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Originally published as JCO Early Release 10.1200/JCO.2009.23.9780 on August 17 2009 © 2009 American Society of Clinical Oncology.
Reply to A. Morabito et al and G. Valabrega et alGerman Breast Group, Neu-Isenburg, Germany On behalf of our coauthors, we would like to thank Morabito et al1 and Valabrega et al2 for raising some important issues with regard to our recently published randomized GBG (German Breast Group) 26 trial3 of treatment with trastuzumab beyond progression in combination with capecitabine (XH) in patients with human epidermal growth factor receptor 2 (HER2) –positive breast cancer compared with those switching to chemotherapy with capecitabine (X) alone because of progressive disease. Morabito et al1 claimed that our trial3 including 156 patients was not large enough to show significant changes in adverse events. They particularly referred to cardiac toxicity, because the incidence of cardiovascular disorders in 13% of patients receiving XH compared with 4% receiving X did not reach the level of significance. They supported their hypothesis of XH being more cardiotoxic by a literature research of 37 studies showing a correlation between time receiving trastuzumab treatment and risk of cardiac dysfunction. However, in the majority of these studies, patients received trastuzumab treatment for 40 weeks or fewer; thereafter the correlation becomes uncertain, and even a plateau phenomenon cannot be excluded. Considering that the average time patients received trastuzumab treatment before entering the GBG 26 trial3 was 45 weeks, and the average time of trastuzumab treatment during the study was 27 weeks, this hypothesis is probably not true for our study, and the analysis by Morabito et al1 cannot be directly compared with the GBG 26 trial. However, we agree with Morabito et al that the GBG 26 trial cannot completely exclude an increase in cardiac toxicity with use of XH. The interpretation of the results must take into account that these patients received 14% more cycles of treatment, and the observation period until progression was 46% longer, compared with patients treated with X alone. Similar to our results, in the EGF100151 trial,4 the combination of lapatinib and capecitabine (XL) resulted in a numerical excess in grades 3 to 4 cardiac events compared with X alone (five events v one event). Therefore, we disagree with Morabito et al1 that the observed benefit of continuing trastuzumab beyond progression is small and impaired by potential cardiac risk. In our opinion, a prolongation of time to progression by 46% is of high importance to patients, and the observed cardiac events were not fatal, nor did they lead to significant or permanent disability. To provide the full picture on cardiac toxicity, we list here all grades 1 to 2 cardiac toxicities observed in our study3 in the XH arm: stenocardia (one instance), reduced pump function (one instance), nonspecified arrhythmia (one instance), arterial hypertension (one instance), circulatory disorder (one instance), and heartache (one instance); and in the X arm: tachycardia (one instance). Valabrega et al2 questioned to what degree the population of our trial3 was representative, because the average number of patients per participating site was as low as 2.4 over a period of 45 months. We agree that some investigators might have chosen patients for participation according to unknown selection criteria, whereas other patients might have continued treatment with trastuzumab outside of the trial. This is a common problem in many trials. Indeed, site accrual was also low in the EGF100151 study4 (2.5 patients per site over 25 months), so one can assume that there was a similar issue. In a prospective observational study5 conducted in Germany between 2001 and 2006, data on 910 patients receiving trastuzumab as clinical routine in 142 centers were collected. Of the 193 patients progressing for the first time under this observation and after at least 1 month of trastuzumab administration, 112 continued to receive trastuzumab beyond progression, and 81 did not. This indicates that the incidence of such patients is indeed rather low. The chance for variations in baseline factors is high in a trial of this sample size, and in fact, the treatment groups in our trial3 showed an imbalance for age at study entry. Therefore, we reported a multivariate analysis performed to adjust the results on time to progression for various known prognostic and/or predictive factors. We demonstrated that age had no significant prognostic value as a single factor and that time to progression remained significantly superior in patients receiving XH compared with patients receiving X when age and other factors were included in the multivariate model. The GBG 26 trial3 was an investigator-initiated study with limited financial resources, so a centralized review could not be performed. However, we implemented several measures for quality assurance like short intervals of 6 weeks for reassessment during the first period of study participation similarly in both arms and performed 100% site monitoring for all efficacy data. We felt reassured of the effectiveness of these measures because we saw comparable rates of primary progression in the two trials exploring an anti-HER2 agent in patients after progression while receiving trastuzumab (15.6% for XH v 23.0% for X in the GBG 26 trial; 13.0% for XL v 23.0% for X in the EGF100151 study4). Valabrega et al2 aptly pointed out that the question of how to treat patients after progression while receiving trastuzumab must be asked again with other agents available today. Therefore, we are waiting for the results of studies directly comparing treatment beyond progression with trastuzumab with switching to other agents, including a study directly comparing XL with XH in patients pretreated with trastuzumab (NCT00820222 [ClinicalTrials.gov] ; www.clinicaltrials.gov). 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: None Stock Ownership: None Honoraria: Gunter von Minckwitz, Roche, GlaxoSmithKline Research Funding: Gunter von Minckwitz, Roche, GlaxoSmithKline; Sibylle Loibl, Roche Expert Testimony: None Other Remuneration: None REFERENCES
1. Morabito A, Piccirillo MC, De Maio E, et al: Trastuzumab beyond progression: Is the risk of cardiac toxicity really not increased? J Clin Oncol 27:e123; 2009. 2. Valabrega G, Aglietta M, Montemurro F: Trastuzumab beyond disease progression: Case closed? J Clin Oncol 27:e121–e122, 2009. 3. 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. 4. Cameron D, Casey M, Press M, et al: A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: Updated efficacy and biomarker analyses. Breast Cancer Res Treat 112:533–543, 2008.[CrossRef][Medline] 5. Jackisch C, Eustermann H, Schoenegg W, et al: Routine clinical usage of trastuzumab (Herceptin) in advanced breast cancer in Germany from 2001 to 2006. Breast Cancer Res Treat 106: 2007 abstr 4059.
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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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