The first primary aim of this project is to detect ESCI, that are considered risk factors for clinically apparent MACE in BC patients treated with photon radiotherapy and chemotherapy. The second is to investigate whether proton therapy results in…
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Brief title
Condition
- Cardiac disorders, signs and symptoms NEC
Synonym
Research involving
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Intervention
Outcome measures
Primary outcome
There are 3 primary endpoints, 2 for functional ESCIs and 1 for morphological
ESCIs:
• The change in left ventricle systolic (dys)function is determined by cECHO
using left ventricle global longitudinal strain (LV-GLS) at 6 and 24 months
after radiotherapy with reference to baseline.
• The change in LV diastolic function (LV-DF) is determined by cECHO, defined
as a decrease of the average of e* septal and e* lateral together at 6 and 24
months after completion of radiotherapy with reference to baseline.
• The increase of diffuse myocardial fibrosis determined by cMRI morphology,
using LV T1 mapping, defined by an increase of the native mean LV myocardial T1
mapping value of the entire population at 6 and 24 after completion of
radiotherapy.
Secondary outcome
The secondary endpoints are measured with cECHO, cMRI and cCT on an exploratory
basis. They can be used to obtain more insight in the different underlying
biological mechanisms of treatment-related cardiac toxicity.
Secondary endpoints measured with echocardiographic parameters - most of which
are considered standard measurements in evaluating cardiac function with cECHO,
except for the strain measurements:
• global longitudinal strain rate;
• global and segmental radial strain rate;
• left ventricular ejection fraction using Simpson*s biplane method;
• left ventricular end-diastolic volume using Simpson*s biplane method;
• left ventricular end-systolic volume using Simpson*s biplane method;
• left-ventricular end-diastolic diameter using M-mode;
• left ventricular mass measured according ASE/EAE guidelines;
• E/A wave ratio;
• E/Ea wave ratio (lateral annulus);
• TAPSE (tricuspid annular plane systolic excursion);
• tricuspid annular S wave;
• pulmonary artery systolic pressure (based on the peak tricuspid regurgitation
velocity estimate and by assuming a right atrial pressure of 5 mmHg);
• left ventricular outflow tract diameter;
• left ventricular outflow tract velocity time integral;
• heart rate;
• cardiac output measured by multiplying heart rate by stroke volume.
Secondary endpoints measured with cMRI parameters are:
• myocardial edema based on T2 mapping;
• perfusion in rest and stress using adenosine;
• presence and extent of focal infarction/fibrosis by late gadolinium
enhancement (LGE) imaging;
• myocardial function based on cine imaging of the left and right ventricle.
Secondary endpoints measured with cCT are:
• Anatomical changes in coronary arteries assessed by cCT occurring 24 months
after radiotherapy, compared to baseline before radiotherapy start;
• Individual description of stenosis or plaques of the 15 segments of the
coronary arteries; left main coronary artery; left anterior descending artery
(LAD); left circumflex artery and right coronary artery and evaluation of
change in the CAC score (Agatston-score). The progression of atherosclerosis
will be defined as an increase in the number of coronary segments containing
any plaque and as an increase in the CAC score of at least 15% before the start
of radiotherapy and 24 months after radiotherapy.
Background summary
Breast cancer (BC) radiotherapy with X-rays (photons = XRT) leads to incidental
cardiac irradiation, resulting in an increased risk of various MAjor Cardiac
Events (MACE). Due to an increased incidence of BC and improved survival, the
prevalence of BC survivors at risk of MACE increases every year. In addition,
recent studies indicate that for the treatment of BC, the addition of
chemotherapy further enhances the risk of MACE, thus affecting quality of life
and increasing morbidity and mortality.
With proton therapy (PT), incidental cardiac dose can be markedly reduced.
However, as this radiation technique is more expensive and limited available,
BC patients are only eligible for PT when they are at high risk of MACE based
on the model-based approach and national selection criteria. Although the
cardiac dose can be markedly reduced with protons, parts of the heart will
still be exposed to a low dose radiation.
Information regarding morphological and functional early subclinical cardiac
injuries (ESCI) induced by XRT that develop into MACE is largely lacking in
scientific literature. Limited data exists on the relationship between
radiation dose to cardiac substructures and ESCI (dose-effect relationship), or
the effect of chemotherapy on this dose-effect relationship. Finally, no data
exist on the effect of proton therapy on the development of ESCI. Information
on ESCI is essential for the development of optimised radiation dose
distributions aiming at reduction of ESCI and subsequent MACE. In addition,
tools are needed to identify BC patients treated with radiotherapy combined
with chemotherapy who are at high risk of future MACE, and who may benefit from
secondary preventive strategies. Potential targets for developing these
strategies will help to avoid or delay progression into clinically apparent
MACE (secondary prevention).
Study objective
The first primary aim of this project is to detect ESCI, that are considered
risk factors for clinically apparent MACE in BC patients treated with photon
radiotherapy and chemotherapy. The second is to investigate whether proton
therapy results in less or different ESCI. Finally, this information is used to
develop prediction models describing the relationship between the radiation
dose to cardiac substructures and ESCI.
In details, we aim to:
1. identify longitudinal morphological and functional ESCI using
echocardiography (cECHO), cardiac magnetic resonance imaging (cMRI) and cardiac
computed tomography (cCT) before and after BC treatment, [prospective
observational cohort study in BC patients treated with photon radiotherapy and
chemotherapy];
2. determine the relationship between 3D-dose distributions to cardiac
substructures and ESCI [WP2] for BC patients treated with XRT and chemotherapy;
3. establish the effect of chemotherapy on the dose-effect relationship between
radiation dose and ESCI by comparing results to those obtained in the
MEDIRAD-EARLY HEART study (XRT alone);
4. explore the effect of proton therapy on the development of longitudinal
morphological and functional ESCI in BC patients treated with PT and
chemotherapy.
Study design
A single centre prospective observational cohort study [n=148] combined with a
prospective explorative cohort study [n=50].
Study burden and risks
Participation in this study does not involve any additional risk to subjects,
besides the risk incurred by additional MRI and CT-scans. Subjects will undergo
2 extra CT-scans. For CT, subjects are subjected to a scanning X-ray beam. The
latest techniques in cCT 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 cCT- scans is very low
and the risks therefore are negligible and the burden low.
Participation in this study may have benefits. When cardiac imaging reveals
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, subjects 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 BC patients
Primary breast conserving surgery or mastectomy for stage I-III invasive
adenocarcinoma of the breast or ductal carcinoma in situ (DCIS)
Age >=18 years at time of adjuvant radiotherapy/(neo)adjuvant chemotherapy
WHO performance status 0-1
Planned radiotherapy to the breast/chest wall with or without the lymph node
areas
Photon radiotherapy based on planning CT-scan, using either 3D CRT, (partial)
IMRT, or (partial) VMAT/RapidArc with or without deep inspiration breath-hold,
or proton therapy in free breathing (1 of more beams technique)
(Neo)Adjuvant chemotherapy (before or after radiotherapy)
Written informed consent
Exclusion criteria
Male breast cancer patients
M1 disease (metastatic Breast cancer)
Previous thoracic of mediastinal radiation
Targeted HER2 therapy not allowed
Medical history of coronary artery disease and/or myocardial infarction and/or
atrial fibrillation
Contraindications to injection of iodinated contrast such as allergy or renal
failure
Pregnancy or lactation
Atrial fibrillation detected during electrocardiogram before radiotherapy
Abnormal echocardiography before radiotherapy defined as: LVEF <50%, and/or
abnormal wall motion
Presence of myocardial infarction detected during cMRI before radiotherapy
cMRI or cCT 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 |
|---|---|
| Other | ClinicalTrials.gov, NCT03575650 |
| CCMO | NL66438.042.18 |