Ovarian Ablation as Adjuvant Therapy for Breast Cancer

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1 Ovarian Ablation as Adjuvant Therapy for Breast Cancer Nancy E. Davidson Ovarian ablation was the first form of systemic treatment for breast cancer. Its efficacy as a palliative treatment for young women with metastatic breast cancer was initially described by Beatson (1) in Its use as a form of adjuvant therapy was suggested shortly thereafter, and the first randomized trials of ovarian ablation in the adjuvant setting began in Although many of these early trials were small and methodologically flawed by modern standards, their combined analysis through the Early Breast Cancer Trialists Collaborative Group (EBCTG) has unequivocally established that ovarian ablation as a single intervention reduces recurrence and increases survival for women under the age of 50 years (2). Indeed, the magnitude of the benefit is similar to that seen with adjuvant chemotherapy or tamoxifen by indirect comparison (3,4). Thus, the possibility that the benefit conferred by adjuvant chemotherapy is in part because of its ability to induce ovarian failure has been raised. Adjuvant studies of ovarian ablation during the last 50 years have focused largely on three major questions. The first trials examined the utility of ovarian ablation versus no postoperative therapy. Increasing use of chemotherapy and the recognition that part of its effects could be related to a chemical castration led to randomized comparisons of adjuvant chemotherapy and ovarian ablation with or without tamoxifen. Finally, several recent trials have examined the possibility that ovarian ablation has additional benefit in young women who have received adjuvant chemotherapy. It is surprising that little information is available comparing ovarian ablation and tamoxifen in the adjuvant setting. FORMS OF OVARIAN ABLATION Surgical oophorectomy was the original form of ovarian ablation. Its advantage is that it causes an immediate and permanent drop in ovarian steroid production. In the past, the surgical complication rate was relatively high, but current methods of laparoscopic surgery have dramatically reduced postoperative morbidity and mortality. Oophorectomy has the second theoretical advantage of reducing risk of ovarian cancer, which could be potentially useful in women who are genetically predisposed to ovarian cancer. The advent of therapeutic radiation led to the design of trials of radiation-induced ovarian ablation. Treatment algorithms were variable, ranging from 450 cgy in one fraction to cgy over five to six fractions. Radiation-induced ovarian ablation is a safe and simple outpatient approach. Its disadvantage is that it may be incomplete or reversible in some women. During the last 20 years, medical ovarian ablation has emerged as a treatment strategy. A number of analogues of luteinizing hormone-releasing hormone (LHRH) have been studied as treatment for breast cancer. Chronic administration of the LHRH agonists leads to a temporary chemical castration. Ovarian production of estrogen is governed by the pulsatile release of LHRH from the hypothalamus. This leads to pituitary production of gonadotropins that then act on the ovary to stimulate steroidogenesis. LHRH agonists bind to pituitary gonadotropin receptors more avidly than to native LHRH. This leads to an initial surge in gonadotropin production, but loss of pituitary LHRH receptors, diminished gonadotropin secretion, and cessation of ovarian steroid production then ensue. Two LHRH analogues are available in the United States (goserelin and leuprolide) and can be administered by monthly injection; neither is currently approved by the U.S. Food and Drug Administration for adjuvant therapy of breast cancer. The possible advantages of LHRH analogues are their ease of administration and reversible effects. Side effects are largely those of menopause. The relative efficacy of surgical, therapeutic radiation, and medical ovarian ablation is not well defined. Indeed, it is generally assumed that these three modalities are equally effective in breast cancer, and the approaches are frequently considered and used interchangeably. Small comparative trials of goserelin with surgery or therapeutic radiation-induced ovarian ablation for treatment of advanced breast cancer have supported this supposition, but it is not known if these results suggesting equivalence in metastatic breast cancer can be extrapolated to the adjuvant setting, where duration of treatment is potentially critical (5). Cytotoxic chemotherapy represents a fourth form of ovarian ablation because of its capacity to cause temporary or permanent ovarian dysfunction in a substantial number of premenopausal women. The risk of chemotherapy-related amenorrhea is directly related to age at time of treatment and varies with type, dose, and duration of chemotherapy. In general, less than 50% of women under 40 years of age will be rendered postmenopausal by standard adjuvant chemotherapy regimens, whereas the majority of women aged 40 or more years of age will become permanently menopausal. Rates of permanent amenorrhea have been reported for several commonly used adjuvant chemotherapy regimens. They range from about 40% after four cycles of doxorubicin and cylophosphamide (AC) with or without four cycles of paclitaxel to nearly 70% for six cycles of oral cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (6 8). Thus, ovarian ablation is potentially an indirect effect of adjuvant chemotherapy. ROLE OF OVARIAN ABLATION The largest body of data regarding the use of ovarian ablation for adjuvant therapy is the EBCTG meta-analysis. Results for the 15-year analysis were collected in 1995 and published in 1996 (2). Updated data from the 2000 EBCTG meta-analysis have been presented in a preliminary fashion, but analysis is still incomplete. The 1995 overview summarized results from 12 of Correspondence to: Nancy E. Davidson, M.D., The Johns Hopkins Comprehensive Cancer Center, 1650 Orleans St., Rm. 409, Baltimore, MD ( davidna@jhmi.edu). See Note following References. Oxford University Press Journal of the National Cancer Institute Monographs No. 30,

2 the 13 randomized studies that assessed ovarian ablation by surgery or irradiation. These trials began before They enrolled 2102 women under age 50 years and 1354 women greater than or equal to 50 years old at randomization. Analysis was focused on the younger women, since no statistically significant impact of ovarian ablation on outcome for the older women (who were presumably mostly postmenopausal) was observed. Five of the trials included routine use of adjuvant chemotherapy, whereas the other trials did not. Selected results from the 1995 EBCTG overview analysis are presented in Table 1. Ovarian ablation led to a 25% ± 7% reduction in the annual odds of recurrence and a 24% ± 7% reduction in the annual odds of death for women who underwent ovarian ablation in the absence of chemotherapy. The benefit is seen in women with both lymph node-negative and lymph node-positive disease. There was a trend for greater efficacy of ablation in women with estrogen receptor (ER)-positive tumors, although this parameter was assessed only in four of the 12 trials, all of which included chemotherapy. The benefit was less pronounced for women who were randomly assigned to ovarian ablation in the presence of chemotherapy (10% ± 9% reduction for recurrence and 8% ± 10% reduction in mortality). These results likely reflect, in part, the fact that many women became postmenopausal as a consequence of adjuvant chemotherapy. Taken together, these analyses established the clinical benefit of ovarian ablation as an adjuvant approach for young women with breast cancer. It is important that this analysis found no difference in vascular deaths or other non-breast cancer deaths between women allocated to ovarian ablation and those who were not so allocated. A number of issues complicate interpretation of these results. Most of these trials were small, limiting statistical power. The analysis was based on patient age rather than on actual menopausal status. The hormone receptor status was frequently not available in these older trials. Since it is probable that the benefits of ovarian ablation are most pronounced in premenopausal women with steroid receptor-positive tumors, the true magnitude of benefit might be diluted. Further, these trials did not address other questions of interest, including 1) the relative efficacy of ovarian ablation and chemotherapy, 2) the value of ovarian ablation in conjunction with chemotherapy, 3) the utility of combined endocrine therapy with ovarian ablation and tamoxifen, and 4) the use of temporary ovarian ablation through the application of LHRH agonists. A number of trials conducted during the last 20 years have begun to shed light on these issues. Table 1. Selected results from the Early Breast Cancer Trialists Collaborative Group overview analysis of ovarian ablation for women under 50 years of age* Patients 15-y disease-free survival, % 15-y survival, % All Control Ovarian ablation 45} P< } P.001 Lymph node-negative no chemotherapy Control Ovarian ablation 75} P.01 77} P.01 Lymph node-positive no chemotherapy Control } P<.001 } P<.001 Ovarian ablation *Data from (2). COMPARISONS OF OVARIAN ABLATION AND CHEMOTHERAPY The recognition that the clinical benefits of adjuvant ovarian ablation and chemotherapy were of similar magnitude by indirect comparison for young women led to several trials comparing these two interventions. A key feature of these newer trials is that they generally define eligibility based on menopausal status rather than on age and frequently restrict entry to women with receptor-positive breast cancer, thus targeting the women who might most likely benefit from an endocrine approach. These trials are summarized in Table 2. Three trials have compared adjuvant ovarian ablation using different modalities with CMF chemotherapy. The Scottish/ Imperial Cancer Research Fund trial randomly assigned 332 premenopausal women with lymph node-positive breast cancer to oophorectomy (with or without prednisolone) or to six to eight cycles of intravenous CMF (with or without prednisolone) (9). There was no difference in event-free or overall survival after a maximum follow-up of 12 years. ER assays were available for 270 tumors. Retrospective analyses of these tissues suggested that oophorectomy was associated with improved survival in patients with ER concentrations greater than or equal to 20 fmol/mg protein, whereas 6 months of oral CMF was more beneficial for patients with ER less than 20 fmol/mg protein. A second trial assessed radiation-induced ovarian ablation or nine cycles of intravenous CMF in 732 women with hormone receptor-positive breast cancer that involved axillary lymph nodes or measured more than 5 cm (10). The 5-year disease-free survival rate was 67% with ovarian ablation and 66% with CMF. Corresponding survival rates were 78% and 82%, respectively. These differences were not statistically significant. Of note is that amenorrhea occurred in 68% of the patients who received CMF. The largest trial of this design, the Zoladex Early Breast Cancer Research Association (ZEBRA) Trial, compared six cycles of oral CMF with 2 years of monthly doses of goserelin in 1640 premenopausal women with lymph node-positive tumors (11). About 80% of the patients had ER-positive tumors and, with a median follow-up of 6 years, disease-free (DFS) and overall survival were equivalent for the two treatments in these women. In contrast, CMF led to a statistically significantly longer DFS and overall survival than goserelin for women with ER-negative breast cancer. In this study, about two thirds of patients regained menstrual function within a year after completion of 2 years of goserelin, whereas 80% of women treated with CMF remained amenorrheic at 3 years. Subset analysis suggested that patients treated with CMF who became amenorrheic after therapy had a longer DFS than those who did not. Patientassessed quality of life was better for goserelin than for CMF during the first 6 months of treatment. Bone loss was substantial with both treatments and improved after completion of goserelin but not after completion of CMF. These results suggest that temporary ovarian ablation using goserelin is a reasonable alternative to CMF chemotherapy for women with lymph nodepositive ER-positive breast cancer. None of these trials used tamoxifen. However, the concept of combined endocrine therapy versus CMF has also been tested in two randomized trials. The Italian Breast Cancer Adjuvant Chemo- Hormone Therapy Cooperative Group 02 study compared oral CMF for 6 months with the combination of ovarian ablation and 68 Journal of the National Cancer Institute Monographs No. 30, 2001

3 Table 2. Randomized trials of chemotherapy versus ovarian ablation with or without tamoxifen as adjuvant therapy* Study Patients No. Treatments Results Reference Nos. Scottish Lymph node-positive 332 CMF 6 8 No difference (9) Oophorectomy Scandinavian Stage II, receptor-positive 732 CMF 9 No difference (10) XRT ZEBRA Lymph node-positive 1640 CMF 6 No difference for ER-positive; (11) Goserelin 2 y CMF better for ER-negative GROCTA 02 Lymph node-positive, receptor-positive 235 CMF 6 No difference (12) Ovarian ablation + tamoxifen 5 y ABCSG 5 Stage I/II, receptor-positive 1045 CMF 6 Better RFS with endocrine therapy (13,14) Goserelin 3 y + tamoxifen 5 y French Lymph node-positive, ER-positive 162 FAC 6 No difference (15) Ovarian ablation + tamoxifen FASG 06 Lymph node-positive, ER-positive 333 FEC 6 Triptoreline + tamoxifen 5 y No difference (16) *Abbreviations used: C cyclophosphamide; A doxorubicin; F 5-fluorouracil; M methotrexate; E epirubicin; XRT radiation therapy; ER estrogen receptor; RFS recurrence-free survival; ZEBRA Zoladex Early Breast Cancer Research Association; GROCTA Italian Breast Cancer Adjuvant Chemo-Hormone Therapy Cooporative Group; ABCSG Austrian Breast Cancer Study Group; FASG French Adjuvant Study Group. 5 years of tamoxifen in 244 premenopausal women with axillary lymph node-positive, steroid receptor-positive breast cancer (12). Ovarian ablation could be carried out by surgery, radiation therapy, or 2 years of goserelin. With a median follow-up of 76 months, there was no difference in DFS or overall survival. There was no obvious difference in outcome with any type of ovarian ablation, although the power of this subset analysis is severely limited by the small sample size. A larger trial of similar design was conducted by the Austrian Breast Cancer Study Group (ABCSG) (13,14). ABCSG 5 compared intravenous CMF for six cycles with goserelin for 3 years and tamoxifen for 5 years in 1045 women with stage I or II steroid receptor-positive breast cancer. At a median follow-up of 42 months, combination endocrine therapy showed a statistically significantly improved recurrence-free survival (RFS) compared with CMF (P.02), but there was no difference in survival. In the CMF group, those women who developed amenorrhea had significantly longer RFS and survival than those who did not. Indeed, the difference favoring combined endocrine therapy in this trial as opposed to the other four CMF trials summarized above may reflect in part a lower likelihood of becoming amenorrheic with six cycles of intravenous CMF compared with six cycles of oral CMF. The addition of tamoxifen to the ovarian ablation but not to the chemotherapy arm may also play an important role. Taken together, results from these five trials suggest that ovarian ablation with or without tamoxifen can provide clinical benefit similar to that seen with 6 months of oral CMF chemotherapy in women with lymph node-positive, receptor-positive breast cancer. In no case was tamoxifen administered to the women who received chemotherapy, a barrier to extrapolation of these results to current adjuvant therapy practices. In addition, given the apparent superiority of anthracycline-containing regimens compared with CMF in the adjuvant setting, a relevant question is whether similar results would be obtained in a comparison of anthracycline-containing combination chemotherapy and ovarian ablation. This question has not been as well studied. One small French trial compared adjuvant chemotherapy with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) with ovarian ablation (oophorectomy or radiotherapy) plus tamoxifen in 162 premenopausal women with lymph node-positive, receptor-positive breast cancer (15). There was no statistically significant difference in DFS or survival in this trial, which stopped early because of poor accrual. A second trial, French Adjuvant Study Group (FASG) 06, compared combined hormonal therapy with 3 years of tamoxifen and triptoreline (another investigational LHRH agonist) with six cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) in 333 premenopausal women with hormone receptor-positive breast cancer involving one to three axillary lymph nodes. With a median follow-up of 54 months, DFS and overall survival were 92% and 97%, respectively, for endocrine therapy and 81% and 93%, respectively, for FEC. These apparent differences were not statistically significant. FEC induced amenorrhea in 42% of patients, a lower incidence than that seen with six cycles of oral CMF (16). Thus, although the available information is more limited, there does not appear to be a substantial difference in outcome for premenopausal women with receptor-positive, lymph node-positive breast cancer who were randomly assigned either to an anthracycline-containing chemotherapy regimen or to ovarian ablation plus tamoxifen. ADJUVANT CHEMOTHERAPY AND OVARIAN ABLATION Adjuvant chemotherapy is a routine part of care for many women with early-stage breast cancer. Thus, a major question is whether the use of ovarian ablation adds to the benefits of adjuvant chemotherapy. This question was addressed in Intergroup (INT) 0101, a trial of chemohormonal therapy in 1503 premenopausal women with lymph node-positive, receptor-positive breast cancer. The trial compared three treatment arms: six cycles of oral CAF, six cycles of CAF followed by 5 years of goserelin (CAFZ), and six cycles of CAF followed by 5 years of goserelin and tamoxifen (CAFZT) (17). The 5-year DFS rates were 67% for CAF, 70% for CAFZ, and 77% for CAFZT, whereas 5-year survival was about 85% for all three arms. Comparison of CAFZT with CAFZ showed a statistically significant DFS advantage with the addition of tamoxifen, whereas comparison of CAFZ with CAF showed no DFS advantage for the addition of goserelin. Preliminary retrospective subset analyses suggest that addition of goserelin may be more beneficial in women younger than 40 years of age at trial entry those women least likely to become postmenopausal after chemotherapy. Final analysis of the impact of amenorrhea, patient age, and serum hormone levels on clinical outcome is in progress. Journal of the National Cancer Institute Monographs No. 30,

4 The Zoladex in Premenopausal Patients (ZIPP) study also permitted assessment of the effects of ovarian ablation in the context of other adjuvant therapy (18,19). That study combined results from four trial groups that used a common 2 2factorial design to evaluate tamoxifen for 2 years, goserelin for 2 years, tamoxifen and goserelin for 2 years, and no endocrine therapy at all in 2648 premenopausal women with early-stage breast cancer of any steroid receptor type. Forty-two percent of women had lymph node-positive disease, and 56% had ER-positive breast cancer. Elective adjuvant chemotherapy was permitted in selected patients according to predetermined plans at each center and was given to 43% of the participants. At a median follow-up of 4.2 years, there was a statistically significant 23% reduction in first events in women who received goserelin (first events in 20% of patients receiving goserelin and 25% of patients not receiving goserelin, P.001). The benefit was less pronounced in patients who received concurrent adjuvant tamoxifen or chemotherapy. There is no statistically significant effect on survival at this time (P.12). A third trial, International Breast Cancer Study Group (IBCSG) VIII, is evaluating whether the combination of CMF followed by goserelin can improve outcome compared with either modality alone in the treatment of premenopausal women with lymph node-negative breast cancer. After surgery, patients are randomly assigned to receive either goserelin for 2 years or six cycles of oral CMF or six cycles of CMF followed by 1.5 years of goserelin. Accrual is complete, and the trial remains in blinded follow-up. Data addressing the value of ovarian ablation after chemotherapy are less robust than those comparing effects of ovarian ablation and chemotherapy. At present, however, they do not provide convincing evidence that both modalities should be routinely employed. OVARIAN ABLATION AND TAMOXIFEN For many years, tamoxifen was not used as adjuvant therapy for premenopausal women because of the belief that it was ineffective in these younger women. The 1995 EBCTG overview demonstrated that this belief was erroneous, because premenopausal women with ER-positive breast cancer derived a substantial benefit from tamoxifen for 5 years. Unfortunately, virtually all adjuvant trials of ovarian ablation were begun before this fact became widely known. Thus, there is essentially no information from randomized trials about the relative effects of tamoxifen, ovarian ablation, or the combination in premenopausal women with early-stage breast cancer. Since tamoxifen has become a mainstay of the management of premenopausal women with receptor-positive breast cancer, this is a critical and unfortunate deficit. As noted above, INT 0101 showed that the addition of tamoxifen to CAFZ improved outcome in premenopausal women with lymph node-positive, receptor-positive breast cancer. Unfortunately, an arm comparing CAF followed by 5 years of tamoxifen is not available to permit direct assessment of CAFZ, CAFZT, and CAF followed by tamoxifen. Two trials are investigating ovarian ablation in the absence of chemotherapy. An Intergroup trial enrolled about 350 premenopausal women with lymph node-negative, receptor-positive breast cancer measuring less than 3 cm. Patients were randomly assigned to receive tamoxifen for 5 years or tamoxifen for 5 years plus any form of ovarian ablation (surgery, radiation therapy, or LHRH agonist for 5 years). The trial was closed prematurely because of poor accrual in an era of increasing chemotherapy use, and it continues in blinded follow-up. A second trial of combined endocrine therapy has completed accrual in Vietnam. Over 700 premenopausal women with early-stage breast cancer clinically have been randomly assigned to oophorectomy and 5 years of tamoxifen either at the time of mastectomy or at the time of relapse. Preliminary results of this trial suggest that adjuvant oophorectomy and tamoxifen led to a statistically significant improvement in 5-year DFS and overall survival compared with initial observation. Only women with steroid receptor-positive tumors benefited from the adjuvant hormone therapy (20). CONCLUSIONS AND FUTURE DIRECTIONS The results from the EBCTG meta-analysis suggest that ovarian ablation represents an effective form of adjuvant systemic therapy for premenopausal women. A number of randomized trials have shown that ovarian ablation with or without tamoxifen and standard chemotherapy regimens like CMF have similar benefits for premenopausal women with early-stage receptorpositive breast cancer. Thus, both the 2001 St. Gallen expert panel (21) and the 2000 National Institutes of Health Consensus Development Conference on Adjuvant Therapy for Breast Cancer (22) have suggested that ovarian ablation is a reasonable adjuvant treatment option for premenopausal women with receptor-positive breast cancer. It appears unlikely, however, that ovarian ablation has any benefit for women with receptornegative breast cancer. A number of questions remain to be answered. These include the following: 1) the importance of amenorrhea as a determinant for premenopausal women with early-stage breast cancer; 2) the optimal duration of ovarian ablation if an LHRH analogue is employed; 3) the value of ovarian ablation after chemotherapy, particularly for women who remain premenopausal after adjuvant chemotherapy; 4) the utility of combined hormone therapy such as ovarian ablation with tamoxifen or aromatase inhibitors; and 5) careful delineation of the long-term side effects of this endocrine approach. REFERENCES (1) Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment. Lancet 1896;2:104 7, (2) Early Breast Cancer Trialists Collaborative Group. Ovarian ablation in early breast cancer: overview of the randomised trials. Lancet 1996;348: (3) Early Breast Cancer Trialists Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. 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