Originally published as JCO Early Release 10.1200/JCO.2003.04.596 on May 5 2003
Journal of Clinical Oncology, Vol 21, Issue 13
(July), 2003: 2597-2599
© 2003 American Society for Clinical Oncology
American Society of Clinical Oncology Technology Assessment Working Group Update: Use of Aromatase Inhibitors in the Adjuvant Setting
Eric P. Winer,
Clifford Hudis,
Harold J. Burstein,
John Bryant,
Rowan T. Chlebowski,
James N. Ingle,
Stephen B. Edge,
Eleftherios P. Mamounas,
Richard Gelber,
Julie Gralow,
Lori J. Goldstein,
Kathleen I. Pritchard,
Susan Braun,
Melody A. Cobleigh,
Amy S. Langer,
Judy Perotti,
Trevor J. Powles,
Timothy J. Whelan,
George P. Browman
From the American Society of Clinical Oncology, Alexandria, VA.
Address reprint requests to American Society of Clinical Oncology, Cancer Policy and Clinical Affairs, 1900 Duke Street, Suite 200, Alexandria, VA 22314; email: guidelines{at}asco.org.
IN DECEMBER 2001, the initial results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) study were presented at the San Antonio Breast Cancer Symposium. At the time of the report, with a median reported follow-up of 33 months, there was a statistically significant improvement in disease-free survival for postmenopausal women who received adjuvant monotherapy with anastrozole in comparison with those who received monotherapy with tamoxifen.1 The American Society of Clinical Oncology (ASCO) convened a Technology Assessment Working Group to review the available data and to develop a series of recommendations regarding the optimal use of aromatase inhibitors as adjuvant breast cancer therapy.2 Since the initial presentation of the ATAC results in 2001, the results of the study have been peer reviewed and published.3 In addition, the United States Food and Drug Administration granted an accelerated approval for the use of anastrozole as adjuvant therapy in September 2002. In December 2002, the updated ATAC results, with a median follow-up of 47 months, were presented at the San Antonio Breast Cancer Symposium.4 Additional data have also become available about bone density, endometrial changes, and quality of life of women who participated in ATAC.5–7
All ASCO Technology Assessments are reviewed on an annual basis and updated as needed. The Technology Assessment Working Group reconvened in December 2002 to review the most recent data, and elected to expand its membership to include two statisticians. The Working Group unanimously decided to issue this brief Update.
The updated results from the ATAC trial continue to show a statistically significant improvement in disease-free survival for anastrozole compared with tamoxifen. The annual risk of first events (distant recurrence, local recurrence, contralateral invasive or noninvasive cancer, or death from other cause) was 14% lower for women in the anastrozole arm than for women in the tamoxifen arm (hazard ratio, 0.86; 95% confidence interval [CI], 0.76 to 0.99). The hazard ratio in the subset of women who are known to have had receptor-positive tumors was 0.82 (95% CI, 0.70 to 0.96).
Table 1 details the first events in the anastrozole and tamoxifen arms of the study. Not shown in the table is the combination arm, which appears to be indistinguishable from the tamoxifen arm in terms of number of events. At a median follow-up of 33 months, the absolute difference in first events between the anastrozole and tamoxifen arms was 62 events (2.0%). With a median follow-up of 47 months, the absolute difference was 59 events (1.9%). The absolute difference in distant recurrence at 33 months was 24 events (0.8%); at 47 months the difference was 27 events (0.9%). To date, there is no reported difference in survival between the two treatment arms. As defined in the original protocol, a first survival analysis will occur when there have been 704 deaths on the two monotherapy arms combined; the ongoing ATAC Steering Committee has final authority over all such decisions (personal correspondence; J. Purvis, 2002). At the time of the updated analysis, almost 3,000 women enrolled in the monotherapy arms of the trial (anastrozole + placebo, or tamoxifen + placebo) had been observed for more than 4 years. Fewer than 400 patients had been observed for 5 or more years.
Toxicity data (Table 2) were also updated at the December 2002 San Antonio conference.8 With a median follow-up of 37 months, the updated toxicity data showed no qualitative differences when compared with the data initially presented in 2001. Women enrolled in the anastrozole arm were statistically less likely to experience hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, ischemic cerebrovascular disease, or deep venous thromboembolism. For example, hot flashes occurred in 40.3% of women taking tamoxifen compared with 35.0% of women taking anastrozole. Both ischemic cerebrovascular events and deep venous thromboembolic events occurred in 1.1% of women taking anastrozole. Among women taking tamoxifen, rates for ischemic cerebrovascular events and deep venous thromboembolic events were 2.3% and 1.8%, respectively. In contrast, women randomly assigned to the tamoxifen arm were statistically less likely to experience a musculoskeletal disorder (arthritis or arthralgia) or a fracture compared with women enrolled in the anastrozole arm. Women taking anastrozole had a 30.3% incidence of musculoskeletal disorder and a 7.1% incidence of fracture, whereas women taking tamoxifen had a 23.7% incidence of musculoskeletal disorder and a 4.4% incidence of fracture.
Since the initial presentation, three substudies of women on the trial have provided further information on the bone, endometrial, and quality-of-life effects of anastrozole and tamoxifen. These data have appeared in abstract form only. Eastell et al7 reported that a year of treatment with anastrozole was associated with a decrease in spine and hip bone mineral density and an increase in bone resorption and bone formation markers, whereas the converse was identified with tamoxifen. Duffy5 reported the results of an endometrial substudy conducted in 279 ATAC participants. In 179 women who had assessable biopsies, there was a nonsignificant trend favoring the anastrozole group in the total number of women with endometrial abnormalities. Fallowfield reported no overall quality of life difference between the two monotherapy arms, although self-reported sexual functioning was worse in women taking anastrozole than in those taking tamoxifen.6
The Technology Assessment Working Group reviewed the updated results and substudy data. There are no substantial differences in either efficacy or toxicity in comparison with the initial presentation. The additional follow-up provides a greater level of assurance, in terms of both toxicity and efficacy, for physicians and their patients who are considering the use of anastrozole in the adjuvant setting. At the same time, it must be recognized that a very small fraction of the study population has been followed for 5 or more years and that the absolute difference in the number of events between the anastrozole arm and the tamoxifen arm has not changed (62 events when reported in 2001 and 59 events when reported in 2002). The hazard ratio (anastrozole/tamoxifen for first events) was 0.83 (95% CI, 0.71 to 0.96; P = .01) in 2001 and 0.86 (95% CI, 0.76 to 0.99; P = .03) in 2002. Considering the cohort of patients with estrogen receptor–positive tumors, the target population for the endocrine therapy under consideration, the hazard ratios (for first events) were 0.78 (95% CI, 0.65 to 0.93) in 2001 and 0.82 (95% CI, 0.70 to 0.96) in 2002. Although one must be cautious not to overinterpret the minor changes, these findings are consistent with a slight attenuation of the benefit of anastrozole in comparison with tamoxifen on the basis of additional follow-up.
After careful consideration, the Working Group unanimously voted to support and maintain the recommendations that were initially released in 2002.2 In the absence of a difference in survival and without an increasing difference in either efficacy or toxicity, the Working Group does not believe that the updated information warrants any change in clinical practice. The Working Group notes that only a small fraction of the study participants have been followed for 5 years, which is considered the duration of tamoxifen associated with maximal benefit. The updated information supports the current recommendation to consider anastrozole in a postmenopausal woman with a hormone receptor–positive tumor who has an absolute or relative contraindication to the use of tamoxifen. For example, some clinicians might consider a woman with an increased risk of thromboembolic or cerebrovascular disease as having a relative contraindication to the use of tamoxifen. It should be emphasized, however, that the ATAC trial enrolled women who were postmenopausal at the time of diagnosis. Aromatase inhibitors, as single agents, have not been evaluated in premenopausal women and are contraindicated outside of a clinical trial. Great caution should be exercised in women who experience chemotherapy-related amenorrhea because some women may have residual ovarian activity and others may regain function of their ovaries over time.9,10
The Working Group looks forward to the availability of additional data from the ATAC trial and multiple other trials evaluating the aromatase inhibitors in the adjuvant setting. The Working Group recognizes that decisions surrounding the use of adjuvant hormonal therapy in postmenopausal women can be complex. Each patient and her physician is advised to carefully weigh the benefits and risks of the available treatment options, considering the woman’s risk of disease recurrence, her overall health status, and her preferences.
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NOTES
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Adopted on April 14th, 2003 by the American Society of Clinical Oncology.
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REFERENCES
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1. Baum M, on behalf of the ATAC Trialists’ Group: The ATAC (Arimidex, Tamoxifen, Alone or in Combination) adjuvant breast cancer trial in post-menopausal women. Breast Cancer Res Treat 69:210, 2001 (abstr 8)
2. Winer EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: Status report 2002. J Clin Oncol 20:3317–3327, 2002[Abstract/Free Full Text]
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8. Sainsbury R, on behalf of the ATAC Trialists’ Group: Beneficial side-effect profile of anastrozole compared with tamoxifen confirmed by additional 7 months of exposure data: A safety update from the ATAC trial. Breast Cancer Res Treat 76:156, 2002 (suppl 1; abstr 633)
9. Braverman AS, Sawhney H, Tendler A, et al: Pre-menopausal serum estradiol (E2) levels may persist after chemotherapy (CT)-induced amenorrhea in breast cancer (BC). Proc Am Soc Clin Oncol 21:42a, 2002 (abstr 164)
10. Bines J, Oleske DM, Cobleigh MA: Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 14:1718–1729, 1996 (comment)[Abstract/Free Full Text]
Submitted April 15, 2003;
accepted April 15, 2003.
Related Correspondence
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JCO 2004 22: 1524-1526
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Related Reply
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JCO 2004 22: 1526-1527
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