECHO-ST, CT or MRI measurements, mixed regression models are 
used. In the second part (anatomical) changes in cardiac biomarkers are correlated with dose 
distribution data. In the third part of the analysis multivariable Normal Tissue Complication 
Probability (NTCP) models are constructed. An integrative clinical-biological risk score is 
developed for individual risk prediction. 
 
 
 

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2. BACKGROUND AND INTRODUCTION 
 
2.1.     Introduction 
 
 
Radiotherapy (RT) plays an important role in the treatment of breast cancer (BC), as over 60% of 
all BC patients are irradiated as part of their curative treatment. BC radiotherapy generally leads to 
coincidental irradiation of the heart, resulting in an increased risk of a variety of heart diseases, 
including ischemic heart disease (IHD), congestive heart failure, arrhythmias, conduction defects, 
valvular disease and pericarditis with relative risks within the range of 1.2 to 3.5 by comparing left-
sided BC patients (with higher exposure to the heart) to right-sided BC patients 1–4. Moreover, 
cardiac damage was shown to be correlated with the mean heart dose with 7.4% rate increase of 
acute coronary events per one Gray (95% confidence interval, 2.9-14.5; P<0.001), with no 
minimum threshold for risk, recently the risk of acute coronary events within the first 9 years after 
RT was confirmed by another publication 4,5. 
The incidence of BC in Europe is still rising while prognosis significantly improved over the last 
decades. Therefore, the prevalence of BC survivors at risk for cardiac complications will gradually 
increase 1,6. There is a clear evidence that RT may cause, in organs and tissues close to the 
planning target volume (PTV), but also in organs at higher distances, an increased risk for late and 
very late clinically relevant side effects that have a major impact on quality of life.  
Technological developments in RT, such as intensity modulated radiotherapy (IMRT)/Volumetric 
modulated arc therapy (VMAT) and deep inspiration breath hold, have allowed for a significant 
reduction of cardiac doses 7. However, as there appears to be no threshold dose below which 
cardiac complications do not appear; radiation-induced cardiac diseases remain potential severe 
late complications of BC radiotherapy.  
Therefore, there is an urgent need for primary and secondary preventive measures. Primary 
prevention includes radiation dose optimisation to the most critical structures of the heart. 
Secondary prevention requires identification of patients at risk as early as possible after RT 
treatment.  
Long before the onset of clinically significant cardiac complications occurring many years after RT, 
subclinical cardiac changes can occur over weeks, months or first years after RT, that can be 
detected using anatomical and functional cardiac imaging or circulating biomarkers. 
 
Anatomical and functional cardiac imaging 
Using a recent advanced echocardiographic technique, automated 2D-speckle-tracking 
echocardiography / cardiac strain, for detecting and quantifying subtle disturbances in left 
ventricular systolic function; strain and strain rate were significantly decreased (mean 5%) during 
the first year following breast RT. In patients with left-sided BC global longitudinal strain and apical 
strain was diminished. The basal regions showed a compensatory increase in function, though not 
enough to compensate for the global functional loss resulting in a decrease in the global 

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longitudinal strain 8–11. Tuohinen et al. also showed deterioration in basal anterior strain segments 
after right-sided radiotherapy, whereas the global function remained unaffected. They also 
observed with tissue Doppler imaging that RT increased ECHO-ST density in the RV free wall and 
in the septum at the end of RT in patients with left-sided BC, but there were no changes observed 
in cardiac ECHO-ST density in patients with right-sided BC 8.  
Cardiac computed tomography (CT) without contrast and coronary computed tomography 
angiography (CTCA) provides morphological information of the coronary arteries, visualization of 
the coronary artery anatomy, determination of plaques and stenosis of the coronary arteries, and 
determination of the calcium artery calcium (CAC) score. This reflects the evolution of coronary 
artery disease. Three studies have measured the amount of CAC in the years following RT 
treatment for BC. In two studies, no elevated CAC scores in BC patients were found 5 to 15.7 
years after RT treatment, whereas 1 study did find an increase in CAC score depending on 
radiation dose to the heart 12–14. Of the studies that did not find a CAC score increase, one did not 
include baseline CAC scores and the other only included a relatively small number of patients, 
which makes it difficult to draw definitive conclusions from these two studies. In young Hodgkin’s 
lymphoma survivors (all under 55 years) elevated CAC scores have been found in the 5 to 35 
years after RT 15–17. Based on the analysis of 15 segments of coronary arteries per patient, an 
increase of calcified and non-calcified plaques of around 15% was observed during a of 2-year 
follow-up. A study concerning the general population investigated CAC scores at baseline and after 
10 years of follow-up 18. The results showed that the diagnosis of cancer and its treatments were 
significantly associated with the development of CAC, even after accounting for cardiac risk 
factors. The results of these studies suggest that RT is associated with increased CAC scores in 
the long term and therefore supports the hypothesis that accelerated atherosclerosis is one of the 
mechanisms contributing to an increase of radiotherapy induced cardiac events after cardiac 
irradiation.  
Finally, with cardiac magnetic resonance imaging (MRI), which is considered the gold standard to 
characterize myocardial tissue and to measure ventricular volumes and function, it has been 
shown that right ventricular systolic function (TAPSE) was decreased in a BC cohort at 24 months 
9. Furthermore, temporary ejection fraction decreases were observed on MRI (in patients treated 
with 3DCRT and not in patients treated with IMRT) at 6 months resolving at 24 months. Left 
(MAPSE) and right (TAPSE) ventricular systolic function determined by MRI were reduced at 24 
months (but still within normal range) for the whole cohort. Furthermore, with T1 mapping, a 
promising technique to quantify morphologic tissue injuries, it was shown in cancer survivors 
(including BC patients) that interstitial/diffuse myocardial fibrosis was elevated 3 years after 
anthracycline-based chemotherapy independent of the underlying cancer or comorbidities, 
suggesting that imaging biomarkers of interstitial fibrosis are related to prior receipt of potentially 
cardiotoxic cancer treatment 19. 
 

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Circulating biomarkers 
Many classical biomarkers (e.g., C-reactive protein, N-terminal pro-B–type natriuretic peptide (NT-
proBNP) and troponin (TnI)) were shown to be potential biomarkers for cardiac damage after 
radiotherapy 20.  In addition, circulating inflammatory cytokines also signed tissue inflammation 21. 
Furthermore, it was shown that irradiation induced acute endothelial activation or dysfunction that 
can be observed many weeks after irradiation and resulting in a pro-inflammatory endothelial 
phenotype. 
Another hypothesis to explore is that the irradiation may be responsible for an increase in the 
circulating levels of certain miRNAs expressed by cells of the heart tissue. Currently, the potential 
function of extracellular miRNAs is being studied intensively, and the first studies have confirmed 
that miRNAs may indeed function in cell-to-cell communication 22. Many studies have reported the 
use of miRNAs as circulating biomarkers for diagnosis or prognosis of cardiovascular diseases. 
Although many of those studies still require replication in multiple independent study populations, 
the results so far strongly suggest that some plasma miRNAs are quite specific for cardiovascular 
pathologies and may be useful for diagnostic and monitoring purposes.  
The complex and multifactorial nature of atherogenesis and development of atherothrombotic 
complications involves numerous interactions between various cell types inside the vascular wall 
(e.g. macrophages and smooth muscle cells) and in the blood (e.g. leukocytes and platelets). One 
relatively recent advance in this area is the discovery of circulating microparticles. High levels of 
circulating microparticles found in many cardiovascular diseases demonstrate the importance of 
platelet, monocyte and endothelial activation and could condition remote sustainability illnesses 23.  
The above described imaging studies have shown that early subclinical cardiac changes occur in 
BC patients after RT. Additionally, classical cardiac biomarkers have been shown to be potential 
candidates to monitor cardiac damage after radiotherapy.  However, primary and secondary 
prevention measures require (exact) knowledge on the relationship between dose exposure to 
specific cardiac structures and (the timing of) early subclinical cardiac changes and their 
occurrence in time.  
So far little has been done on elucidating the specific relationships between doses to cardiac 
structures and subsequent early cardiac toxicity in the published imaging or biomarker studies. 
 
2.2. Summary and proposed study  
The above described imaging studies have shown that early subclinical cardiac changes occur in 
BC patients after RT. Additionally, classical cardiac biomarkers have been shown to be potential 
candidates to monitor cardiac damage after radiotherapy.  However, primary and secondary 
prevention measures require (exact) knowledge on the relationship between dose exposure to 
specific cardiac structures and (the timing of) early subclinical cardiac changes and their 
occurrence in time. So far little has been done on elucidating the specific relationships between 

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doses to cardiac structures and subsequent early cardiac toxicity in the published imaging or 
biomarker studies.  
MEDIRAD-EARLY HEART therefore aims to determine early (i.e., within 24 months) 
cardiovascular changes after BC radiotherapy using imaging and circulating biomarkers and to 
determine the relation with radiation dose to a variety cardiac structures. 
 
3. OBJECTIVES OF THE TRIAL  
 
3.1. General objectives  
MEDIRAD-EARLY HEART is part of the MEDIRAD project. The MEDIRAD project aims to 
enhance the scientific basis and clinical practice of radiation protection in the medical field and 
thereby addresses the need to understand and evaluate the health effects of low dose ionizing 
radiation exposure from diagnostic and therapeutic imaging and from off-target effects in 
radiotherapy. 
MEDIRAD will pursue 3 major operational objectives: First, it will improve organ dose estimation 
and registration to inform clinical practice, optimize doses, set recommendations and provide 
adequate dosimetry for clinical-epidemiological studies of effects of medical radiation. Second, it 
aims to evaluate and understand the effects of medical exposures, focusing on the two major 
endpoints of public health relevance: cardiovascular effects of low to moderate doses of radiation 
from RT in BC treatment including understanding of mechanisms; and long-term effects on cancer 
risk of low doses from CT in children. Third, it will develop science-based consensus policy 
recommendations for the effective protection of patients, workers and the public. 
The specific objective of the MEDIRAD-EARLY HEART study is to gain more insight in the 
relationship between radiation dose distributions to the heart, to different anatomical cardiac 
substructures, during RT and early cardiovascular changes (within two years). 
 
Primary objective: to identify the most important cardiac imaging (ECHO-ST, CT and MRI) and 
circulating biomarkers of radiation-induced cardiovascular changes arising in the first 2 years after 
BC RT and to develop Normal Tissue Complication Probability (NTCP) models integrating these 
biomarkers combined with dose metrics of cardiac structures based on 3D-dosimetry. 
 
Secondary objectives: 
 
To formulate recommendations for implementation of these multivariable NTCP models in 
primary and secondary prevention strategies to ultimately develop stratified therapeutic and 
diagnostic approaches (overarching aim of MEDIRAD): 
o Improvement of RT planning techniques to spare cardiac structures, or even 
selection for proton therapy; 
o First guidelines for cardiac follow up programs in high-risk BC patients;  
 
To implement a European repository of patient dose and imaging data (overarching aim of 
MEDIRAD WP2.4.1). 

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3.2. Endpoints 
3.2.1. Primary endpoints 
The primary endpoints are defined as a mean decrease in Global Longitudinal Strain or Global 
Longitudinal Strain Rate, determined by cardiac ECHO-ST, of at least 2.5% between baseline and 
24 months after RT (Erven et al, Int J Radiation Oncol Biol Phys, 2012; Lo et al, In J Radiation 
Oncol Biol Phys, 2015). 
 
3.2.2. Secondary enpoints 
Secondary endpoints are other imaging and circulating biomarkers, defined as: 
 
Secondary echocardiographic measurements are:  
o Left ventricular ejection fraction using Simpson’s biplane method 
o Left ventricular end-diastolic volume using Simpson’s biplane method 
o Left ventricular end-systolic volume using Simpson’s biplane method 
o Left-ventricular end-diastolic diameter using M-mode 
o Left ventricular mass measured according ASE/EAE guidelines 
o Global and segmental radial strain rate 
o E/A wave ratio 
o E/Ea wave ratio (lateral annulus) 
o TAPSE (triscuspid annular plane systolic excursion) 
o Tricuspid annular S wave 
o Pulmonary artery systolic pressure (based on the peak tricuspid regurgitation velocity 
estimate and by assuming a right atrial pressure of 5 mmHg) 
o Left ventricular outflow tract diameter 
o Left ventricular outflow tract velocity time integral 
o Heart rate 
o Cardiac output measured by multiplying heart rate by stroke volume 
 
CT: to measure anatomical changes in coronary arteries assessed by cardiac CT occurring 24 
months after RT compared with baseline before RT start. 
o Individual description of stenosis or plaques of the 15 segments of the coronary arteries; 
left main coronary artery (LM); left anterior descending artery (LAD), left circumflex artery 
(LX) and right coronary artery (RCA) and evaluation of change in CAC score. 
o The progression atherosclerosis will be defined as an increase of the number of 
coronary segments containing any plaque and as an increase of the calcium score, of at 
least 15% between baseline and 24 months after RT.  
 
MRI: to evaluate myocardial tissue abnormalities assessed by cardiac MRI occurring 6 to 24 
months after RT compared with baseline before RT start. 
o Cardiac MRI-parameters include: morphology, function, tissue characterization by 
delayed enhancement and pre-/post-contrast T1 mapping (at 15 minutes). 
o The corresponding main MRI-endpoint is defined by an increase of the native mean 
myocardial T1 mapping value of at least 7% (Germain et al. Clin Med Insight Cardiol 
2014) 
 
Circulating biomarkers: to measure temporal changes in circulating biomarkers occurring at 
the end of RT, 6 to 24 months after RT compared with baseline before RT start.  
o The following circulating biomarkers are assessed:  

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 
Classical markers of cardiac injury: C-reactive protein, Troponin I, Troponin T, B-
type natriuretic peptide (BNP), NT-Pro BNP, beta2-Microglobulin, Galectin 3 
 
Inflammatory cytokines: IL-6, IL-8, IL-18, TNFα 
 
Endothelial activation and dysfunction: sVCAM-1, s-ICAM-1, E-Selectin, P-
Selectin, vWF, PAI-1, Fibrinogen, Thrombomodulin, TGFβ1 
 
Microparticles: 
CD14(monocytes), 
CD31(endothelial), 
CD41(platelets), 
CD3(lymphocyte), CD235a(erythrocyte) 
 
MicroRNAs: miR-1, miR-133, miR-208, miR-499, miR-126, miR-130, miR-145, 
miR-181, miR-150, miR-155, miR-223, miR-17, miR-18, miR-22, miR-34, miR-92, 
miR-140, miR-182, miR-199, miR-423 and miR-590. 
 
circulating DNA methylation 
o Endpoint are defined as a significant increase or decrease in each biomarker between 
time points. 
 
4. PATIENT SELECTION CRITERIA 
 
Female unilateral BC patients treated at one of the five  participating centres with postoperative 
modern planning-CT based RT alone after breast conserving surgery, and who are aged 40-75 
years at the time of RT. 
Inclusion criteria: 
 
Female unilateral breast cancer patients 
 
Treated with primary breast conserving surgery for stage I-III invasive adenocarcinoma 
of the breast or ductal carcinoma in situ (DCIS) 
 
Age between 40-75 years at time of start radiotherapy 
 
WHO performance status 0-1 
 
Planned for radiotherapy alone to the breast with or without the lymph node areas 
 
Radiotherapy based on planning-CT scan using either 3D-CRT, IMRT, or 
VMAT/RapidArc 
 
Written Informed consent 
Non inclusion criteria: 
 
Male breast cancer patients 
 
Neoadjuvant or adjuvant chemotherapy 
 
M1 disease (metastatic breast cancer) 
 
Medical history of coronary artery disease and/or myocardial infarction and/or atrial 
fibrillation 
 
Previous thoracic or mediastinal radiation 
 
Contraindications to injection of iodinated contrast such as allergy or renal failure 
 
Pregnancy or lactation 
 

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Exclusion criteria 
 
Atrial fibrillation detected during electrocardiogram before radiotherapy  
 
Abnormal echocardiography before radiotherapy defined as: LVEF<50%; longitudinal 
strain ≤ -16%; longitudinal strain rate <-1%, and/or abnormal wall motion 
 
Presence of myocardial infarction detected during MRI before radiotherapy 
 
CTCA or cardiac MRI results before radiotherapy requiring revascularisation 
 
► See CRF ELIGIBILITY  in appendix for further details 
 
 
5. TRIAL DESIGN 
 
MEDIRAD EARLY HEART is a multicentre prospective cohort study that will include 250 female 
BC patients treated with post-operative RT alone after primary breast conserving surgery to assess 
imaging and circulating cardiac biomarkers the first 2 years following RT. 
 
6. THERAPEUTIC REGIMENS, EXPECTED TOXICITY, DOSE MODIFICATION 
 
6.1. Radiotherapy   
 
All patients will undergo computerized tomography (CT) in treatment position to prepare the 
treatment plan. 
 
6.2.  Patient positioning 
 
The patient will be immobilized with an appropriate immobilization aid in supine position. Patients 
will be treated according to own center specificities (active breathing control for left BC, for left and 
right BC, …) in order to lower the cardiac dose as much as possible. 
 
 
6.3. Planning CT scan acquisition 
 
A planning CT-scan is made with the patient in treatment position with the immobilisation device in 
place, according to own center specificities regarding breathing control. Slice thickness of 
maximum 2 mm will be used  
Images will be constructed with at least 512 x 512 pixel matrix. DRRs (digitally reconstructed 
radiographs) of all beams including the orthogonal verification beam pair will be generated from the 
planning CT scan for comparison with portal images. 
 
 
 
 

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6.4. Target volumes and organs at risk 
 
The definition of target volumes will be in accordance with the ICRU 50 report. 
 
6.4.1. Gross tumour volume (GTV) 
Not applicable. 
6.4.2. Clinical target volume (CTV) 
The CTV includes the entire breast with the exclusion of the skin (5 mm). 
6.4.3. Planning target volume (PTV) 
To account for set up errors, a CTV-PTV margin is used according to institutional standards. 
6.4.4. Organs at risk (OAR) 
For all centres of investigation, the following OAR will be delineated: Contralateral breast, lung, 
heart. 
In addition, other OAR could be delineated according to the routine of centres: heart structures, 
LAD coronary, oesophagus and thyroid (in case of periclavicular lymph nodes are irradiated). 
6.5. Treatment planning  
The total dose for the breast will be in accordance with center practices (50 Gy/25 fractions, or 
40.05 Gy/15 fractions or isoeffective schemes). The possible boost can be applied with photons or 
electrons both sequentially or simultaneously.  
6.5.1. Limit of dose in organs at risk 
In all cases, dose will be prescribed according to the ICRU criteria and dose constrains are 
according to QUANTEC. Algorithms are used for the calculation of the dose distribution, 
considering lack of homogeneity in the tissue 
6.5.2. Irradiation techniques 
The treatment techniques based on planning-CT scan consist of 3D-CRT, IMRT, or 
VMAT/RapidArc.  
6.5.3. Patient position verification 
To ensure quality of positioning, patient positioning is verified. This can be done with MV imaging 
(Electronic Portal Imaging Device, EPID) or with kV imaging (cone beam CT). 

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7. CLINICAL EVALUATION, LABORATORY TESTS AND FOLLOW-UP 
 
7.1. Before inclusion  
In each centre, radiation oncologists will enable first contact with women diagnosed with breast 
cancer: during first visit with the radiation oncologist, he/she will present the study and its 
implications to women patients for whom radiation therapy is planned. This consultation is 1 to 4 
weeks before the start of radiotherapy, depending on the center. The radiation oncologist will 
ensure that women meet the criteria for inclusion in the study and study information leaflet detailing 
the protocol will be given with a consent form (►see INFORMATION LETTER and INFORMED 
CONSENT FORM in Appendix). 
 
7.2. Before start of treatment protocol 
 
About 1 to 2 weeks before the start of radiotherapy, during the visit for the RT planning-CT, women 
agreeing to participate in the study will give their signed written informed consent form and will then 
be considered as included. Cardiac MRI will not be mandatory for inclusion in EARLY HEART 
Study (in contrast with ECHO-ST, CT and BLOOD). 
► See CRF ELIGIBILITY, CRF CANCER , CRF planned RT and CRF CARDIOLOGY, in appendix 
for further details 
From this inclusion visit on, women's follow-up protocol will be realized. Before start of RT the 
following interventions will have to be performed: 
 
Cardiac imaging: 
o An electrocardiogram to detect any arrhythmia followed by an Automated 2D-speckle-
tracking echocardiography (ECHO-ST) the most commonly used modality to evaluate 
myocardial dysfunction and a new technique of assessing myocardial deformation; 
► See CRF ECHO-ST in appendix for further details 
o Computed tomography (CT) by using both low dose non enhanced and enhanced CT 
scans to evaluate coronary artery lesions by assessing morphological information 
including plaques and stenosis of the arteries, and determination of the CAC score; 
► See CTCA PROTOCOL and CRF in appendix for further details 
o Cardiac magnetic resonance imaging (MRI) for the measurement of ventricular function,  
size of the two heart chambers, and wall thickness; tissue characterization by delayed 
enhancement; and pre-/post-contrast T1 mapping mapping and pre contrast T2 
mapping of the left ventricle. 
► See MRI PROTOCOL and  CRF in appendix for further details 
 
Circulating biomarkers (BLOOD) will be based on a panel of circulating classical and novel 
blood-based biomarkers (see 7.5 Blood samples for biomarkers analysis for further details) 
Furthermore, toxicity will be assessed according CTCAE 4.03 and patient rated outcome 

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measures. ► See CRF TOXICITY in appendix for further details 
 
 
7.3. During treatment  
As planned in routine follow up of patients in each center, toxicity will be assessed according 
CTCAE 4.03 and patient rated outcome measures. 
 
7.4. Subsequent follow-up 
During subsequent follow up imaging and circulating biomarkers will be assessed at specific time 
points after RT up to 24 months:  
● At the end of RT: BLOOD.  
● Six months after RT: ECHO-ST, MRI, BLOOD. 
● Two years after RT: Electrocardiogram and ECHO-ST, MRI, CT, BLOOD. 
Furthermore, in addition to routine follow-up of patients in each center, acute and late toxicity will 
assessed according CTCAE 4.03 and patient rated outcome measures at the end of RT, 6 months, 
and 24 months after RT. 
 
7.5. Blood samples for biomarkers analysis 
Each patient will have 4 blood samples. For each blood sample, 30mL of blood will be collected 
and divided in 6 tubes of 5 mL as follows: 2 tubes heparin; 2 tubes EDTA; 2 tubes CITRATE (2 x 
5ml). 
Blood samples will be collected: before RT, at the end of RT, 6 months after RT and 24 months 
after RT. Once blood sample is collected, a standard operation procedure will be followed ► See 
BLOOD PROTOCOL in appendix for further details. 
All prepared aliquots of 500 µl (approximately 30 aliquots per patient per blood sample) will be 
stored and freeze at –80°C in the local investigating center for a short time period of few weeks or 
months (depending on the capacity of storage of the local center), and then periodically sent with a 
medical specialized carriers to University of Bristol which is the centre for central storage of 
aliquots for biomarkers analysis (Workpackage 4.2.2 Preclinical and clinical identification of 
standard and innovative biomarkers of radiation-induced cardiovascular toxicity). 
All blood samples and aliquots will be labelised using the same anonymised code assignment for 
patient as the one used in CRF. 
Once received at University of Bristol, for each patient at each time of blood sample, 20 aliquots 
will be used for biomarkers analysis, the 10 remaining aliquots will enter a long term storage 
collection for 15 years. After 15 years, all aliquots will be destroyed except if a patient asks for 
early destroy of her aliquots. Aliquots of the long term storage collection could only be used in the 
frame of research on cardiovascular diseases. 
Responsible party for EARLY HEART aliquots collection: Pr Constanza Emanueli, Bristol Heart 

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Institute, School of Clinical Sciences, University of Bristol, Bristol Royal Infirmary, Upper Maudlin 
Street, BS2 8HW, Bristol, United Kingdom. 
 
8. FLOWCHART 
The flow chart below gives an overview of the EARLY HEART study design and the main 
procedures that subjects will undergo during this research.  
 
In the Standard Follow-up Program only toxicity assessment (CTCAE 4.03) is performed. ECHO-
ST, CT, MRI and BLOOD are performed for the research study. 
 
 
Baseline 
At the 
end of  
RT 
6 ms 
24 ms 
Informed Consent 
X 
 
 
 
In‐ and exclusion criteria 
X 
 
 
 
Medical history 
X 
 
 
 
Electrocardiogram (ECG) 
followed by ECHO-ST 
X 
 
X 
(ECHO 
alone, 
no ECG) 
X 
CT 
X 
 
 
X 
MRI 
X 
 
X 
X 
BLOOD 
X 
X 
X 
X 
Toxicity assessment (CTCAE 
4.03) 
 
X 
X  
X 
 
9. STATISTICAL CONSIDERATIONS 
 
9.1. Study Design 
MEDIRAD EARLY HEART is a multicentre prospective cohort study that will include female BC 
patients treated with post-operative RT alone after primary breast conserving surgery to assess 
imaging and circulating cardiac biomarkers the first 2 years following RT. 
 
9.2. Sample Size 
The sample size was based on a statistical power of 80%, an alpha-risk of 5%, the definition of the 
primary endpoint (a decrease in the global and segmental longitudinal strain or strain rate of at 
least 2.5%) and baseline measurements hypothesis (mean global longitudinal strain before RT : -
16.5% ± 2.1% from Dalen et al, European Journal of Echocardiography : the Journal of the 
Working Group on Echocardiography of the European Society of Cardiology. 2010) Considering 
paired test for comparisons, but also possible lost to follow-up due to death or other reason, the 
inclusion of 250 women is necessary for EARLY-HEART study.  
 

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Centre 
Recruitment rate per month 
Total number of patients to 
recruit in 1 year 
IRSN 
4.2 
50 
UMCG 
5 
70 
TUM-MED 
4.6 
55 
CCUL 
2.1 
25 
ICO 
4.2 
50 
Total 
 
250 
 
 
9.3. Analysis plan 
 
IRSN and UMCG will be in charge of main statistical analysis in close collaboration with other 
investigating centres. 
The analysis plan consists of three stages:  
Stage I: Descriptive analysis  
Means, standard deviations, percentages, ranges and confidence intervals of 95 % are used to 
summarize:  
- The questionnaire medical data;  
- The 2D-speckle-tracking echocardiography (ECHO-ST) measurements including strain and strain 
rate.  
- The Coronary computed tomography angiography (CT) measurements including mean number of 
coronary segments with plaques and/or stenosis, and CAC score (Agatston, Volume), total and per 
coronary artery; 
- The MRI measurements include ventricular function, size of the heart chambers and wall 
thickness, tissue characterization by delayed enhancement and pre-/post-contrast T1 mapping of 
the left ventricle;  
- The measurements of all biomarkers;  
- Dose distribution to the several heart substructures including ventricles and coronaries arteries.  
Paired non-parametric tests (Wilcoxon signed rank test to compare medians, McNemar and 
Bowker to compare paired proportions). The correlation between the different covariates will be 
investigated using the Spearman's rank correlation coefficient.  
 
Stage II: Radiation-induced Cardiovascular Changes Models (RCCM)  
The Radiation-induced Cardiovascular Changes Models (RCCM) aim to investigate the dose-

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response relationships between 3D-dimensional dose distributions in cardiac substructures and 
cardiovascular changes in term of imaging and circulating biomarkers time-kinetics occurring in the 
2 years after radiotherapy for breast cancer (before RT, 6 and 24 months after RT). 
To investigate the time course of continuous variables extracted from ECHO-ST, CT or MRI 
measurements, mixed regression models are used since these longitudinal data present a 
hierarchical structure where serial measurements are nested within individuals over time. In this 
framework, a variable selection is possible by an AIC or BIC model selection or by incorporating a 
lasso or an elastic net penalty especially for the imaging and circulating biomarkers selection. To 
investigate some non-linear predictor effects, a fractional polynomial approach could be 
considered.  
The radiation exposure could be included in this model by several ways: point wise dosimetric 
parameters (mean dose, Dx or Vx), DVH reduction equivalent uniform dose (EUD) or through a 
functional data analysis approach by estimating a functional coefficient associated to a functional 
predictor (here the DVHs or the probability density function).  
To exploit the richness of the longitudinal global or regional strain curves, a myocardial deformation 
analysis will be conducted using a functional mixed effect model to deal with the infinite-
dimensional functional responses measured at multiple time points.  
 
Stage III: NTCP and functional NTCP models (F-NTCP).  
In presence of cardiac toxicity outcome, a multimetric NTCP modelling is constructed through time-
dependent covariates and time dependent coefficients Cox model.  
The individualized risk estimation is calculated from an integrative clinical-biologic risk score 
obtained at the end of a variable selection process (lasso or elastic-net partial likelihood 
penalization for example).  
The radiation exposure could be included in this model by several ways: point wise dosimetric 
parameters (mean dose, Dx or Vx), DVH reduction equivalent uniform dose (EUD).  
Using a time-dependent Cox regression performed in a functional data analysis way, a functional 
NTCP model (F-NTCP) will provide a volume-effect functional parameter which allows a risk 
weighting across the considered dose range and especially for the lowest one. 
 
Furthermore, as a complementary approach for cardiovascular risk modelling, the cardiac imaging 
and circulating biomarkers will be integrated into a mechanistic model of cardiovascular disease, 
including atherosclerosis (Work package 4.3 Cardiovascular risk modelling, HMGU). 
 

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10. REPORTING ADVERSE EVENTS 
 
This is a prospective observational cohort study in which radiotherapy and other oncologic 
treatments will be performed according to current standard of the participating centres without 
additional risks.  
Serious adverse events related to blood samples or cardiac imaging exams are not expected. The 
subjects with possible abnormal findings are referred for further examination in accordance with 
normal procedures in each country.  
Minor adverse events are those related to blood samples and cardiac imaging exams.  
- 
Blood collection (pain at veins at the elbow, allergy to products used to clean the skin, 
hematoma)  
- 
Echocardiography is based on the use of ultrasound. This is a non-invasive method of 
investigation, non-traumatic and painless. It can be repeated and there are no 
contraindications. It has not known side effects. It lasts about 15 minutes.  
- 
The CT lasts about 20-30 minutes. The CT requires the injection of iodinated contrast with 
contraindications (renal failure, allergy). The injection of iodinated contrast material is made 
in  compliance with the contraindications of the latter. The place of injection is done simply 
at the arm vein. Potential side effects of iodine contrast include flushing, and (mild) skin 
rash. 
- 
For CT, patient is subject to a scanning X-ray beam. This examination is relatively simple, 
painless, and safe if one respects the contra-indications. The examination can be done as 
an outpatient without hospitalization. In terms of radiation dose, the latest techniques in 
cardiac CT achieve very low levels of radiation, equivalent to one to two years of natural 
background radiation (average of 2.4 mSv / year), considered acceptable for exam 
screening for which the radiation-induced risk should be minimal or nil.   
- 
Nitroglycerine may be administered prior to the CT angiography, which is a safe and often 
used medication for patients with CAD. Side effects include flushing, headache and 
hypotension, and will not be given to patients with a low blood pressure, left ventricular 
outflow obstruction or using sildenafil or related medication. 
- 
Betablockers may be used in patients with a fast heart rate before CT. Beta-blockers are 
used by many patients and regarded as safe. They should not be given to patients with 
hypotension or conduction disorders as described in the contra-indications to the study. 
- 
MRI is based on magnetic field and radio waves. This examination is relatively simple, 
painless, and safe if one respects the cons-indications. The examination can be done as an 
outpatient without hospitalization. MRI is the safest of the advanced imaging techniques. 

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However, it is known that for certain patients who undergo MRI examinations, the 
experience may be associated with emotional distress, anxiety and claustrophobia, which 
could limit the consent of patients to participate in our study. MRI lasts about 45 minutes. 
This point must be considered in the design of the study by proposing additional MRI 
examinations as an option in the protocol (in contrast with blood collection, ECHO-ST and 
CT that would be mandatory).  
- 
Cardiac MR including gadolinium (Dotarem 0.2 mmol/kg) enhancement will be performed. 
Potential side effects of gadolinium include brief headache, nausea (feeling sick) and 
dizziness for a brief time following the injection. Allergic reactions are rare. 
 
The investigator will inform the patients and the reviewing accredited Medical research ethics 
committee if anything occurs, on the basis of which it appears that the disadvantages of 
participation may be significantly greater than was foreseen in the research proposal. The 
study will be suspended pending further review by the accredited Medical research ethics 
committee, except insofar as suspension would jeopardise the subjects’ health. The 
investigator will take care that all subjects are kept informed.  
 
11. ETHICAL CONSIDERATIONS 
 
11.1. Regulation statement 
 
This study will be conducted in accordance with the Declaration of Helsinki (amended at the 64th 
WMA General Assembly, Fortaleza, Brazil, October 2013) (appendix 1) and in accordance with the 
principles of ‘Good Clinical Practice’ and the Medical Research Involving Human Subjects Act 
(WMO).  
 
11.2. Recruitment and consent 
 
The study aims and procedure will be explained orally and in writing in a study information leaflet to 
each eligible patient, by each specific participating centre. All study patients are also informed that 
she will be part of a larger European study.   
The patients will have ample opportunity to ask questions they might have and they will have 48 
hours to consider the implications of the study before deciding to participate.  
Patients consent will be noted on an informed consent form compliant with the local and ethical 
regulations.  
If during the study the patient for whatever reason no longer wishes to participate, she can 
withdraw her consent at any time.  
All countries involved in the multicentre study will contact the local ethics committee and are 
familiar with the national procedures. Prior to the start of the study, the protocol has to be approved 

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by the medical ethics review committee of the participating institution. Approval will be indicated in 
writing with reference to the final protocol number and date. 
 
11.3. Objection by minors or incapacitated subjects 
 
Not applicable. 
 
11.4. Benefits and risks assessments, group relatedness 
 
Participation in this study does not involve any additional risk to patients, besides the risk incurred 
by additional MRI and CT-scans. Patients will undergo 2 extra CT-scans. For CT, patient is subject 
to a scanning X-ray beam. The latest techniques in CTCA achieve very low levels of radiation 
(below 4mSv) , equivalent to one to two years of natural background radiation (average of 2.4 mSv 
/ year), considered acceptable for exam screening for which the radiation-induced risk should be 
minimal or nil. Additionally, compared to the radiation dose of the treatment the dose of the extra 
CT scans is very low and the risks therefore are neglible and the burden low. 
 
Participation in this study may have benefits. When cardiac imaging reveal severe abnormal 
findings, such as the presence of severe coronary artery disease which may require a 
revascularization or specific treatment due to the presence of a myocardial infarction, patients even 
in absence of symptoms will be excluded of the present study and referred to the cardiologist . In 
absence of severe coronary artery disease, all results of cardiac imaging will be blinded to the 
medical staff in order to avoid changes in medical treatment likely to mask effects of XRay 
radiation which the main objective of the present study.  
 
11.5. Compensation for injury 
 
The sponsor has an insurance which covers for damage to research subjects through injury or 
death caused by the study protocol interventions (not breast cancer treatment RT). 
The insurance should cover for damage related to EARLY HEART research (ie CTCA, ECHO-ST, 
blood samples, MRI) but not related to RT treatment, until the end of EARLY HEART follow-up. 
 
 
12. DATA COLLECTION, DATA MANAGEMENT, MONITORING AND PUBLICATION 
 
12.1. Data management  
 
The data managed during, and used by, MEDIRAD will be managed by the different partners 
throughout the project. A project-internal Data Management Board will ensure data is stored 

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securely and according to international standards, both from a technical as well as an ethical 
standpoint (de-identification, anonymization). The Data Management Board includes a data 
manager for each center, responsible for the data generated by their clinical/research work and is 
chaired and overseen by a Project Data Manager from ISGlobal. Information on the data generated 
during the project (source, volume, standards, storage, exploitation and accessibility) is shown in 
the data management overview below:    
Data 
generated or 
stored 
Source 
Volume 
Standards 
used 
Storage, 
curation & 
preservation 
Exploitation & 
accessibility 
Cardiac 
imaging data 
(ECHO-ST, 
CT and MRI) 
Adult female 
BC patients 
undergoing 
RT and RT 
treating 
physicians in 
participating 
centres 
250; 
numerous 
scans and 
images for 
each subject 
eCRF  
Anonymised 
eCRFs on 
secure central 
server at IRSN. 
All 
questionnaires 
stored in locked 
filling cabinets 
with limited 
access 
For study 
activities ,  
only 
accessible to 
local 
investigators 
involved in the 
study 
DICOM 
Anonymised 
dose and 
imaging data 
on centralized 
MEDIRAD-
ENACT 
database at 
UMCG. Non-
identifiable 
study ID to link 
different 
databases 
 
In all cases, relevant metadata will be stored alongside of the data, as well as software and 
documentation for future use. Weekly backups of data and images will be made to ensure security 
of collected data. 
 
 

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12.2. eCRF 
Wherever possible, all non-imaging/dose (non-DICOM) data will be entered directly into an 
anonymised eCRF on a secure central database at IRSN. The Source Identification List will identify 
any data to be recorded directly in the eCRF (i.e., no prior written or electronic record of data), and 
which data should be considered source data. 
Where needed, paper source documents can be used. An audit trail will maintain a record of initial 
entries and changes made; reasons for change; time and date of entry; and user name of person 
authorizing entry or change. For each subject enrolled, an eCRF must be completed and 
electronically signed by the principal investigator or authorized delegate from the study staff. If a 
subject withdraws from the study, the reason must be noted on the end of study form of the eCRF. 
If a subject is withdrawn from the study because of a treatment limiting adverse event, thorough 
efforts should be made to clearly document the outcome. 
The investigator should ensure the accuracy, completeness and timeliness of the data recorded in 
the eCRF and in all required reports. 
 
12.3. Dose data repository; storage of DICOM data 
 
The MEDIRAD-ENACT database of partner UMCG will be used for MEDIRAD EARLY-HEART to 
enable integrated data-collection, quality control and management for the clinical study on low-
dose radiation-induced early cardiovascular changes after BC therapy.  
A centralised integrated imaging and dose repository will be set up to serve the needs of the 
research and studies carried out in MEDIRAD based on anonymised data (Work Package 2.4.1 ). 
 
All participating centres will transfer relevant DICOM-data (i.e. imaging, planning-CT scans, RT-
STRUCT, RT-DOSE, CTCA and MRI (all native images from all series with and without additional 
image (including additional image (T1 and T2 mapping, aortic 3D images... ))) to the ENACT data 
bank managed by UMCG.  The ENACT environment provides easy and secure upload of 
(image/DICOM) data to a central archive located at the UMCG. De-identification of the (image) 
data will be performed at the site of origin before sending according to a de-identification strategy. 
After upload, researchers involved in the reading of the imaging data will be provided access to the 
ENACT environment using a virtual workspace with two-way authentication (login + SMS-token). 
The virtual workspace can be accessed from any location and from different platforms 
(Windows/Apple/Linux) allowing selection of expert readers to perform the reading regardless of 
their location. Each reader will be provided with an identical workspace with the same software 
tools and imaging data, no subsequent transfer of (imaging) data is needed except a secured 
transfer of all anonymized Cardiac CT and Cardiac MR from the ENACT database to Université 
Paris Descartes which is Core center for reading all CTCA and Cardiac MRI of patients included in 

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EARLY 
HEART 
Study 
(Responsible 
party: 
Professor 
Elie 
Mousseaux, 
Univ 
Paris 
Descartes).Indeed for analysis of cardiac imaging, ENACT transfer of DICOM anonymized images 
will be required by the core lab in order to used research softwares dedicated to specific tasks and  
softwares routinely used by expert readers. Electronic CRF will be filled by the core lab during such 
analysis. 
 
Within the ENACT environment automated segmentation of all cardiac structures (including 
coronary arteries) is performed to ensure uniformity of the segmentation procedure between 
centres. In addition, storage of all DICOM-data in ENACT will enable co-registration of the different 
imaging data. 
 
12.4. Monitoring and quality assurance 
 
IRSN is designated as the leading organism of the multicentre EARLY-HEART study.  
We call the sponsors of the study the organisms that coordinate the study at the scale of centre: 
IRSN for France, UMCG for Netherlands, TUM-MED for Germany and CCUL for Portugal, ICO for 
Spain. Each sponsor will have a representing person.  
Each medical centre (IRSN, UMCG, TUM-MED, CCUL, ICO, UPDescartes) will have a Local 
Management team including a representing person of sponsor, a Principal Investigator, a Local 
clinical research associate (Monitor).  
 
To ensure the EARLY-HEART study management, a Clinical Operations Management and 
Support group will be composed including the study leader (IRSN Researcher) in collaboration with 
French, Dutch, German, Portuguese and Spanish Local Managing teams. The Clinical Operations 
Management and Support group will decide on the type of monitoring undertaken, either onsite, 
remote or central, and the frequency and focus of monitoring visits will be determined by the risk 
rating allocated. The intervals for monitoring visits may be revised dependent on subject enrolment 
rate, quality issues, site compliance or other trial issues. This group will meet regularly for global 
Management of the study.  
At the scale of each centre, the Local Clinical Research Associate (Monitor) will perform monitoring 
tasks in accordance with the protocol specific requirements. 
 
Study monitoring plan (monitoring visits etc.)  
These monitoring visits will be supervised by the leader of the EARLY-HEART study, in 
collaboration with Monitors of each centre. To limit costs travels at this stage, these visits will be 
“virtual”, the leader and Monitors having teleconference meetings. 
 
 

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Monitoring visits:  
1.1 Initiation visit (M4)  
The Initiation Visit will be conducted prior to site activation to confirm preparedness for protocol 
execution, satisfactory site facilities, clarify the applicable regulations and requirements of the 
protocol, carefully review the process of implementing the protocol at the site and conduct any 
necessary training prior to activating the site for enrolment.  
1.2 First monitoring visit (M4)  
The First Monitoring Visit will be conducted at the beginning of inclusion to confirm subjects’ rights 
are being protected; the study is being conducted according to the protocol and applicable 
regulations; confirm accurate reporting of subject safety data and study endpoints.  
1.3 Interim monitoring visits  
The Interim monitoring visits will be conducted regularly to confirm subjects’ rights are being 
protected; the study is being conducted according to the protocol and applicable regulations; 
confirm accurate reporting of subject safety data and study endpoints.  
1.4 Close out visit (M39)  
A Close-Out Visit will be conducted to ensure that all study data and other study documentation is 
complete and accurate and that all study records have been reconciled.  
The Local monitors will meet the Local Principal Investigators at each of the above-mentioned 
visits to discuss study progress and issues.  
 
Any significant deviation from the planned monitoring timelines will be explained and documented 
in the monitoring visit report and the plan amended if appropriate. If the site does not enrol any 
patients or enrolment is stopped, regular monitoring visits will not be scheduled. If there is an 
extended gap in trial activities the monitor will ensure that site staffs are appropriately trained when 
trial activities recommence.  
 
The monitor should complete and sign a Trial Monitoring Visit Document at each visit, including:  
2.1 Recruitment  
The study specific recruitment plan and recruitment timeframe as per specific protocol.  
2.2 Eligibility  
The following inclusion and exclusion criteria should be checked in full as per Protocol  
2.2.1 Inclusion and exclusion criteria  
All subjects participating in the study should meet ALL the inclusion criteria and NONE of the 
exclusion criteria. Any deviations from the inclusion/exclusion criteria should be documented as a 
protocol breach/deviation.  
2.3. Primary/Secondary endpoints: As per Protocol 
 
 

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12.5. Quality assurance 
 
Imaging 
At the start of the project, criteria will be determined for imaging protocols and image quality. 
Example CT and MR scans will be collected from all participating scan sites with the protocol as 
defined by the MEDIRAD proposal. All collected scans will be provided through the ENACT 
workspace and the selected image reading experts will assess the quality of the scans and the 
correct setting and performance of the scan protocols.  
When additional scanning is required using phantoms, these phantoms should be made available 
or bought to assure scan quality. All data acquired can, again, be made available in the 
workspaces of the experts. 
 
Sample Management  
Each centre is initially responsible for its sample management and the IRSN (researcher of the 
Epidemiology laboratory) will be in charge of the whole cohort data management (including data of 
the 5 centres).  
At a local scale, data (from questionnaires, medical examinations, biomarker measurements) will 
be put in local database. For control of data, data consistency checks to detect inconsistencies and 
outliers present in the questionnaires will be programmed (about 5 case reports selected at 
random and checked to ensure consistency and quality of data collected in medical questionnaires 
and report forms, and verifying the accuracy of a limited number of major information gathered).  
Then the 5 local databases will be centralized in one big EARLY-HEART database at IRSN and a 
final quality control will be carried out on a sample of √ n + 1 subjects drawn randomly. The final 
database will be fixed once all control data and coding will have been finished. 
 
12.6. Anonymization of data 
 
All files used for analysis will be anonymized to ensure patient privacy. 
Anonymization will be performed as follows: Central data management (IRSN) will give out a study 
number for each participating patient based on a randomised code assignment list. Only the 
Principal investigator and the data management will have access to the source data.  
 
12.7. Retention of records 
 
In each center, only the principal investigators and the data management will have access to the 
source data. All data will be stored during a period of twenty years. 
 
 
 

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12.8. Amendements 
 
A ‘substantial amendment’ is defined as an amendment to the terms of the MERC application, or to 
the protocol or any other supporting documentation, that is likely to affect to a significant degree: 
the safety or physical or mental integrity of the subjects of the trial; 
the scientific value of the trial; 
the conduct or management of the trial; or 
the quality or safety of any intervention used in the trial. 
All substantial amendments will be notified to the MREC. 
Non-substantial amendments will not be notified to the accredited MREC, but will be recorded and 
filed by the sponsor.  
< Examples of non-substantial amendments are typing errors and administrative changes like 
changes in names, telephone numbers and other contact details of involved persons mentioned in 
the submitted study documentation.> 
 
12.9. Annual progress report 
 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited MREC 
once a year. Information will be provided on the date of inclusion of the first subject, numbers of 
subjects included and numbers of subjects that have completed the trial, serious adverse events/ 
serious adverse reactions, other problems, and amendments.  
 
12.10. Temporary halt and (prematurely) end of study report 
 
The investigator will notify the accredited MREC of the end of the study within a period of eight 
weeks. The end of the study is defined as the last patient’s last visit.  
 
The investigator will notify the MREC immediately of a temporary halt of the study, including the 
reason of such an action. 
 
In case the study is ended prematurely, the investigator will notify the accredited MREC within 
fifteen days, including the reasons for the premature termination. 
 
Within one year after the end of the study, the investigator will submit a final study report with the 
results of the study, including any publications/abstracts of the study, to the accredited MREC. 
 
13. TRIAL INSURANCE 
 
An insurance against the legal liability resulting from medical procedures will be present. 

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14. PUBLICATION POLICY 
 
The trial will be registered at clinicaltrials.gov and published in a major scientific journal regardless 
of its results. MEDIRAD will follow an open access approach to its peer-reviewed scientific 
publications. All publications will be under the name of the consortium, and all authors involved will 
be listed either in the by-line or in an appendix in such a way that all authors will be found on 
literature searches. All scientific publications will be available through open access repositories 
such as 
OpenAIRE (www.openaire.eu) and/or the project website; the scientific and clinical communities 
will clearly benefit from the freely accessible publications of the MEDIRAD methodology and 
results in high impact journals. 
The results of the project will be disseminated by publishing in international, peer-reviewed journals 
and proceedings of scientific conferences, after any intellectual property has been secured. 
Authors will endeavour to target journals with the widest audiences and highest impact in the 
clinical, public health, biology and radiation protection fields. Wherever possible gold open access 
options will be chosen. 
 
The scientific coordinator of the MEDIRAD project, Prof. Elisabeth Cardis (ISGlobal), in 
consultation with the clinical coordinator, Prof. Guy Frija (UPDescartes), are responsible for the 
review and final approval of all publications. 
 
15. REFERENCES 
 
1. 
Clarke, M. et al. Effects of radiotherapy and of differences in the extent of surgery for early 
breast cancer on local recurrence and 15-year survival: an overview of the randomised 
trials. Lancet (London, England) 366, 2087–106 (2005). 
2. 
Darby, S. C., McGale, P., Taylor, C. W. & Peto, R. Long-term mortality from heart disease 
and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 
300,000 women in US SEER cancer registries. Lancet. Oncol. 6, 557–65 (2005). 
3. 
Giordano, S. H. et al. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J. 
Natl. Cancer Inst. 97, 419–24 (2005). 
4. 
Darby, S. C. et al. Risk of ischemic heart disease in women after radiotherapy for breast 
cancer. N. Engl. J. Med. 368, 987–98 (2013). 
5. 
van den Bogaard, V. A. B. et al. Validation and Optimization of a Cardiac NTCP Model for 
Breast Cancer Patients Based on Cardiac Substructures and 3-dimensional Dose 
Distributions. Int. J. Radiat. Oncol. Biol. Phys. 96, S4–S5 (2016). 

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6. 
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), E. B. C. T. C. G. et al. Effect 
of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast 
cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised 
trials. Lancet (London, England) 378, 1707–16 (2011). 
7. 
Taylor, C. W. et al. Exposure of the Heart in Breast Cancer Radiation Therapy: A Systematic 
Review of Heart Doses Published During 2003 to 2013. Int. J. Radiat. Oncol. 93, 845–853 
(2015). 
8. 
Tuohinen, S. S. et al. Early effects of adjuvant breast cancer radiotherapy on right 
ventricular systolic and diastolic function. Anticancer Res. 35, 2141–7 (2015). 
9. 
Heggemann, F. et al. Cardiac Function After Multimodal Breast Cancer Therapy Assessed 
With Functional Magnetic Resonance Imaging and Echocardiography Imaging. Int. J. 
Radiat. Oncol. Biol. Phys. 93, 836–44 (2015). 
10. 
Erven, K. et al. Subclinical cardiotoxicity detected by strain rate imaging up to 14 months 
after breast radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 85, 1172–8 (2013). 
11. 
Erven, K. et al. Acute Radiation Effects on Cardiac Function Detected by Strain Rate 
Imaging in Breast Cancer Patients. Int. J. Radiat. Oncol. 79, 1444–1451 (2011). 
12. 
Tjessem, K. H. et al. Long-term Cardiac Mortality After Hypofractionated Radiation Therapy 
in Breast Cancer. Int. J. Radiat. Oncol. 87, 337–343 (2013). 
13. 
Chang, M. et al. Coronary Calcium Scanning in Patients after Adjuvant Radiation for Early 
Breast Cancer and Ductal Carcinoma In situ. Front. Oncol. 3, 253 (2013). 
14. 
Mast, M. E. et al. Less increase of CT-based calcium scores of the coronary arteries. 
Strahlentherapie und Onkol. 192, 696–704 (2016). 
15. 
Andersen, R. et al. Relation of Coronary Artery Calcium Score to Premature Coronary Artery 
Disease in Survivors &gt;15 Years of Hodgkin’s Lymphoma. Am. J. Cardiol. 105, 149–152 
(2010). 
16. 
Apter, S. et al. Cardiovascular calcifications after radiation therapy for Hodgkin lymphoma: 
computed tomography detection and clinical correlation. Coron. Artery Dis. 17, 145–51 
(2006). 
17. 
Rademaker, J. et al. Coronary artery disease after radiation therapy for Hodgkin’s 
lymphoma: coronary CT angiography findings and calcium scores in nine asymptomatic 
patients. AJR. Am. J. Roentgenol. 191, 32–7 (2008). 
18. 
Whitlock, M. C. et al. Cancer and Its Association With the Development of Coronary Artery 
Calcification: An Assessment From the Multi-Ethnic Study of Atherosclerosis. J. Am. Heart 
Assoc. 4, e002533–e002533 (2015). 
19. 
Jordan, J. H. et al. Anthracycline-Associated T1 Mapping Characteristics Are Elevated 
Independent of the Presence of Cardiovascular Comorbidities in Cancer Survivors. Circ. 
Cardiovasc. Imaging 9, e004325- (2016). 
20. 
D’Errico, M. P. et al. N-terminal pro-B-type natriuretic peptide plasma levels as a potential 

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biomarker for cardiac damage after radiotherapy in patients with left-sided breast cancer. Int. 
J. Radiat. Oncol. Biol. Phys. 82, e239-46 (2012). 
21. 
Ito, T. & Ikeda, U. Inflammatory cytokines and cardiovascular disease. Curr. Drug Targets. 
Inflamm. Allergy 2, 257–65 (2003). 
22. 
Creemers, E. E., Tijsen, A. J. & Pinto, Y. M. Circulating MicroRNAs: Novel Biomarkers and 
Extracellular Communicators in Cardiovascular Disease? Circ. Res. 110, 483–495 (2012). 
23. 
Boulanger, C. M. et al. Circulating microparticles from patients with myocardial infarction 
cause endothelial dysfunction. Circulation 104, 2649–52 (2001). 
 
 

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16. APPENDICES 
 
Declaration of Helsinki 
 
INTRODUCTION  
 
The World Medical Association has developed the Declaration of Helsinki as a statement of ethical 
principles to provide guidance to physicians and other participants in medical research involving 
human subjects. Medical research involving human subjects includes research on identifiable 
human 
material 
or 
identifiable 
data. 
 
It is the duty of the physician to promote and safeguard the health of the people. The physician's 
knowledge 
and 
conscience 
are 
dedicated 
to 
the 
fulfilment 
of 
this 
duty. 
 
The Declaration of Geneva of the World Medical Association binds the physician with the words, 
"The health of my patient will be my first consideration," and the International Code of Medical 
Ethics declares that, "A physician shall act only in the patient's interest when providing medical 
care which might have the effect of weakening the physical and mental condition of the patient."  
 
Medical progress is based on research, which ultimately must rest in part on experimentation 
involving 
human 
subjects. 
 
In medical research on human subjects, considerations related to the well-being of the human 
subject 
should 
take 
precedence 
over 
the 
interests 
of 
science 
and 
society. 
 
The primary purpose of medical research involving human subjects is to improve prophylactic, 
diagnostic and therapeutic procedures and the understanding of the aetiology and pathogenesis of 
disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must 
continuously be challenged through research for their effectiveness, efficiency, accessibility and 
quality.  
 
In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic 
procedures 
involve 
risks 
and 
burdens.  
 
Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights. Some research populations are vulnerable and need special 
protection. The needs of the economically and medically disadvantaged must be recognised. 
Special attention is also required for those who cannot give or refuse consent for themselves, for 
those who may be subject to giving consent under duress, for those who will not benefit personally 
from the research and for those for whom the research is combined with care.  
 
Research Investigators should be aware of the ethical, legal and regulatory requirements for 
research on human subjects in their own countries as well as applicable international 
requirements. No national ethical, legal or regulatory requirement should be allowed to reduce or 
eliminate any of the protections for human subjects set forth in this Declaration. 
 
 
 
BASIC 
PRINCIPLES 
FOR 
ALL 
MEDICAL 
RESEARCH  
 
It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of 
the 
human 
subject.  
 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 

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information, and on adequate laboratory and, where appropriate, animal experimentation. 
 
Appropriate caution must be exercised in the conduct of research, which may affect the 
environment, 
and 
the 
welfare 
of 
animals 
used 
for 
research 
must 
be 
respected. 
 
The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol. This protocol should be submitted for consideration, 
comment, guidance, and where appropriate, approval to a specially appointed ethical review 
committee, which must be independent of the investigator, the sponsor or any other kind of undue 
influence. This independent committee should be in conformity with the laws and regulations of the 
country in which the research experiment is performed. The committee has the right to monitor 
ongoing trials. The researcher has the obligation to provide monitoring information to the 
committee, especially any serious adverse events. The researcher should also submit to the 
committee, for review, information regarding funding, sponsors, institutional affiliations, other 
potential 
conflicts 
of 
interest 
and 
incentives 
for 
subjects.  
 
The research protocol should always contain a statement of the ethical considerations involved 
and should indicate that there is compliance with the principles enunciated in this Declaration.  
 
Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person. The responsibility for 
the human subject must always rest with a medically qualified person and never rest on the subject 
of 
the 
research, 
even 
though 
the 
subject 
has 
given 
consent.  
 
Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the 
subject or to others. This does not preclude the participation of healthy volunteers in medical 
research. 
The 
design 
of 
all 
studies 
should 
be 
publicly 
available. 
 
Physicians should abstain from engaging in research projects involving human subjects unless 
they are confident that the risks involved have been adequately assessed and can be satisfactorily 
managed. Physicians should cease any investigation if the risks are found to outweigh the potential 
benefits 
or 
if 
there 
is 
conclusive 
proof 
of 
positive 
and 
beneficial 
results.  
 
Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject. This is especially important 
when 
the 
human 
subjects 
are 
healthy 
volunteers.  
 
Medical research is only justified if there is a reasonable likelihood that the populations in which the 
research 
is 
carried 
out 
stand 
to 
benefit 
from 
the 
results 
of 
the 
research.  
 
The subjects must be volunteers and informed participants in the research project. 
 
The right of research subjects to safeguard their integrity must always be respected. Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the patient's 
information and to minimise the impact of the study on the subject's physical and mental integrity 
and 
on 
the 
personality 
of 
the 
subject. 
 
In any research on human beings, each potential subject must be adequately informed of the aims, 
methods, sources of funding, any possible conflicts of interest, institutional affiliations of the 
researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. 
The subject should be informed of the right to abstain from participation in the study or to withdraw 
consent to participate at any time without reprisal. After ensuring that the subject has understood 
the information, the physician should then obtain the subject's freely-given informed consent, 
preferably in writing. If the consent cannot be obtained in writing, the non-written consent must be 
formally 
documented 
and 
witnessed.  
 

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When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under 
duress. In that case the informed consent should be obtained by a well-informed physician who is 
not engaged in the investigation and who is completely independent of this relationship.  
 
For a research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the investigator must obtain informed consent from the 
legally authorised representative in accordance with applicable law. These groups should not be 
included in research unless the research is necessary to promote the health of the population 
represented and this research cannot instead be performed on legally competent persons.  
 
When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition to the 
consent 
of 
the 
legally 
authorised 
representative.  
 
Research on individuals from whom it is not possible to obtain consent, including proxy or advance 
consent, should be done only if the physical/mental condition that prevents obtaining informed 
consent is a necessary characteristic of the research population. The specific reasons for involving 
research subjects with a condition that renders them unable to give informed consent should be 
stated in the experimental protocol for consideration and approval of the review committee. The 
protocol should state that consent to remain in the research should be obtained as soon as 
possible 
from 
the 
individual 
or 
a 
legally 
authorised 
surrogate. 
 
Both authors and publishers have ethical obligations. In publication of the results of research, the 
investigators are obliged to preserve the accuracy of the results. Negative as well as positive 
results should be published or otherwise publicly available. Sources of funding, institutional 
affiliations and any possible conflicts of interest should be declared in the publication. Reports of 
experimentation not in accordance with the principles laid down in this Declaration should not be 
accepted 
for 
publication.  
 
 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE 
 
The physician may combine medical research with medical care, only to the extent that the 
research is justified by its potential prophylactic, diagnostic or therapeutic value. When medical 
research is combined with medical care, additional standards apply to protect the patients who are 
research subjects. 
The benefits, risks, burdens and effectiveness of a new method should be tested against those of 
the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use 
of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic 
method 
exists. 
See 
footnote  
 
At the conclusion of the study, every patient entered into the study should be assured of access to 
the best proven prophylactic, diagnostic and therapeutic methods identified by the study. 
 
The physician should fully inform the patient which aspects of the care are related to the research. 
The refusal of a patient to participate in a study must never interfere with the patient-physician 
relationship. 
 
In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do 
not exist or have been ineffective, the physician, with informed consent from the patient, must be 
free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. 
Where possible, these measures should be made the object of research, designed to evaluate 
their safety and efficacy. In all cases, new information should be recorded and, where appropriate, 
published. The other relevant guidelines of this Declaration should be followed.  
 
 

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Appendix 
INFORMED CONSENT FORM 
 
 
MEDIRAD EARLY-HEART 
Study on early detection of cardiovascular changes after radiotherapy for breast cancer 
 
 
Name of Principal Investigator: To complete for local investigating center 
 
Name of Organization: To complete for local investigating center 
 
Name of Sponsor:  
- European Commission Horizon 2020 - MEDIRAD project Implications of MEDIcal low  dose 
RADiation exposure  - Agreement 755523 
-  Local investigating center  to complete 
 
Name of Proposal and version: EARLY HEART Study, version 1.2 July 5th 2017 
 
 
Madam, 
 
This information letter is for women who attend hospital X, and who we are inviting to participate in 
research EARLY-HEART Study on early detection of cardiovascular changes after radiotherapy for 
breast cancer. 
 
This Informed Consent Form has two parts: 
• 
Information Sheet (to share information about the research with you) 
• 
Certificate of Consent (for signatures if you agree to take part) 
 
You will be given a copy of the full Informed Consent Form. 
 
 
PART I: INFORMATION SHEET 
 
 
Introduction 
 
I am Dr/Pr X, working for the Hospital X. We are doing research on cardiovascular changes that 
may arise after radiotherapy for breast cancer. I am going to give you information and invite you to 
be part of this research. You do not have to decide today whether or not you will participate in the 
research. Before you decide, you can talk to anyone you feel comfortable with about the research. 
 
Context and Purpose of the study  
 
For the treatment of your breast cancer, you will receive radiotherapy treatment in our hospital. The 
efficacy of radiotherapy in the treatment of breast cancer has been validated by several researches 
and is now a standard. During radiotherapy, in addition to the breast, some organs close to the 
chest wall receive an irradiation part, in particular the heart.  During your treatment with 
radiotherapy, an optimal balance is going to be sought allowing irradiating your breast as well as 
possible while minimizing as much as possible irradiation of your heart. However, heart irradiation 
may sometimes induce long-term cardiac complications in some infrequent cases. As life 
expectancy in general and after treatment of breast cancer is increasingly favorable, research on 
possible cardiac consequences for patients who have been treated for breast cancer is important. 

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The purpose of our study is to enhance knowledge on the possible cardiovascular changes that 
may arise in the first 2 years after radiotherapy, taking into account your individual risks factor as 
well as the dose of irradiation that your heart will have received.  
Our study should allow us formulating possibly necessary recommendations for future prevention 
strategies and for future improvement of radiotherapy technique to spare cardiac structures.  
 
Participant selection 
 
We are inviting all patients with breast cancer aged between 40 and 75 years old who are going to 
be treated with radiotherapy without chemotherapy to participate in the research. Patients who 
would have already been treated with radiotherapy for breast cancer or thoracic irradiation, or 
patients who already present cardiovascular diseases can’t be included. Moreover, if we discover 
during cardiac examination at the beginning of the study that you would need a specific cardiac 
medical care, you should be excluded from our study in order to benefit for your situation the most 
adapted cardiac follow up. 
 
Voluntary Participation 
 
Your participation in this research is entirely voluntary. It is your choice whether to participate or 
not. Whether you choose to participate or not, all the services you receive at this hospital will 
continue and nothing will change. If you choose not to participate in this research project, you will 
be offered the follow up that is routinely offered in this hospital for breast cancer. You may change 
your mind later and stop participating even if you agreed earlier. 
 
Procedures and Protocol 
 
During and after your radiotherapy for breast cancer, you will have regular visits with the radiation 
oncologist. If you participate in our study, you will have additional visits and cardiac imaging 
examinations as well as regular blood samples. We give you the details below: 
 
A. Unfamiliar Procedures 
For this study, we ask you before the start of radiotherapy and at regular intervals up to 2 years 
after radiotherapy to submit you to 3 cardiac imaging and blood tests to determine the markers of 
heart damage. 
Cardiac echography: 
To study the functioning of your heart, a cardiac echography with ultrasound will be performed. An 
cardiac echography works with sound waves and is a secure and non-harmful method of getting a 
picture of your heart. With an ultrasound study, the shape, construction, function of pump and 
function of heart valves and blood circulation can be visualized. 
Computed tomography coronary angiography: 
To determine the calcium and limestone content of your coronary arteries, a CT scan will be 
performed before treatment begins and 6 and 24 months after treatment. Calcium in the coronary 
arteries indicates arteriosclerosis which is the most important cause of cardiovascular disease. The 
calcium score is based on the principle that calcium does not pass X-rays. When the calcium score 
is too high, then we can only say that the risk of heart disease is greater. 
Cardiac Magnetic Resonance Imaging: 
With MRI, or magnetic resonance imaging, the heart and blood vessels are replicated before 
treatment and 6 and 24 months after treatment. With an MRI, the shape, construction, narrowing of 
the coronary arteries and function of the pump and the operation of heart valves and blood 
circulation can be visualized. It can then be determined if the heart tissue is damaged and has a 
lack of oxygen or if the heart tissue is healthy. 
Blood samples: 
Cardiac biomarkers will be quantified and identified in your blood to determine the damage of the 
heart. If the heart and coronary arteries are damaged, these substances end up in the blood. The 
amount of cardiac markers in the blood gives an idea of the extent of damage to the heart. Blood 
tests are used to determine the concentrations of cardiac markers. 
Using a part of your blood samples, we will analysis a list of biomarkers that is based on current 

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knowledge. This part of blood samples obtained during this research procedure will be used only 
for this research, and will be destroyed after 2 years, when the research is completed.  
However, as research is advancing, the list of biomarkers to study the cardiotoxicity of radiotherapy 
could be enlarged in the future, including any new circulating biomarkers that would be discovered 
in the coming years. So, if you agree, the other part of your blood samples may be stored for 
duration longer than the research purpose, 15 years, this biological collection being justified to 
analyze possible new biomarkers and improve knowledge. The Responsible party for this 
biological collection is Professor Constanza Emanueli form the Bristol Heart Institute, School of 
Clinical Sciences, University of Bristol, Bristol Royal Infirmary, Upper Maudlin Street, BS2 8HW, 
Bristol, United Kingdom. 
 
 
B. Description of the Process 
By being included in the EARLY HEART study, your participation in this research will require the 
following steps: 
 
At inclusion, before radiotherapy, you will have: 
- 
a participation questionnaire, completed by your radiation oncologist, to check that you are 
eligible for the study. Medical information will also be recorded in an observation book. 
- 
a consultation with a cardiologist, during which a medical questionnaire will be completed 
and an electrocardiogram performed 
- 
a blood sample, for the measurement of biomarkers of cardiovascular disease (6 tubes of 
blood) 
- 
a cardiac echography (non-invasive and painless technique) will be performed 
- 
a computed tomography coronary angiography 
- 
a cardiac magnetic resonance imaging 
 
Just at the end of the radiation therapy, you will have: 
- 
a consultation of end of radiotherapy with your radiation oncologist 
- 
a blood sample (6 tubes of blood) 
 
Six months after radiotherapy: 
- 
a follow-up consultation with your radiation oncologist  
- 
a blood sample (6 tubes of blood) 
- 
a cardiac echography  
- 
a cardiac magnetic resonance imaging 
 
Two years after radiotherapy: 
- 
a follow-up consultation with your radiation oncologist  
- 
a blood sample (6 tubes of blood) 
- 
a cardiac echography  
- 
a computed tomography coronary angiography 
- 
a cardiac magnetic resonance imaging 
 
The total duration of your participation is therefore 2 years. All information collected will be coded 
to preserve your anonymity. 
 
Risks and Benefits: 
 
Risks:  
You will be subjected to a total of maximum 8 cardiac imaging tests and 4 blood tests to determine 
cardiac markers. To determine the calcium score, two additional CT scans should be performed for 
irradiation in addition to the scheduled CT Scan for radiotherapy. Compared to the radiation dose 
you receive for breast cancer radiotherapy, the additional dose for this scientific study is limited. 
We therefore assume that these scans will have no effect on your health. 
 
The additional exams will be combined as much as possible with the appointments you have for 
your treatment. However, for logistical reasons, this will not always be possible and you will be 
asked to come to the hospital. 
 

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Benefits:  
When a cardiac damage appears that requires a visit from a cardiologist, you will benefit early 
medical care. 
 
More generally, the results of this study may lead in the future to improvements in current 
irradiation techniques, as well as better prevention strategies for cardiac follow up in patients 
treated with breast radiotherapy. 
 
You will be irradiated according to the current standard and therefore you will not benefit from any 
direct benefit from your participation in this study. 
 
Reimbursements 
 
As a result of your participation, we may reimburse travels costs for your additional travels to the 
hospital for the study. 
 
Confidentiality 
 
The information that we collect from this research project will be kept confidential. Information 
about you that will be collected during the research will be put away and no-one but the 
researchers will be able to see it. Any information about you will have a number on it instead of 
your name. Only the researchers will know what your number is and we will lock that information 
up with a lock and key. It will not be shared with or given to anyone except the five other European 
Research centers that are involved in the study. 
 
Right to Refuse or Withdraw 
 
You do not have to take part in this research if you do not wish to do so. You may also stop 
participating in the research at any time you choose. It is your choice and all of your rights will still 
be respected. 
 
Insurance 
 
For possible negligent or non-negligent harms during your participation in our study, it is XXX 
insurance policies which applies to this study. Please contact the Principal Investigator (Dr XX) if 
you would like further information about the insurance arrangements which apply to the study. 
 
Who to Contact 
If you have any questions you may ask them now or later, even after the study has started. If you 
wish to ask questions later, you may contact: 
Dr/Pr XX name of the local Principal investigator  
Dr / Pr XX name of the referent local cardiologist 
Dr / Pr XX name of the local referent radiologist 
 
 
This proposal has been reviewed and approved by the Medical Research Ethical Committee 
of XX, which is a committee whose task it is to make sure that research participants are 
protected from harm.   
 
 
You can ask me any more questions about any part of the research study, if you wish to. Do you 
have any questions?   
 
 
The next part of the Informed Consent From (Part II: Certificate of consent for MEDIRAD 
EARLY HEART Study ) for signatures is on the next page  
 

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PART II: CERTIFICATE OF CONSENT   MEDIRAD EARLY HEART STUDY 
 
Certificate of consent to participate to the clinical study EARLY HEART for the study on 
early detection of cardiovascular changes after radiotherapy for breast cancer 
 
Statement by the patient 
 
I have read the information letter for EARLY HEART Study, or it has been read to me.  
 
I have had the opportunity to ask questions about it and any questions that I have asked have 
been answered to my satisfaction.   
 
I have understood that I do not have to take part in this research if I  do not wish to do so and 
refusing to participate will not affect my treatment in any way.  I will still have all the benefits that I 
would otherwise have at this hospital. I may stop participating in the research at any time that I 
wish without losing any of my rights as a patient here. My treatment at this hospital will not be 
affected in any way 
 
I consent voluntarily to participate as a participant in this research  
 
I also consent specifically for long term blood sample storage and use   □ Yes      □ No  
 
Print Name of Participant__________________ 
 
 
 
 
 
Signature of Participant ___________________ 
Date ___________________________ 
 
Day/month/year 
 
  
 
 
 
 
 
 
Statement by the radiation oncologist taking consent 
 
I have accurately read out the information letter to the potential participant, and to the best of my 
ability made sure that the participant understands that the following interventions will be done: 
1.  Cardiac echography before radiotherapy, 6 months and 24 months after radiotherapy 
2. Electrocardiogram before radiotherapy and 24 months after radiotherapy 
3.  Cardiac CT before radiotherapy and 24 months after radiotherapy 
4. Cardiac MRI before radiotherapy, 6 months and 24 months after radiotherapy 
5. Blood samples before radiotherapy, at the end of radiotherapy, 6 months and 24 months after 
radiotherapy 
 
I confirm that the participant was given an opportunity to ask questions about the study, and all 
the questions asked by the participant have been answered correctly and to the best of my ability. I 
confirm that the individual has not been coerced into giving consent, and the consent has been 
given freely and voluntarily.  
   
A copy of this Informed Consent Form has been provided to the participant. 
 
Print Name of Researcher/person taking the consent________________________ 
 
 
 
 
Signature of radiation oncologis  taking the consent__________________________ 
Date ___________________________ 
 
 
 
                 Day/month/year 
 
 
 
 

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Appendix 
CRF ELIGIBILITY 
 
Inclusion Number: ………. 
Date of the visit   :………….. 
 
 
Date of Birth: ………………….   
 
 Inclusion Criteria (check each point) 
o Female breast cancer patients 
o Treated with primary breast conserving surgery for stage I-III invasive adenocarcinoma 
of the breast or ductal carcinoma in situ (DCIS) 
o Age between 40-75 years at time of start radiotherapy 
o WHO performance status 0-1 
o Planned for radiotherapy alone to the breast with or without the lymph node areas 
o Radiotherapy based on planning-CT scan using either 3D-CRT, IMRT, or 
VMAT/RapidArc 
o Written Informed consent 
 
 Non Inclusion Criteria (check each point) 
 
o Male breast cancer patients 
o Neoadjuvant or adjuvant chemotherapy 
o M1 disease (metastatic breast cancer) 
o Medical history of coronary artery disease and/or myocardial infarction and/or atrial 
fibrillation 
o Previous thoracic or mediastinal radiation 
o Contraindications to injection of iodinated contrast such as allergy or renal failure 
o Pregnancy or lactation 
 
 
 

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Appendix 
CRF CANCER 
 
Inclusion Number: ………. 
Date of the visit   :………….. 
 
 
Date of Birth: ………………….   
 
 
● Left breast   □             Right breast  □    
●  Date of the surgery  : ………………. 
●  Type of surgery :    breast conserving surgery  □          mastectomy □ 
 
● Axillary lymph node exploration :  
axillary sentinel lymph node biopsy □                axillary lymph node dissection □           
 
● Histology :    In situ □        invasive □ 
 
● Size (mm) :…………………………….. 
 
● Regional  lymph nodes (N) 
□ NX (Regional lymph nodes cannot be assessed (eg, previously removed)) 
□ N0 (No regional lymph node metastasis) 
□ N1  (Metastasis to movable ipsilateral level I, II axillary lymph node(s)) 
□ N2 (Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted or in clinically detected* 
ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasis) 
□ N2a (Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures) 
□ N2b (Metastases only in clinically detected* ipsilateral internal mammary nodes and in the absence of clinically 
evident level I, II axillary lymph node metastases) 
□ N3 (Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s), with or without level I, II axillary node 
involvement, or in clinically detected * ipsilateral internal mammary lymph node(s) and in the presence of clinically 
evident level I, II axillary lymph node metastasis; or metastasis in ipsilateral supraclavicular lymph node(s), with or 
without axillary or internal mammary lymph node involvement)  
□ N3a (Metastasis in ipsilateral infraclavicular lymph node(s)) 
□ N3b (Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)) 
□ N3c (Metastasis in ipsilateral supraclavicular lymph node(s)) 
● Grade :  Grade 1 □          Grade 2 □          Grade 3 □ 
●  Vascular invasion  : yes □    no □ 
●  Presence of a component  in situ :   yes □     no □ 
●  Multifocality : yes □      no □ 

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● Her-2 :    negative □      positive  (amplification or overexpression) □      
●  Oestrogen Receptor: negative □     positive  □ 
●  progesterone receptor: negative □    positive  □ 
●  Menopause  : No □    Yes  □   Since : ……………………………… 
 
●  Hormone therapy    Yes  □     No □ 
If yes, which one :   Tamoxifene □        Aromatase inhibitors □          Others □ 
Date of the beginning of hormone therapy  : ………………. 
 
●  Date of the beginning of radiotherapy : ………………………………….. 
●  Irradiation volumes :  
Breast     □               Chest wall    □ 
Nodes :  Yes □   No □ 
        If yes,  
             Supraclavicular node :  Yes □   No □ 
             Infraclavicular (subclavicular) node :  Yes □   No □ 
             Internal Mammary node :  Yes □   No □ 
             Axillary node: Yes □   No □ 
 
●  Boost :   Yes □     No □ 
   

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Appendix 
CRF PLANNED RT 
 
 
Inclusion Number: ………. 
Date of the visit   :………….. 
 
 
Date of Birth: ………………….   
 
 
● Type of radiotherapy :  
              3D-CRT  □          IMRT   □         VMAT/RapidArc □        
 
● Breath hold :  
              yes  □          no   □          
 
● Boost electrons/photons:  
 
             photons  □         electrons   □          
 
 
 
Complete : 
Dose/fraction 
Number of 
fractions 
Total Dose 
Comments, if any : 
Breast or Chest wall  
 
 
 
 
Boost 
 
 
 
 
 
 
 
 

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Appendix 
CRF RT TOXICITY 
 
 
Inclusion Number: ………. 
Date of the visit   :………….. 
 
 
Date of Birth: ………………….   
 
 
Precise if it is : during radiotherapy □ 
                            at the end of radiotherapy □   
                            6 months after the end radiotherapy □    
                            2 years after the end of radiotherapy □ 
 
Acute toxicity of grade >2 : 
Dermatitis  Yes  □   No □ 
Chest wall/breast pain  Yes  □   No □,  
Edema  Yes  □   No □,  
Breast and arm  Yes  □   No □ 
Esophagitis  Yes  □   No □ 
 
 
Late toxicity of grade >2 : 
Telangiectasia   Yes  □   No □ 
Fibrosis in boost and out boost area    Yes  □   No □ 
Global cosmetic result   Yes  □   No □ 
Edema breast, edema arm  Yes  □   No □ 
Function of the shoulder   Yes  □   No □ 
Chest wall/breast pain   Yes  □   No □ 
Rib fracture  Yes  □   No □ 
Brachial plexopathy   Yes  □   No □ 
Pneumonitis   Yes  □   No □ 
 
  
 

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Appendix 
CRF CARDIOLOGY 
 
Inclusion Number: ………. 
Date of the visit   :………….. 
 
 
Visit 1 at baseline □                         Visit at 2 years □ 
Date of Birth: ………………….   
Weight : ……………kg 
Size : ……m…………… 
 
• 
Blood Pressure - Hypertension 
Systolic Blood Pressure : ………..mmHg 
Diastolic blood Pressure : …………mmHg 
     Treatment  □ Yes       □ No    
Hypertension:   □ Yes       □ No Defined as having Systolic BP > 140 or Diastolic BP > 90 mmHg, 
or treatment for  hypertension 
 
• 
Tobacco  : 
            □  Non smoker           
                □ Former smoker  
                        -  Year of beginning: ………………..   Year of stop : ………………….       
                               Mean Number of cigarettes/day during the smoking period: ………………. 
                □  Active Smoker  
                        -  Age or year of beginning ………………..    
                               Mean Number of cigarettes/day : ………………. 
 
• 
Diabetes :  
□  No         
     □  Yes     □ type 1            □ type2   
            - Beginning of the diabetes (year) :  ………………………………    
          Actual treatment  :………………………………………………………..       
    
• 
Cholesterol: 
LDL Cholesterol mg/dL:………………….. 
HDL Cholesterol mg/dL…………………….. 
Total Cholesterol mg/dL: …………….. 
Triglycerides : ……………….. 
Treatment for hypercholesterolemia (statin) : □ Yes        □ No   
SI conversion factors: To convert total, HDL, and LDL cholesterol from mmol/L to mg/dL , divide by 
0.0259; triglyceride to from mmol/L to mg/dL , divide by .0113.  
    
● Fasting glucose :……………………………… mmol /L    
 
● Urea:……………………………… mmol /L    
 
● Creatinine : …………………… μmol/L   
 
● eGFR (MDRD formula) : ……………. mL/min per 1.73 m² 

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  -> < 50 ml/min/1.73 m²    □ Yes        □ No      (if yes, the patient should be excluded of the 
study (exclusion criteria) ) 
 
● β HCG 
…………………… mmol /L    
 
 
●  Electrocardiogram (ECG) 
 
Atrial fibrillation detected  □ Yes        □ No          (if yes, the patient should be excluded of the 
study (exclusion criteria) ) 
 
ECG sign of myocardial Infarction □ Yes        □ No      if yes, the patient should be excluded of 
the study (exclusion criteria) ) 
 
 
Other medical cardiology treatment  □ Yes        □ No   
If yes, precise in clear: …………………………………….. 
 
 
Specific part of CRF at Visit 2 at 2 years follow up:  
 
The medical cardiology treatment has been introduced or changed since V1 at inclusion 
□ Yes        □ No   
 
If yes precise the date :   ………………………..  
 
Modification of the ECG compared to the ECG at inclusion □ Yes        □ No 
 
Occurrence of Cardiovascular Event since inclusion □ Yes        □ No 
 
Occurrence of cardiac symptoms, □ Yes        □ No  
 
►If Yes to event or symptoms,  
please specify  the date and type of event or symptoms (dyspnea, palpitation, chest pain…), death, 
myocardial infarct, heart failure, hospitalization for cardiac diseases, atrial fibrillation or other 
significant arrhythmia,  stroke  etc… 
…………………………………………………………………………………………………………… 
………………………………………………………………………………………………………….. 
 
 
 
 

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Appendix 
LOCAL CRF ECHO-ST 
 
Inclusion Number: ………. 
Date of the visit   :………….. 
 
 
Date of Birth: ………………….   
Name and version of the of the ultrasound system:   
o 
General Electric Health Care , version: 
o 
Philips, version: 
o  
Siemens,  version: 
o 
Toshiba, veesion  
o 
Other to precise:  
 
Precise if it is : before radiotherapy □ 
                            6 months after the end radiotherapy □    
                            2 years after the end of radiotherapy □ 
 
o 
Global longitudinal strain: ……………… 
o 
Segmental longitudinal strain (Segment 1 to 16) : ……………… 
o 
Global longitudinal strain rate: ……………… 
o 
Segmental longitudinal strain rate (Segment 1 to 16) : ……………… 
o 
Global radial strain : ……………… 
o 
Segmental radial strain (Segment 1 to 16) : ……………… 
o 
Global radial strain rate: ……………… 
o 
Segmental radial strain rate (Segment 1 to 16) : ……………… 
o  
Left ventricular ejection fraction using Simpson’s biplane method: ……………… 
o 
Left ventricular end-diastolic volume using Simpson’s biplane method: ……………… 
o 
Left ventricular end-systolic volume using Simpson’s biplane method: ……………… 
o 
Left-ventricular end-diastolic diameter using M-mode: ……………… 
o 
Left ventricular mass measured according ASE/EAE guidelines: ……………… 
o 
E/A wave ratio : ……………… 
o 
E/Ea wave ratio (lateral annulus) : ……………… 
o 
TAPSE (triscuspid annular plane systolic excursion) : ……………… 
o 
Tricuspid annular S wave : ……………… 
o 
Pulmonary artery systolic pressure (based on the peak tricuspid regurgitation velocity 
estimate and by assuming a right atrial pressure of 5 mmHg) : ……………… 
o 
Left ventricular outflow tract diameter: ……………… 
o 
Left ventricular outflow tract velocity time integral: ……………… 
o 
Heart rate: ……………… 
o 
Cardiac output measured by multiplying heart rate by stroke volume: ……………… 
 
In case of abnormal echocardiography before radiotherapy defined as: LVEF<50%; 
longitudinal strain ≤ -16%; longitudinal strain rate <-1%, and/or abnormal wall motion, the 
patient should be excluded of the study (exclusion criteria) ) 
 
 

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Appendix 
CTCA  PROTOCOL  AND LOCAL CRF AT TIME OF ACQUISITION 
 
 Objectives of Cardiac and aortic CT 
 
• 
To estimate scores of calcification in each main coronary arteries (LM, LAD, Cx, RC), in 
aortic valve and in each segment of the thoracic aorta (ascending, arch and descending aorta) by 
using non enhanced CT. 
• 
To estimate plaque and stenosis in all the 16 coronary artery segments by using CT 
angiography. 
• 
To estimate global score per artery and per patient of calcification and plaque along 
coronary arteries and thoracic aorta. 
• 
To estimate evolution of such scores between basal CT and CT at 2 years after XRay 
radiation. 
 
 Protocol 
 
1. Non enhanced CT 
 
o Data acquisition parameters: 
 
Slice collimation 0.5 - 0,6 mm (the smallest one) 
 
Tube voltage 120 kV.  
 
Tube current dependent on local expertise, typically 50-100 mAs 
 
Diastolic imaging 
 
Please note heart rate during scan acquisition, or save ECG’s during 
acquisition in the patient folder. 
o Acquisition range: 
 
Include the entire heart and thoracic aorta within the field of view 
 
Cranial demarcation: origin of supra aortic branches 
 
Caudal demarcation: at least until RV/LV apex, including all pericardial 
adipose tissue (or more caudal). 
o Reconstruction process 
 
One series with the conventional local calcium score method including 2.4 to 
3- mm slice thickness, associated with1.2-1.5 increment (half the slice 
thickness) and 220 mm FOV; conventional reconstruction without iterative 
reconstruction. 
 
Second series with 1 mm thick slices with 0.5 mm increment and 220 mm 
FOV and some iterative reconstruction, leading to close signal to noise ratio 
regarding the first 2.4-3 mm slice thickness series (the iterative 
reconstruction will be fixed in each center at the beginning of the study in 
relation with the corelab). 
 

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 Enhanced CT  
 
o Data acquisition parameters: 
 
Slice collimation 0.5 - 0,6 mm (the smallest one) 
 
Tube voltage 80 - 120 kV 
 
Tube current dependent on local expertise and tube modulation 
 
Diastolic imaging, including RR interval coverage from to 30 to 80% 
 
Please note heart rate during scan acquisition, or save ECG’s during 
acquisition in the patient folder. 
 
Injection: quantity, rate depending on patient size and circulation; 100 ml of 
maximal volume of a solution with >= 350 ml/l of a iodinated contrast 
medium. 
 
Betablokers if Heart rate > 60 /min 
 
Sublingual Nitrate always 
 
o Acquisition range: 
 
Include entire heart with all coronaries within the field of view (the aorta is 
not required here) 
 
Caudal demarcation: at least until RV/LV apex 
o Reconstruction process 
 
One series with 0.5 - 0.625 mm and half slice thickness increment with 220 
mm FOV and some iterative reconstruction and optimal filter based on the 
local expertise and CT system. The series will included different ECG timing 
between 30 to 80% of the RR interval 
 
 Local CRF at time of CT Acquisition 
 
Inclusion Number: ………. 
Study Date:………….. 
 
Date of Birth: ………………….   
Weight :…………… 
 
 
Height : ………………. 
 
Name and version of the of the CT system:  
o 
Siemens  version: ……………………. 
o 
General Electric Health Care , version:………………….. 
o 
Toshiba, version:…………………….. 
o 
Philips, version :…………………. 
o 
Other to precise: …………………. 
 
Non enhanced series:  
 
Heart rate in bpm:…………… 
 
Reconstruction 1 without iteration:  
 
 
Slice thickness (mm): ……………………. 
 

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Reconstruction 2 with 1 mm thick and iteration: 
 
Iteration mode: expressed as the vendor name with the associated strength:   
 
 
 
Enhanced series: 
 
Contrast medium: 
 
 
Name of the CM:………………. 
 
 
Iodinated Concentration of the CM in g/l : ………………… 
 
Slice thickness in mm:………………. 
Heart rate in bpm:………………….. 
 
Betablokers given at time of CT:  
yes  
no 
 
Nitrate during CTA:   
 
yes  
no 
 
 
Reconstruction:  
 
 
Slice thickness (in mm): ………….. 
 
 
Increment (in mm):……………… 
 
 
Iteration mode: expressed as the vendor name with the associated  strength:  …… 
 
Local Analysis given to the Patients and to the medical staff in charge of the patient: 
Is there a >= 50% stenosis of the left main coronary artery: Yes  
No 
Is there > =70% stenosis of the proximal Left Anterior Descending artery (LAD1):  
Yes  
No 
If yes : an ischemic test have been done :  
 
Yes 
 
No 
A coronary revascularization has been done: 
 
Yes 
 
No 
 
A revascularization means that the patient will be excluded of the study and follow up. 
 
Other information (calcium score, other CTA results) will be blinded to the clinician team 
…………………………………………………………. 
 
 

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Appendix 
CARDIAC MRI PROTOCOL  AND LOCAL CRF AT TIME OF ACQUISITION 
 
 
 Objectives of Cardiac Magnetic Resonance 
• 
To estimate systolic and diastolic pressure during acquisition 
• 
To estimate aortic strain at 2 levels (ascending aorta and descending aorta) at the level of 
pulmonary bifurcation leading to distensibility, local pulse wave velocity estimates. 
• 
To estimate regional pulse wave velocity of the aortic arch (Phase contrast) 
• 
To estimate global function of the left and right ventricle: End diastolic volume, end-systolic 
volume, and mass and derived estimates with stroke volume, ejection fraction, wall stress and 
remodeling indices.  
• 
To estimate systolic left and right atrial areas.  
• 
To estimate native myocardial T1 of the left ventricular wall by using 2 small axis levels 
(base and mid left ventricle). 
• 
To estimate myocardial T2 (oedema) of the left ventricular wall by using the same 2 small 
axis levels (base and mid left ventricle). 
• 
To detect and quantitate late gadolinium enhancement between 10 and 14 min after 
Gadolinium injection 
• 
To estimate the myocardial post gadolinium T1 and extra cellular volume at 15 minute at 
the same 2 small axis levels as native myocardial T1 
 
Most variables will be estimated by the core lab only, by using the same software for included 
patients. 
 
 Protocol 
 
1- Blood sample at the time of CMR to estimate the hematocrit if no other blood sample has been 
done the same day.  
 
2- Scout 
 
3- Calibration before parallel imaging. 
 
4- Axial SSFP cine series with 8-12 levels to widely cover right and left atrium. 2 to 3 levels per 
breath hold using 12-16 ; at least 40 cardiac phases / level 
 
5-Small axis SSFP cine series from apex to base with 2 to 3 levels per breath hold.   
i. 
shim well center on the left ventricle 
ii. 
FOV < 360 mm,  
iii. At least 50 phases / level 
iv. With high image quality without aliasing or parallel imaging artefact on ventricles 
 

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Blood pressure 1  Systolic BP :………….. 
 
Diastolic BP :  …………… 
 
6- T1 MAP (MOLLI) before Gadolinium : 2 small axis views (basal/median) 1 level per breath hold : 
scheme 5(3)3(3)3 with immediate control to obtain high image quality. 
 
7- T2 MAP (3 to 5 echo) before Gadolinium  in the same 2 small axis views (basal/median). 1 level 
per breath hold: with immediate control to obtain high image quality. 
 
8- Aortic SSFP or SPGR 3D series in sagittal and oblique direction to cover the all thoracic aorta 
(to estimate the length between ascending and descending aorta) in free breathing 
 
9- Contrast enhanced angiography of the thoracic aorta acquired by using  sagittal oblique 
direction during injection of 0.2 mmol/kg gadoterate meglumine (Dotarem, Guerbet, Villepinte, 
France) and breath hold. 
 
Blood pressure 2  Systolic BP :…….. 
Diastolic BP :  ………… 
 
10- Aortic SSFP or SPGR 2D I breath hold 1 minute after injection: perpendicular to both the 
ascending and descending aorta at the level of the pulmonary artery bifurcation, as detected in 
series 8. Control for the optimal image (shim +++) to obtain high image quality to have an 
automated detection of aortic borders. Do not hesitate to rescan after gadolinium injection at the 
end of examination. 
 
Blood pressure 3  Systolic BP :………… 
 
Diastolic BP :  ………… 
 
11- Aortic Phase contrast in free breathing perpendicular to both the ascending and descending 
aorta at the level of the pulmonary artery bifurcation, as detected in series 7. Only one VPS, VENC 
= 160 cm/sec, at least 50 cardiac phases, optimal spatial resolution and FOV in less than 2 
minutes. Please verify the absence of aliasing (spatial and velocity aliasing). Do not hesitate to 
rescan at the end of examinationr. 
 
12-Radial SSFP cine series with 2,3- and 4 chamber views of the left ventricle ; at least 40 cardiac 
phase, optimal FOV. 
 
13- Scout cine IR to detect optimal TI of the inversion recovery sequence 
 
14- Optimal inversion recovery sequence to detect Late Gadolinium enhancement in one or 

MEDIRAD-EARLY HEART  Clinical Study protocol 
 
 
Version 1.2, July 5th 2017 
 
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several breath hold between 10 and 14 minutes post gadolinium injection. 
 
15- T1 MAP post Gado 15-16 minutes : at the two same pre-gadodilium levels. 
 
 Local CRF at time of CMR Acquisition 
 
Inclusion Number: ………. 
Study Date:………….. 
 
Date of Birth: ………………….   
Weight :…………… 
 
 
Height : ………………. 
 
Name and version of the of the CMR system:  
o 
Siemens  version:  
o 
General Electric Health Care , version: 
o 
Philips, version : 
o 
Other to precise:  
 
Intensity of the Magnet 
o 3T 
o 1.5 T 
o other 
 
Hematocrit the day of CMR:…..     % 
 
Blood pressures 1  Systolic BP in mmHg :……  
Diastolic BP :  …… 
 
Blood pressures 2  Systolic BP in mmHg :…….. 
Diastolic BP :  ………. 
 
Blood pressures 3  Systolic BP in mmHg :………. 
Diastolic BP : ……….  
 
Does the patient present signs of myocardial infarction:    
                 o  No     o  Yes  
 
If yes, this information should be given to the medical staff in charge of the patient. 
 
Please note that, when the patient required a vascularization or when a myocardial 
infarction is detected, the patient should be excluded from the study. 
 
 
Open question concerning the transfer of images:………………. 
 
 
 

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Version 1.2, July 5th 2017 
 
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Appendix 
BLOOD SAMPLE PROTOCOL 
 
 
 
Blood collection 
≈ 30 ml 
EDTA (2 x 5 ml) 
Citrate (2 x 5 ml) 
NEW biomarkers 
DNA methylation 
Classical biomarkers 
Heparin (2 x 5 ml) 
Plasma preparation: centrifugation 1500 x g, 15 min  
Prepare aliquots of 500 µl, freeze at –80°C, then send to: 
Bristol Heart Institute of Univ Bristol =blood collection centre for 
EARLY HEART 
Biomarkers will then be analyzed by : 
Univ Bristol (Great Britain), IRSN (France) and SCK•CEN (Belgium) 
Platelet-poor plasma preparation: 
centrifugation 13500 x g, 5 min