Trial Information

The Magnetic Resonance Imaging Evaluation of Doxorubicin Cardiotoxicity

Doxorubicin (Adriamycin) is one of the most widely used chemotherapy agents, despite its
well-known causation of cardiac toxicity. Doxorubicin causes apoptotic cell death, as shown
with uptake of antimyosin antibodies on nuclear medicine studies (1,2). Myocyte damage is
dose-related, and produces left ventricular dysfunction that may lead to clinically
significant heart failure, especially in patients with limited cardiac reserve. An estimated
7% of patients develop doxorubicin-related congestive heart failure (CHF) after a cumulative
dose of 550 mg/m2 (3).

Methods to detect and prevent doxorubicin-induced cardiotoxicity have been investigated for
years. Serial evaluation of left ventricular function using Multigated Acquisition (MUGA)
scans (radionuclide angiocardiography) was proposed over 20 years ago as one method for
detecting cardiotoxicity (4). More sophisticated nuclear imaging (PET) has not been able to
demonstrate early changes of cardiotoxicity (5). There are a number of potential indicators
of early cardiotoxicity such as toxic effects on the right ventricle and on left ventricular
diastolic (vs. systolic) function that MUGA is not optimally suited to demonstrate. Even
earlier, an imaging manifestation of cell death could provide the first clue to impending
cardiotoxicity (1,2,6). Cardiac MR (CMR) has the potential to address all of these facets
of doxorubicin toxicity. Biventricular function can be assessed from cine images, and CMR
is well-established as a highly reliable method for cardiac functional assessment. Of even
greater potential interest, cell injury and death can be demonstrated using gadolinium
enhancement, both for myocardial infarction (focal enhancement) as well as myocarditis (both
focal and diffuse enhancement) (7,8). Doxorubicin toxicity may in fact share
pathophysiological characteristics with myocarditis (9). It is our hypothesis that CMR will
be able to show both functional and cellular (infarct, microinfarct, or myocarditis-type)
effects of doxorubicin toxicity as determined during and at the conclusion of doxorubicin
therapy. Specifically, we hypothesize that myocardial tissue will demonstrate a greater
increase in signal (decrease in T1 after contrast administration) after chemotherapy as
compared to before chemotherapy.

Methods 1. Patient Selection: Ten patients selected to receive doxorubicin for breast cancer
treatment will be recruited from Oncology Services at the Sylvester Cancer Center and
Jackson Memorial Hospital. This pilot study will select patients who are at increased
likelihood to develop cardiotoxicity, due to borderline cardiac function at baseline,
advanced age, or the anticipation of a high cumulative dose of administered doxorubicin.
Patients who will receive radiation therapy to the left chest during chemotherapy (i.e.,
left breast cancer) will be excluded so as to eliminate possible cardiotoxic effects from
radiation. CMR studies will be performed at no charge to the patient, supported by the
sponsor of this study. CMR imaging will be subject to IRB approval, informed consent, and
HIPAA regulations. Contrast-enhanced CMR will be obtained at three time points:

1. Prior to the first dose of doxorubicin (image characteristics will serve as control
values to indicate later changes).

2. After first cycle of doxorubicin.

3. At conclusion of therapy, typically 4-6 cycles; cumulative dose of 360 to 600 mg/m2
doxorubicin.

In addition to standard screening for contraindications to MR imaging, patients will be
evaluated for estimated Glomerular Filtration Rate (GFR) within 30 days prior to each MR
scan. This is to avoid the rare but potential complication of Nephrogenic Systemic Fibrosis
in patients with severe or end-stage renal failure who receive gadolinium MR contrast (10).
GFR will be calculated from serum creatinine, patient age, gender, and race, using the MDRD
GFR Calculator ( Stephen Z. Fadem, M.D.) at:

http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm

Patients will not undergo contrast-enhanced MR unless calculated GFR is equal to or greater
than 60 mL/min/1.73 m2

2. Imaging: CMR will be performed on the Siemens 1.5T Sonata located at the University of
Miami Outpatient Diagnostic Imaging Center. It is anticipated that each scan will require
approximately 60 minutes. Three imaging planes (short axis [SA] series through the
ventricles, and individual 4 chamber [4CV] and 2 chamber [2CV] views) will be utilized.
Sequences will consist of:

A. Precontrast imaging:

1. T1-weighted (SA series)

2. TI scout (single mid-ventricular SA) [The TI scout sequence obtains images at multiple
inversion (TI) times at a single slice level]

3. TrueFISP cine gradient echo imaging (SA series, 2CV, 4CV)

B. Postcontrast imaging: after 0.1 mmol/kg OptiMARK intravenous

1. 1 minute post-injection: TI scout (single mid-ventricular SA)

2. 2-4 minutes post-injection: Turboflash inversion recovery (single mid-ventricular SA)
at serial TI values to determine time of myocardial nulling

3. 5 minutes post-injection: TI scout (single mid-ventricular SA)

4. 6-9 minutes post-injection: Turboflash inversion recovery (single mid-ventricular SA)
at serial TI values to determine time of myocardial nulling

5. 10-14 minutes post-injection: Segmented IR delayed imaging using TI of myocardial
signal nulling (SA series, 2CV, 4CV)

6. 15 minutes post-injection: TI scout (single mid-ventricular SA)

7. 16-19 minutes post-injection : Turboflash inversion recovery (single mid-ventricular
SA) at serial TI values to determine time of myocardial nulling

8. 20 minutes post-injection: TI scout (single mid-ventricular SA)

9. 21 minutes post-injection : T1-weighted (SA series)

3. Analysis: ANOVA will be used to assess for differences in measured values of the discrete
variables listed in A, B, C, and D below. Data will be analyzed for all three imaging
sessions together using ANOVA, and for each pair of sessions (pretreatment vs. first cycle
of doxorubicin, first cycle of doxorubicin vs. maximum cumulative dose, and pretreatment vs.
maximum cumulative dose) using the paired t-test (or Wilcoxon signed-rank test if variances
unequal). The MR image sets will be analyzed in random order.

A. TrueFISP cine: analysis will utilize the ARGUS software package on the Siemens system.
End-diastolic and end-systolic endocardial contours will be generated using a semi-automated
technique whereby initial manual contouring is followed by automated contour generation,
which are then manually edited before final calculations are performed.

1. Ejection fraction (biventricular) and ventricular volumes (end-systole and
end-diastole).

2. Diastolic left ventricular function I. 1/3 peak filling rate (PFR) II. 1/3 filling
fraction (1/3 FF)

3. Wall motion: The AHA 17-segment model will be utilized (6 segments each at basal,
mid-ventricular, and near-apical levels, and a single apical segment). A five-point
scale will be assigned to each segment (normal, mildly hypokinetic, severely
hypokinetic, akinetic, dyskinetic). Summed values will yield a single measure of
contractility for each imaging study.

B. T1-weighted

Region-of-interest signal intensity in the myocardium will be measured in the mid-left
ventricular free wall, the mid-interventricular septum, and skeletal muscle for both
precontrast and postcontrast T1-weighted imaging. We will calculate a variable representing
"percent enhancement" for each location as follows:

% enhancement = signal intensity (postcontrast) - signal intensity (precontrast) signal
intensity (precontrast)

C. The TI scout image sets will provide a single TI value of optimal myocardial nulling as
well as an exponential curve to reflect the T1 recovery of myocardium at each time point of
acquisition (precontrast, 1 minute postcontrast, 5 minutes postcontrast, 15 minutes
postcontrast, 20 minutes postcontrast). The TI scout will be performed at multiple time
points due to the dynamic nature of tissue enhancement after gadolinium administration.

D. The turboflash inversion recovery image (mid-ventricular) will provide an alternative
single TI value of optimal myocardial nulling at each time point of acquisition (2-4
minutes, 6-9 minutes, and 16-19 minutes postinjection). The turboflash inversion recovery
image will be performed at multiple time points due to the dynamic nature of tissue
enhancement after gadolinium administration.

E. Segmented IR delayed imaging will provide images of the entire myocardium which will be
evaluated for focal myocardial signal hyperintensities, whether due to infarction or
myocarditis. The optimum TI value determined from (D) above will be used. If identified,
lesions will be manually contoured with use of the irregular region of interest tool on the
console. The infarct size will then be calculated as total infarct area multiplied by the
section thickness and the specific gravity (assumed to be 1.05 g/mL) of the myocardium.

Medical records will provide data regarding cardiac morbidity or mortality.