Do Receptor-Positive, Postmenopausal Women Need Adjuvant Chemotherapy? Robert S. Mocharnuk, MD Disclosures 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.[1] 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.[1] 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[2] 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[3] 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.[1] 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.[4] 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. The benefits of chemotherapy for women younger than 50 years of age, based upon hormone receptor status, are shown in Table 1. Table 1. National Institutes of Health Consensus Conference Data Hormone Receptor Status Decrease in Relative Risk of Relapse Decrease in Relative Risk of Death ER-negative 43% 32% ER-positive 38% 29% ER, estrogen receptor Examining the previously presented EBCTCG overview data in women younger than aged 50 years, the following results were observed (Table 2). Table 2. European Breast Cancer Trialists' Cancer Group Data Treatment Regimen Decrease in Relative Risk of Relapse Decrease in Relative Risk of Death Tam vs observation 45% 20% Chemotherapy/tam vs tam 19% 11% Tam, tamoxifen Selecting out those patients who received anthracycline treatment vs cyclophosphamide/methotrexate/5-fluorouracil (CMF) demonstrated the importance of anthracycline therapy regardless of age, nodal status, or hormone receptor status (Table 3). Table 3. Subset Early Breast Cancer Trialists' Collaborative Group Data Anthracycline Status Decrease in Relative Risk of Relapse Decrease in Relative Risk of Death No 18% 12% Yes 23% 15% While older phase 3 studies (SWOG 7078, Ludwig 111, GROCTA, and NOIC-MA4) demonstrated no benefit to combination chemoendocrine therapy, newer trials like the International Breast Cancer Study Group IX and NSABP-20 presented conflicting results. The negative findings of the former may be attributable to the shorter duration of chemotherapy given, the fact that CMF may be more effective in patients with metastatic breast cancer, and differences in tumor biology (with a greater percentage of well-differentiated tumors found in older women). If one stratifies patients according to strict biomarker equivalency, response to chemoendocrine therapy equalizes across age groups. Chemoendocrine therapies employing anthracycline-based regimens have been shown to improve disease-free and overall survival in NSABP-16 and the French Adjuvant Study Group (FASG)-07.[5] In the Breast Cancer Intergroup Trial 0100, which randomized 1500 patients to receive cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) plus tamoxifen vs tamoxifen, 32% of patients were aged 65 years or older and 13% were older than 70 years of age. Disease-free survival at 5 years was 76% in the CAF-plus-tamoxifen arm vs 67% in the tamoxifen-alone arm, and a 5% overall survival difference was seen at 5 years. An 8-year update of SWOG 8814, to be presented at the upcoming American Society of Clinical Oncology meeting, continues to show both disease-free and overall survival benefits to combined chemoendocrine therapy over endocrine treatment alone at 8 years (Table 4). Table 4. Update of the Southwest Oncology Group 8814 Data Survival Data Tamoxifen Alone CAF Plus Tamoxifen Disease-free survival 55% 67% Overall survival 67% 73% CAF, cyclophosphamide, doxorubicin, and 5-fluorouracil While tumor grade, HER-2 status, and other factors will continue to influence treatment decisions; for the present, anthracycline-based adjuvant chemoendocrine therapy confers a significant survival advantage and should continue to be offered to patients. In a short second affirmative presentation, Dr. Howell pointed out that the need for such a debate merely emphasizes the ongoing doubts under which clinicians struggle.[1] He criticized Dr. Albain's reliance on premature NIH consensus conference data that are still being analyzed, and further argued about the EBCTCG overview findings because of the "indirect" comparisons being made. Relying strictly upon the direct comparisons that are made, the 11% added reduction in death observed cannot be construed to represent an absolute 11% reduction in death in favor of chemoendocrine therapy. This miniscule benefit must be weighed against the toxic side effects of chemotherapy that, according to Dr. Gelber's prior assessment, just aren't worth it. Citing NSABP-16 is disingenuous because this study included patients with ER-negative tumors. Finally, SWOG 8814, which has never been published outside of an abstract, used some rather "novel" randomization techniques in assigning more than 1000 patients to the chemoendocrine therapy arms while only 300 were treated with tamoxifen alone. Dr. Davidson responded to Dr. Howell by asking what is considered beneficial, who judges that benefit, and what is the level of evidence forming both.[1] In discussing benefit, the standards for analysis have always been improvement in survival, decreased recurrence, and palliation of symptoms for incurable disease. Q-TwiST is not a standard measuring device and should not be used to determine benefit. As for who should judge response, Dr. Davidson emphatically insisted that this right falls to the patient, in spite of family, physician, insurance status, governmental, or societal input. Supporting the use of chemotherapy, she cited a study by Lindley and colleagues[6] in which 86 patients with breast cancer were questioned as to whether they were willing to undergo 6 months of chemotherapy in order to derive a 5% benefit. About 65% of patients opted for the chemotherapy. And lest her non-American colleagues pass this off as merely "Yankee madness," Dr. Davidson cited even more extreme findings in support of chemotherapy among Dutch and Australian women surveyed.[7,8]. Dr. Peto, of Oxford, United Kingdom, member of the EBCTCG consortium, concluded emphatically that a benefit to chemoendocrine therapy exists in women older than aged 50 years, and this opinion is further supported by the conclusions of Intergroup trial 0100, NSABP-16, NSABP-20, and SWOG 8814.[1] At this point, several comments and questions were taken from the audience. One gentleman observed that what physicians think is not necessarily the same as what physicians actually do in clinical practice. Another gentleman observed that while chemotherapy may indeed enhance survival, he was personally not willing to risk the loss of cognitive function typically observed in older patients. A lady indicated that characterization of 3 different ER expression patterns by microarray analysis may render this entire discussion moot if it can be determined which expression patterns warrant treatment beyond hormonal suppression. Another individual observed that a subset of postmenopausal patients whose tumors highly express ER do worse when given chemotherapy. This was seconded by another who remarked that ER-positive tumors are indeed a "mixed bag," and that some postmenopausal women who continue to produce estrogen may uniquely benefit from the addition of chemotherapy. Finally, a lady argued that it was unfair to rely upon the patient to make her own treatment decisions since this issue is too complicated even for most oncologists to decide. Dr. Albain concluded by stating that not all of the supportive evidence is derived from subset analysis and that anthracycline-based regimens are usually necessary. In addition, in her opinion, improvements in supportive care have made Q-TwiST analysis obsolete. Dr. Rose responded that endocrine therapy is really the first of the targeted therapies for breast cancer, and as such, is innovative rather than archaic (just like CAF chemotherapy). Q-TwiST is not in itself an end point, but rather a tool for direct comparison of regimens. If chemotherapy is no better than tamoxifen alone, then perhaps the use of selected estrogen receptor modulators will improve upon tamoxifen's effects. Finally, Dr. Rose suggested that American physicians do not factor cost/benefit analysis into their treatment decisions. If they did, 15 women would have to undergo chemotherapy in order to derive an average 1 month of improved overall survival. An audience vote, taken before and immediately after this debate, continued to show half in support of and half opposed to the use of adjuvant chemoendocrine therapy in postmenopausal patients with ER-positive tumors. References 1. Rose C, Howell A, Albain K, Davidson N. Oxford union style debate. This house believes that adjuvant chemotherapy offers negligible benefit to receptor positive postmenopausal women. Program and abstracts of the 3rd European Breast Cancer Conference; March 19-23, 2002; Barcelona, Spain 2. Gelber RD, Cole BF, Goldhirsch A, et al. Adjuvant chemotherapy plus tamoxifen compared with tamoxifen alone for postmenopausal breast cancer: meta-analysis of quality-adjusted survival. Lancet. 1996;347:1066-1071. 3. Cole BF, Gelber RD, Gelber S, et al. Polychemotherapy for early breast cancer: an overview of the randomised clinical trials with quality-adjusted survival analysis. Lancet. 2001;358:277-286. 4. National Institutes of Health Consensus Development Panel. National Institutes of Health Consensus Development Conference state: adjuvant therapy for breast cancer. Nov 1-3, 2000. J Natl Cancer Inst Monogr. 2001;30:5-15. 5. Gerard JP, Hery M, Gedouin M, et al. Postmenopausal women with node-positive resectable breast cancer. Tamoxifen vs FEC 50 (6 cycles) vs FEC 50 (6 cycles) plus tamoxifen vs control -- preliminary results of a 4-arm randomised trial. The French Adjuvant Study Group. Drugs. 1993;45(suppl 2):60-67. 6. Lindley C, Vasa S, Sawyer WT, et al. Quality of life and preferences for treatment following systemic adjuvant therapy for early-stage breast cancer. J Clin Oncol. 1998;16:1380-1387. 7. Jansen SJ, Kievit J, Nooij MA, et al. Patients' preferences for adjuvant chemotherapy in early-stage breast cancer: is treatment worthwhile? Br J Cancer. 2001;84:1577-1585. 8. Simes RJ, Coates AS. Patient preferences for adjuvant chemotherapy of early breast cancer: how much benefit is needed? J Natl Cancer Inst Monogr. 2000;30:146-152. Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. 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