Combined Endocrine Blockade in Premenopausal Breast Cancer: A Superior Therapeutic Option for Adjuvant Management?
Authors: Manish Kohli, Mir Ali Khan, Paulette Mehta, Laura Hutchins
Journal: Journal of Clinical Oncology (2003)

To the Editor: We read with great interest the two articles and the editorial in the December 15, 2002 issue of the Journal of Clinical Oncology, concerning adjuvant hormonal treatment of breast cancer. [1]2][3] In both studies, the authors compared a "standard" cyclophosphamide, methotrexate fluorouracil-(CMF-) only treatment arm with goserelin 1 or goserelin plus tamoxifen. 2 According to Jonat et al, 1 "goserelin offers an effective, well-tolerated alternative to CMF chemotherapy in the management of premenopausal patients with ER-[estrogen receptor-] positive and node-positive early breast cancer."According to Jakesz et al, 2 "complete endocrine blockade with goserelin and tamoxifen is superior to standard chemotherapy in premenopausal women with hormone-responsive stage I and II breast cancer."In the editorial commenting on these two studies, Kathleen Pritchard asked, "Is it time for another paradigm shift?" 3 If this question is asked in the context of the previously mentioned studies, the answer might be, "Not yet."Let us repeat what we all know.First, anthracyclinecontaining regimens yield superior results, both for recurrence-free survival (absolute difference at 5 years, 3.2%) and overall survival (absolute difference at 5 years, 2.7%). 4In both the Jonat et al and Jakesz et al studies, the control arm was patients receiving CMF.We know that 4 months of doxorubicin and cyclophosphamide is clearly equivalent to 6 months of CMF 5 ; however, we also know that there are regimens that are clearly superior to CMF 6,7 that have been defined in previously reported studies. 8 Second, tamoxifen was associated with a highly significant improvement in recurrence-free survival (absolute difference at 10 years, 14.9%-15.2%)and in overall survival (absolute difference at 10 years, 5.5%-10.9%) in ER-positive women. 9In the article by Jonat et al 1 and in the accompanying editorial, 3 it was acknowledged that there were only 177 women with ER-positive disease who were randomly selected to chemotherapy, or to chemotherapy plus tamoxifen in the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview.According to the Jonat et al and the accompanying editorial, although widely used in practice, not enough data were available to support the addition of tamoxifen after standard chemotherapy in premenopausal patients, and this argument was used as a justification for lack of tamoxifen use in the control groups.However, both in the recently published studies, as well as in all other studies cited in the editorial that compared ovarian ablation with chemotherapy (mostly with CMF), the chemotherapy plus tamoxifen regimen is apparently lacking.So "177" is better than "zero," and as a general rule, absence of proof does not mean proof of absence.On the other side, Jakesz et al, 2 in addressing the choice of treatment in the control arm, stated that when Austrian Breast and Colorectal Cancer Study Group Trial 5 was launched in 1990, the data of the EBCTGG overview were largely unknown; therefore, CMFonly, the chemotherapeutic regimen of choice at that time, was chosen.However, knowing the data at present, we do not accept CMF without tamoxifen as a "standard" in this group, and so we can not come to the same conclusion of Jakesz et al, who reported that "complete endocrine blockade with goserelin and tamoxifen is superior to standard chemotherapy in premenopausal woman with hormone responsive stage I and II breast cancer".We still do not know what is the "best standard" chemotherapy for lymph node-positive, ER-positive premenopausal breast cancer; however, we absolutely know what is not.CMF without tamoxifen is clearly not a sufficient treatment in this group of patients.Studies with a control arm of anthracycline-based chemotherapy plus tamoxifen are definitely and urgently needed in order that the conclusions of Jakesz et al be better received.After reading the results of these two trials, we draw a conclusion that is different from those reported.Ovarian ablation with goserelin is equivalent to CMF without tamoxifen, and goserelin plus tamoxifen is more effective than CMF without tamoxifen.If one has a premenopausal patient with ER-positive, lymph node-positive breast cancer, goserelin plus tamoxifen is a good alternative to treating her with intravenous CMF without tamoxifen while achieving the same results.Is there anyone who would treat such a patient with CMF only?