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Journal of Clinical Oncology, Vol 22, No 8 (April 15), 2004: pp. 1524-a-1526 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.165
Adjuvant Use of Anastrozole in Breast Cancer
Wolfson Institute of Preventive Medicine, London, UK To the Editor: We were surprised by the conclusions reached by the American Society of Clinical Oncology (ASCO) technology assessment committee regarding the role of anastrozole as an adjuvant treatment in early breast cancer.1 Their conclusions were based on a brief 10-minute oral presentation of the updated data at the San Antonio Breast Cancer Conference.2 We would like to address some of the issues raised therein and supply further explanatory data on the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. A prime concern was the apparent diminution of the recurrence advantage of anastrozole over tamoxifen in the update, based on a nonsignificant increase in the hazard ratio. As can be seen in Figure 1, this was as a result of fluctuations in the unstable tail of the survival curve. At the time of the main analysis there was an artifactual and unrealistic separation of the curves in favor of anastrozole after 42 months because of a small numbers of events, which we chose not to disclose, as it was certain to be spurious. However, the events after this time were included in the summary hazard ratios and P values in keeping with good practice. With more data, the curves have stabilized, leading to slightly less significant P values. However, the curves are virtually unchanged for the first 42 months, indicating that the recurrence benefit of anastrozole in this period is not being lost, and the larger separation at year 4 compared with year 3 suggests an increasing benefit of anastrozole with longer follow-up.
Regarding the maturity of the trial, we agree that more time is needed to assess distant recurrences and breast cancer mortality, and we remain committed to evaluating these end points. However, a substantial number of patients have now completed 4 years of treatment and the side effect profile has remained virtually unchanged since our main report.3,4 In particular, there is no indication of any acceleration of fracture rates on anastrozole.5 We will continue to be vigilant for any late effects but feel confident that the updated report4 will accurately reflect the side effect profile for a full 5 years of active treatment. Much has been made of the carry-over effect of tamoxifen in years 5 to 9, after completing 5 years of treatment. Such an effect should be expected when treatment is curative in a proportion of patients, who will continue to benefit indefinitely. We would anticipate a similar, if not larger, effect for anastrozole. However, even in the very unlikely scenario of no carry-over effect of anastrozole in years 5 to 9, the 22% benefit seen in receptor-positive patients in years 0 to 4 is large enough to more than balance the carry-over benefit of tamoxifen over placebo in years 5 to 9. Thus, after 10 years of follow-up, anastrozole is unlikely to be less efficacious than tamoxifen and will retain a more favorable side-effect profile. A more likely scenario is that the difference in recurrence rates will continue to increase, but time will tell in this regard. It should be pointed out that the seminal paper on chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) was published with a 27-month median follow-up and no survival advantage.6 However, despite its toxicities, CMF was adopted rapidly by many oncologists,7 and certainly before survival data were available. We also note that anastrozole has been adopted as the control arm in the widely approved ongoing US Intergroup MA-27 trial, and aromatase inhibitors are being adopted as control treatments in several other new trials. More generally, we would also like to question the wisdom of publishing full reports based on unpublished data taken from oral presentations. This has occurred on at least one previous occasion,8 where data from the International Breast Cancer Intervention Study I trial were reported before peer-reviewed publication. Apart from factual inaccuracies in Winer et al1 (distant recurrences cited therein refer only to distant recurrences as a first event and omit distant recurrences after local recurrences), interpretations are not based on a full peer-reviewed picture of the data. Citations also become inaccurate, as the abstracts cited do not contain the data presented in the ASCO technical report, and this report may become cited as the primary reference, inhibiting full publication by the trial investigators. It would be helpful if the Journal of Clinical Oncology would clarify its position regarding references to non–peer-reviewed data. In summary, we are concerned about the process leading to the publication of these reports and question the conclusion reached in this particular case. Evidence is emerging that anastrozole may be superior to tamoxifen as an adjuvant treatment for postmenopausal women both in terms of efficacy and side effects. At present, the superiority is not fully established, but, in our view, anastrozole should be considered as a co-equal first-line option (along with tamoxifen) for hormonal treatment in all postmenopausal women with hormone receptor-positive early breast cancer. Authors' 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. Owns stock (not including shares held through a public mutual fund): John Forbes, AstraZeneca. Acted as a consultant within the last 2 years: Jack Cuzick, AstraZeneca; Manuel Constenla, AstraZeneca; Jean Paul Guastalla, AstraZeneca; Anthony Howell, AstraZeneca; Jeffrey Tobias, AstraZeneca; Michael Baum, AstraZeneca; Mitch Dowsett, AstraZeneca; Rob Coleman, AstraZeneca. Performed contract work within the last 2 years: Aman Buzdar, AstraZeneca; Joan Houghton, AstraZeneca; Norman Williams, AstraZeneca. Served as an officer or member of the Board of a company: Jean Paul Guastalla, AstraZeneca. Received more than $2,000 a year from a company for either of the last 2 years: Jack Cuzick, AstraZeneca; Aman Buzdar, AstraZeneca; John Forbes, AstraZeneca; Jean Paul Guastalla, AstraZeneca; Joan Houghton, AstraZeneca; Anthony Howell, AstraZeneca; Gershon Locker, AstraZeneca; Jeffrey Tobias, AstraZeneca; John Mackey, AstraZeneca; Michael Baum, AstraZeneca; Mitch Dowsett, AstraZeneca; Richard Sainsbury, AstraZeneca; Rob Coleman, AstraZeneca.
REFERENCES
1. Winer EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology Technology Assessment Working Group Update: Use of Aromatase Inhibitors in the Adjuvant Setting. J Clin Oncol 21:2597-2599, 2003 2. Buzdar A: The ATAC (Arimidex or Tamoxifen, Alone or in Combination) trial in postmenopausal women with early breast cancer, updated efficacy results based on a median follow-up of 47 months. Breast Cancer Res Treat 77:295, 2003 (abstr 13)[CrossRef] 3. Sainsbury R: Beneficial side-effect profile of anastrozole compared with tamoxifen confirmed by additional 7 months of exposure data: A safety update from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. Breast Cancer Res Treat 76:S156, 2002 (abstr 633; suppl 1) 4. Baum M, Buzdar A, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer. Cancer 98:1802-1810, 2003[CrossRef][Medline] 5. Locker GY, Eastell R: The time course of bone fractures observed in the ATAC (Arimidex or Tamoxifen, Alone or in Combination) trial. Proc Am Soc Clin Oncol 22:25, 2003 (abstr 98) 6. Bonadonna G, Brusamolino E, Valagussa P, et al: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 294:405-410, 1976[Abstract]
7. Mariotto A, Feuer EJ, Harlan LC, et al: Trends in use of adjuvant multi-agent chemotherapy and tamoxifen for breast cancer in the United States: 1975-1999. J Natl Cancer Inst 94:1626-1634, 2002
8. Chlebowski RT, Col N, Winer EP, et al: American Society of Clinical Oncology technology assessment of pharmacologic interventions for breast cancer risk reduction including tamoxifen, raloxifene and aromatase inhibition. J Clin Oncol 20:3328-3343, 2002 Related Article
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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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