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…
ID
Source
Brief title
Condition
- Cardiac disorders, signs and symptoms NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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).
Secondary outcome
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:
* 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, TNF*
* Endothelial activation and dysfunction: sVCAM-1, s-ICAM-1, E-Selectin,
P-Selectin, vWF, PAI-1, Fibrinogen, Thrombomodulin, TGF*1
* 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.
Background summary
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.
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. 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. 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.
Study objective
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).
Study 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.
Study burden and risks
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).
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. 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.
Patients will not benefit from participation with the study. However, hhen
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
Hanzeplein 1
Groningen 9713 GZ
NL
Hanzeplein 1
Groningen 9713 GZ
NL
Listed location countries
Age
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
Exclusion criteria
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;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
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL62360.042.17 |
| Other | Submitted, identificationnumber to be received by IRSN |