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Doxorubicin-associated Cardiac Remodeling Followed by CMR in Breast Cancer Patients

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ClinicalTrials.gov Identifier: NCT03000036
Recruitment Status : Completed
First Posted : December 21, 2016
Last Update Posted : December 21, 2016
Sponsor:
Collaborator:
Fundação de Amparo à Pesquisa do Estado de São Paulo
Information provided by (Responsible Party):
Otavio Rizzi Coelho Filho, University of Campinas, Brazil

Brief Summary:
Twenty-seven breast cancer women without heart failure, underwent CMR imaging (3T-Achieva, Philips) before and 3 times serially after 4-cycles of adjuvant DOX (60mg/m2). CMR assessed left ventricular (LV) ejection fraction (EF), T1 mapping pre and post gadolinium and late gadolinium enhancement imaging. Biomarkers were obtained before and 72 hours after each DOX-cycle.

Condition or disease Intervention/treatment Phase
Breast Cancer Female Doxorubicin Induced Cardiomyopathy Drug: Doxorubicin Device: Achieva, Philips Medical Systems (3T magnet) Drug: Gadoterate Meglumine Not Applicable

Detailed Description:

This prospective cohort study was performed at the State University of Campinas, Brazil. The Institutional Review Board of the State University of Campinas approved the study and all participants provided informed consent. Female patients with breast cancer who received anthracycline (doxorubicin or daunorubicin or epirubicin) as part of their chemotherapy protocol were enrolled in the study.

Detailed medical history, standard anthropometric data, and measurement hemogram, troponin, CKMB, cholesterol, serum glucose, CRP and biomarkers were obtained.

As in adults, chronic anthracycline-related cardiotoxicity typically presents early, within one year after termination of chemotherapy and the peak time for the appearance of symptoms of heart failure is about three months after the last anthracycline dose, patients underwent CMR before and three times serially after DOX (two, five and twelve months).

Patients were imaged in supine position in a 3T magnet (Achieva, Philips Medical Systems, Best, The Netherlands). The CMR protocol consisted of electrocardiographically gated cine imaging with steady state free-precession to assess left ventricular (LV) function and LV mass. For imaging of late gadolinium enhancement (LGE) we used an inversion-recovery-prepared, gradient-echo sequence with segmented acquisition, which was triggered every other heartbeat. LGE images were acquired during end-expiratory breath-holding for slices matching the slice locations for cine imaging, starting within 10 min after bolus administration of a cumulative dose of 0.2 mmol/Kg of gadoterate meglumine (Dotarem, Guerbet, Aulnay-sous-Bois, France). T1 was performed with a Look-Locker sequence with a non-slice-selective adiabatic inversion pulse, followed by segmented gradient-echo acquisition for 17 times after inversion, covering approximately two cardiac cycles. The Look-Locker sequence was performed in a single short-axis slice at the level of the mid left ventricle. T1 imaging was repeated in the same LV short-axis slice, once before and five to seven times after the injection of gadolinium to cover an approximately 30-min period of slow contrast clearance.

All images were analyzed with MASS CMR software (Mass Research, Leiden University Medical Center, Leiden, the Netherlands). For LV mass and function quantification, the endocardial and epicardial borders of the LV myocardium were manually traced on short-axis cine images at end-diastole and systole. Papillary muscles were excluded from LV mass, and LV mass was indexed to body surface area.

For each Look-Locker image series, the endocardial and epicardial borders of the LV were traced and divided into six standard segments. Signal intensity versus time curves for each segment and the blood pool were used to determine segmental T1* by nonlinear, least-squares fitting to an analytic expression for the magnitude signal measured during the inversion recovery. T1 was calculated from the T1* and the amplitude parameters to correct for the effects of radiofrequency pulses applied during the inversion recovery.

Pairs of R1 values for myocardial tissue and blood data were fit with a two-space water-exchange model of equilibrium transcytolemmal water exchange. The myocardial extracellular volume fraction (ECV) and the intracellular lifetime of water (τic), a cell size-dependent parameter, were adjustable parameters of this model. The measured blood hematocrit was a fixed parameter of the model. All R1 measurements for each patient were used to fit the model to determine ECV and τic.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Doxorubicin-associated Cardiac Tissue Remodeling Followed by CMR of Myocardial Extracellular Volume and Myocyte Size in Breast Cancer Patients
Study Start Date : July 2012
Actual Primary Completion Date : January 2015
Actual Study Completion Date : July 2016


Arm Intervention/treatment
Cardiovascular Magnetic Resonance
Twenty-seven female patients were imaged in a 3T magnet after consecutively enrolled in the study if they had received a breast cancer diagnosis at the Center for Integral Attention to Women's Health (University of Campinas) and had prescribed endovenous doxorubicin as part of their chemotherapy regimen.
Drug: Doxorubicin
Patients had prescribed endovenous doxorubicin as part of their chemotherapy regimen (mean cumulative dose 102,66 mg/m2, administered in 4 doses with 21 days interval).
Other Name: Adriamycin

Device: Achieva, Philips Medical Systems (3T magnet)
Patients were imaged in supine position in a 3T magnet (Achieva, Philips Medical Systems, Best, The Netherlands). The protocol consisted of electrocardiographically gated cine imaging with steady state free-precession to assess left ventricular (LV) ejection fraction and LV mass. For imaging of late gadolinium-DTPA enhancement (LGE) we used an inversion-recovery-prepared, gradient-echo sequence with segmented acquisition, which was triggered every other heartbeat. LGE images were acquired during end-expiratory breath-holding, after administration of Dotarem. T1 was performed with a Look-Locker sequence with a non-slice-selective adiabatic inversion pulse, followed by segmented gradient-echo acquisition for 17 times after inversion, covering approximately two cardiac cycles. T1 imaging was repeated in the same LV short-axis slice, once before and five to seven times after the injection of gadolinium to cover an approximately 30-min period of slow contrast clearance.
Other Name: Cardiovascular Magnetic Resonance (CMR)

Drug: Gadoterate Meglumine
LGE images were acquired starting within 10 min after bolus administration of a cumulative dose of 0.2 mmol/Kg of gadoterate meglumine (Dotarem, Guerbet, Aulnay-sous-Bois, France).
Other Name: Dotarem




Primary Outcome Measures :
  1. Quantification of fibrosis index by Cardiac Magnetic Resonance [ Time Frame: two years ]
    Estimate the extracellular volume fraction derived from gadolinium-DTPA partition Coefficient of the myocardium

  2. Intracellular lifetime of water (τic) by Cardiac Magnetic Resonance [ Time Frame: two years ]
    This metric estimates the myocyte size using Cardiac Magnetic Resonance T1 mapping data


Secondary Outcome Measures :
  1. Left ventricular mass by Cardiac Magnetic Resonance [ Time Frame: two years ]
    Electrocardiographically gated cine imaging with steady state free-precession to assess left ventricular mass.

  2. Left ventricular volumes by Cardiac Magnetic Resonance [ Time Frame: two years ]
    Electrocardiographically gated cine imaging with steady state free-precession to assess left ventricular volume.

  3. Left ventricular ejection fraction by Cardiac Magnetic Resonance [ Time Frame: two years ]
    Electrocardiographically gated cine imaging with steady state free-precession to assess left ventricular ejection fraction.

  4. Left ventricular myocardial edema fraction by Cardiac Magnetic Resonance [ Time Frame: two years ]
    Using T2-weighted sequences to visualize myocardial edema


Other Outcome Measures:
  1. Ultra-sensitive troponin [ Time Frame: two years ]
    Cardiac troponin (ng/mL)



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Breast cancer and had prescribed an anthracycline agent as part of their chemotherapy regimen

Exclusion Criteria:

  • Strict contraindications to MRI
  • Acute or chronic kidney failure
  • Previously diagnosed myocardial infarction, heart failure, valvular disease or cardiomyopathy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03000036


Locations
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Brazil
State University of Campinas
Campinas, São Paulo, Brazil, 13083-887
Sponsors and Collaborators
University of Campinas, Brazil
Fundação de Amparo à Pesquisa do Estado de São Paulo
Investigators
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Principal Investigator: Otávio R. Coelho-Filho, MD, MPH, PhD University of Campinas, Brazil

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Otavio Rizzi Coelho Filho, Professor, University of Campinas, Brazil
ClinicalTrials.gov Identifier: NCT03000036     History of Changes
Other Study ID Numbers: DOX-0675014600011
First Posted: December 21, 2016    Key Record Dates
Last Update Posted: December 21, 2016
Last Verified: December 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Otavio Rizzi Coelho Filho, University of Campinas, Brazil:
Breast cancer
Doxorubicin
Cardiovascular Magnetic Resonance
T1 mapping
Additional relevant MeSH terms:
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Doxorubicin
Liposomal doxorubicin
Breast Neoplasms
Cardiomyopathies
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Heart Diseases
Cardiovascular Diseases
Gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Chelating Agents
Sequestering Agents