Chemoendocrine therapies that include tamoxifen(Drug information on tamoxifen) (Nolvadex) are often used as postoperative adjuvant therapy for breast cancer. Combination therapy with tegafur(Drug information on tegafur)a fluoropyrimidine anticancer drug first approved in Japanand tamoxifen has been evaluated in meta-analyses in the first and second Adjuvant Chemoendocrine Therapy for Breast Cancer (ACETBC) studies.[1,2] In these studies, the efficacy of the combination of uracil and tegafur in a 4:1 molar ratio (UFT) (which yields higher 5-fluorouracil [5-FU] concentrations in tumors and greater antitumor activity than achieved with tegafur alone in advanced/recurrent breast cancer) was compared with that of tamoxifen. Tamoxifen was shown in the Early Breast Cancer Trialists Collaborative Group (EBCTCG) report to be highly active in estrogen receptor (ER)-positive breast cancer.
The current study was designed to examine the theory that tamoxifen plus UFT is more effective than tamoxifen alone in patients with stage II breast cancer whose tumors are ER-positive. The results are described here.
Female patients with stage II (TNM classification, Union International Contre le Cancer [UICC] 1972) primary breast cancer who were 1) £ 75 years of age at the time of surgery, 2) undergoing curative surgery including mastectomy plus axillary lymph node dissection, and 3) found to be ER-positive, were eligible for the study. Patients with noninvasive cancer, bilateral cancer, double cancer, inflammatory breast cancer, or breast cancer during pregnancy and lactation were excluded. Postoperative radiation therapy, surgical endocrine therapy (such as oophorectomy), and white blood cells < 3,000/µL, platelets < 100,000/µL, aspartate aminotransferase > 60 U/L, alanine aminotransferase > 60 U/L in preoperative laboratory tests were also reasons for exclusion.
All patients received an intravenous injection of mitomycin(Drug information on mitomycin) (13 mg/m²) on the day of surgery. Patients determined to be ER-positive were randomly allocated to two treatment groups: those in group A received tamoxifen orally at a dose of 20 mg/day beginning on day 14 after surgery for 2 years; in group B, UFT was administered orally at a dose of 400 mg/day together with tamoxifen at a dose of 20 mg/day.
Distribution of background factors for patients in the therapeutic groups was determined by t test, c² test, and U test. The survival and relapse-free survival rates were calculated by the Kaplan-Meier method, and the differences in the groups, by the log-rank test. The distribution of incidences of adverse reactions in the therapeutic groups was measured by c² test. It was determined for all tests that there was a significant difference when the P value was < .05.
Registered Patients and Characteristics
From November 1988 to May 1992, 444 patients were enrolled in the trial. Among them, eight patients were deemed ineligible, including one with no cancer, three with noninvasive cancer, one in stage IIIa, one aged ³ 76 years, and two treated with other than the allocated therapy. Accordingly, 213 patients in group A (97.3%) and 223 patients (99.1%) in group B were found to be eligible for evaluation. There were no significant variations between the groups in distribution of major background factors, such as age, menopausal status, tumor diameter, number of lymph node metastases, or histologic type (Table 1).
A total of 78% of patients were followed for 5 years after surgery. The 5-year survival rates were 93.0% for group A and 95.4% for group B, indicating no significant difference in survival between patients receiving mitomycin + tamoxifen vs mitomycin + tamoxifen + UFT (P = .033). Thirteen patients in group A and nine in group B died, including six in each group who died from the disease. The 5-year relapse-free survival rates were 83.1% for group A and 90.7% for group B, demonstrating a significant advantage for treatment with mitomycin plus tamoxifen plus UFT (P = .020) (Figure 1).
In subset analyses, a significantly higher 5-year relapse-free survival rate was associated with group B therapy than with group A therapy among patients with metastases in one to three lymph nodes (P = .012) and among postmenopausal patients (P = .019) (Table 2). Twenty-five patients (11.7%) in group A and 15 (6.7%) in group B experienced a recurrence of disease. Lung metastases occurred as the first recurrent site in seven patients (3.3%) in group A and two (0.9%) in group B (P = .077) (Table 3).
Administered Dose and Adverse Reactions
The average dose of mitomycin was similar for the two groups (18.9 mg for group A and 18.8 mg for group B). The average dose of tamoxifen was 14.9 g (102% of the predetermined dose) for group A and 15.3 g (105% of the predetermined dose) for group B. The average dose of UFT was 264.5 g, corresponding to 91% of the predetermined dose.
Although the incidence of leukopenia, anorexia, nausea/vomiting, general fatigue, and pigmentation was higher in the group receiving combination therapy with uracil and tegafur (UFT), no adverse reactions were considered serious (Table 4).
A number of trials have examined the therapeutic effect of chemoendocrine therapy in advanced metastatic breast cancer. Our results and the meta-analysis of the first ACETBC Study Group trial indicated a lower rate of recurrence and a longer survival rate following treatment with tegafur and tamoxifen vs tegafur alone in patients with stages II and IIIa breast cancer. The benefit was particularly evident among the subgroups of patients who were ER-positive or postmenopausal.
In the current study, the combination of UFTwhich exhibited a higher response rate for advanced/recurrent breast cancer than tegafurwith tamoxifen was evaluated in the treatment of stage II, ER-positive patients with breast cancer. Induction therapy with mitomycin was employed based on evidence of efficacy in a previous trial. The 5-year survival rate was higher with the UFT combination than with tamoxifen, although the difference was not significant. On the other hand, the 5-year relapse-free survival was significantly greater with the UFT plus tamoxifen combination, in particular among lymph nodepositive (with one to three metastases) and postmenopausal patients.
Fisher et al reported similar results with a regimen of doxorubicin(Drug information on doxorubicin) (Adriamycin) plus cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan) and tamoxifen. In that study (National Surgical Adjuvant Breast and Bowel Project B-16), treatment was also effective in node-positive patients aged ³ 50 years and more significantly, in ER-positive patients. The International Breast Cancer Study Group also reported a positive effect with CMF (cyclophosphamide, methotrexate(Drug information on methotrexate), 5-FU) plus tamoxifen in node-positive, postmenopausal, ER-positive patients. In the Treatment Recommendations of the International Consensus Panel on the Treatment of Primary Breast Cancer, chemotherapy with tamoxifen was recommended for node-negative high-risk patients and node-positive patients who were ER-positive and postmenopausal. The results of the present study appear to support this policy.
On the other hand, the present study revealed a 5% higher relapse-free survival rate in premenopausal patients receiving the UFT combination than in the tamoxifen-alone group, although this was not significant. Meta-analysis by the EBCTCG indicated the efficacy of chemotherapy in premenopausal patients. Thus, the combination of tamoxifen plus UFT in premenopausal patients should be studied further.
The adverse reactions of leukopenia, anorexia, nausea/vomiting, general fatigue, and pigmentation occurred at greater frequency in the group receiving the UFT combination. However, no adverse reactions were considered serious, and it was concluded that tamoxifen plus UFT is safe to use in this population.
Combination therapy with mitomycin and tamoxifen and UFT is a useful postoperative chemoendocrine treatment for patients with stage II, ER-positive breast cancer. Adverse effects associated with the regimen are relatively mild.