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Originally published as JCO Early Release 10.1200/JCO.2009.23.9327 on August 17 2009 © 2009 American Society of Clinical Oncology.
Trastuzumab Beyond Progression: Is the Risk of Cardiac Toxicity Really Not Increased?Clinical Trials Unit, National Cancer Institute of Naples, Naples, Italy To the Editor: The article by von Minckwitz et al1 reported the first randomized trial, to our knowledge, assessing the question of continuing trastuzumab beyond progression. The results of the study showed superior efficacy of continuation of trastuzumab in combination with capecitabine compared with capecitabine alone in terms of response rate and time to progression, although no survival advantage was demonstrated. Moreover, the authors declared that continuation of trastuzumab beyond progression was not associated with increased toxicity and that these results compared favorably to those of the lapatinib trial.2 However, the study had several limitations, including the small number of patients (32% of the planned sample size) because of premature closure of the trial, slow accrual, and absence of an independent assessment of response or progression, as observed by the authors themselves. Regarding sample size, it might not have been large enough to show significant differences in adverse events between the two arms, and the trial could have been underpowered to make definite statements about safety. In particular, cardiovascular disorders of any grade were observed in 13% of patients treated with trastuzumab beyond progression (grades 3 to 4 in 5% of patients) and in only 4% of patients treated with capecitabine as a single agent. In our opinion, this difference should be considered clinically significant, although it did not reached statistical significance (P = .07). Cardiac tolerability of trastuzumab is an important issue in patients with breast cancer, also taking into account the progressive migration of trastuzumab to the adjuvant setting and the greater frequency of long-term surviving patients with breast cancer.3 We reviewed the available evidence regarding the incidence of cardiac dysfunction associated with trastuzumab therapy in metastatic breast cancer, and we explored whether available data are suggestive for the identification of factors associated with trastuzumab cardiotoxicity that could eventually be used to estimate risk in clinical practice. In a PubMed search conducted in March 2009, we found that 37 of 52 published clinical trials of trastuzumab in metastatic breast cancer had information on both cardiac toxicity and treatment duration. Time receiving trastuzumab was associated with an increased risk of developing any grade of cardiac toxicity, as shown in Figure 1. This information might be of value, considering that 80% of patients in the study by von Minckwitz et al1 had previously received trastuzumab for a long period of time (> 24 weeks) and that up to 60 cycles of trastuzumab beyond progression were administered. Therefore, the opportunity of continuing trastuzumab administration in progressive patients with a non–cross-resistant chemotherapeutic regimen should be considered with caution, in our opinion, given the relatively small benefit suggested by the von Minckwitz et al study and the fact that this small study did not definitely rule out risk of cardiac toxicity.
AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENT The Clinical Trials Unit is partially supported by the non-profit Associazione Italiana per la Ricerca sul Cancro. REFERENCES
1. von Minckwitz G, du Bois A, Schimdt M, et al: Trastuzumab beyond progression in human epidermal growth factor receptor 2–positive advanced breast cancer: A German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol 27:1999–2006, 2009. 2. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743, 2006. 3. Perez EA, Rodeheffer R: Clinical cardiac tolerability of trastuzumab. J Clin Oncol 22:322–329, 2004.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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