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Journal of Clinical Oncology, Vol 25, No 35 (December 10), 2007: pp. 5662-5663 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.2182
Use of Trastuzumab for Metastatic Breast Cancer in Australia: Inaccurate Results and Alternative Interpretation of FindingsMedical Oncology, Mount Hospital, Perth, Australia
Medical Oncology, Epworth Freemasons Hospital, Melbourne, Australia To the Editor: In the study by Pearson et al1 published in the Journal of Clinical Oncology (August 20, 2007), the authors have identified four areas of concern regarding the use of trastuzumab in Australia for the treatment of metastatic breast cancer: infrequent cardiac monitoring, use outside regulatory indications, continued use beyond disease progression, and drug wastage due to ampoule size. Although we recognize the importance of the article and the need to monitor the use of drugs in the real-world setting, we are concerned about the accuracy of the reported finding that only 3% of Australian patients with metastatic breast cancer undergoing trastuzumab treatment have regular cardiac monitoring. Reports of this study in the local media may lead to undue anxiety that patients are receiving inadequate medical monitoring, and that this drug is being used unsafely or inappropriately by oncologists. The calculation of the figure for cardiac monitoring was derived by extracting information from three Medicare Australia Databases. Using these data, it was determined that during the years 2001 to 2005, only 47 patients across Australia were undergoing regular cardiac monitoring. This appears to be a significant underestimation of the actual situation. As practicing oncologists, we have collected prospective information for all clinic patients under our care and maintained this in a secure database. In the period under consideration, we have identified at least 55 women treated with trastuzumab-based therapy for metastatic disease. All patients underwent regular cardiac monitoring, either by multiple-gated acquisition scan or echocardiogram. This number exceeds the 47 patients quoted in the article, raising doubt to the accuracy of the conclusions. In a cohort of 41 of these patients, an average of five episodes of cardiac monitoring were undertaken during trastuzumab treatment and normal left ventricular ejection measurements were ensured. Although we recognize that not all practitioners will follow the well-publicized cardiac monitoring guidelines for the safe use of trastuzumab, we find it highly unlikely that we are the only practitioners performing regular cardiac monitoring in Australia. The discrepancy between the study results and individual data collected by two clinicians highlights the difficulty in gaining accurate information about cancer treatments and outcomes, unless uniform patient-specific databases are maintained. The authors' second finding that 22% of patients received trastuzumab outside the regulatory label appears to be an overestimation. The authors define off-label usage as any nontaxane agent with trastuzumab, and include 44 patients receiving a platinum agent with a taxane (Table 31). Although it is possible that some of these patients received platinum and trastuzumab alone, which would be an off-label usage, it is likely that some of the 44 patients were receiving a combination of taxane, platinum, and trastuzumab (which the label indication does not specifically preclude) and these patients should not have been included in the off-label calculations. The use of platinum compounds with a taxane and trastuzumab is based on preclinical and clinical data indicating improved efficacy.2 The registration of cancer drug therapies in Australia requires significant improvements in outcomes to be demonstrated in large randomized trials. Although we do not support the use of drugs outside the label indication, there is a need to consider the reasons for clinicians prescribing outside the label; in particular, the use of vinorelbine and trastuzumab (VH), after failure of the approved taxane-trastuzumab (TH) combination. Clinical efficacy and acceptable toxicities for the VH regimen have been reported in several nonrandomized trials, and the use of VH has become an accepted option in many parts of the world.3-5 Unfortunately, it is unlikely that a randomized trial of sufficient size to satisfy the requirements of regulatory authorities will ever be conducted, given the numbers of patients required and the development of new drugs that compete for the same patient pool. This is supported by the recently published results from a randomized trial of VH versus TH, which closed early due to poor accrual. Despite the inability to accrue the 250 patients required to distinguish a 17% difference in response rates between the two regimens, the study demonstrated comparable efficacy and tolerability in the 81 patients evaluated.6 The conclusions on trastuzumab use beyond progression were based on a comparison of the patients' time on treatment (median, 12.5 months) and the published data from the study by Slamon et al7 that led to the drug's approval (median, 6.9 months). When viewed in isolation, this does appear to support the possibility of use beyond progression. However, more recent trials of TH combinations have shown a longer time to progression from 11.7 to 13 months, which approximates the treatment duration seen in the Australian program.8,9 We agree with the authors that a reduction in drug wastage and cost could be achieved with greater variation in the ampoule size. We also recognize the importance of this article, and support the authors' aims of assessing the use of trastuzumab in the setting of a government-funded access scheme. However, we are concerned that some of the major findings and conclusions are inaccurate, and may not reflect the actual practice of Australian oncologists treating women with human epidermal growth factor receptor 2–positive advanced breast cancer. 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: Arlene Chan, Sanofi-aventis (C), Roche (C); Richard de Boer, Sanofi-aventis (C) Stock Ownership: None Honoraria: Arlene Chan, Sanofi-aventis, Roche; Richard de Boer, Sanofi-aventis Research Funding: Arlene Chan, Sanofi-aventis Expert Testimony: None Other Remuneration: None REFERENCES
1. Pearson S-A, Ringland CL, Ward RL: Trastuzumab and metastatic breast cancer: Trastuzumab use in Australia—Monitoring the effect of an expensive medicine access program. J Clin Oncol 25:3688-3693, 2007 2. Burris HI, Yardley D, Jones S, et al: Phase II trial of trastuzumab followed by weekly paclitaxel/carboplatin as first-line treatment for patients with metastatic breast cancer. J Clin Oncol 22:1621-1629, 2004 3. Burstein H, Lyndsay N, Harris P, et al: Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: Multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 21:2889-2895, 2003 4. Jahanzeb M, Mortimer J, Yunus F, et al: Phase II trial of weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2+ metastatic breast cancer. Oncologist 7:410-417, 2002 5. Chan A, Untch M, Petruzelka L, et al: Navelbine and trastuzumab combination as first line therapy for HER 2- overexpressing metastatic breast cancer (HER2 + MBC) is a highly active and safe regimen: Final results of multinational trial. Presented at 25th Annual San Antonio Breast Cancer Symposium, December 3-6, 2003, San Antonio, TX 6. Burstein H, Keshaviah A, Baron AD: Trastuzumab plus vinorelbine or taxane chemotherapy for Her2-overexpressing metastatic breast cancer: The Trastuzumab and Vinorelbine or Taxane study. Cancer 110:965-972, 2007[Medline] 7. Slamon D, Leyland-jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001 8. Marty M, Cognetti F, Maraninchi D, et al: Efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: Results of a randomized phase II—Trial by the M77001 Study Group. J Clin Oncol 23:4265-4274, 2005 9. Robert N, Leyland-jones B, Asmar L, et al: Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 24:2786-2792, 2006
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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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