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Journal of Clinical Oncology, Vol 23, No 24 (August 20), 2005: pp. 5434-5436 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.015
Testing Chemotherapy for Breast Cancer: Timing Is EverythingBreast Cancer Medicine Service, Solid Tumor Division, Department of Medicine, Memorial Sloan-Kettering Cancer Center, and Department of Medicine, Joan & Sanford I. Weill Medical College of Cornell University, New York, NY A quarterback, throwing a football to his receiver, aims to where his partner is running, not where he is or was. So it should go with clinical trials. As we plan them, we have to recognize that the players are often moving down the field and if we aim directly at them, the ball will land behind our moving target. In this issue, Jones et al1 report on a trial (Tax 311) that was planned in the early 1990s, asking a then-important comparative question of taxane efficacy. It enrolled patients from 1994 to 2001 and now, in 2005, it is clear that the players have moved a bit. New treatments (trastuzumab and bevacizumab), new chemotherapy administration schedules (weekly), new supportive care (antiemetics, growth factors, bisphosphonates), and new agents (capecitabine, gemcitabine, vinorelbine) have joined, and changed,2,3 the game. Given these changes, how do we interpret the results of Tax 311? The arrival of the taxanes in the early 1990s, first paclitaxel and then docetaxel, certainly changed the management of metastatic and—more recently—early-stage breast cancer.3-12 Paclitaxel was first approved for use in metastatic breast cancer in 1994 at a dose of 175 mg/m2 intravenously during 3 hours every third week, and it quickly became one of the most widely used drugs in oncology. It was found to have a toxicity and efficacy profile that varied with dose and schedule and is now widely used as a low-dose, weekly, 1-hour infusion.13-16 Docetaxel was approved in 1999 at dose of 100 mg/m2 intravenously during 1 hour every third week for use in advanced breast cancer; this was suggested to have a different activity and toxicity profile compared with those of paclitaxel.17 Docetaxel has been used over a somewhat more narrow range of doses and schedules compared with that of paclitaxel.18-21 Because their mechanisms of action and resistance are similar (although not necessarily the same) and with their recent incorporation into numerous adjuvant therapy trials in which cure is the goal, there have been extensive debate and discussion among clinicians regarding the better agent.22-27 This debate is complicated by variations not only in the choice of drug, but also the dose and schedule, and the precise disease setting. Nevertheless, indirect comparisons between them have been made for more than a decade. The recent availability of another taxane (nanoparticle albumen-bound paclitaxel) further complicates this discussion.28 The results of the study by Jones et al1 are clear. Docetaxel at 100 mg/m2 every third week is more active than paclitaxel 175 mg/m2 on the same schedule in patients with metastatic breast cancer. The primary end points of the trial were objective response rate and toxicity. The secondary end points included duration of response, time to progression, overall survival, and quality of life. In the intention-to-treat analysis, there was no statistically significant difference in response, but there was a trend favoring docetaxel. For the secondary end points, docetaxel was statistically significantly superior, with a 2-month longer median time to progression and a 2.5-month longer median overall survival. Given the trend toward increased response rate in the intention-to-treat analysis, and the statistical significance achieved for response in the assessable patient subset, these results seem internally consistent and support the conclusion that, at the specific doses and schedules tested, docetaxel is more active than paclitaxel. Interestingly, there were no significant differences in quality of life as measured by the Functional Assessment of Cancer Therapy–Breast instrument, although toxicities were more frequent and severe with docetaxel. All of the treatment-related deaths on this study occurred with docetaxel and there was an increase in neurotoxicity with docetaxel compared with paclitaxel, although this latter finding could be confounded by the greater number of cycles given to the patients treated longer with the more active agent. One can conclude that there is no free lunch: the increased benefits of docetaxel come with modestly increased risks. Given the broad use of taxanes as single agents and in combinations, this is an important result and could inform the interpretation of ongoing and completed clinical trials in both the metastatic and adjuvant settings.29,30 At the same time, it is no small challenge for clinicians to integrate the present findings into an area of practice that has moved beyond the early 1990s when this trial was planned. The present demonstration that docetaxel has greater antitumor activity than paclitaxel 175 mg/m2 during 3 hours every third week may no longer be particularly relevant, given that this paclitaxel dose and schedule has also been shown to be inferior to other taxane regimens in several randomized trials. Weekly paclitaxel at a dose of 80 to 100 mg/m2, nanoparticle albumen-bound paclitaxel at a dose of 260 mg/m2, and a variety of combinations—including one with gemcitabine that was not particularly toxic—have each been shown to be superior to paclitaxel (Table 1). 15,31,32 This leads to a question for which there are no answers: How this dose and schedule of docetaxel compare with any of these taxane singlets and doublets that have been shown to be superior to paclitaxel 175 mg/m2? Although we can all recognize the impossibility of addressing this broad range of comparisons under the current clinical trials system, it highlights how little we really know and how difficult clinical decision making will remain with regard to this issue. One can imagine that the emergence of a classification system, based perhaps on gene expression, will lead us to even more nuanced questions in this regard.33-35 For example, are there biologic subtypes of breast cancer (basaloid for example) that derive greater benefit from taxanes in general or one taxane in particular?
This is not to suggest that the report by Jones et al1 is unimportant. Not only does it clearly document an improvement in overall survival based on drug choice, but, in another sphere, it also reminds us how important it is to complete and report our studies in a much more efficient and expedited fashion. The many treatment changes tested and incorporated during the 11 years since the first patients were randomly assigned onto the Tax 311 trial, cloud and perhaps diminish the significance of this positive result. Although it was planned using best available data regarding dosing and treatment schedules, clinicians have since come to administer lower doses of docetaxel frequently, an entirely different schedule of paclitaxel and, just in the past months, nanoparticle albumen-bound paclitaxel. I am sure that it is disappointing to all of us, including Jones et al, that this study, which began accrual in 1994 and was still open in 2001, accrued an average of only about 64 patients per year internationally in a disease that kills about 110 people per day in the United States alone. Clearly we have a shared need to focus our efforts not only on asking the right questions, but also on getting the right answers in a timely fashion. Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members has indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000–99,999 (C)
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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