Late effects of adjuvant oophorectomy and chemotherapy upon premenopausal breast cancer patients.

Between 1978 and 1981 we conducted a trial (Trial II) in premenopausal and perimenopausal breast cancer patients with 4 or more metastatic axillary lymph nodes. 327 evaluable patients were randomized after at least a total mastectomy and axillary clearance to receive either a combination chemotherapy with cyclophosphamide, methotrexate, 5-fluorouracil, and low-dose prednisone (CMFp), or surgical oophorectomy followed by the same CMFp therapy (Ox + CMFp). Cytotoxic drugs were administered for 12 4-week courses. At a median follow-up of 96 months, the 8-year disease-free survival (DFS) percentages (+/- s.e.) for CMFp and Ox + CMFp were 30% +/- 4% and 37% +/- 4%, respectively (p = 0.17). The overall survival percentages were 41% +/- 4% and 50% +/- 4%, respectively (p = 0.20). In a subgroup analysis by estrogen receptor content of the primary, the differences were observed in patients with tumors classified as ER+ (8-year DFS: 26% +/- 7%, 41% +/- 7%; p = 0.09) but not in those with ER- tumors (8-year DFS: 29% +/- 7%, 25% +/- 7%; p = 0.92). Analysis of sites of first relapse showed that the difference between the two treatment groups can be entirely attributed to the reduction in bone metastases in the oophorectomized group (Ox + CMFp). We conclude that for very high risk premenopausal breast cancer patients, the effects of oophorectomy added to an adjuvant cytotoxic regimen will be observed late in the patients' follow-up period. We hypothesize that the reduction of relapses in distant sites is due to the extended effects of the endocrine therapy.