EDITORIAL

Ovarian Ablation as Adjuvant Therapy for Premenopausal Women With Breast Cancer—Another Step Forward

Joseph L. Pater, Wendy R. Parulekar

Affiliation of authors: National Cancer Institute of Canada Clinical Trials Group, Queen's University, Kingston, Ontario, Canada.

Correspondence to: Joseph L. Pater, MD, National Cancer Institute of Canada Clinical Trials Group, Queen's University, Kingston, Ontario, Canada K7L 3N6 (e-mail: jpater{at}ctg.queensu.ca)

The role of ovarian suppression in the management of localized, newly diagnosed breast cancer in premenopausal women has been the subject of controversy for some time (1). In this issue of the Journal, results from an International Breast Cancer Study Group (IBCSG) trial (2) that addresses this question add further support for the use of ovarian suppression. However, as the authors imply, the results are best seen as a step in the pathway to the delineation of the true value of ovarian suppression in contemporary patient management.

The IBCSG trial compared, in a group of 1063 premenopausal patients, three treatment strategies: 1) "classical" CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy, 2) CMF followed by ovarian suppression with goserelin, and 3) goserelin alone. Overall, there were no statistically significant differences among the regimens, but in a preplanned subgroup analysis, patients with estrogen receptor (ER)–negative tumors assigned to receive CMF or CMF followed by goserelin had better outcomes than patients assigned to goserelin, whereas patients with ER-positive tumors had very similar outcomes regardless of treatment strategy. In a more exploratory analysis, the benefits of ovarian suppression appeared most striking in younger women with ER-positive tumors (2).

The value of the results of the IBCSG trial (2) is best appreciated in the context of previous evidence concerning the impact of ovarian suppression in the management of premenopausal women with breast cancer. Since cytotoxic chemotherapy was first shown to be useful, it has been argued that it is beneficial for premenopausal women with breast cancer because it causes premature menopause. Studies to date have not resolved the issue, although evidence appears to support the hypothesis of a dual mechanism of action of chemotherapy in this patient population of premenopausal women: direct cytotoxicity and ovarian suppression resulting from chemotherapy-induced ovarian failure. There is ample preclinical and clinical evidence that supports a direct cytotoxic mechanism of action. Metastatic breast cancer is sensitive to chemotherapy, and the efficacy of adjuvant chemotherapy extends to those patients in whom ovarian failure would appear to have little or no impact, i.e., premenopausal patients with hormone receptor–negative tumors and postmenopausal patients (3).

The evidence supporting the gonadotoxic mechanism of action of chemotherapy is indirect but compelling biologically. Chemotherapy, particularly with alkylators such as cyclophosphamide, can cause ovarian fibrosis with a concomitant loss of function. Furthermore, amenorrhea and premature menopause are well known side effects of adjuvant chemotherapy for breast cancer (4). Although the meta-analysis demonstrating a highly clinically significant benefit of ovarian ablation, in terms of recurrences and death, mainly compared the roles of radiation-induced and surgery-induced castration with control (i.e., no ovarian ablation), there is no scientific reason why chemotherapy-induced ovarian failure would not confer benefit, particularly in patients with hormone receptor–positive disease (5). However, because there are no mature randomized phase III data that directly test this question, and the results of subset analyses of completed phase III studies using amenorrhea as a surrogate marker of ovarian failure are inconsistent (6), the extent of benefit rendered by chemocastration is unknown.

The IBCSG trial (2) addressed the use of ovarian suppression both as a replacement for and as a supplement to cytotoxic chemotherapy. Both questions have been addressed in previous trials (710). Four published studies (710) have compared various forms of ovarian ablation, with or without the addition of tamoxifen, to CMF chemotherapy given intravenously or orally. All trials showed equal or superior outcomes for the non–chemotherapy-containing arms although, similar to the IBCSG study (2), none were designed with sufficient power to demonstrate formal equivalence between the study arms. On the basis of all of the available evidence, however, it seems very likely that ovarian ablation can achieve results comparable to those from studies of CMF chemotherapy in premenopausal women with hormone receptor–positive breast cancer.

The addition of ovarian ablation to chemotherapy has been less well studied, and the IBCSG trial provides the most extensive published information to date. The authors indicate that, similar to their own findings, an intergroup trial of 1500 patients led by the Eastern Cooperative Oncology Group, and presented at the American Society for Clinical Oncology annual meeting in 1999 (11), failed to demonstrate a statistically significant advantage to adding goserelin to chemotherapy regimens. The results of a trial conducted much earlier (12) that added oophorectomy to chemotherapy were also negative. However, none of these studies explored a strategy of confining the use of ovarian suppression to women who do not become postmenopausal with chemotherapy—an approach that the evidence summarized above suggests would be most helpful.

What are the implications for practicing physicians? To date, there is little supporting evidence for the addition of ovarian ablation to all premenopausal patients who are candidates for chemotherapy. With respect to substitution of ovarian ablation for chemotherapy, it would be reasonable to offer this treatment option to patients with hormone receptor–positive disease who are candidates for CMF or adriamycin and cyclophosphamide (AC) chemotherapy. Patient preferences regarding the impact of typical side effects of chemotherapy versus those of premature menopause are especially important to consider in this circumstance. Because of the lack of data on the efficacy of ovarian ablation compared with regimens shown to be superior to CMF (13) or AC (14), ovarian ablation should not be recommended routinely to premenopausal patients who would otherwise be treated with these newer regimens.

In conclusion, the IBCSG trial (2) and previous trials have served the very useful purpose of demonstrating that ovarian ablation is a viable treatment alternative for at least some premenopausal women with breast cancer (1). However, we agree with the authors (2) that the way forward is to study, in randomized trials, the selective use of ovarian suppression in women who are not rendered menopausal by chemotherapy. Although, on the basis of limited evidence (15), the administration of tamoxifen in this setting has become a standard of care, we also agree that now is an opportune time to examine whether an aromatase inhibitor will prove to be a superior alternative, because the results of recent trials (16,17) indicate that complete suppression of estrogen production may be a better strategy than blocking its action at the receptor level.

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