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Journal of Clinical Oncology, Vol 23, No 13 (May 1), 2005: pp. 2900-2902 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.827
Type II Chemotherapy-Related Cardiac Dysfunction: Time to Recognize a New EntityDepartments of Cardiology and Clinical Cancer Prevention and Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 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.1 However, the form of chemotherapy-related 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.2 Later analyses by Von Hoff et al3 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/m2 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,4 and later Mackay et al,5 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.6 Methods to mitigate type I CRCD include prolonged infusional administration schedules7 and use of the free-radical scavenger dexrazoxane.8 Liposomal delivery systems and less-toxic analogs are being actively explored.9 Relatively recently, doxorubicin was shown to be considerably more cardiotoxic than had been previously recognized10; 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.11 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.12 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.13 Until recently, cardiac dysfunction manifested by left-ventricular 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 clinical and mechanistic differences between the cardiac effects of trastuzumab and those of anthracyclines. The differences between trastuzumab and anthracycline CRCD and the implications associated with these differences are now sufficiently clear to identify a variant form of myocardial dysfunction, which we now categorize as type II CRCD, and that is exemplified by trastuzumab cardiac effects. The following features of type II CRCD highlight its profound contrasts with type I CRCD: it is not dose-related, does not appear to occur in all patients, is expressed in a broad range of severity when it does occur, and is not associated with identifiable ultrastructural abnormalities.14-16 The reported CRCD rate for trastuzumab absent any anthracycline treatment is 3% (2% [New York Heart Association] class III or IV severity). This rate increases to 5% (4% class III/IV) when an anthracycline is given before trastuzumab,17 likely reflecting anthracycline-associated myocardial damage that reduces the reserves available to compensate for the sequential effect of trastuzumab.18 CRCD increases substantially more when trastuzumab is given concurrently with an anthracycline. For example, the reported overall CRCD rate for trastuzumab combined with doxorubicin and cyclophosphamide is 27% (16% class III/IV).17 Type II CRCD appears to be highly reversible, whereas type I is not, which is perhaps the greatest distinction between the two. The reported rate of improvement within months of standard medical management of CHF associated with trastuzumab is 79%.17 Trastuzumab CRCD also can improve spontaneously and during active treatment with the agent.18,19 Table 1 compares type I and type II CRCD.
The mechanisms of type I and type II CRCD are complex and clearly different. Type I CRCD is due, at least in part, to iron-based oxygen free-radical–induced oxidative stress on cardiac muscle cells. Free radicals induce the peroxidation of myocyte membranes and subsequent influx of intracellular calcium. Mitochondrial dysfunction also has been noted with and correlates with morphologic changes seen in type I CRCD.1,15,16 The molecular basis of type II CRCD is beginning to be elucidated.20-23 Trastuzumab is the first molecular-targeted chemotherapy agent shown to cause significant CRCD. The mechanism of trastuzumab-related CRCD involves, at least in part, the ErbB2 pathway. This agent binds to the extracellular domain of the HER-2 protein and thus blocks ErbB2 signaling required for the growth, repair, and survival of cardiomyocytes, which help in maintaining cardiac contractility, function, and structure.20 HER-2 activates transcription factors such as AP-1, which is involved in regulating cardiac hypertrophy, and nuclear factor-kappa B, which is involved in the cellular response to stress.21 ErbB2 signaling is highly complex, involving multiple ligand classes, cell systems, and pathway interactions. ErbB2 signaling in cardiac muscle cells is essential for the prevention of dilated cardiomyopathy. Conditional mutant mice carrying a cardiac-restricted deletion of ErbB2 developed chamber dilation, wall thickening, and decreased contractility.20,22,23 The implications and consequences of type I CRCD are so ingrained in our clinical experiences that any form of cardiac dysfunction is likely to be considered potentially irreversible, long-term, and capable of appearing years or decades following therapy. Type II CRCD, however, appears to be largely reversible and short-lived. The characteristics of type I and type II CRCD are too different to be regarded as extremes of a single, broad entity. Nevertheless, the two entities may coexist in a single patient. For example, trastuzumab substantially increases CRCD in patients treated concurrently with anthracycline (as described in this commentary), which is consistent with preclinical data showing that a HER-2 antibody24 or the cardiac-restricted deletion of ErbB220,22 can increase susceptibility to anthracycline cytotoxicity (eg, myofibrillar damage). Recognizing distinct type I and type II CRCDs will allow for planning cancer chemotherapy based on true cardiac risk and, possibly, for alternative cardiac monitoring for anticipated type II effects. Trastuzumab exemplifies type II CRCD issues that are likely to have increasing clinical implications as more HER-2-targeted agents and approaches (eg, dual HER-1/HER-2-targeting agents and combinations aimed at HER-2 and other targets) become available for clinical testing in breast and other neoplasias, both for treatment and prevention.25-27 For example, HER-2 is highly overexpressed in breast ductal carcinoma in situ, which has important implications for using HER-2-targeted approaches for preventing breast cancer in high-risk patients.26 Type II CRCD issues also may be relevant to an increasing number of other primarily molecular-targeted agents with more cytostatic (than cytotoxic) activity profiles and with promise for cancer therapy and prevention.27 It is time to recognize the new entity, type II CRCD, which represents an important advance in the understanding and management of heart effects associated with cancer chemotherapy. Note: This work was supported in part by grant CA16672 (M.D. Anderson Cancer Center Support Grant) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Honoraria: Michael S. Ewer, Pfizer. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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