Efficacy of UFT Plus Tamoxifen for Breast Cancer
Objective: We conducted a prospective multicentre, collaborative randomised study on postoperative adjuvant therapy in patients with stage II primary breast cancer to evaluate the effect of a combination of tegafur and uracil (UFT) on tamoxifen (TAM) plus mitomycin (MM) in patients with estrogen-receptor-positive [ER(+)] breast cancer and TAM on UFT + MM in patients with estrogenreceptor-negative [ER(-)] breast cancer.
Methods: MM (13 mg/m) was intravenously administered on the day of surgery for all patients, after which patients with ER(+) were randomised to TAM 20 mg/ day (treatment A) or TAM 20 mg/day and UFT 400 mg/day (treatment B). Patients who were ER(-) were randomly allocated UFT 400 mg/day (treatment C) or TAM 20 mg/day and UFT 400 mg/day (treatment D). TAM and UFT were administered orally for 2 years, starting on day 14 after surgery.
Endpoints: 5-year disease-free survival (5y DFS), 5-year overall survival (5y OS), and safety.
Results: The study commenced in November 1988 and the data cut-off was May 1997 after follow-up of the last patient for 5 years. A total of 765 patients with stage II breast cancer were enrolled. 436 patients with ER(+) [group A: 213, group B: 223] and 317 patients with ER(-) [group C: 162, group D: 155] breast cancer were eligible for this study. The rate of 5y DFS was 83.1% for group A and 90.7% for group B (p = 0.020). There was a significant difference in 5y DFS between the two groups among postmenopausal and positive lymph node metastases patients. The incidence of adverse reactions was 4% for group A and 18% for group B (p < 0.05). The rate of 5y DFS was 77.1% for group C and 85.5% for group D (p = 0.063). The rate of 5y OS was 84.7% for group C and 89.8% for group D (p = 0.216). The incidence of adverse reactions was 18% in group C and 11% in group D (p = 0.06).
Conclusion: UFT in combination with TAM + MM showed higher efficacy than TAM + MM as a postoperative combination therapy for breast cancer in patients with ER(+) breast cancer. A trend was observed in favour of the addition of TAM to UFT + MM in postmenopausal and lymph node metastases-negative patients with ER(-) breast cancer.
The combined effects of chemoendocrine therapy where tamoxifen (TAM) is used in combination with chemotherapy using cyclophosphamide (CPM), methotrexate (MTX) and fluorouracil (5- FU) [CMF therapy] as postoperative adjuvant therapy for breast cancer have been studied, as well as the effects of TAM therapy in combination with other chemotherapy. Oral fluorinated pyrimidine-derivative compounds were chosen as chemotherapy for breast cancer because MTX was not approved in Japan for the treatment of breast cancer until 1994. Enomoto and Abe initiated two clinical trials of TAM in combination with tegafur (FT) in 1982, and reported that three-year survival was higher for TAM in combination with FT than for FT alone.
UFT is a combination of FT and uracil, and has been shown to maintain higher 5-FU concentrations in tumours compared with FT. In a double-blind, comparative study of FT and UFT conducted in advanced/recurrent breast cancer patients, the results demonstrated that the response rate was higher for UFT than for FT.
Mitomycin (MM) has been reported to be effec-tive as an induction therapy for postoperative breast cancers and is generally used in Japan. Yoshimoto et al. reported that MM as adjuvant with chemotherapy using cyclophosphamide therapy prolonged the 10-year disease-free survival (CPM), methotrexate (MTX) and fluorouracil (5- (DFS) rate of patients with stage I-III breast cancer FU) [CMF therapy] as postoperative adjuvant ther-over the control group (p = 0.0083). Furthermore, Yamase et al. reported the efficacy of MM as adjuvant therapy especially for the early stage of breast cancer. However, the efficacy of adjuvant therapy with MM alone is not sufficient.
Based on these findings, it was considered worth evaluating combination therapy consisting of UFT and TAM as postoperative adjuvant therapy for breast cancer with induction therapy with MM. We therefore conducted a multicentre, collaborative study to evaluate the combined effect of UFT and TAM in patients with stage II primary breast cancer. In patients with estrogen-receptor-positive [ER(+)] breast cancer, TAM was used as a control drug as its efficacy has been demonstrated by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG). In patients with estrogen-receptor-negative [ER(-)] breast cancer, UFT was used as a control drug because chemotherapy is generally indicated for ER(-) breast cancer patients.
Objective: We conducted a prospective multicentre, collaborative randomised study on postoperative adjuvant therapy in patients with stage II primary breast cancer to evaluate the effect of a combination of tegafur and uracil (UFT) on tamoxifen (TAM) plus mitomycin (MM) in patients with estrogen-receptor-positive [ER(+)] breast cancer and TAM on UFT + MM in patients with estrogenreceptor-negative [ER(-)] breast cancer.
Methods: MM (13 mg/m) was intravenously administered on the day of surgery for all patients, after which patients with ER(+) were randomised to TAM 20 mg/ day (treatment A) or TAM 20 mg/day and UFT 400 mg/day (treatment B). Patients who were ER(-) were randomly allocated UFT 400 mg/day (treatment C) or TAM 20 mg/day and UFT 400 mg/day (treatment D). TAM and UFT were administered orally for 2 years, starting on day 14 after surgery.
Endpoints: 5-year disease-free survival (5y DFS), 5-year overall survival (5y OS), and safety.
Results: The study commenced in November 1988 and the data cut-off was May 1997 after follow-up of the last patient for 5 years. A total of 765 patients with stage II breast cancer were enrolled. 436 patients with ER(+) [group A: 213, group B: 223] and 317 patients with ER(-) [group C: 162, group D: 155] breast cancer were eligible for this study. The rate of 5y DFS was 83.1% for group A and 90.7% for group B (p = 0.020). There was a significant difference in 5y DFS between the two groups among postmenopausal and positive lymph node metastases patients. The incidence of adverse reactions was 4% for group A and 18% for group B (p < 0.05). The rate of 5y DFS was 77.1% for group C and 85.5% for group D (p = 0.063). The rate of 5y OS was 84.7% for group C and 89.8% for group D (p = 0.216). The incidence of adverse reactions was 18% in group C and 11% in group D (p = 0.06).
Conclusion: UFT in combination with TAM + MM showed higher efficacy than TAM + MM as a postoperative combination therapy for breast cancer in patients with ER(+) breast cancer. A trend was observed in favour of the addition of TAM to UFT + MM in postmenopausal and lymph node metastases-negative patients with ER(-) breast cancer.
The combined effects of chemoendocrine therapy where tamoxifen (TAM) is used in combination with chemotherapy using cyclophosphamide (CPM), methotrexate (MTX) and fluorouracil (5- FU) [CMF therapy] as postoperative adjuvant therapy for breast cancer have been studied, as well as the effects of TAM therapy in combination with other chemotherapy. Oral fluorinated pyrimidine-derivative compounds were chosen as chemotherapy for breast cancer because MTX was not approved in Japan for the treatment of breast cancer until 1994. Enomoto and Abe initiated two clinical trials of TAM in combination with tegafur (FT) in 1982, and reported that three-year survival was higher for TAM in combination with FT than for FT alone.
UFT is a combination of FT and uracil, and has been shown to maintain higher 5-FU concentrations in tumours compared with FT. In a double-blind, comparative study of FT and UFT conducted in advanced/recurrent breast cancer patients, the results demonstrated that the response rate was higher for UFT than for FT.
Mitomycin (MM) has been reported to be effec-tive as an induction therapy for postoperative breast cancers and is generally used in Japan. Yoshimoto et al. reported that MM as adjuvant with chemotherapy using cyclophosphamide therapy prolonged the 10-year disease-free survival (CPM), methotrexate (MTX) and fluorouracil (5- (DFS) rate of patients with stage I-III breast cancer FU) [CMF therapy] as postoperative adjuvant ther-over the control group (p = 0.0083). Furthermore, Yamase et al. reported the efficacy of MM as adjuvant therapy especially for the early stage of breast cancer. However, the efficacy of adjuvant therapy with MM alone is not sufficient.
Based on these findings, it was considered worth evaluating combination therapy consisting of UFT and TAM as postoperative adjuvant therapy for breast cancer with induction therapy with MM. We therefore conducted a multicentre, collaborative study to evaluate the combined effect of UFT and TAM in patients with stage II primary breast cancer. In patients with estrogen-receptor-positive [ER(+)] breast cancer, TAM was used as a control drug as its efficacy has been demonstrated by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG). In patients with estrogen-receptor-negative [ER(-)] breast cancer, UFT was used as a control drug because chemotherapy is generally indicated for ER(-) breast cancer patients.