Chemoendocrine therapies that include tamoxifen
(Nolvadex) are often used as postoperative adjuvant therapy for
breast cancer. Combination therapy with tegafura
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
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 (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
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
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
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 (Adriamycin) plus 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,
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.
1. Abe O: The role of chemoendocrine agents in postoperative adjuvant
therapy for breast cancer: Meta-analysis of the first collaborative
studies of postoperative adjuvant chemoendocrine therapy for breast
cancer (ACETBC). Breast Cancer 1:1-9, 1994.
2. Yoshida M, Abe O, Uchino J, et al: Meta-analysis of the second
collaborative study of adjuvant chemoendocrine therapy for breast
cancer (ACETBC) in patients with stage II, estrogen receptor positive
breast cancer. Breast Cancer 4:93-101, 1997.
3. Tashori H, Nomura Y, Ohsaki A: A double-blind comparative study of
tegafur (FT) and UFT (a combination of tegafur and uracil) in
advanced breast cancer. Jpn J Clin Oncol 24:212-217, 1994.
4. Systemic treatment of early breast cancer by hormonal, cytotoxic,
or immune therapy. 133 randomized trials involving 31,000 recurrences
and 24,000 deaths among 75,000 women. Early Breast Cancer
Trialists Collaborative Group. Lancet 339:1-15, 1992.
5. Uchino J, Samejima N, Tanabe T, et al: Positive effect of
tamoxifen as part of adjuvant chemoendocrine therapy for breast
cancer. Br J Cancer 69:767-771, 1994.
6. Yoshimoto M, Kasumi F, Watanabe S, et al: Ten-year follow-up
mitomycin C single-agent adjuvant chemotherapy for breast cancer, in
Taguchi T, Andrysek O (eds): New Trends in Cancer, Chemotherapy with
Mitomycin C, pp 58-67. Tokyo, Excerpta Medica, 1987.
7. Fisher B, Redmond C, Legault-Poisson S, et al: Postoperative
chemotherapy and tamoxifen compared with tamoxifen alone in the
treatment of positive-node breast cancer patients aged 50 years and
older with tumors responsive to tamoxifen: Results from National
Surgical Adjuvant Breast and Bowel project B-16. J Clin Oncol
8. The International Breast Cancer Study Group: Effectiveness of
adjuvant chemotherapy in combination with tamoxifen for node-positive
postmenopausal breast cancer patients. J Clin Oncol 15:1385-1394, 1990.
9. Goldhirsh A, Wood WC, Senn H, et al: Meeting highlights:
International consensus panel on the treatment of primary breast
cancer. J Natl Cancer Inst 87:1441-1445, 1995.