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

December 18, 2016 updated by: Otavio Rizzi Coelho Filho, University of Campinas, Brazil

Doxorubicin-associated Cardiac Tissue Remodeling Followed by CMR of Myocardial Extracellular Volume and Myocyte Size in Breast Cancer Patients

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

27

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Brazil
    • São Paulo
      • Campinas, São Paulo, Brazil, 13083-887
        • State University of Campinas

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: 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 Names:
  • 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 Names:
  • 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 Names:
  • Dotarem

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
two years
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
two years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
two years
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.
two years
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.
two years
Left ventricular myocardial edema fraction by Cardiac Magnetic Resonance
Time Frame: two years
Using T2-weighted sequences to visualize myocardial edema
two years

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Ultra-sensitive troponin
Time Frame: two years
Cardiac troponin (ng/mL)
two years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Campinas, Brazil

Collaborators

Fundação de Amparo à Pesquisa do Estado de São Paulo

Investigators

  • Principal Investigator: Otávio R. Coelho-Filho, MD, MPH, PhD, University of Campinas, Brazil

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2012

Primary Completion (Actual)

January 1, 2015

Study Completion (Actual)

July 1, 2016

Study Registration Dates

First Submitted

November 28, 2016

First Submitted That Met QC Criteria

December 18, 2016

First Posted (Estimate)

December 21, 2016

Study Record Updates

Last Update Posted (Estimate)

December 21, 2016

Last Update Submitted That Met QC Criteria

December 18, 2016

Last Verified

December 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DOX-0675014600011

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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