Clinical trial NCT03297346: Early Detection of Cardiovascular Changes After Radiotherapy for Breast Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Breast Cancer Female
Keywords: radiotherapy
cardiovascular changes
cardiac imaging
circulating biomarkers
dosimetry
Lead sponsor: Institut de Radioprotection et de Surete Nucleaire
Sponsor class: OTHER_GOV
Collaborators: name: Academisch Ziekenhuis Groningen
name: Technical University of Munich
name: Institut Català d'Oncologia
name: Hospital de Santa Maria, Portugal
name: University of Paris 5 - Rene Descartes
First posted: 2017-09-29
Enrollment: 250
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: Breast cancer (BC) radiotherapy leads to coincidental radiation of the heart, resulting in increased risk of a variety of heart diseases. Identifying BC patients with the highest risk of radiation-induced cardiac complications is crucial for developing strategies for primary and secondary prevention. Little has been done on the relationship between dose distribution to different anatomical cardiac structures during radiotherapy and early cardiovascular changes that may lead to cardiac complications.

In the framework of the European project MEDIRAD, the EARLY-HEART multicenter prospective cohort was launched in August 2017, involving 5 investigating centers from France, Netherlands, Germany, Spain and Portugal. With 250 BC patients prospectively followed for 2 years, the main objective is to identify and validate the most important cardiac imaging (echocardiography, computed tomography coronary angiography, cardiac magnetic resonance imaging) and circulating biomarkers of radiation-induced cardiovascular changes arising in the first 2 years after BC radiotherapy.

Detailed description: EARLY-HEART is a multicentre prospective cohort study that will include 250 female primary breast cancer cases aged 40-75 years treated with postoperative radiotherapy (RT) alone after breast-conserving surgery using modern planning-CT based RT technologies and followed for 2 years after RT in one of the 5 participating hospitals. In addition to the standard follow-up, patients will need to give repeated blood samples and will undergo repeated cardiac imaging:

* Functional and anatomical cardiac imaging biomarkers will be based on automated 2D-speckle-tracking echocardiography (ECHO-ST); Computed Tomography Coronary Angiography (CT) and cardiac magnetic resonance imaging (MRI).
* Circulating biomarkers (BLOOD) will be based on a panel of multiple classical or novel blood-based biomarkers.

Imaging and circulating biomarkers measurements will be assessed at baseline before RT (ECHO, CT, MRI, BLOOD); at the end of RT (BLOOD); 6 months after RT (ECHO, MRI, BLOOD) and 24 months after RT (ECHO, CT, MRI, BLOOD).

Changes in functional and anatomical cardiac imaging and circulating biomarkers between unexposed status before RT and exposed status after RT at different time points will be first analysed to evaluate the effects of RT on the heart.

All relevant DICOM-data (including planning-CT scans and the ECHO, MRI and CT) will be centralized to the MEDIRAD-ENACT database managed by University of Groningen for automated segmentation of all cardiac substructures (including coronary arteries) to ensure uniformity of the segmentation procedure between centres. The RT planning CTs will be used to generate dose volume histograms and 3D dose maps of the heart and cardiac substructures in order to correlate the localization of any cardiovascular change with the anatomical dose distribution.

In the presence of a cardiac outcome, a multimetric Normal Tissue Complication Probability (NTCP) individual risk model will be constructed and an integrative clinical-biologic risk score will be developed for individual risk prediction.

Eligibility criteria: 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
* World Health Organisation (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 three dimensional conformal radiation therapy (3D-CRT), Intensity-modulated radiotherapy (IMRT), or Volumetric Arc Therapy (VMAT/RapidArc)
* Written Informed consent

Exclusion 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
* Atrial fibrillation detected during electrocardiogram before radiotherapy
* Abnormal echocardiography before radiotherapy defined as: Left Ventricular Ejection Fraction\<50%; longitudinal strain ≤ -16%; longitudinal strain rate \<-1%, and/or abnormal wall motion
* Presence of myocardial infarction detected during MRI before radiotherapy
* CT or MRI results before radiotherapy requiring revascularisation

Primary outcomes:
measure: Number of patients with decreased myocardial function assessed by echocardiography
timeFrame: 2 years after radiotherapy (baseline measurements performed before radiotherapy)
Secondary outcomes:
measure: Changes in myocardial function measurements assessed by echocardiography
timeFrame: 6 months and 2 years after radiotherapy (baseline measurements performed before radiotherapy)
measure: Anatomical changes in coronary arteries assessed by cardiac CT
timeFrame: 2 years after radiotherapy (baseline measurements performed before radiotherapy)
measure: Myocardial tissue abnormalities assessed by cardiac MRI
timeFrame: 6 months and 2 years after radiotherapy (baseline measurements performed before radiotherapy)
measure: Changes in circulating biomarkers measurements
timeFrame: at the end of radiotherapy (through radiotherapy completion, an average of 5 weeks after starting date of radiotherapy), 6 months and 2 years after radiotherapy (baseline measurements performed before radiotherapy)
Other outcomes:
Locations:
city: Toulouse
country: France
facility: IRSN - Clinique Pasteur
city: Munich
country: Germany
facility: Klinikum rechts der Isar der Technischen Universität München
city: Groningen
country: Netherlands
facility: Academisch Ziekenhuis Groningen
city: Lisbon
country: Portugal
facility: Associação para Investigação e Desenvolvimento da Faculdade de Medicina
city: Girona
country: Spain
facility: Institut Català d'Oncologia
Study officials:
affiliation: Institut de Radioprotection et de Sûreté Nucléaire
name: Sophie Jacob, PhD
role: STUDY_CHAIR
References:
citation: Locquet M, Spoor D, Crijns A, van der Harst P, Eraso A, Guedea F, Fiuza M, Santos SCR, Combs S, Borm K, Mousseaux E, Gencer U, Frija G, Cardis E, Langendijk H, Jacob S. Subclinical Left Ventricular Dysfunction Detected by Speckle-Tracking Echocardiography in Breast Cancer Patients Treated With Radiation Therapy: A Six-Month Follow-Up Analysis (MEDIRAD EARLY-HEART study). Front Oncol. 2022 Jun 28;12:883679. doi: 10.3389/fonc.2022.883679. eCollection 2022.
citation: Walker V, Crijns A, Langendijk J, Spoor D, Vliegenthart R, Combs SE, Mayinger M, Eraso A, Guedea F, Fiuza M, Constantino S, Tamarat R, Laurier D, Ferrieres J, Mousseaux E, Cardis E, Jacob S. Early Detection of Cardiovascular Changes After Radiotherapy for Breast Cancer: Protocol for a European Multicenter Prospective Cohort Study (MEDIRAD EARLY HEART Study). JMIR Res Protoc. 2018 Oct 1;7(10):e178. doi: 10.2196/resprot.9906.