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Hormonal Ablation

Nancy E. Davidson, M.D.

Ovarian ablation was the first form of adjuvant systemic therapy used in premenopausal women with early-stage breast cancer. A 1995 meta-analysis summarized results from 12 of the 13 randomized studies that assessed ovarian ablation by irradiation or surgery; these trials all began before 1980 (EBCTCG, 1996). Because menopausal status was not uniform across these studies, analysis was directed at the 2,102 women in the studies under the age of 50, most of whom were likely to be premenopausal. Ovarian ablation led to a 25 ± 7 percent reduction in the annual odds of recurrence, and a 24 ± 7 percent reduction in the annual odds of death, for women who underwent ovarian ablation in the absence of chemotherapy. The benefit appeared significant for both node-negative and node-positive women. There was a trend for greater efficacy of ablation in women with estrogen receptor-positive tumors, although this was only assessed in 4 of the 12 trials, all of which included chemotherapy. The benefit was less pronounced for women who were randomized to ovarian ablation in the presence of chemotherapy (10 ± 9 percent and 8 ± 10 percent, respectively). It is expected that this analysis will be updated and expanded with 20 years of followup later this year.

More recent trials have expanded and refined our knowledge in this field. They have focused largely on two questions: What are the relative effects of adjuvant chemotherapy and ovarian ablation with or without tamoxifen in premenopausal women? Does ovarian ablation have additional benefit in young women who have received adjuvant chemotherapy? Key features of some of these newer trials are careful (but variable) definition of premenopausal status, enrollment of women with steroid receptor-positive tumors, and the use of luteinizing hormone-releasing hormone (LH-RH) agonists to effect a temporary “chemical” castration.

Two trials have compared adjuvant ovarian ablation to cyclophosphamide, methotrexate, fluorouracil (CMF) chemotherapy. The Scottish/ICRF trial of 332 premenopausal women with node-positive breast cancer showed no difference in event-free or overall survival after a maximum followup of 12 years (SCTBG, 1993). Estrogen receptor (ER) assays were available for 270 tumors; retrospective analyses suggested that oophorectomy was associated with improved survival in patients with ER concentrations >= 20 fmol/mg protein, while six months of oral CMF was more beneficial for patients with ER <= 20 fmol/mg protein. A second trial assessed ovarian ablation and nine cycles of IV CMF in 732 women with hormone receptor-positive breast cancer that involved lymph nodes or that measured more than 5 cm (Ejlertsen, Dombernowsky, Mouridsen, et al., 1999). The 5-year disease-free survival (DFS) rate was 67 percent with ovarian ablation and 66 percent with CMF; corresponding survival rates were 78 percent and 82 percent respectively (nonsignificant). Amenorrhea occurred in 68 percent of the patients receiving CMF. Together, these trials suggest that oophorectomy and CMF chemotherapy have similar effects in women with node-positive breast cancer. Results of a third trial (ZEBRA) that compared CMF with goserelin, a LH-RH agonist, in women with early-stage breast cancer of any receptor type should be available at the time of the consensus conference. If part by its ability to ablate ovarian function, leading to a state of estrogen withdrawal.

The concept of combined endocrine therapy has also been tested in two trials using CMF. The GROCTA 02 study compared oral CMF with 2 years of goserelin and 5 years of tamoxifen in 244 women with node-positive ER-positive breast cancer (Boccardo, Rubagotti, Amoroso, et al., 1998). Five-year disease-free survival was 69 percent for CMF and 72 percent for goserelin-tamoxifen (not significant), and survival was identical at 87 percent.

A larger trial of similar design was conducted by the Austrian Breast Cancer Study Group [ABCSG] (Jakesz, Hausmaninger, Samonigg, et al., 1999). ABCSG compared IV CMF for six cycles with goserelin for 3 years, and tamoxifen for 5 years, in 1,045 women with stage I and II steroid receptor-positive breast cancer. At a median followup of 42 months, combination endocrine therapy showed a significantly improved recurrence-free survival (RFS) compared with CMF ( p=0.02), without an impact on survival. In the CMF group, those women who developed amenorrhea had significantly better RFS and survival than those who did not. A third trial compared six cycles of IV FEC (an anthracycline-containing regimen) with 3 years of tamoxifen and triptoreline (another LH-RH agonist) in 333 premenopausal women with hormone receptor-positive breast cancer involving 1 to 3 nodes (Roche, Kerbrat, Bonneterre, et al., 2000). With median followup of 54 months, disease-free survival and overall survival were 92 percent and 97 percent, respectively, for endocrine therapy, and 81 percent and 93 percent for FEC; these differences are not significant. FEC induced amenorrhea in 42 percent of patients. Thus, these three trials suggest that combined endocrine therapy has effects similar to those of adjuvant chemotherapy, although it is not likely that any of these trials had the statistical power to document true equivalence.

Adjuvant chemotherapy is a routine part of care for many women with node-positive breast cancer. Thus, a second question is whether the use of ovarian ablation adds to the benefits of adjuvant chemotherapy. This question was addressed in INT 0101, a trial of chemohormonal therapy in 1,503 premenopausal women with node-positive, receptor-positive breast cancer (Davidson, O’Neill, Vukov, et al., 1999). The trial compared three treatment arms: six cycles of oral CAF, six cycles of CAF followed by 5 years of goserelin (CAF->Z), and six cycles of oral CAF followed by 5 years of goserelin and tamoxifen (CAF->ZT). The 7-year disease-free survival rates were 58 percent for CAF, 64 percent for CAF->Z, and 73 percent for CAF->ZT. Comparison of CAF->ZT with CAF->Z showed a significant disease-free survival rate advantage with the addition of tamoxifen (p =0.0025), while comparison of CAFZ with CAF showed no disease-free survival rate advantage for the addition of goserelin (p =0.0955). Survival at 7 years was similar for all three arms: 77 percent for CAF, 78 percent for CAF->Z, and 80 percent for CAF_ZT. Final analysis of the impact of amenorrhea, patient age, and serum hormone levels on clinical outcome is in progress.

The ZIPP trial also permitted assessment of the effects of ovarian ablation in the context of other adjuvant therapy (Baum, 1999). That study combined results from four trial groups that used a common 2x2 design to evaluate tamoxifen for 2 years, goserelin for 2 years, tamoxifen and goserelin for 2 years, and no endocrine therapy, in 2,631 premenopausal women with early-stage breast cancer of any steroid receptor type (56 percent node-negative). Elective adjuvant chemotherapy was permitted in selected patients according to predetermined plans and was given to 43 percent of the participants. At a median followup of 4.2 years, there was a statistically significant 23 percent reduction in first events in women who received goserelin (first events in 20 percent of patients with goserelin and 25 percent of patients without goserelin, (p=0.001). The benefit was less pronounced in patients who received concurrent adjuvant tamoxifen or chemotherapy. There is no significant effect on survival at the present time ( p=0.12).

Available data suggest that both adjuvant ovarian ablation with or without tamoxifen and CMF chemotherapy have similar benefits for premenopausal women with early-stage breast cancer. Thus, ovarian ablation (± tamoxifen) appears to be a reasonable alternative to CMF chemotherapy for selected women with receptor-positive breast cancer. It appears unlikely, however, that ovarian ablation has a benefit for women with receptor-negative tumors.

A number of questions remain to be answered. These include (1) the importance of amenorrhea as a determinant of outcome for premenopausal women with early-stage breast cancer; (2) the optimal duration of ovarian ablation if an LH-RH agonist is employed; (3) the relative efficacy of ovarian ablation and other types of adjuvant chemotherapy (e.g. CAF, AC, or AC followed by paclitaxel); (4) the additional value of ovarian ablation after chemotherapy, particularly for women who remain premenopausal after adjuvant chemotherapy; and (5) the value of combined hormone therapy.

References

Baum M. Adjuvant treatment of premenopausal breast cancer with Zoladex and tamoxifen. [abstract]. Breast Cancer Res Treat 1999;57:30. No Abstract Available.

Boccardo F, Rubagotti A, Amoroso D, Mesiti M, Minutoli N, Aldrighetti D, et al. CMF versus tamoxifen (tam) plus goserelin (gos) as adjuvant treatment of ER positive (ER+) pre-perimenopausal breast cancer (ca) patients (pts). Preliminary results of the GROCTA 02 study. [abstract]. Proc Am Soc Clin Oncol 1998;17:99a. Abstract.

Davidson NE, O’Neill A, Vukov A, Osborne CK, Martino S, White D, et al. Effect of chemohormonal therapy in premenopausal node (+) receptor (+) breast cancer: an Eastern Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Ovarian ablation in early breast cancer: overview of the randomised trials. Lancet 1996;348:1189-96. Abstract.

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Ovarian ablation in early breast cancer: overview of the randomised trials. Lancet 1996;348:1189-96. Abstract.

Ejlertsen B, Dombernowsky P, Mouridsen HT, Kamby C, Kjaer M, Rose C., et al. Comparable effect of ovarian ablation (OA) and CMF chemotherapy in premenopausal hormone receptor positive breast cancer patients. [abstract]. Proc Am Soc Clin Oncol 1999;18:66a. Abstract.

Jakesz R, Hausmaninger H, Samonigg H, Kubista E, Depisch D, Fridrik M, et al. Comparison of adjuvant therapy with tamoxifen and goserelin vs CMF in premenopausal stage I and II hormone-responsive breast cancer patients: four-year results of Austrian Breast Cancer Study Group (ABCSG) Trial 5. [abstract]. Proc Am Soc Clin Oncol 1999;18:67a. Abstract.

Roche HH, Kerbrat P, Bonneterre J, Fargeot P, Fumoleau P, Monnier A, et al. Complete hormonal blockade versus chemotherapy in premenopausal early-stage breast cancer patients with positive hormone-receptor (HR+) and 1-3 node-positive (N+) tumor: results of the FASG 06 trial. [abstract]. Proc Am Soc Clin Oncol 2000;19:72a. Abstract.

Scottish Cancer Trials Breast Group (SCTBG) 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;341:1293-9. Abstract.