UFT (uracil and tegafur(Drug information on tegafur)) was developed in Japan as an oral antineoplastic agent that combined the fluorouracil(Drug information on 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 colorectal cancer.
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 If grade 2 toxicity reappeared, therapy was withdrawn.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 1.
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 requiring hospitalization.
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 et al.
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.