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Journal of Clinical Oncology, Vol 25, No 34 (December 1), 2007: pp. 5532-5533 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.0657
Reversibility of Trastuzumab Cardiotoxicity: Is the Concept Alive and Well?Department of Cardiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
Florida Cancer Research Institute, Davie, FL To the Editor: We appreciate the insightful review, "Trastuzumab-Related Cardiotoxicity: Calling Into Question the Concept of Reversibility," by Telli et al in the August 10 issue of the Journal of Clinical Oncology.1 The main conclusion of the article, namely that there is a vital need for long-term follow-up of patients who have been treated with cardiotoxic regimens including those containing trastuzumab, is incontrovertible; the article reaches this conclusion, however, without addressing some important considerations. Although the authors address the mechanism of cardiotoxicity of trastuzumab, it is now well recognized that the effect on the heart of this agent is quite different from that of the best studied of the anticancer cardiotoxic drugs, namely doxorubicin. Although many common clinical features are shared, the inherent differences between the cardiotoxicity of doxorubicin and trastuzumab, most apparent from the well-described cardiac biopsy changes of the former that have not been observed with similar expressions of clinical toxicity in the latter, provide the most compelling evidence. It was this, among other important distinctions including the lack of a clear cumulative-dose relationship for trastuzumab cardiotoxicity and the apparent ability to tolerate rechallenge to the drug after recovery, that led us to first propose the terms type I and type II chemotherapy-related cardiac dysfunction. Type I, associated with the anthracyclines, results, at least to some degree, in the destruction of myocytes; type II tends to be associated more with a loss of contractility (a form of stunning or hibernation), a phenomenon not unique to trastuzumab, and one that is less likely to be associated with myocyte death and more likely to be reversible.2 The reversibility was substantiated subsequently in two articles describing clinical experience from the M.D. Anderson Cancer Center (Houston, TX) that appeared in these pages. In one series of 38 patients who experienced cardiac dysfunction after trastuzumab, all 38 recovered, albeit 32 of 38 received specific cardiac interventions; 25 of these patients went on to be rechallenged and 22 of those tolerated the reintroduction of trastuzumab.3,4 To our knowledge, no data from any of the adjuvant trastuzumab trials are inconsistent with these observations; in fact, both the National Surgical Adjuvant Breast and Bowel Project B-31 report and the Herceptin Adjuvant (HERA) trial report discuss these distinctions as well as the reversibility of cardiotoxicity.5,6 Nevertheless, late toxicity remains a formal possibility, and the fact that in the National Surgical Adjuvant Breast and Bowel Project B-31 trial late changes have persisted is disconcerting. However the B-31 trial was neither designed to evaluate reversibility nor late cardiac dysfunction, in part, perhaps, because at the time this trial was conceived it was largely assumed that cardiotoxicity related to anticancer drugs was qualitatively equal and sufficiently well understood. We know that this is not the case, and it is hoped that new trials now being considered will study this problem prospectively. In analyzing the B-31 data we must consider that all of these patients had received an anthracycline; it is unlikely that we will be able to separate the cardiac effects of the anthracycline from those of trastuzumab. We do, however, have some strong hints: first, in the HERA trial the lower incidence of cardiotoxicity may well have been due to the much longer time interval between the administration of the anthracycline and the onset of trastuzumab treatment (89 days in the HERA trial), or may have been due, at least in part, to the higher post-anthracycline ejection fraction required for continuation in that trial.6 In the Breast Cancer International Research Group 006 trial we saw much less cardiotoxicity in the nonanthracycline arm. These facts cannot be ignored. What we can learn from these reports is that trastuzumab exacerbates the cardiotoxicity of anthracyclines; both new research and analysis of the results of the adjuvant trials support this view.7,8 Although it seems clear that the myocardium exposed to oxidative stress may be much more sensitive to transient additional insults, and trastuzumab may well provide such an insult (thereby serving as a catalyst to induce additional irreversible damage), the cardiotoxicity of trastuzumab by itself in patients treated with trastuzumab in the first-line metastatic breast cancer setting has not been associated with high levels of irreversible cardiac death or severe heart failure. In the adjuvant trials there was only one reported cardiac death among the more than 10,000 patients in the adjuvant trials who were treated on the trastuzumab arms, and the majority of patients treated on those arms were also treated with an anthracycline. To date, we are not aware of any patients in the adjuvant trial who developed congestive heart failure on the trastuzumab arm and are waiting for cardiac transplantation. The data suggest that we are dealing more with an anthracycline-related problem than a trastuzumab-related problem. The data also add important insight to the concept that the effect of trastuzumab as expressed in the cardiotoxicity seen in patients exposed to both anthracyclines and trastuzumab, on the one hand, may well be an intensification of the anthracycline component, whereas on the other hand, it may be a direct dysfunction that is probably largely reversible. We agree that surveillance is vital in this population but, as has been pointed out by Telli et al,1 the benefits for HER-2–positive breast cancer patients are compelling. At this time there are no data that negate the concept that the inherent toxicity of trastuzumab is largely reversible, and much data are available to support that view; the combination of trastuzumab and an anthracycline gains increasing importance in the setting of this new information. Although it is always scientifically sound to revisit issues in the face of new data, the concept of reversibility of trastuzumab cardiotoxicity, at least for now, seems to remain very much alive and well. 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: Michael S. Ewer, Hoffmann-La Roche Inc (C), Supratek Pharma (C), Cell Therapeutics Inc (C) Stock Ownership: None Honoraria: Michael S. Ewer, GlaxoSmithKline, Hoffmann-La Roche Inc, Sanofi-aventis; Elizabeth Tan-Chiu, Pfizer Inc, Genentech, GlaxoSmithKline Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. Telli M, Hunt SA, Carlson RW, et al: Trastuzumab-related cardiotoxicity: Calling into question the concept of reversibility. J Clin Oncol 25:3525-3533, 2007 2. Ewer M, Lippman S: Type II chemotherapy-related cardiac dysfunction: Time to recognize a new entity. J Clin Oncol 23:2900-2902, 2005 3. Ewer M, 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 23:7820-7827, 2005 4. Guarneri B, Lenihan DJ, Velero 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 5. 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 B31. J Clin Oncol 23:7811-7819, 2005 6. Suter T, Procter M, van Veldhuisen DJ, et al: Trastuzumab-associated cardiac adverse effects in the Herceptin Adjuvant Trial. J Clin Oncol 25:3859-3865, 2007 7. de Korte MA, de Vries EG, Lub-de Hooge MN, et al: (111) Indium-trastuzumab visualises myocardial human epidermal growth factor receptor 2 expression shortly after anthracycline treatment but not during heart failure: A clue to uncover the mechanism of trastuzumab-related cardiotoxicity. Eur J Cancer 43:2046-2051 8. Ewer M: The anthracycline-trastuzumab interaction: Up-regulated binding may provide vital mechanistic insight. Eur J Cancer 43:2024-2025, 2007[CrossRef][Medline] Related Reply
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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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