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Journal of Clinical Oncology, Vol 26, No 12 (April 20), 2008: pp. 2052-2053 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.5044
Trastuzumab-Related Cardiotoxicity in the Herceptin Adjuvant TrialDivision of Medical Oncology, Institute for Cancer Research and Treatment, Torino, Italy
Unit of Cardiology, Institute for Cancer Research and Treatment, Torino, Italy To the Editor: The updated analysis of cardiac adverse effects in the Herceptin Adjuvant (HERA) trial provides convincing evidence that the administration of trastuzumab sequentially after adjuvant chemotherapy and/or radiation therapy is safe.1 Not only was the rate of symptomatic congestive heart failure (CHF) quite low, but only 4.3% of the patients needed permanent trastuzumab discontinuation on account of cardiotoxicity, either symptomatic or asymptomatic. The incidence of cardiac events in the HERA trial compares favorably with that observed in the two North American trials, where trastuzumab was administered concomitantly with paclitaxel and on completion of four cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2).2 The rate of symptomatic congestive CHF was approximately 4% but most importantly, because of protocol criteria, approximately 25% of the patients in the North American trials were not able to receive the intended treatment with trastuzumab, either on account of a significant drop in the left ventricular ejection fraction (LVEF) after AC (6.7%), or because of cardiac toxicity occurring during trastuzumab treatment (18.9%). Therefore, beyond the efficacy data, the sequential strategy has become popular also because it appears to be the safest when cardiac toxicity is concerned. One obvious critical question at this point is whether the cardiac safety of trastuzumab reported by the HERA investigators will be reproduced in the general population of patients treated outside clinical trials by the same sequential approach. McArthur and Chia3 analyzed trastuzumab use in the clinical practice in British Columbia and found that the incidence of trastuzumab discontinuation because of cardiac dysfunction was 21.6% (18 patients) in 102 patients receiving trastuzumab according to the sequential strategy. Despite the fact that a substantial number of patients were able to resume and complete trastuzumab therapy after appropriate treatment (12 of 18), the combined incidence of temporary and permanent trastuzumab discontinuation was superior to that found in the HERA trial.
We conducted an audit of 52 consecutive patients (median age, 51 years; range, 27 to 74 years) with high-risk HER-2–positive early breast cancer receiving adjuvant trastuzumab at our Institution between January 2006 and September 2007. All patients received sequential trastuzumab according to the HERA trial design.4 Adjuvant chemotherapy consisted of either fluorouracil 600 mg/m2, epi-doxorubicin 90 mg/m2, and cyclophosphamide 600 mg/m2 for six cycles or fluorouracil 500 mg/m2, epi-doxorubicin 100 mg/m2, and cyclophosphamide 500 mg/m2 for three cycles, followed by docetaxel 100 mg/m2 for three cycles. A total of six patients (12%; 95% CI, 5% to 23%) had to discontinue treatment, one because of severe CHF, another because of a mild CHF (class II according to the New York Heart Association) and four because of asymptomatic cardiac toxicity fulfilling the HERA trial criteria for definitive trastuzumab discontinuation. Only one of these patients was able to resume trastuzumab after appropriate cardiologic therapy and LVEF recovery. All the 52 patients underwent baseline ultrasonographic LVEF before adjuvant chemotherapy. Not unexpectedly, we found that median LVEF values were significantly reduced as a result of anthracycline-based adjuvant chemotherapy (67% v 62%, Fig 1B). Four of the six patients developing cardiac toxicity had had a
We then compared the incidence of cardiotoxicity requiring treatment discontinuation in the 52 patients receiving adjuvant trastuzumab with that of 122 consecutive patients (median age, 55 years; range, 35 to 79 years) receiving trastuzumab concomitant with chemotherapy (mainly taxanes or vinorelbine) for metastatic HER-2–positive breast cancer at our Institution between September 1999 and September 2007 (data extracted from our Institutional database). In this latter group of patients, who underwent LVEF evaluations every 3 to 4 months for at least one year if not progressing, six patients had to stop trastuzumab: two experienced CHF and the other four had significant but asymptomatic LVEF reductions (combined rate 5%; 95% CI, 2% to 10%). We found a strong trend towards a higher incidence of cardiotoxicity requiring treatment discontinuation in operable than in patients with metastatic breast cancer receiving trastuzumab (Fig 1A). This finding is not surprising because guidelines for trastuzumab discontinuation in patients with metastatic breast cancer who develop asymptomatic LVEF drops are usually more relaxed, due to its palliative role in this setting. However, it is of concern that in early breast cancer, where trastuzumab has shown a curative role, a substantial amount of patients in the current clinical practice may need trastuzumab discontinuation, even if the "sequential" HERA-like strategy is employed. Additional efforts should be aimed at increasing the rate of patients who are able to complete the intended adjuvant trastuzumab treatment in the clinical practice. This might achieved by refining the algorithms for cardiac monitoring and treatment discontinuation according to LVEF changes in asymptomatic patients, including those caused by prior anthracycline-based adjuvant chemotherapy.5 Furthermore, prospective studies are needed in order to explore potential cardioprotective measures as well as less cardiotoxic chemotherapy programs for patients who are most likely to develop trastuzumab-related cardiac dysfunctions. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES
1. 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 2. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005 3. McArthur HL, Chia S: Cardiotoxicity of trastuzumab in clinical practice. N Engl J Med 357:94-95, 2007 4. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659-1672, 2005 5. Rastogi P, Jeong J, Geyer CE, et al: Five year update of cardiac dysfunction on NSABP B-31: A randomized trial of sequential doxorubicin/cyclophosphamide (AC)->paclitaxel (T) vs. AC->T with trastuzumab (H). J Clin Oncol 25:6s, 2007 (suppl; abstr LBA513)[CrossRef] Related Reply
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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10% LVEF loss between baseline and pretrastuzumab LVEF values (range, 12% to 17%). 
