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

Breast Cancer Female Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03000036
• Other study ID #: DOX-0675014600011
• Status: Completed
• Phase: N/A
• First received: November 28, 2016
• Last updated: December 18, 2016
• Start date: July 2012
• Est. completion date: July 2016

Study information

• Verified date: December 2016
• Source: University of Campinas, Brazil
• Contact: n/a
• Is FDA regulated: No
• Health authority: Brazil: Ethics Committee
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 27
• Est. completion date: July 2016
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 75 Years

Eligibility

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 Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Breast Cancer Female
• Breast Neoplasms
• Cardiomyopathies
• Doxorubicin Induced Cardiomyopathy

Intervention

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).

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.

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).

Locations

Country	Name	City	State
Brazil	State University of Campinas	Campinas	São Paulo

Sponsors (2)

Lead Sponsor	Collaborator
University of Campinas, Brazil	Fundação de Amparo à Pesquisa do Estado de São Paulo

Country where clinical trial is conducted

Brazil, 

References & Publications (25)

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* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Ultra-sensitive troponin	Cardiac troponin (ng/mL)	two years	No
Primary	Quantification of fibrosis index by Cardiac Magnetic Resonance	Estimate the extracellular volume fraction derived from gadolinium-DTPA partition Coefficient of the myocardium	two years	No
Primary	Intracellular lifetime of water (tic) by Cardiac Magnetic Resonance	This metric estimates the myocyte size using Cardiac Magnetic Resonance T1 mapping data	two years	No
Secondary	Left ventricular mass by Cardiac Magnetic Resonance	Electrocardiographically gated cine imaging with steady state free-precession to assess left ventricular mass.	two years	No
Secondary	Left ventricular volumes by Cardiac Magnetic Resonance	Electrocardiographically gated cine imaging with steady state free-precession to assess left ventricular volume.	two years	No
Secondary	Left ventricular ejection fraction by Cardiac Magnetic Resonance	Electrocardiographically gated cine imaging with steady state free-precession to assess left ventricular ejection fraction.	two years	No
Secondary	Left ventricular myocardial edema fraction by Cardiac Magnetic Resonance	Using T2-weighted sequences to visualize myocardial edema	two years	No