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© 2002 American Society for Clinical Oncology
Adjuvant Therapy for Premenopausal Women With Breast Cancer: Is It Time for Another Paradigm Shift?Toronto Sunnybrook Regional Cancer Centre, Toronto, Ontario, Canada We shall not cease from exploration and the end of all our exploring will be to arrive where we started . . . and know the place for the first time. "Little Gidding V," T.S. Eliot (The Complete Poems and Plays, 1909-1950, New York, Harcourt, Brace & World) OVARIAN ABLATION as therapy for metastatic breast cancer has been known to be effective since the turn of the century, and it has been recommended as adjuvant therapy for nearly as long.1,2 However, small, underpowered, randomized studies in the 1950s, 1960s, and 1970s left the role of this modality in the adjuvant setting uncertain.3,4 The initial 1984 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Overview, however, using the powerful technique of meta-analysis, clearly showed that adjuvant ovarian ablation (with or without prednisone) resulted in prolonged relapse-free and overall survival.5,6 Further EBCTCG analyses have shown that, while adjuvant ovarian ablation is superior to no systemic adjuvant therapy, the addition of adjuvant ovarian ablation to adjuvant chemotherapy adds little compared with the effects of adjuvant chemotherapy alone.7 The 2000 Oxford Overview also contains data from three as yet unpublished trials in which the addition of goserelin to chemotherapy is either marginally or no better than chemotherapy alone (A. Goldhirsch, personal communication, March 2002).8,9 It has also been suggested, however, that ovarian suppression—as reflected by amenorrhea—may be a major mechanism of action of adjuvant chemotherapy in premenopausal women. Many investigators have reported that women who develop amenorrhea have improved relapse-free and overall survival compared with those women whose menses persist after adjuvant chemotherapy.10-13 Furthermore, the fact that premenopausal women derive a greater proportional benefit from adjuvant chemotherapy than postmenopausal women would suggest that some of the activity of adjuvant chemotherapy may be mediated by an endocrine mechanism.14 In this issue of the Journal of Clinical Oncology, Jakesz et al15 and Jonat et al16 present two of the first full publications from a group of recently conducted trials comparing endocrine therapy with combination cytotoxics as adjuvant treatment for premenopausal women. The results of other major trials of similar design have been presented over the last 2 years, but only one other has been published as a full report.17 In their well-conducted study, Jakesz et al randomized 1,034 premenopausal women with estrogen receptor (ER)–positive or progesterone (PgR)-positive breast cancer to receive either (1) goserelin for 3 years plus tamoxifen for 5 years or (2) cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy. This comparison clearly demonstrated that relapse rates were significantly reduced in favor of endocrine therapy with goserelin and tamoxifen (17.2% v 20.8%; P = .037) while local recurrences were even more dramatically affected (4.7% v 8.0%; P = .015). A non–statistically significant trend in favor of the endocrine approach was also observed in overall survival (P = .195). Of interest, the rates of distant metastases were similar in the two treatment arms. Jonat et al,16 unlike Jakesz et al,15 did not restrict study entry to ER- or PgR-positive patients, but allowed women with negative or unknown ER status to enter their study. Their trial design also differed in that CMF chemotherapy was compared with goserelin alone given for 2 years, without the use of tamoxifen in either arm. Similar to the results seen by Jakesz et al, however, Jonat et al showed that in women with ER-positive breast cancer (approximately 75% of those in the study), goserelin given for 2 years was equivalent to CMF for disease-free (hazard ratio [HR], 1.01) and overall survival (HR, 0.99). In ER-negative and ER-unknown patients, CMF was superior, however, to goserelin, for disease-free survival (HR, 1.76 and 2.0, respectively) and for overall survival (HR, 1.77 for ER-negative and ER-unknown combined). Jakesz et al15 also demonstrated that in the CMF-treated group, the induction of amenorrhea was associated with a positive effect on relapse-free survival. In addition, older women were more likely to become amenorrheic. Jakesz et al, in their discussion, attribute this improved outcome to age, with amenorrhea as a related, but noncausative, covariate. It seems, from other available data, however, that reduced ovarian function (as reflected by amenorrhea) may be the causative factor and age only an underlying predictor of the likelihood of becoming amenorrheic. Jonat et al also suggest that amenorrhea in CMF-treated women was associated with an improved relapse-free survival. In their trial, amenorrhea was also strongly correlated with older age. Jonat et al16 suggest that, while the overall results of their study show that CMF is superior to goserelin, there is such a strong interaction with ER status that the overall analysis is comparatively meaningless. Therefore, the results for ER-positive and ER-negative subgroups must be considered separately. Thus they conclude that goserelin, given for 2 years, offers an effective, well-tolerated alternative to CMF for premenopausal women with ER-positive, node-positive early breast cancer. Jakesz et al,15 in turn, suggest that for the premenopausal woman with ER-positive or PgR-positive, node-negative or node-positive breast cancer, ovarian ablation with goserelin for 3 years given with tamoxifen for 5 years may be not only an acceptable but a preferred alternative to CMF chemotherapy. Considerable other data now support these points of view. A recent publication by Boccardo et al17 compared CMF chemotherapy to tamoxifen plus ovarian suppression and showed no statistically significant difference between combined endocrine therapy and CMF. The preliminary data of the French Adjuvant Study Group 06 trial of Roche et al18 show a trend toward an advantage for complete hormonal blockade over chemotherapy. Data have also been presented in a preliminary fashion from the International Breast Cancer Study Group VIII trial comparing CMF to ovarian suppression,19 from a French trial comparing fluorouracil, doxorubicin, and cyclophosphamide to ovarian suppression and tamoxifen, and from a trial by Ejlertsen et al20 comparing ovarian ablation to CMF chemotherapy, all in premenopausal, hormone receptor–positive patients. Each of these trials suggests equivalent outcomes from either an endocrine approach or from CMF chemotherapy. These data build on similar results from older trials from the Scottish group21 which compared CMF with surgical ovarian ablation and from a Scandinavian group which compared CMF with ovarian radiation. Thus there are now strong data to suggest that ovarian ablation alone is probably equivalent to CMF-type chemotherapy in premenopausal women with ER-positive or PgR-positive breast cancer. Furthermore, these data suggest that the combination of ovarian ablation and tamoxifen may provide an even better endocrine approach, at least equivalent and probably superior to CMF-type adjuvant chemotherapy in this group of women. Thus it may well be that a patient who today, in most of North America, would be treated with CMF or an equivalent chemotherapy regimen such as doxorubicin and cyclophosphamide (AC),22 and who has ER-positive or PgR-positive disease, could be equally well treated by a combination of ovarian ablation (by surgical, irradiation, or medical suppressive means) plus tamoxifen. Should endocrine therapy alone become the standard adjuvant treatment for premenopausal women with ER-positive or PgR-positive breast cancer? Or should chemotherapy remain the core of standard therapy, with or without the addition of tamoxifen or ovarian ablation? There are currently few data to support the addition of ovarian ablation to adjuvant chemotherapy. Both the EBCTCG Overview7 and the three currently available studies adding goserelin to CMF (A. Goldhirsch, personal communication, March 2002); to cyclophosphamide, doxorubicin, and fluorouracil (CAF)8; or to any chemotherapy9 suggest little if any benefit from the addition of ovarian ablation or goserelin. The INT 0101 trial compared (1) CAF alone, (2) CAF plus goserelin, and (3) CAF plus goserelin plus tamoxifen. The addition of tamoxifen and goserelin to CAF did produce significantly better disease-free and overall survival, but the addition of goserelin alone showed only marginal benefit.8 In the EBCTCG Overview there are only 177 women23 with ER-positive disease who were randomized to chemotherapy or to chemotherapy plus tamoxifen. Although several large trials testing this question have completed accrual (European Organization for Research and Treatment of Cancer, International Breast Cancer Study Group IX, National Cancer Institute of Canada Cancer Treatment Group MA.12), none have sufficient patient events for analysis, and no data are available from any of the trials. Thus, while the addition of tamoxifen to chemotherapy in the premenopausal adjuvant setting has become an accepted standard in North American practice, there remain remarkably few data to support its use. And what of newer chemotherapeutic regimens for premenopausal women? Early enthusiasm for the role of AC followed by paclitaxel, in comparison with AC alone, has waned since relapse-free survival and overall survival have not held up well in 3-year follow-up.24,25 This was particularly true in the ER- and PgR-positive subset, where little benefit is apparently seen for the addition of paclitaxel.24,25 A National Cancer Institute of Canada Cancer Treatment Group trial by Levine et al,26 however, continues to report superior disease-free and overall survival after nearly 9 years of median follow-up in women treated with cyclophosphamide, epirubicin, and fluorouracil (CEF), compared with the classic Bonadonna CMF regimen in the premenopausal node-positive setting (M. Levine, personal communication, April 2002). Furthermore, recent reports have suggested that docetaxel, doxorubicin, and cyclophosphamide may be superior to fluorouracil, doxorubicin, and cyclophosphamide27 and that the CEF 100 regimen may be superior to CMF regimens.28-30 There are problems, however, with many of these intratrial comparisons. The CMF that has been compared with ovarian ablation and tamoxifen in the trials described in this editorial is not, in most cases, the classic Bonadonna CMF regimen with oral cyclophosphamide, originally compared with surgery alone in the mid-1970s.31 While the Canadian CEF regimen has been well tested against this classic CMF regimen, trials such as that of docetaxel, doxorubicin, and cyclophosphamide versus fluorouracil, doxorubicin, and cyclophosphamide27 and fluorouracil, epirubicin, and cyclophosphamide versus CMF29 have used "control" regimens that either have never been compared with no-treatment control arms in the adjuvant setting (fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2)27 or are variations on the original (the CMF in fluorouracil, epirubicin, and cyclophosphamide v CMF).29 This makes it difficult to be certain that many of these newer chemotherapies are actually better than standard CMF or the CMF variants which are commonly used. The marginal benefit for anthracycline-containing regimens seen in the EBCTCG Overview14 is also difficult to interpret because the regimens are a mixture of those that are clearly equivalent to CMF (AC x 4)22 and others that are clearly superior (Canadian CEF).26,27 Further to the optimal treatment regimen for this group of women, it is clear from the data presented by Jonat, Jakesz, and others that while the side effect profiles differ for endocrine compared with CMF therapy, neither approach is without its problems. While risks of infection, hair loss, and nausea are clearly greater with cytotoxics, they are over fairly quickly, while the endocrine effects of 2 or 3 years of goserelin, which produces all of the side effects of rapid menopause, are severe and universal. On the other hand, when goserelin is discontinued, many patients resume menstruating and the vasomotor and other side effects of menopause disappear. In contrast, many of the patients treated with adjuvant CMF are left with long-term menopausal symptoms. Thus it is not obvious that one treatment approach is necessarily superior to the other in terms of side effects. Rather, it would seem that differing toxicity profiles could provide a spectrum of choice for patient and clinician. Furthermore, additional trials are required to answer a number of questions that remain unanswered at present. Are there newer types of chemotherapy that are actually superior to an "optimal" endocrine approach in the premenopausal woman? Is there a more "optimal" endocrine approach in premenopausal women than those that have been tested? Could ovarian ablation plus an aromatase inhibitor be superior to ovarian ablation plus tamoxifen? What benefit is there in adding ovarian ablation, with or without tamoxifen, to best chemotherapy? What benefit is there in adding best chemotherapy to optimal endocrine therapy as defined by either ovarian ablation with tamoxifen or ovarian ablation with an aromatase inhibitor? How long should ovarian ablation be used? Is 2 or 3 years of goserelin equivalent to permanent ovarian ablation? And, if we have the courage to step back and discard our current assumptions, we could perhaps reexamine the most fundamental question of all: Is adjuvant chemotherapy required at all for premenopausal women with ER- or PgR-positive tumors? Perhaps we should seriously consider a trial in which optimal endocrine adjuvant therapy would be compared with optimal cytotoxic adjuvant therapy in order to answer this question, and thereby provide additional options in this group of women. In summary, while many questions remain to be answered, it seems clear that we must begin to think of endocrine therapy as a legitimate alternative to chemotherapy in the adjuvant treatment of women with receptor-positive breast cancer. This form of targeted therapy has probably been greatly underused in North America and perhaps in other parts of the world as well, while chemotherapy has been considered "King." In the meantime, we will await with great interest the results of completed but unreported and currently active clinical trials, as well as the design and conduct of new studies that will test many of these as yet unanswered questions. REFERENCES 1. Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma: Suggestions for a new method of treatment with illustrative cases. Lancet 2: 104-107, 1896 2. Schinzinger A: Ueber carcinoma mammae. Verh Dtsch Ges Chir 18: 28-29, 1889 3. Nissen-Meyer R: Ovarian suppression and its supplement by additive hormonal treatment, in Namer M, Lalanne CM (eds): Hormones and Breast Cancer. Paris, France, L’Institut National de la Santé et de la Recherche Médicale, 1975, pp 151-158 4. Meakin JW, Allt WEC, Beale FA, et al: Ovarian irradiation and prednisone following surgery and radiotherapy for carcinoma of the breast. Breast Cancer Res Treat 3: 45-48, 1983 5. Pritchard KI: Ovarian ablation as adjuvant therapy for premenopausal women with early breast cancer: Phoenix arisen? Lancet 339: 95-96, 1992 (editorial)[CrossRef][Medline] 6. Early Breast Cancer Trialists’ Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 339: 71-85, 1992[Medline] 7. Early Breast Cancer Trialists’ Collaborative Group: Ovarian ablation in early breast cancer: An overview of the randomized trials. Lancet 348: 1189-1196, 1996[CrossRef][Medline] 8. Davidson N, O’Neill A, Vukov A, et al: Effect of chemohormonal therapy in premenopausal, node (+), receptor (+) breast cancer: An Eastern Cooperative Oncology Group phase III intergroup trial (E5188, INT-0101). Proc Am Soc Clin Oncol 18: 67a, 1999 (abstr 249) 9. Baum M, Rutgers E: Zoladex and tamoxifen as adjuvant therapy in premenopausal breast cancer: A randomized trial by the Cancer Res Campaign (CRC) Breast Cancer Trials Group, the Stockholm Breast Cancer Study Group, the South-East Sweden Breast Cancer Group and the Gruppo Interdisciplinare Valutazione in Interventi in Oncologia. Breast 8: 233, 1999
10. Goldhirsch A, Gelber R, Castiglione-Gertsch M: The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients: The International Breast Cancer Study Group. Ann Oncol 1: 183-188, 1990 11. Bianco AR, Del Mastro L, Gallo C, et al: Prognostic role of amenorrhea induced by adjuvant chemotherapy in premenopausal patients with early breast cancer. Br J Cancer 63: 799-803, 1991[Medline] 12. Jonat W: Zoladex versus CMF adjuvant therapy in pre/peri-menopausal breast cancer: Tolerability and amenorrhoea comparisons. Proc Am Soc Clin Oncol 19: 87a, 2000 (abstr 333) 13. Richards MA, O’Reilly SM, Howell A, et al: Adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with axillary node-positive breast cancer: An update of the Guy’s/Manchester trial. J Clin Oncol 8: 2032-2039, 1990[Abstract] 14. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomized trials. Lancet 352: 930-942, 1998[CrossRef][Medline]
15. Jakesz R, Hausmaninger H, Kubista E, et al: Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: Evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer—Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol 20: 4621-4627, 2002
16. 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 20: 4628-4635, 2002
17. Boccardo F, Rubagotti A, Amoroso D, et al: Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor–positive pre-/perimenopausal breast cancer patients: Results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial. J Clin Oncol 18: 2718-2727, 2000 18. 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 19: 72a, 2000 (abstr 279) 19. Gelber RD, Goldhirsch A, Castiglione M, et al: Premenopausal oophorectomy versus CMF chemotherapy in stage II breast carcinoma: The International Breast Cancer Study Group (IBCSG). Lancet 342: 305, 1993 (letter)[CrossRef][Medline] 20. 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 18: 66a, 1999 (abstr 248) 21. Scottish Cancer Trials Breast Group: Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: The Scottish trial. Lancet 341: 1293-1298, 1993[Medline] 22. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8: 1483-1496, 1990[Abstract] 23. Bramwell VH, Pritchard KI: Tamoxifen added to adjuvant chemotherapy in premenopausal women with early breast cancer: Is it standard practice or still a subject for study? Eur J Cancer 35: 1625-1627, 1999[CrossRef][Medline] 24. Henderson IC, Berry D, Demetri G, et al: Improved disease-free (DFS) and overall survival (OS) from the addition of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients (pts) with node-positive primary breast cancer (BC). Proc Am Soc Clin Oncol 17: 101a, 1998 (abstr 390A) 25. National Institutes of Health Consensus Development Conference Statement: Adjuvant chemotherapy for breast cancer. NIH Consensus Development Statement 5: 12, 1985 (letter) 26. Levine MN, Bramwell VH, Pritchard KI, et al: A randomized trial of cyclophosphamide, epirubicin, fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, fluorouracil in premenopausal women with node positive breast cancer. J Clin Oncol 16: 2651-2658, 1998[Abstract] 27. Nabholtz J-M, Pienkowski T, Mackey J, et al: Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: Interim analysis of the BCIRG 001 study. Proc Am Soc Clin Oncol 21: 36a, 2002 (abstr 141)
28. French Adjuvant Study Group: Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: Five-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol 19: 602-611, 2001 29. Coombes RC, Bliss JM, Wils J, et al: Adjuvant cyclophosphamide, methotrexate and fluorouracil versus fluorouracil, epirubicin and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: Results of a randomized trial. J Clin Oncol 14: 35-45, 1996[Abstract] 30. Bonneterre J, Roche H, Bremond A, et al: A randomized trial of adjuvant chemotherapy with FEC 50 vs FEC 100 for node-positive operable breast cancer early report. Proc Am Soc Clin Oncol 15: 82a, 1996 (abstr 104) 31. Bonadonna G, Brusamolino E, Valagussa P, et al: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 294: 405-410, 1976[Abstract]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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