Type II Chemotherapy-Related Cardiac Dysfunction: Time to Recognize a New Entity
Authors: Michael S. Ewer, Scott M. Lippman
Journal: Journal of Clinical Oncology (2005)

Cancer chemotherapy can affect the heart in a variety of ways. Fluorouracil and capecitabine may initiate coronary artery spasm, high-dose cyclophosphamide can induce a hemorrhagic myonecrosis, and paclitaxel is associated with dysrhythmia. However, the form of chemotherapyrelated cardiac dysfunction (CRCD) of the greatest interest and concern among oncologists and cardiologists is that which directly involves the myocardium, is manifested by a decreased left-ventricular ejection fraction, and which may progress to congestive heart failure; this form is the focus of our brief commentary. CRCD came to the forefront of concerns over chemotherapy in the early 1970s, when anthracyclines were shown to exhibit cumulative– dose-related cardiac dysfunction. Later analyses by Von Hoff et al of cardiac function in more than 2,000 anthracycline-treated patients demonstrated the relative safety of low cumulative dosages and the dramatically increased incidence of congestive heart failure at higher cumulative dosages. A cumulative dose of 550 mg/m of doxorubicin, the most commonly used anthracycline, was felt to balance antitumor benefits and the risk of cardiac dysfunction, keeping this risk at acceptable levels. Billingham et al, and later Mackay et al, correlated anthracycline-associated cardiac failure with structural abnormalities that they identified in electron-microscopic analyses of cardiac biopsy material. Vacuoles, myofibrillar disarray and dropout, and at higher cumulative dosages, myocyte necrosis occurred in the cardiac ultra structure. These anthracycline-associated abnormalities and their related cardiac dysfunction constitute an entity that should now be considered type I CRCD since, as we will demonstrate, it differs from another type of CRCD, which has been described more recently and does not entail the myocardial damage of type I CRCD. Type I CRCD is well understood. Risk factors associated with an increased likelihood of this adverse effect have been identified and commonly are associated with increased left-ventricular end-diastolic pressure. Methods to mitigate type I CRCD include prolonged infusional administration schedules and use of the free-radical scavenger dexrazoxane. Liposomal delivery systems and less-toxic analogs are being actively explored. Relatively recently, doxorubicin was shown to be considerably more cardiotoxic than had been previously recognized; in addition, it is currently believed that type I cardiac damage takes place from the earliest administrations of the drug, that the toxicity follows a simple mathematical relationship, and that once a threshold level of damage takes place, cell death ensues. Although the cardiovascular system may compensate for the cell loss, myocardial damage predominantly expressed clinically by left-ventricular dysfunction remains, making the patient more vulnerable to sequential stresses that may arise from a variety of causes including infections and cardiomyopathies of other etiology. Noninvasive tests to quantify and follow the extent of such cardiac changes have been suboptimal because of their lack of sensitivity and because the heart and the circulatory system have considerable reserves. Until recently, cardiac dysfunction manifested by leftventricular failure in association with any chemotherapeutic agent has been compared with doxorubicin cardiac dysfunction. All drugs with any documented degree of such an effect have been thought to have qualitatively similar cardiac effects and long-term sequelae. This thinking has been challenged recently by a relatively new cancer (of the breast) biotherapy agent, trastuzumab, which is a monoclonal antibody targeted at the molecule HER-2. The initial cardiac toxicity ascribed to trastuzumab was thought to be either less severe than, or as yet below the threshold for, typical cardiac changes associated with anthracyclines. Subsequently, results of extensive tests and clinical experience with trastuzumab revealed true JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 23 NUMBER 13 MAY 1 2005