Combination therapy consisting of
cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), and
5-fluorouracil (5-FU) (CAF) is among the standard therapies for
advanced and recurrent breast cancer. Chemoendocrine therapy
combining CAF with an endocrine therapy like tamoxifen (Nolvadex) has
been evaluated extensively.
Hansen et al administered 5-FU via continuous infusion to patients
with refractory metastatic breast cancer and obtained a response rate
of 32% (eight of 25 patients) without causing myelosuppressive
adverse reactions (white blood cell count < 3,000/µL,
platelets < 100,000/µL). Uracil and tegafur in a 4:1 molar
ratio (UFT) has been found to produce sustained high 5-FU
concentrations in tumors. Administration of UFT and a continuous
infusion of 5-FU at an equal molar ratio generates blood 5-FU levels
with similar area under the concentration-time curves.[2-4] UFT
administered alone was associated with high response rates of 32% and
38% for advanced and recurrent breast cancer, respectively.[5,6]
We designed a combination-therapy program of cyclophosphamide,
doxorubicin, UFT, and tamoxifen (CAUT) in an attempt to reduce
adverse reactions in the bone marrow system caused by bolus
administration of cyclophosphamide, doxorubicin, and 5-FU. We also
hoped to establish an outpatient treatment and determine its efficacy
Patients with histologically confirmed, advanced (stage IIIB, IV, and
inflammatory) breast cancer or recurrent breast cancer, aged 20 to
under 75 years, and a performance status of 0 to 2 were entered into
this study. Patients who were excluded included those who had
received prior anthracyclines, endocrine therapy, and/or
immunotherapy within the previous 2 weeks, chemotherapy within 4
weeks, or radiation therapy within 6 weeks, as well as those with
Doxorubicin 30 mg/m² was administered intravenously on day 1.
UFT capsules 300 mg/m² and cyclophosphamide tablets 65 mg/m²
were administered orally for 2 weeks beginning on day 1, followed by
drug suspension for 1 week. Tamoxifen 20 mg/day was administered
orally on days 1 to 21. This schedule was repeated every 3 weeks.
Administration of granulocyte colony-stimulating factor was allowed,
at the physicians discretion, for patients with fever and a
reduction in white blood cell count to < 2,000/mL or for patients
with a reduction in white blood cell count to < 1,000/mL.
Antiemetics were also permitted.
Administration of cyclophosphamide, doxorubicin, and UFT was
suspended in the event of adverse reactions ³
grade 2; tamoxifen administration was suspended when adverse events ³
grade 3 occurred. The therapeutic period was 12 weeks (four cycles)
or longer. The total doxorubicin dose was limited to 350 mg/m².
Antitumor effects and adverse events were classified according to the
General Rules for Clinical and Pathological Recording of Breast
Cancer in Japan. Survival rates were calculated according to the
Kaplan-Meier method, and significance was determined by the log-rank test.
From February 1995 to December 1996, 20 patients were registered, of
whom 19 were eligible (one patient with a performance status of 3 was
excluded). The characteristics of the eligible patients are shown in Table
The antitumor efficacy of CAUT is shown in Table
2. One patient experienced a complete response, and there were
10 partial responses. Three patients experienced no change, and five
had progressive disease, yielding an overall response rate of 58% (11
of 19 patients; 95% confidence interval, 29% to 87%). In terms of
lesion site, antitumor activity was observed in soft tissue in 73% of
patients (eight of 11), in bone in 38% of patients (three of eight
patients), in lung/pleura in 20% of patients (one of five patients),
and in liver in 50% of patients (two of four). The complete response
period was 28 days.
Four patients with stage IIIB breast cancer had partial responses,
with a median duration of 55.5 days (2.25 cycles of CAUT). One
patient was transferred to radiation therapy and three underwent
surgery, including one breast-conserving surgery (Table
3). The patient with stage IV disease experienced a partial
response. Among patients with recurrent breast cancer, one had a
complete response and five had partial responses. In these patients,
the median time to response was 94 days (four cycles of
CAUT)longer than the response that was observed among patients
with stage IIIB breast cancer. The response period for the patient
achieving a complete response was 28 days, and for patients with a
partial response, the response period ranged from 51 to 464 days
(median, 201 days) (Table 4).
The survival curves for the 12 patients with recurrent breast cancer
are shown in Figure 1. The
patient with a complete response survived 220 days, and the two
patients with no change survived 350 and 454 days after the start of
therapy. The survival rate at 1,001 days after the start of therapy
was 80% among the five patients experiencing a partial response,
whereas all four patients with progressive disease died by day 554.
The prognoses for patients with complete response, partial response,
and no change were better than those for patients with progressive
disease (P = .068).
All adverse events ³ grade 3 are
shown in Table 5. According to
the number of events ³ grade 3,
leukopenia was observed in six patients (31.6%) (³
grade 4 in one), erythropenia in one (5.3%), alopecia in four
(21.1%), and generalized malaise in one (5.3%). One patient developed
grade 4 leukopenia, and one of the five patients with grade 3
leukopenia (the patient with a complete response) had an accompanying
fever; both patients received granulocyte colony-stimulating factor
and recovered. The other patients recovered after therapy was withdrawn.
Combination therapy with cyclophosphamide, doxorubicin, and 5-FU is
one of the standard chemotherapies for advanced and recurrent breast
cancer. Many variations and combinations with endocrine therapy have
been employed. We examined the efficacy and safety of chemoendocrine
therapy using oral UFT in place of continuous-infusion 5-FU with the
addition of tamoxifen (CAUT).
In a comprehensive efficacy evaluation of this regimen, the response
rate was 58% (11 of 19 patients). The response rates were highest in
soft tissue, followed in order by liver and bone. Response rates were
lowest in lung/pleura. Only a small number of patients had liver
metastases; however, this combination therapy can be expected to be
effective in these patients. Response rates were higher in the
postmenopausal patients (67%) than in the premenopausal patients
(43%); and this therapy was effective regardless of estrogen receptor
status (67% for estrogen receptor-positive patients and 60% for
estrogen receptor-negative patients). Although only a small number of
patients had received previous treatment, there was a 50% response
rate in this patient subgroup.
Adverse reactions in the bone marrow system were mild, and the grade
of alopecia was low. As for gastrointestinal adverse reactions, grade
2 anorexia and nausea/vomiting were observed in only 26% and 21% of
patients, respectively; no gastrointestinal adverse reactions ³
grade 3 were observed.
A combination therapy designed by replacing intravenous 5-FU in CAF
with UFT with the addition of tamoxifen (CAUT) was administered to
patients with advanced and recurrent breast cancer. This regimen was
associated with relatively mild adverse reactions compared with
anthracycline-based treatment, and achieved a satisfactory response
rate of 58%. These findings suggest that CAUT is a useful approach,
applicable to outpatient treatment of advanced and recurrent breast cancer.
1. Hansen R, Quebbeman E, Beatty P, et al: Continuous 5-fluorouracil
infusion in refractory carcinoma of the breast. Breast Cancer Res
Treat 10:145-149, 1987.
2. Hirata K, Sasaki K, Yamamitsu S, et al: A comparison of
5-fluorouracil concentration of 5-fluorouracil drip infusion versus
oral UFT in plasma of same patients. Gan To Kagaku Ryoho
3. Namatame K, Sasaki E, Ko Y, et al: A double-blind comparison of
FUra plasma concentration by oral (UFT) vs continuous intravenous
infusion (5-FU). Gan To Kagaku Ryoho 20:2417-2419, 1993.
4. Ho DH, Pazdur R, Covington W, et al: Comparison of
pharmacokinetics in patients receiving continuous 5-fluorouracil
infusion and oral uracil plus
N1-(2¢-tetrahydrofuryl)-5-fluorouracil. Clin Cancer Res
5. Ota K, Taguchi T, Kimura K: Report on nationwide pooled data and
cohort investigation in UFT phase II study. Cancer Chemother
Pharmacol 22:333-338, 1988.
6. Tashiro H, Nomura Y, Osaki 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 24:212-216, 1994.