Testing Chemotherapy for Breast Cancer: Timing Is Everything

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 al 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, 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. Paclitaxel was first approved for use in metastatic breast cancer in 1994 at a dose of 175 mg/m 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 lowdose, weekly, 1-hour infusion. Docetaxel was approved in 1999 at dose of 100 mg/m 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. Docetaxel has been used over a somewhat more narrow range of doses and schedules compared with that of paclitaxel. 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. 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. The results of the study by Jones et al are clear. Docetaxel at 100 mg/m every third week is more active than paclitaxel 175 mg/m 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 intentionto-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 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 24 AUGUST 2