Do Receptor-Positive, Postmenopausal Women Need Adjuvant Chemotherapy?
Robert S. Mocharnuk, MD
In a modified Oxford debate held at the 3rd European Breast Cancer Conference, Dr. Carsten Rose, from Lund, Denmark, and Dr. Anthony Howell, from Manchester, United Kingdom, defended the proposition that "adjuvant chemotherapy offers negligible benefit to receptor-positive, postmenopausal women" against Dr. Kathy Albain, from Illinois, and Dr. Nancy Davidson, from Maryland.
The affirmative team declared that their position would be supported by the results of randomized clinical trials comparing the benefits of tamoxifen alone vs chemotherapy plus tamoxifen. Legitimate end points for discussion included survival as well as quality-adjusted time without symptoms or toxicity (Q-TwiST).
Other considerations included cost of therapy as it relates to collective benefit.Having defined the terms of the debate, Dr. Rose reviewed a large number of studies whose results often conflict with each other. In a large 1996 meta-analysis (3920 women aged 50 years and older) of 9 trials included in the worldwide overview conducted by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Gelber and colleagues concluded that adjuvant chemotherapy did not add to survival.
Collectively, the EBCTCG trials enrolled more than 15,000 women. An 8% gain in absolute survival at 15 years favored those receiving combination treatment, and this translated into a 19% reduction in relative risk of relapse with a relative death risk reduction of 11%.
Unfortunately, many of these women had estrogen receptor (ER)-negative tumors, so the absolute benefit in ER-positive women cannot be measured.A 2001 EBCTCG update by Cole and colleagues reviewed the results of 47 studies with more than 18,000 women enrolled. Women older than aged 50 years with poor estrogen or positive ER expression were analyzed with a median follow-up of 10 years.
Women with ER-positive tumors who received both chemotherapy and tamoxifen enjoyed a 6.3-month relapse-free survival advantage with a 2.8-month overall survival advantage over women given only tamoxifen. Women with ER-negative tumors derived a 5.5-month relapse-free survival advantage with a 3.7-month overall survival advantage over those receiving tamoxifen alone.
Cole and his collaborators concluded that regardless of ER status, the benefits of combination chemoendocrine therapy were essentially the same.Highlighting individual studies within this meta-analysis, Dr. Rose reviewed subset data from the Danish Breast Cancer Cooperative Group, which enrolled nearly 700 women in each of 3 treatment arms, one with tamoxifen alone, another with chemotherapy plus tamoxifen, and a third with radiation plus tamoxifen.
At a 12-year median follow-up, no differences were observed between the treatment arms.Anticipating his opponents, Dr. Rose argued that while some of the chemotherapy regimens in these older trials are inadequate by today's standards, so too did some trials employ subtherapeutic doses and schedules of tamoxifen. Nevertheless, other studies, including the National Surgical Breast and Bowel Project (NSABP) 20, showed only a 2% survival advantage at 5 years with chemotherapy plus tamoxifen vs tamoxifen alone in ER-positive tumors, but failed to show any benefit whether patients were postmenopausal or not.
Anticipating discussion about the Southwest Oncology Group trial 8814, Dr. Rose noted that in spite of the fact that 50% to 60% of all breast cancer diagnoses occur in women older than 65 years of age, only 9% of women in this trial were aged 65 years or older. This raises some questions regarding the reliability of these data.
In conclusion, no significant overall survival differences have been shown in ER-positive, postmenopausal women whether they were treated with combination chemoendocrine therapy or endocrine therapy alone.
Furthermore, no differences in quality of life (Q-TwiST) were recorded, particularly in the EBCTCG studies. Costs and toxicity for women undergoing chemotherapy are assuredly higher, and the database from which the opposing team will attempt to make its own argument is severely underrepresented by older women.
Dr. Kathy Albain began her advocacy for combined chemotherapy and tamoxifen in ER-positive postmenopausal women by posing a couple of questions of her own. First, does chemotherapy work less effectively as women age?
Second, is chemotherapy less effective in tumors expressing hormone receptors? Supportive evidence for her position was derived from the same sources as Dr. Rose's, although her discussion also included trials comparing chemotherapy vs no treatment as well as chemotherapy vs tamoxifen.
The initial findings of a National Institutes of Health (NIH) consensus conference published in the Journal of the National Cancer Institute indicated an overall survival benefit to chemotherapy in women older or younger than 70 years of age, regardless of positive or negative nodal status.
While the numbers are too small to allow further extrapolations, it is fair to conclude that age greater than or less than 50 years is an artificial cut point, even though the benefit of chemotherapy does appear to decline with age.
Annals of Oncology, 8/02
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