Adjuvant Chemotherapy for Postmenopausal Lymph Node-Negative Breast Cancer: It Ain't Necessarily So
Authors: A. C. Wolff
Journal: JNCI Journal of the National Cancer Institute (2002)

Adjuvant chemotherapy in older women diagnosed with lowrisk, estrogen receptor (ER)-positive breast cancer still inspires controversy. In fact, there is very little information on polychemotherapy in women aged 70 years or older (1), a direct result of our long-standing failure as cancer investigators to recruit older women to clinical trials. In this issue of the Journal, the International Breast Cancer Study Group (IBCSG) presents the results of the IBCSG Trial IX (2). Between 1988 and 1999, 1669 postmenopausal women with lymph node-negative breast cancer were stratified by ER status and randomly assigned to receive either 5 years of tamoxifen alone or three cycles of “classical” CMF (oral cyclophosphamide on days 1–14 plus intravenous methotrexate and 5-fluorouracil on days 1 and 8, repeated every 28 days), followed by 5 years of tamoxifen. An interesting feature of this tamoxifen-based trial is that patients with ERnegative disease continued to be enrolled until the most recent publication of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) tamoxifen overview in 1998 (3). This design de facto created two studies within the same trial: one study examining the role of CMF followed by tamoxifen versus tamoxifen alone in 1217 postmenopausal women with lymph node-negative, ER-positive breast cancer and a second study comparing the same regimens in 382 postmenopausal women with lymph node-negative, ER-negative breast cancer. The results indicate no benefit from the addition of chemotherapy to tamoxifen in the larger ER-positive stratum but show a statistically significant and meaningful survival benefit in the smaller ER-negative stratum. The IBCSG findings in lymph node-negative, ER-positive patients must be viewed in the context of two other important pieces of evidence: the 1995 EBCTCG overview of polychemotherapy for early breast cancer (1) and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-20 trial (4), which enrolled 2306 preand postmenopausal lymph nodenegative, ER-positive breast cancer patients. These patients received 5 years of tamoxifen alone versus six cycles (rather than three cycles) of classical CMF or MF with concurrent initiation of 5 years of tamoxifen. The 1995 overview included data from 18 000 women in 47 trials of prolonged chemotherapy versus no chemotherapy. This overview analysis showed an overall benefit from the addition of 3–6 months of polychemotherapy to tamoxifen versus tamoxifen alone with statistically significant reductions in the annual odds of recurrence (19% ± 3% [mean ± standard deviation]) and death (11% ± 4%) (1). Within each age category, the proportional risk reduction with polychemotherapy was the same with or without adjuvant tamoxifen, but the 1995 overview indicated a greater proportional risk reduction with polychemotherapy that favored younger women over older women (1). In contrast, the proportional risk reduction in the annual odds of recurrence (47% ± 3%) and death (26% ± 4%) observed with 5 years of tamoxifen was not affected by age (3). A limitation of these data is that three of the largest trials ever conducted on the role of chemotherapy when added to tamoxifen had been activated shortly before 1990 and, therefore, were not included in the 1995 overview. These trials were IBCSG IX (1669 postmenopausal patients) and NSABP B-20 (2306 preand postmenopausal patients) in lymph node-negative disease and Southwest Oncology Group (SWOG) 8814/Intergroup Trial (INT) 0100 (1477 postmenopausal patients) in lymph node-positive disease (5). The IBCSG IX trial recruited 1217 patients with ER-positive disease. These patients were all likely to be postmenopausal because of a more detailed (and more precise) definition of menopause that took into account age and history of amenorrhea compared with the age criteria used by the NSABP. In fact, as noted by the IBCSG IX investigators, it is possible that some (or many) of the 358 women aged 50–54 years among the 1264 women enrolled in the aged-50-years-or-older stratum of NSABP B-20 were perior premenopausal at study entry. This is a group in which at least some of the benefit obtained with cytotoxic chemotherapy could be compounded by its temporary or permanent ovarian suppression effect, which could add to the antiestrogen effects of tamoxifen in premenopausal women. The accrual figures further substantiate the claim from the IBCSG IX investigators that this is the largest trial examining the role of chemotherapy followed by tamoxifen in a lymph node-negative, postmenopausal population, even if only the ER-positive stratum is considered. Its sample size allowed a statistical design with 80% power to detect a 33% relative reduction in relapse risk in the ER-positive stratum and a 50% relative reduction in the ER-negative stratum. The 5-year results are quite clear: At this time, there is no observed benefit from the addition of CMF followed by tamoxifen in the larger ER-positive stratum for either disease-free survival (DFS; relative risk [RR] 0.99, 95%