UFT (uracil and tegafur) was developed in Japan as an oral
antineoplastic agent that combined the fluorouracil (5-FU) prodrug
tegafur with uracil in a 1:4 molar ratio.
In the United States and Europe, UFT plus oral leucovorin (a
combination being developed under the trade name Orzel) has been
reported to produce objective responses and survival rates similar to
those achieved with standard intravenous 5-FU plus leucovorin in
metastatic colorectal cancer patients, with reduced toxicity.[1,2]
Although UFT has been commercially available for the treatment of
colorectal cancer in Japan since 1984, knowledge of and experience
with UFT plus leucovorin are relatively limited in Japan. This phase
II study was conducted to evaluate the efficacy and safety of this
combination in the treatment of Japanese patients with metastatic
The regimen used for the study had two unique characteristics: a
low-dose of leucovorin (15 mg/day), which was reported by Saltz et al
to achieve a 25% response rate, and a dose-intensive schedule of
oral UFT, administered for 5 consecutive days followed by a 2-day
rest period. This dose-intensive schedule has been shown to produce
greater inhibition of tumor growth and improved survival compared
with responses reported with conventional daily doses administered to
tumor-bearing rats. In addition, this dose-intensive schedule was
associated with favorable compliance in a clinical trial.
From July 1997 to June 1999, we studied 20 patients aged 38 to 80
years with histologically confirmed advanced or metastatic colorectal
cancer. Eligible patients had (1) Zubrod performance status greater
than 2; (2) at least one measurable lesion; (3) adequate
hematologic, hepatic, and renal function; and (4) life expectancy
over 3 months. A wash-out period of at least 4 weeks between any
previous chemotherapy and this trial was required for patients
treated with prior chemotherapy for metastatic disease.
Treatment consisted of oral UFT 400 mg/m²/day (in two doses q 12
h) and leucovorin 15 mg/day (in three doses q 8 h) for 5 days,
followed by a 2-day rest period for a 28-day cycle. In the event of
grade 2 toxicity, the dose of UFT was reduced to 250 mg/m²/day
in subsequent courses. If grade 2 toxicity reappeared, therapy was
withdrawn. Response and toxicity were recorded according to World
Health Organization (WHO) criteria.
All 20 patients were evaluable for response and toxicity.
Pretreatment characteristics are outlined in Table
A total of 90 cycles of chemotherapy were delivered, with a median of
4.5 cycles per patient (range, 2 to 12). Nine patients received five
or more courses. The median UFT dose was 380 mg/m² per cycle,
which corresponded to 95% of the planned dose.
One patient achieved a complete response (CR) (5%) and six achieved
partial responses (PR) (30%), for an overall response rate of 35%
(95% confidence interval, 14.1% to 55.9%) (Table
2). Greater efficacy was demonstrated in lung metastases, with a
response rate of 62.5% (five of eight patients). Response rates were
16.7% (one of six) and 42.9% (6 of 14) in patients treated with or
without 5-FU or 5-FUcontaining chemotherapies, respectively.
Median response duration was 95 days (range, 77 to 234 days) and
median time to progression was 127 days (range, 50 to 360 days) for
patients receiving UFT plus leucovorin. Median survival was 228+ days
(range, 81 to 540 days): 310 days for patients who achieved a CR or
PR, and 205 days for nonresponders. Six patients remain alive.
The combination of UFT plus leucovorin was well tolerated by patients
in the study. Grade 1 or 2 diarrhea, nausea/vomiting, and elevated
transaminase levels were observed in two (10%), one (5%), and two
(10%) patients, respectively. Grade 3 or 4 toxicity included diarrhea
and mucositis (Table 3). All
grade 3 or 4 toxicity was completely resolved with discontinuation of
treatment. There were no treatment-related deaths or toxicity
The results of this phase II trial of UFT plus leucovorin compare
favorably with those of other phase II trials conducted in the United
States and Europe.[3,8,9,10] Although these trials evaluated slightly
different doses of both UFT and leucovorin, the 35% response rate
reported in this study is similar to the rates reported in other
trials, which ranged from 25% to 40%. Median survival times in other
trials ranged from 8.2 to 15.8 months, which was longer than the
reported survival of 7.6+ months (with six patients alive) in this trial.
Greater efficacy for UFT plus leucovorin was demonstrated in patients
with lung metastases, with a 62.5% (five of eight patients) response
rate. Pazdur et al reported a response rate of 46.2% (6 of 13) in
pulmonary metastasis. The high response rate in our study was mainly
the result of targeting a population of patients with lesions < 3
cm and fewer than five metastases, with the exception of one patient
(data not shown). In contrast, the response rate in hepatic
metastasis was 10.0%, which was considerably lower than the 42.9% (18
of 42 patients) reported by Pazdur et al , because four patients
received adjuvant 5-FU chemotherapy and three patients were treated
with 5-FU arterial infusion prior to this study.
In the other two phase II trials, patients received UFT 300
mg/m²/day for 28 days followed by a 7-day rest, with a UFT dose
intensity of 1,680 mg/m²/wk.[1,2] However, in our trial, the UFT
dose intensity was 2,000 mg/m²/wk. Despite this intensive
regimen, grade 3 or 4 diarrhea and mucositis occurred in only 10% and
5% of patients in our study, respectively. These percentages were
similar to those reported in other trials.[3,8,9,10] No severe
myelosuppression was recorded in our study and these acceptable
adverse effects allowed us to maintain 95% of the planned UFT dose.
This dose-intensive schedule with mild toxicity produced a better
response rate than the 25% response rate previously reported by Saltz
UFT plus leucovorin showed promising activity and acceptable toxicity
in the treatment of patients with metastatic colorectal cancer in
Japan. This combination may also be useful in the postoperative,
oral, adjuvant setting for patients in Japan.
1. Pazdur R, Douillard JY, Skilling JR, et al: Multicenter phase III
study of 5-fluorouracil (5-FU) or UFT in combination with leucovorin
(LV) in patients with metastatic colorectal cancer (abstract 1009).
Proc Am Soc Clin Oncol 18:263a, 1999.
2. Carmichael J, Popiela T, Radstone D, et al: Randomized comparative
study of Orzel (oral uracil/tegafur [UFT] plus leucovorin [LV]) vs
parenteral 5-fluorouracil (5-FU) plus LV in patients with metastatic
colorectal cancer (abstract 1015). Proc Am Soc Clin Oncol 18:264a, 1999.
3. Saltz LB, Leichman CG, Young CW, et al: A fixed-ratio combination
of uracil and tegafur (UFT) with low-dose leucovorin: An active oral
regimen for advanced colorectal cancer. Cancer 75:782-785, 1995.
4. Sadahiro S, Mukai M, Tokunaga N, et al: Preliminary study on the
optimal dosage schedule for oral tegafur/uracil (UFT) chemotherapy.
Int J Clin Oncol 3:7-12, 1998.
5. Sadahiro S, Ohki S, Takahashi S, et al: Pilot study of the new
dose intensive oral UFT schedule as adjuvant chemotherapy for
colorectal cancer (abstract 1054). Proc Am Soc Clin Oncol 17:274a, 1998.
6. Zubrod C, Schneiderman M, Frei J: Appraisal of methods for study
of chemotherapy of cancer in man: Comparative therapeutic trial of
nitrogen mustard and thietylene thiophosphoramide. J Chron Dis
7. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of
cancer treatment. Cancer 42:207-214, 1981.
8. Pazdur R, Lassere Y, Rhodes V, et al: Phase II trial of uracil and
tegafur plus oral leucovorin: An effective oral regimen in the
treatment of metastatic colorectal carcinoma. J Clin Oncol
9. Gonzalez-Baron M, Feliu J, de la Gandara I, et al: Efficacy of
oral tegafur modulation by uracil and leucovorin in advanced
colorectal cancer: A phase II study. Eur J Cancer 31A:2215-2219, 1995.
10. Sanchiz F, Milla A: Tegafur-uracil (UFT) plus folinic acid in
advanced rectal cancer. Jpn J Clin Oncol 24:322-326, 1994.
11. Hoff PM, Pazdur R: UFT plus oral leuco-vorin: A new oral
treatment for colorectal cancer. Oncologist 3:155-164, 1998.