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ELSEVIER EJC Supplements Vol 2 No. 9 (2004) 51-53 ^^^^^^^^^^
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E16. Amenorrhoea, aromatase inhibitors, tamoxifen or a
combination in premenopausal women
R. Jakesz
Department of General Surgery, Vienna Medical School, Wäringer Gürtel 18-20, Vienna 1090, Austria
The ovary is the major site of oestrogen production in premenopausal women. Removal of the ovaries in premenopausal patients with breast cancer has long been recognised to potentially alter the course of disease. This procedure leads to a marked reduction in the circulating levels of oestrogen. It has been shown that ovariectomy given as an adjuvant treatment reduces the odds of recurrence or death by approximately 25%.
Goserelin and other luteinising hormone-releasing hormone (LHRH) analogues produce reversible ovarian suppression by downregulating gonadotropin release via the LHRH receptors of the pituitary gland. Down-regulated receptors lead to an inhibition of LH secretion, which causes a blockade in ovarian function.
Currently, there are at least five different kinds of adjuvant treatment in premenopausal patients presenting with hormone-responsive tumours:
1. Chemotherapy
2. Tamoxifen
3. Ovarian ablation
4. LHRH analogue
5. LHRH analogue combined with tamoxifen
1. Chemotherapy
From a pooled analysis of 1115 premenopausal patients with oestrogen-receptor (ER) positive tumours, the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) obtained data showing adjuvant chemotherapy applied alone induced a significant 33%, and a non-significant 20%, risk reduction in the annual odds of recurrence and death [1]. However, we do not yet know whether anthracycline-containing regimens produce superior results in this setting.
* Tel.: +43 1 40400 6916; fax: +43 1 40400 6918. E-mail address: raimund.jakesz@meduniwien.ac.at.
There is currently little doubt that the effect of adjuvant chemotherapy is age-dependent. Thus, chemotherapy is much more effective in premenopausal than in postmenopausal women. The patient's age plays a key role for those experiencing amenorrhoea after chemotherapy, as younger women are less likely to become permanently amenorrhoeic upon such treatment [2]. Several relevant trials and retrospective analyses have specified that chemotherapy induces an outcome in patients undergoing amenorrhoea that is significantly superior to that shown by women who do not experience an interruption of menses [3,4]. In particular, overall prognosis is markedly increased in patients who experience chemotherapy-induced amenorrhoea. Cyclo-phosphamide, methotrexate and fluorouracil- (CMF) and fluorouracil, doxorubicin, and cyclophosphamide-(FAC) or taxane-containing regimens induce amenor-rhoea in 60-70% and 30-50% of patients, respectively.
2. Tamoxifen
There is no direct comparison between tamoxifen and polychemotherapy in premenopausal patients with hormone-responsive breast cancer. The EBCTCG overview of randomised trials with tamoxifen has shown that the administration of 5 years of tamoxifen in patients younger than 50 years of age leads to a relative risk reduction in the annual odds of recurrence of approximately 45% and in the odds of death of approximately 32% [5]. Although the number of subjects randomised in these studies amounted to no more than 1327, tamoxifen can safely be stated to have at least an effect equal to polychemotherapy in inducing a reduction in recurrence. Furthermore, investigations have suggested ta-moxifen is significantly active in reducing mortality, an effect which is lacking for polychemotherapy. However, final conclusions are still to be drawn as to whether
1359-6349/$ - see front matter © 2004 Published by Elsevier Ltd. doi:10.1016/j.ejcsup.2004.08.015
tamoxifen is indeed as effective as adjuvant polyche-motherapy in the premenopausal setting.
3. Ovarian ablation
Among the currently available therapies for premenopausal early-stage breast cancer, ovarian ablation, together with aromatase inhibition, is applied to decrease oestrogen production.
The EBCTCG 1996 overview included a total of 2102 women under 50 years of age who had participated in a series of randomised trials investigating ovarian ablation applied alone in early breast cancer [6]. ER status was known in such studies - totalling 993 patients - investigating this treatment modality plus cytotoxic chemotherapy versus the same chemotherapy. The results of these trials clearly indicate that ovarian ablation significantly reduced the annual odds of death and recurrence regardless of patients' nodal status. However, ovarian ablation showed no activity in the presence of adjuvant chemotherapy.
Two trials have directly compared chemotherapy and ovarian ablation with patient numbers totalling over 1000 [7,8]. Neither investigation showed a significant difference between the two randomised groups. Am-enorrhoea occurred in 68% of the patients receiving 3-weekly CMF. These two trials unmistakably indicate that permanent surgery- or radiotherapy-induced ovarian ablation has significant activity - comparable to that produced with CMF-based chemotherapy - in patients with hormone-responsive tumours.
4. LHRH analogue
LHRH analogues have been shown to be effective treatment for advanced breast cancer, providing a similar clinical benefit to surgical oophorectomy in terms of progression-free survival (PFS) and overall survival (OS) [9,10]. Thus, they appear to be ideal tools to induce a hormone profile of - reversible - castration without surgical or radio-therapeutic interventions.
Two clinical trials of different maturity have compared CMF-based chemotherapy with LHRH analogues given for 2 years. The Zoladex Early Breast Cancer Research Association (ZEBRA) trial randomised more than 1600 patients to receive either 2 years of goserelin or 6 cycles of CMF [11]. OS rates were absolutely identical in the presence of ER-positive disease. However, in patients with receptor-negative tumours, CMF was shown to be significantly superior to goserelin in terms of survival. This leads to the conclusion that the efficacy of endocrine treatment is restricted to patients with hormone-responsive tumours. Second, the Takeda Adjuvant Breast cancer study with Leu-
prorelin Acetate (TABLE) compared an LHRH analogue with CMF in 600 premenopausal patients with hormone-responsive, node-positive breast cancer [12]. At 3 years follow-up, the TABLE trial evidenced no significant difference between the two arms under investigation, but there was a significantly lower amount of serious adverse events in the endocrine treatment group.
The results of these two investigations clearly indicate that induction of amenorrhoea by the administration of LHRH analogues in approximately 2000 premenopau-sal patients with hormone-responsive tumours has effects that are comparable to those of CMF-based chemotherapy in terms of recurrence-free survival (RFS).
5. LHRH analogue combined with tamoxifen
In advanced breast cancer, combination endocrine treatment with an LHRH analogue plus tamoxifen has been shown to be superior to treatment with either LHRH or tamoxifen alone, as measured by the objective response rate, median PFS and OS [13].
In the adjuvant setting, the Austrian Breast & Colorectal Cancer Study Group (ABCSG) Trial 5 compared a combination of LHRH analogue and ta-moxifen with CMF [14]. More than 1000 premeno-pausal patients with hormone-responsive tumours were randomised between 6 cycles of CMF intravenously (i.v.) and combination endocrine treatment consisting of 3 years goserelin and 5 years tamoxifen. After 6 years of follow-up, patients receiving combination endocrine treatment showed significantly better RFS rates than those treated with CMF. Conversely, other trials with similar designs have indicated no difference between patients given chemotherapy and those receiving a combination of LHRH analogue and tamoxifen [15,16].
Finally, another ongoing multicentre, randomised investigation in Austria, ABCSG Trial 12, is currently investigating whether the combination of goserelin and anastrozole is superior to goserelin plus tamoxifen. More than 1000 patients have been randomised so far.
References
1. Early Breast Cancer Trialists' Collaborative Group. Polchemo-therapy for early breast cancer: an overview of the randomised trials. Lancet 1998, 352, 930-942.
2. Bines J, Oleske DM, Cobleigh MA. Ovarian function in premeno-pausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 1996, 14, 1718-1729.
3. Del Mastro L, Venturini M, Sertoli MR, et al. Amenorrhea induced by adjuvant chemotherapy in early breast cancer patients: prognostic role and clinical implications. Breast Cancer Res Treat 1997, 43, 183-190.
4. Pagani O, O'Neill A, Castiglione M, et al. Prognostic impact of amenorrhea after adjuvant chemotherapy in premenopausal breast cancer patients with axillary node involvement: results of the International Breast Cancer Study Group (IBCSG) Trial VI. Eur J Cancer 1998, 34, 632-640.
5. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998, 351, 1451-1467.
6. Early Breast Cancer Trialists' Collaborative Group. 1998. Ovarian ablation in early breast cancer: an overview of the randomised trials. Lancet 1996, 348, 1189-1196.
7. Scottish Cancer Trials Breast Group and ICRF Breast Unit, Guy's Hospital, London. Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: the Scottish Trial. Lancet 1993, 341, 1293-1298.
8. Ejlertsen B, Dombernowsky P, Mouridsen HT, et al. Comparable effect of ovarian ablation (OA) and CMF chemotherapy in premenopausal hormone receptor positive breast cancer patients (PRP). Proc Am Soc Clin Oncol 1999, 18, 66a (abstr 248).
9. Boccardo, Rubagotti A, Perrotta A, et al. Ovarian ablation versus goserelin with or without tamoxifen in pre-perimenopausal patients with advanced breast cancer: results of a multicentric Italian study. Ann Oncol 1994, 5, 337-342.
10. Taylor CW, Green S, Dalton WS, et al. Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premeno-pausal patients with receptor-positive metastatic breast cancer: an intergroup study. J Clin Oncol 1998, 16, 994-999.
11.Jonat W, Kaufmann M, Sauerbrei W, et al. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast
cancer. The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 2002, 20, 4628-4635.
12. Schmid P, Untch M, Wallwiener D, et al. Cyclophosphamide, methotrexate and fluorouracil (CMF) versus hormonal ablation with leuprorelin acetate as adjuvant treatment of node-positive, premenopausal breast cancer patients: preliminary results of the TABLE-study. Anticancer Res 2002, 22, 2325-2332.
13. Klijn, JGM, Beex LVAM, Mauriac L, et al. Combined treatment with buserelin and tamoxifen in premenopausal breast cancer: a randomized study. European Organisation for Research and Treatment of Cancer - Breast Cancer Cooperative Group. J Natl Cancer Inst 2000, 92, 903-911.
14. Jakesz R, Hausmaninger H, Kubista E, et al. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophospha-mide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer - Austrian Breast & Colorectal Cancer Study Group Trial 5. J Clin Oncol 2002, 20, 4621-4627.
15. Boccardo F, Rubagotti A, Amoroso D, et al. Cyclophosphamide, methotrexate, and fluouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre/ perimenopausal breast cancer patients: Italian Breast Cancer Adjuvant Study Group 02 randomized trial. J Clin Oncol 2000, 18, 2718-2727.
16. Roche HH, Kerbrat P, Bonneterre J, et al. Complete hormonal blockade versus chemotherapy in premenopausal early-stage breast cancer patients (pts) with positive hormone-receptor (HR+) and 1-3 node-positive (N+) tumor: results of the FASG 06 Trial. Proc Am Soc Clin Oncol 2000, 19, 72a (abstr 279).
