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: