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Journal of Clinical Oncology, Vol 23, No 12 (April 20), 2005: pp. 2863-2864 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.505
In Reply:Program in Gynecologic Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA I thank the authors of the MA17 trial for their comments regarding my Editorial on early stopping rules. I have chosen to address their objective concerns and will not respond to comments regarding my competency as a clinical investigator. The authors contend that disease-free survival (DFS) is an appropriate surrogate for overall survival (OS) in their study, and take issue with the first recommendation proposed in my editorial.1 This recommendation states: "Improvement in PFS [progression-free survival] or DFS should not generally be used as an early stopping criterion, unless there are convincing data in the same setting to show that prolongation of PFS is a reliable surrogate for improved OS or QOL [quality of life]." I think that this is a fair and reasonable recommendation, and I do not believe that MA17 meets this criterion. Although there are many clinical trials of adjuvant hormonal therapy that show good concordance between DFS and OS, MA17 was not designed as a classical adjuvant trial and is asking a question in a unique patient population for which there is very little precedent. In MA17, a hormonal intervention (letrozole) was made 5 years after completion of primary adjuvant therapy (tamoxifen), as opposed to investigation of the more traditional strategy of instituting adjuvant therapy shortly after diagnosis.2 From a biologic perspective, this is not simply a semantic distinction, since the patient populations may be very different in these two circumstances. The population studied in MA17 has been exposed to selection pressure imposed by tamoxifen over a 5-year period, during which enrichment of tamoxifen-unresponsive clones will occur. In fact, my initial reaction to MA17 was that introducing letrozole after 5 years of tamoxifen is more analogous to early treatment of persistent/recurrent disease, as opposed to adjuvant treatment of minimal volume, newly diagnosed disease. Since we are already well aware of differences in outcome between treatment administered in the adjuvant setting (as classically defined) compared with the persistent/recurrent disease setting, why should we assume that a prolongation of DFS will necessarily be associated with an OS advantage in the population studied in MA17? In my opinion, there is no good reason for making this assumption, and these considerations made it imperative for the authors to formally demonstrate the impact of the observed improvement in DFS on important clinical outcomes (ie, by not stopping the trial unless either an OS or QOL end point had been met). Interestingly, the authors appropriately included OS as an end point in MA17, presumably because of the unique nature of their patient population and the uncertain value of DFS as a surrogate for OS in this particular setting. If OS was originally deemed to be an important end point, it follows that the conduct of the trial should have permitted enough follow-up to assess the effects of letrozole on OS with confidence. I would also add that even if concordance between DFS and OS is eventually observed in MA17, a single study does not prove that this relationship can be generalized to all other agents studied in the same clinical setting. The second point that deserves discussion is whether it is appropriate to use DFS as a surrogate for QOL in this setting without a formal demonstration that QOL is improved (or at least not impaired) with long term treatment. Please note my emphasis on long-term treatment. The authors state: "Even in the absence of data that formally quantify the impact of these events on quality of life, we think that women can judge for themselves what adverse effects they would be willing to tolerate to avoid them." Although this statement will understandably have emotional resonance with patients, I believe that it fails to capture the complexity of the issues. For any therapy, patients deserve to know what the likelihood of benefit is, and then be given an opportunity to balance this against the possibility of side effects. The smaller the likelihood of benefit, the more important is the need to fully define the side effects so that an informed decision can be made. At the time of MA17's publication, letrozole was estimated to reduce the development of recurrences or new breast cancers by approximately one event per 100 patients treated per year.3 I am not saying that this is unimportant, but I wonder how many patients realize that they have a low chance of deriving benefit from the drug, and yet all will be exposed to its potential side effects (which have not been fully defined because the study was terminated)? In other words, it may be more likely that a given patient's QOL will be negatively influenced by drug-related side effects in the long term, rather than be positively influenced by prevention of disease recurrence. To complicate matters further, the benefit of the drug will most likely diminish with time, as the likelihood of breast cancer relapse decreases in a given patient, and yet certain drug-related side effects such as osteoporosis may be cumulative. QOL instruments that address issues related to energy level, mood, cognitive function, activities of daily living, libido, and so on are a major step forward in our ability to address these issues, and QOL was a formal end point of the MA17 trial. However, early study closure has now compromised our ability to determine the impact of long-term letrozole therapy on QOL and to balance this against the low likelihood that the drug will prevent breast cancer recurrence in a given patient. Although the authors are certainly entitled to express their personal opinions regarding the relationship between DFS and QOL, I would have been more interested in the personal opinions of the 5,187 women enrolled on MA17, obtained after long-term follow-up. They are the ones taking the drug, they are the ones experiencing side effects, and they are the ones at risk for recurrence. I do not think that we are smart enough to predict how DFS will impact QOL in the absence of guidance from our patients, as determined objectively in the context of a well-designed clinical trial. The investigators of both MA17 and GOG178 have conducted studies that will undoubtedly serve as important milestones in the clinical investigation of breast and ovarian cancers, respectively.2,4 The fact that early study closure has generated controversy should not diminish the importance of their findings. However, there is room for more than one point of view, and I have no doubt that continued healthy debate of this issue will lead to improvements in the design and implementation of future clinical trials. Author's Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have 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. Research Funding: Stephen A. Cannistra, Pfizer, Aventis. For a detailed description of these 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 of Information for Contributors found in the front of every issue. REFERENCES
1. Cannistra SA: The ethics of early stopping rules: Who is protecting whom? J Clin Oncol 22:1542-1545, 2004
2. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003
3. Burstein HJ: Beyond tamoxifen- extending endocrine treatment for early stage breast cancer. N Engl J Med 349:1857-1859, 2003
4. Markman M, Liu PY, Wilczynski S, et al: Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 21:2460-2465, 2003
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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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