Long-term results of International Breast Cancer Study Group Trial VIII: adjuvant chemotherapy plus goserelin compared with either therapy alone for premenopausal patients with node-negative breast cancer

Abstract

Background: The International Breast Cancer Study Group Trial VIII compared long-term efficacy of endocrine therapy (goserelin), chemotherapy [cyclophosphamide, methotrexate and fluorouracil (CMF)], and chemoendocrine therapy (CMF followed by goserelin) for pre/perimenopausal women with lymph-node-negative breast cancer.

Patients and methods: From 1990 to 1999, 1063 patients were randomized to receive (i) goserelin for 24 months (n = 346), (ii) six courses of 'classical' CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy (n = 360), or (iii) six courses of CMF plus 18 months goserelin (CMF→ goserelin; n = 357). Tumors were classified as estrogen receptor (ER) negative (19%), ER positive (80%), or ER unknown (1%); 19% of patients were younger than 40. Median follow-up was 12.1 years.

Results: For the ER-positive cohort, sequential therapy provided a statistically significant benefit in disease-free survival (DFS) (12-year DFS = 77%) compared with CMF alone (69%) and goserelin alone (68%) (P = 0.04 for each comparison), due largely to the effect in younger patients. Patients with ER-negative tumors whose treatment included CMF had similar DFS (12-year DFS CMF = 67%; 12-year DFS CMF→ goserelin = 69%) compared with goserelin alone (12-year DFS = 61%, P= NS).

Conclusions: For pre/perimenopausal women with lymph-node-negative ER-positive breast cancer, CMF followed by goserelin improved DFS in comparison with either modality alone. The improvement was the most pronounced in those aged below 40, suggesting an endocrine effect of prolonged CMF-induced amenorrhea.

Figure 1.

Kaplan–Meier estimates of disease-free survival (A,D), overall survival (B,E), and breast cancer-free interval (C,F) by treatment according to cohorts defined as estrogen receptor positive (A–C) and estrogen receptor negative (D–F) in the International Breast Cancer Study Group Trial VIII.

Figure 2.

Kaplan–Meier estimates of disease-free survival (A,D), overall survival (B,E), and breast cancer free interval (C,F) by treatment according to age cohorts within the estrogen receptor-positive cohort in IBCSG Trial VIII. The younger (<40 years) cohort is on the left (A–C).

Figure 3.

Subpopulation Treatment Effect Patten Plot showing 5-year (A) and 12-year (B) DFS percentages by treatment group according to overlapping subpopulations of age at randomization for 851 patients in the estrogen receptor-positive cohort.

Figure 4.

Percentage of patients enrolled in the IBCSG Trial VIII with amenorrhea during each month from randomization according to treatment. (A) Results for patients aged 39 years or younger; (B) the results for patients aged 40 years or older. Reprinted by permission from Journal of the National Cancer Institute [8]. Gos, goserelin; SE, standard error.