Similar Efficacy for Ovarian Ablation Compared With Cyclophosphamide, Methotrexate, and Fluorouracil: From a Randomized Comparison of Premenopausal Patients With Node-Positive, Hormone Receptor–Positive Breast Cancer

Bent Ejlertsen,  Journal of Clinical Oncology, Vol 24, No 31 (November 1), 2006: pp. 4956-4962

Danish Breast Cancer Cooperative Group Registry, Copenhagen;

PURPOSE: To compare the efficacy of ovarian ablation versus chemotherapy in early breast cancer patients with hormone receptor–positive disease.

PATIENTS AND METHODS: We conducted an open, randomized, multicenter trial including premenopausal breast cancer patients with hormone receptor–positive tumors and either axillary lymph node metastases or tumors with a size of 5 cm or more. Patients were randomly assigned to ovarian ablation by irradiation or to nine courses of chemotherapy with intravenous cyclophosphamide, methotrexate, and fluorouracil (CMF) administered every 3 weeks.

RESULTS: Between 1990 and May 1998, 762 patients were randomly assigned, and the present analysis is based on 358 first events. After a median follow-up time of 8.5 years, the unadjusted hazard ratio for disease-free survival in the ovarian ablation group compared with the CMF group was 0.99 (95% CI, 0.81 to 1.22). After a median follow-up time of 10.5 years, overall survival (OS) was similar in the two groups, with a hazard ratio of 1.11 (95% CI, 0.88 to 1.42) for the ovarian ablation group compared with the CMF group.

CONCLUSION: In this study, ablation of ovarian function in premenopausal women with hormone receptor–positive breast cancer had a similar effect to CMF on disease-free and OS. No significant interactions were demonstrated between treatment modality and hormone receptor content, age, or any of the well-known prognostic factors.
 
The overview published by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) in 1996 clearly established that ovarian ablation by surgery or ovarian irradiation significantly improves disease-free and long-term survival in premenopausal women with early breast cancer. In addition, the most recent EBCTCG overview showed that a similar effect could be obtained by ovarian suppression with a luteinizing hormone–releasing hormone inhibitor. Ovarian ablation by surgery or pelvic irradiation was assessed directly against polychemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) by the Scottish Cancer Trials Breast Group and the Imperial Cancer Research Fund Breast Unit at Guy's Hospital in a small trial of 332 premenopausal patients, and they detected no significant overall differences in event-free or overall survival (OS). In addition, three trials have compared 2 years of ovarian suppression with goserelin or leuprorelin acetate directly with CMF-based chemotherapy in premenopausal breast cancer patients. In the Zoladex Early Breast Cancer Research Association trial, 1,640 patients with node-positive breast cancer were randomly assigned to goserelin compared with CMF. The International Breast Cancer Study Group trial VIII included patients with node-negative breast cancer and randomly assigned 346 patients to goserelin, 361 patients to CMF, and 358 patients to CMF followed by goserelin. Finally, results from an interim analysis have been published including 227 patients with node-positive disease from the Takeda Adjuvant Breast Cancer Study with leuprorelin acetate.  Patients included in the three fully reported trials were unselected regarding hormone receptor status. Subset analyses of the Zoladex Early Breast Cancer Research Association and International Breast Cancer Study Group VIII trials demonstrated equivalence between ovarian suppression and CMF in patients with estrogen receptor (ER) –positive disease, whereas superiority of ovarian ablation compared with CMF was established in the Scottish trial. In contrast, CMF was consistently superior to ovarian ablation or suppression in ER-negative patients.

Our trial was designed to compare the effects of ovarian ablation and CMF on disease-free survival (DFS) and OS in premenopausal women with hormone receptor–positive breast cancer. We report the results of the preplanned analysis conducted 5 years after closure of recruitment. By random assignment, patients were allocated to ovarian ablation or CMF. Ovarian ablation was performed by irradiation, and the requested limits of the pelvic portals used were from the inferior border of the fifth lumbar vertebra to the lowermost aspect of obturator foramen and 1 to 2 cm lateral of the inner pelvic sidewalls. The field arrangement involved the use of anterior and posterior fields against the minor pelvic region. The intended dose was a median absorbed dose in the target volume of 15 Gy administered in 5 fractions over a 1-week period using a linear accelerator. Locoregional radiotherapy was carried out according to regional guidelines.