UFT is an oral antineoplastic drug combining uracil and tegafura
prodrug of 5-fluorouracil (5-FU)in a 4:1 molar ratio. Uracil
inhibits the degradation of 5-FU to inactive metabolites, resulting
in increased plasma and tumor 5-FU concentrations. UFT has been
available commercially in Japan since 1984 and has been used in the
treatment of and as adjuvant chemotherapy for bladder cancer, both as
a single agent and in combination with other anticancer drugs.
Results of phase I and phase II studies in Japan exploring the
activity of UFT in the treatment of bladder cancer[2,3] are described herein.
Pooled data from phase II trials of UFT in bladder cancer in Japan
are shown in Table 1. In these
trials, oral UFT was administered at 300 to 600 mg/day in two or
three divided doses, without interruption, for more than 4
weeks.[4,5] There were 57 patients entered into these phase II
studies, of whom 47 were evaluable for response. Among evaluable
patients, 15 (32%) responded to UFT therapy, including nine with a
complete response, for an overall response rate of 32%. Stable
disease was noted in 55% (26/47), and disease progression occurred in
13% (6/47) of evaluable patients.
Of the 47 evaluable patients, 35 had superficial (stages Ta, T1) and
12 had advanced (stages T2 to T4) bladder cancer. Responses,
including the nine complete responses, occurred in 11 of 35 patients
with superficial bladder cancer. Four of 12 advanced bladder cancer
patients responded to UFT, although none achieved complete response.
The maximum response was obtained for approximately 8 to 9 weeks
after starting therapy, and response duration ranged from 2 to 15
months in cases of complete response.
Toxicity criteria used in these phase II studies were slightly
different from current criteria. The toxicity observed in the
studies, nonetheless, was mild and reversible. Almost one half of the
entered patients experienced mild toxicityprincipally
gastrointestinal effects including anorexia, nausea and vomiting,
diarrhea, and stomatitis. Hematologic toxicity was rare: only one
case of mild leukopenia was reported.[4,5]
Shida et al have observed that UFT toxicity occurs in a
dose-dependent manner (Table 2).
Toxicity was observed in 56% of patients receiving 600 mg/day of
UFT, including 12% who discontinued UFT treatment. Toxicity was less
frequent (24%) among patients receiving 300 mg/day of UFT.
Other fluorinated pyrimidines have activity as depicted in Table
UFT as Adjuvant Chemotherapy
Based on this evidence of activity with UFT in superficial bladder
cancer, we initiated a prospective study to determine the potential
of long-term oral UFT in preventing intravesical recurrence of
superficial bladder cancer. The study schema is illustrated in Figure
1. A total of 112 patients with newly diagnosed superficial
transitional cell carcinoma of the bladder (stages Ta, T1 and grades
G1 or G2) were randomly assigned after complete tumor resection by
transurethral endoscopic surgery to receive either UFT (300 to 400
mg/day po for 2 years) or no anticancer therapy (control group). UFT
treatment was initiated within 14 days after surgery and was
continued on a daily basis for 2 years.
Among the 112 patients entered into the study, seven were excluded
from analysis, leaving 105 patients eligible for assessment. Patient
characteristics and tumor features were similar between the two
groups. After a median follow-up period of 24.5 months, the cancer
recurrence rate, outlined in Table 4,
was 25.7% in the UFT group and 43.3% in the control group (P = .015,
log-rank test). The median disease-free interval (Figure
2) was significantly longer in the UFT group (790 days) than in
the control group (508 days) (P < .05). Patients with relatively
small or single tumors, in particular, had a significant difference
(P = .03 and P = .012, respectively) in recurrence rate with UFT
therapy vs the control group.
Toxicity associated with UFT administration was acceptably low.
Eleven of 57 patients (19%) entered in the UFT arm experienced some
toxicity, primarily consisting of gastrointestinal
symptomsnausea, vomiting and diarrhea (7%), skin pigmentation
(7%), mild liver dysfunction (3.5%), and mild thrombocytopenia (1.8%).
These results suggest that long-term UFT administration after
transurethral resection can effectively prevent recurrence of
superficial bladder cancer.
Fluorinated pyrimidines such as 5-FU and tegafur have been shown to
be effective against bladder cancer, with mild toxicity when properly
used.[7,8] UFT is a mixture of uracil and
N-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) in a 4:1 molar ratio.
Uracil competitively inhibits dihydropyrimidine dehydrogenase (DPD),
an enzyme that degrades 5-FU to an inactive form. Thus, UFT
administration increases tumor concentration of 5-FU. When UFT was
administered orally, the maximum 5-FU concentration in bladder cancer
tissue was found to be 4 and 10 times higher than that occurring in
normal bladder epithelium and peripheral blood, respectively.
Our preliminary analysis by radiotherapypolymerase chain
reaction of gene expression of DPD in bladder cancer tissue, done
in collaboration with Kathleen and Peter Daneneberg of the University
of Southern California, showed that almost one half of tumors had
high DPD expression, which, it has been suggested, reduces the effect
of 5-FU. Thus, therapy for bladder cancer with UFT, which may inhibit
the DPD enzyme, has potential value. In fact, in the pooled phase II
data, oral UFT produced a greater response rate in bladder cancer
patients than did oral 5-FU, as shown in Table
Since intravesical recurrence of superficial bladder cancer (stages
Ta, T1) after transurethral resection occurs frequently, effective
adjuvant therapy to reduce the recurrence rate is greatly needed. Our
theory that UFT might prevent recurrence of superficial bladder
cancer with relatively low toxicity has been borne out by the results
of the prospective, randomized trial described herein. Patients
receiving UFT after transurethral resection for newly diagnosed
bladder cancer showed a significantly lower recurrence rate than did
untreated control patients. Stratification by grade, multiplicity,
and tumor size indicated that the anticancer effect of UFT was
particularly significant among patients with single small lesions
less than 1 cm in diameter.
One of the basic concepts of systemic anticancer chemotherapy is to
use the highest dose possible with side effects still tolerable by
the patient to achieve maximum tumor response. In the case of
adjuvant chemotherapy, however, the regimens might have as low a
level of toxicity as possible to allow for the safe completion of
long-term chemotherapy even after major surgery.
Based on accumulated evidence, oral UFT should be a useful approach
to preventing recurrence of bladder cancer, although our data did not
define dosage and duration recommendations for adjuvant therapy with
this agent. These clarifications await further examination in formal
Oral UFT is an effective and relatively safe agent for the treatment
of bladder cancer, yielding responses in almost one third of
patients, especially those with superficial bladder cancer. In
addition, long-term UFT administration after transurethral resection
for superficial bladder cancer was shown to effectively prevent
recurrence of disease, again with tolerable toxicity when used properly.
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of uracil or cytosine on the antitumor activity of clinical dose of
1-(2-tetrahydro-furyl)-5-fluorouracil and level of 5-fluorouracil in
rodents. Gann 70:209-214, 1979.
2. Taguchi T, Furue H, Koyama Y, et al: Phase I study of UFT. Jpn J
Cancer Chemotherapy 7:966-972, 1980.
3. Taguchi T: Experience with UFT in Japan. Oncology 11(suppl
4. Shida K, Yamanaka H, Ito Y, et al: Phase II study of UFT for
malignant tumors of urinary organs. Jpn J Cancer Chemotherapy
5. Asahi T, Matumura Y, Ozaki Y, et al: Clinical effect of UFT on
bladder cancer. Jpn J Cancer Chemotherapy 9:503-507, 1982.
6. Kubota Y, Hosaka M, Fukushima S, et al: Prophylactic oral UFT
therapy for superficial bladder cancer. Cancer 71:1842-1845, 1993.
7. Nagamoto A, Kubota Y, Shuin T, et al: Phase II study of oral 5-FU
tablet on bladder cancer. Jpn J Cancer Chemotherapy 16:845-850, 1989.
8. Omori H, Matumura Y, Yoshimoto J, et al: Phase II study of oral
5-FU tablet on bladder cancer. Jpn J Cancer Chemotherapy
9. Takayama H, Konami T, Konishi T, et al: Studies on 5-FU
concentration in serum and bladder tumor tissue after oral
administration of UFT. Acta Urologica Japonica 32:1449-1453, 1986.
10. Lentz H-J, Leichman CG, Daneneberg K, et al: Thymidilate synthase
expression in adenocarcinoma of the stomach: A predictor for primary
tumor response and overall survival. J Clin Oncol 14:176-182, 1996.