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Journal of Clinical Oncology, Vol 22, No 15 (August 1), 2004: pp. 3199-3200 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.058
Phase III Study of Letrozole Versus Tamoxifen As First-Line Therapy of Advanced Breast Cancer in Postmenopausal Women: Analysis of Survival and Update of Efficacy From the International Letrozole Breast Cancer GroupThe University of Texas M.D. Anderson Cancer Center, Houston, TX To the Editor: In an updated study, Mouridsen et al1 compared long-term efficacy and overall survival after first-line treatment of advanced breast cancer with letrozole versus tamoxifen. I have concerns with the conclusions drawn from this article, particularly those relating to a proposed early survival benefit for letrozole. While the data from the trial initially appear impressive, with improvements in the primary end point of time to progression for letrozole versus tamoxifen, their significance may be due to several confounding factors. The first is the poor performance of tamoxifen, which does not equate with what would generally be expected, based on prior reported values from the literature in a similar setting.2-4 This study, therefore, fails to either demonstrate convincing superiority for letrozole or present a clear picture of the relative efficacy of the two agents. This study had a specific cross-over design: patients received randomized treatment until progression or discontinuation due to other reasons. Patients then still eligible for hormonal therapy could be crossed over to the alternative treatment in a double-blind fashion and continued until further progression. While the use of the cross-over design was an attempt to reflect clinical practice, in that patients progressing on one endocrine agent may be switched to another as second-line therapy, this design may make results difficult to interpret. In prospectively planned analyses, the mature data at 32 months follow-up (at which point many patients had crossed over to the alternative treatment) did not show any significant benefit for letrozole over tamoxifen in overall survival (OS; P = .53 by protocol log-rank test). Additional exploratory analyses were then used to suggest that there might, however, be a survival benefit of letrozole at earlier time points. These exploratory findings are difficult to evaluate, as neither confidence intervals for the difference between the two arms, nor the number of deaths recorded in each randomized group, were reported. Furthermore, early benefits do not reflect the original end point of the study. Further exploratory analyses were used to suggest that letrozole had a survival advantage over tamoxifen "well beyond 2 years". Such subgroup analyses are open to bias—particularly as the subgroups are defined by information obtained after randomization (ie, whether or not patients crossed over); a selection that is well-recognized as being open to major bias. In addition, no information was provided to summarize the baseline characteristics for these subgroups, so the reader cannot determine the extent to which patients in one subgroup differed from the other and hence evaluate the potential clinical applicability of such findings. While it is likely that cross-over therapy did have a confounding effect, this trial was specifically designed to evaluate the effects of cross-over, and therefore the attempts to analyze only the efficacy of the first treatment before cross-over should not be over-interpreted. The statement in the discussion: "...and the descriptive analysis of OS in patients whose time to death was censored at cross-over suggested that first-line letrozole may have a survival advantage over tamoxifen well beyond 2 years" is not justified by the data presented in this article. An additional point of concern is that OS from the date of cross-over was longer for patients crossing from tamoxifen to letrozole than from letrozole to tamoxifen. These data may perhaps indicate that patients who receive tamoxifen as first-line therapy for advanced breast cancer and then cross-over to letrozole fare better in terms of OS than those who receive letrozole first. This observation may explain why the survival curve for the tamoxifen group was worse than the letrozole curve over the first 18 months, but then closed the gap and crossed the letrozole curve. This is merely a retrospective, subgroup-type observation, which probably has similar credibility to the subgroup data actually included in the publication. Mature data from anastrozole5 and letrozole1 first-line studies have failed to show significant survival advantages for aromatase inhibitors over tamoxifen. This is not surprising, as multiple additional therapies, which can confound the trial findings, are offered to these patients following progression after initial benefit from endocrine therapy. If studies were carried out in an environment where very few patients have access to additional therapies and only received protocoled therapies, it might be anticipated that survival advantages would become evident. Indeed, data from one first-line study are available and demonstrate a mature survival benefit for an aromatase inhibitor over tamoxifen.6 Aromatase inhibitors are now under evaluation in the adjuvant setting, where a significantly higher proportion of the trial population treated with aromatase inhibitors will remain free of disease, and their true survival benefits over tamoxifen will become evident. Author's Disclosure of Potential Conflicts of Interest The following author 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. Honoraria: Aman U. Buzdar, AstraZeneca, Pfizer. Research Funding: Aman U. Buzdar, AstraZeneca, Novartis, Pfizer. 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 form and the ‘Disclosures of Potential Conflicts of Interest' section of Information for Contributors found in the front of every issue. REFERENCES
1. Mouridsen H, Gershanovich M, Sun Y, et al: Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: Analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 21:2101-2109, 2003
2. Bonneterre J, Thurlimann B, Robertson JF, et al: Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: Results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 18:3748-3757, 2000
3. Nabholtz JM, Buzdar A, Pollak M, et al: Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: Results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 18:3758-3767, 2000
4. Buzdar AU: Superior efficacy of letrozole versus tamoxifen as first-line therapy. J Clin Oncol 20:876-878, 2002 5. Nabholtz JM, Bonneterre J, Buzdar A, et al: Anastrozole (Arimidex) versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: Survival analysis and updated safety results. Eur J Cancer 39:1684-1689, 2003 6. Milla-Santos A, Milla L, Portella J, et al: Anastrozole versus tamoxifen as first-line therapy in postmenopausal patients with hormone-dependent advanced breast cancer: A prospective, randomized, phase III study. Am J Clin Oncol 26:317-322, 2003[CrossRef][Medline]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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