Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity.

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

[1]  R. Benjamin,et al.  Adriamycin cardiomyopathy—risk factors , 1977, Cancer.

[2]  C. Shapiro,et al.  Cardiac safety of liposomal anthracyclines. , 2004, Seminars in oncology.

[3]  R. Benjamin,et al.  A mathematical model for doxorubicin cardiotoxicity: Added evidence for the concept of sequential stress , 2004 .

[4]  Michael S Ewer,et al.  Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. , 2004, Circulation.

[5]  G. Hortobagyi,et al.  Normal cardiac biopsy results following co-administration of doxorubicin (A), Cyclophosphamide (C) and trastuzumab (H) to women with HER2 positive metastatic breast cancer , 2004 .

[6]  D. V. Von Hoff,et al.  Risk factors for doxorubicin-induced congestive heart failure. , 1979, Annals of internal medicine.

[7]  Kuo-Fen Lee,et al.  Essential roles of Her2/erbB2 in cardiac development and function. , 2004, Recent progress in hormone research.

[8]  T. Suter,et al.  Cardiotoxicity associated with trastuzumab (Herceptin) therapy in the treatment of metastatic breast cancer. , 2004, Breast.

[9]  S. Lippman,et al.  The convergence of cancer prevention and therapy in early-phase clinical drug development. , 2004, Cancer cell.

[10]  H. Gibbs,et al.  Cardiotoxicity in patients receiving transtuzumab (Herceptin): primary toxicity, synergistic or sequential stress, or surveillance artifact? , 1999, Seminars in oncology.

[11]  G. Hortobagyi,et al.  Her-2/neu gene amplification in ductal carcinoma in situ of the breast. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[12]  J. Speyer Cardiac dysfunction in the trastuzumab clinical experience. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  C. Carrasco,et al.  Assessment of anthracycline cardiomyopathy by endomyocardial biopsy. , 1994, Ultrastructural pathology.

[14]  S. Wallace,et al.  Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. , 1982, Annals of internal medicine.

[15]  J. Mason,et al.  Anthracycline cardiomyopathy monitored by morphologic changes. , 1978, Cancer treatment reports.

[16]  D. Sawyer,et al.  Modulation of Anthracycline-Induced Myofibrillar Disarray in Rat Ventricular Myocytes by Neuregulin-1&bgr; and Anti-erbB2: Potential Mechanism for Trastuzumab-Induced Cardiotoxicity , 2002, Circulation.

[17]  H. Gibbs,et al.  Late doxorubicin‐associated cardiotoxicity in children , 1994, Cancer.

[18]  S. Swain,et al.  Congestive heart failure in patients treated with doxorubicin , 2003, Cancer.

[19]  C. Hudis,et al.  Cardiac dysfunction in the trastuzumab clinical trials experience. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  E. Perez,et al.  Clinical cardiac tolerability of trastuzumab. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  Bert Vogelstein,et al.  Combinatorial chemoprevention of intestinal neoplasia , 2000, Nature Medicine.

[22]  J. Pitha,et al.  A clinicopathologic analysis of adriamycin cardiotoxicity , 1973, Cancer.

[23]  Carmen Birchmeier,et al.  Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[24]  D. Lenihan,et al.  Reversibility of trastuzumab-induced congestive heart failure in patients previously treated with anthracyclines , 2004 .

[25]  P. Vici,et al.  The current and future role of dexrazoxane as a cardioprotectant in anthracycline treatment: expert panel review , 2003, Journal of Cancer Research and Clinical Oncology.

[26]  Susumu Minamisawa,et al.  ErbB2 is essential in the prevention of dilated cardiomyopathy , 2002, Nature Medicine.