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Journal of Clinical Oncology, Vol 25, No 34 (December 1), 2007: pp. 5533-5534 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.1036
In ReplyDepartment of Medicine, Division of Medical Oncology, Stanford University, Stanford, CA
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA We agree with Drs Ewer and Tan-Chiu that the issues of cardiotoxicity of the anthracyclines and trastuzumab are important and intimately related. Slamon et al demonstrated that the risk of cardiac dysfunction can be reduced significantly with the nonanthracycline regimen of docetaxel, carboplatin, and trastuzumab.1 However, this risk is not eliminated, and approximates that seen with the nontrastuzumab anthracycline-containing regimen of doxorubicin, cyclophosphamide, and docetaxel, both in terms of symptomatic (0.4%) and asymptomatic left ventricular dysfunction (8.6%). Experience with anthracycline cardiotoxicity demonstrates that estimates of short-term cardiotoxicity may significantly underestimate long-term toxicity.2,3 This is consistent with the prevailing concept that cardiac injury from any cause can initiate the process of negative remodeling and lead to progressive left ventricular dysfunction over time.4 Normalization of left ventricular ejection fraction after acute injury does not imply that the heart will be unaffected by the injury in the long term. The M.D. Anderson experience of trastuzumab-related cardiotoxicity, as referenced by Ewer and Tan-Chiu, is important.5,6 Substantiating long-term cardiac tolerability of trastuzumab in patients with metastatic disease, however, is problematic; these patients have incurable disease and short survival. By only including metastatic breast cancer patients treated with trastuzumab for longer than 1 year, the analysis by Guarneri et al represents a biased population and does not report on the outcome of patients who may have experienced early cardiac events.5 In this analysis, among 28% of patients who developed a cardiac event, 26 patients who discontinued treatment were later rechallenged, and 10 (38%) of 26 patients developed recurrent cardiac events. Furthermore, responsiveness to medical therapy does not equate with reversibility of cardiotoxicity. The need for ongoing heart failure therapy in 84% of patients in the series described by Ewer and Tan-Chiu has vastly different implications for patients treated in the adjuvant setting.6 The long-term cardiac safety of trastuzumab is unknown. Achieving adequate cardiac follow-up in the adjuvant trials has been challenging, and these data are incomplete. Until additional data are available, the degree to which trastuzumab-related cardiotoxicity is reversible (or not) will remain in question. As a top priority, we need to ensure through thoughtful clinical trial design that long-term cardiac data are collected prospectively. Early evidence suggests that factors other than anthracyclines may modify the risk of trastuzumab-related cardiotoxicity.7,8 Additional research will improve our understanding of these determinants and lead to strategies for improved risk assessment, early detection, and prevention of cancer therapy–related cardiotoxicity. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure 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 in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Robert W. Carlson, Genentech (C); Alice E. Guardino, Genentech (C) Stock Ownership: None Honoraria: Alice E. Guardino, Genentech Research Funding: Robert W. Carlson, Genentech; Alice E. Guardino, Genentech Expert Testimony: None Other Remuneration: None REFERENCES 1. Slamon D, Eiermann W, Robert N, et al: BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC->T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC->TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients. Presented at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 14-17, 2006 2. Steinherz LJ, Steinherz PG, Tan CT, et al: Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 266:1672-1677, 1991 3. Pein F, Sakiroglu O, Dahan M, et al: Cardiac abnormalities 15 years and more after adriamycin therapy in 229 childhood survivors of a solid tumour at the Institut Gustave Roussy. Br J Cancer 91:37-44, 2004[CrossRef][Medline] 4. Hunt SA, Abraham WT, Chin MH, et al: ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure)— Developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation, Endorsed by the Heart Rhythm Society. Circulation 112:e154-e235, 2005 5. Guarneri V, Lenihan DJ, Valero V, et al: Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: The M.D. Anderson Cancer Center Experience. J Clin Oncol 24:4107-4115, 2006 6. Ewer MS, Vooletich MT, Durand J-B, et al: Reversibility of trastuzumab-related cardiotoxicity: New insights based on clinical course and response to medical treatment. J Clin Oncol 23:7820-7826, 2005 7. Tan-Chiu E, Yothers G, Romond E, et al: Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 23:7811-7819, 2005 8. Suter TM, Procter M, van Veldhuisen DJ, et al: Trastuzumab-associated cardiac adverse effects in the Herceptin Adjuvant trial. J Clin Oncol 25:3859-3865, 2007
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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