Imaging of Cardiotoxicity

Abstract

A driamycin (ADR; doxorubicin HCl), is a potent anthracycline chemotherapeutic agent that is effective against a wide range of human malignancies, such as leukemias, lymphomas, and many solid tumors. For many malignancies (eg, breast cancer, lymphoma), it is the most effective single agent. The use of ADR has been limited, however, by the development of a dose-dependent cardiomyopathy induced by this antineoplastic agent. The overall incidence of clinical cardiotoxicity for patients treated with ADR is approximately 2%, with the incidence of congestive heart failure increasing to 10% at 500 mg/m and to over 40% at 700 mg/m. The cardiac-specific injury of ADR is usually irreversible, although aggressive support for a low cardiac output may reverse the dysfunction in some patients. Nevertheless, once ADR-induced heart failure has been diagnosed, the prognosis is poor; mortality varies from 30 to 60%. It is also noteworthy that various other commonly used antineoplastic agents, cyclophosphamide, 5-fluorouracil, paclitaxel, streptozotocin, bevacizumab (Avastin), etoposide, bleomycin, tamoxifen, and trastuzumab (Herceptin), as well as radiation therapy, which is commonly used as an adjuvant to lumpectomy, are also cardiotoxic, although different mechanisms may be involved. Therefore, the development of sensitive methods for early detection of drugor radiation-induced cardiotoxicity in individual patients could greatly facilitate the management of a wide range of neoplastic diseases. Development of ADR-induced cardiomyopathy is dose dependent and cumulative. To reduce the incidence of cardiotoxicity, limiting treatment with this agent to a total lifetime dose of ADR of 550 mg/m is recommended. However, the individual response to ADR is highly variable, and bolus administration of up to 900 mg/m has been reported without evidence of heart failure; up to 1,500 mg/m has been administered by continuous infusion without evidence of cardiotoxicity. In some patients, drug resistance, rather than toxicity, is dose limiting; in other instances, restriction of ADR therapy to the recommended guidelines may lead to the premature discontinuation of treatment in patients who might otherwise benefit from higher doses. Conversely, some patients may be highly sensitive to ADR, experiencing toxicity at doses that are lower than the recommended limit. Patients with cardiac disorders or with previous radiation therapy to the mediastinum are generally excluded from ADR treatment protocols. It has also been reported that in some pediatric cases, for which treatment with ADR was well within the recommended limit, congestive heart failure developed several years after treatment. Consequently, the availability of a sensitive, noninvasive method for assessing the early onset of ADR cardiomyopathy in the individual patient would have a significant clinical impact. At the present time, there does not appear to be any effective method for predicting which patients will develop ADR-induced heart failure or for sensitively detecting its onset at a very early stage, when administration can effectively be discontinued or useful treatment for cardiomyopathy can be initiated. Current methods of assessing cardiotoxicity are limited to measurement of cardiac function by radionuclide ventriculography (RNV), echocardiography, and detection of tissue damage by percutaneous endomyocardial biopsy. RNV is not particularly sensitive for detecting early damage as assessed by endomyocardial biopsy scores. In combination with exercise, RNV sensitivity improves, but at the expense of specificity. Artifactual errors of 5% or more in ejection fraction measurements are common. Therefore, it has been recommended that a combination of RNV or echocardiography and biopsy examinations be employed in the From the Department of Radiology, University of Pennsylvania, Philadelphia, PA; Department of Radiology, University of Florida, Miami, FL; and Division of Cardiovascular Disease, Department of Medicine, University of Alabama in Birmingham, Birmingham, AL.