Fluorouracil (5-FU) remains the mainstay in the systemic treatment of colorectal cancer, in both the adjuvant and advanced-disease settings. Over the past 40 years, this drug has been widely used in a variety of schedules and formulations. Prior to the development of continuous- infusion schedules, a daily administration for 5 days was shown to be the most effective schedule. A major advance in 5-FU therapy came with recognition that the addition of leucovorin resulted in a significant improvement in response rates. A variety of 5-FU/folinic acid schedules have been used, with no definitive consensus on the most effective regimen. Active schedules include the Mayo regimen, which uses a daily-times-five schedule; the Machover regimen, which is similar to the Mayo regimen, apart from the use of high-dose leucovorin; the 2-week De Gramont regimen; and a weekly high-dose regimen given over 24 hours.
Other groups have evaluated infusional 5-FU regimens and these have shown superiority over conventional bolus schedules.[6,7] However, there are limitations and side effects associated with infusional regimens, and bolus-modulated 5-FU schedules are still widely used. Novel formulations enabling continuous exposure to fluorinated pyrimidines, while avoiding the side effects of continuous-infusion chemotherapy, could be considered a major advance in cancer therapy.
Tegafur/uracil (UFT) comprises 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) and uracil in a molar ratio of 1:4. Fujii et al identified an increase in concentrations of 5-FU in tumors with coadministration of uracil. In vivo studies have indicated that UFT resulted in higher 5-FU uptake in tumors relative to normal tissues, with UFT more active than tegafur in many human xenograft models.
UFT has been evaluated in a number of phase I/II studies in the United States, including studies using both high- and low-dose leucovorin. A phase I/II study performed at The M.D. Anderson Cancer Center showed that dose-limiting toxicity occurred at a UFT dose of 450 mg/m2, using a fixed dose of leucovorin 150 mg. In that study, patients were treated for 28 days, followed by a 7-day rest period. At this dose, dose-limiting toxicity was comprised of diarrhea, abdominal pain, and subacute obstruction, with mild myelosuppression.
Following this determination, the recommended dose for phase II at M.D. Anderson was 350 mg/m2, administered in three divided doses per day. The initial seven patients were treated at this dose, but diarrhea, anorexia, and nausea became dose limiting, and subsequent patients were treated at 300 mg/m2, with 150 mg leucovorin. At this lower dose, side effects were acceptable, with 18 partial responses and 1 complete response among 45 patients. At Roswell Park Cancer Institute, two partial responses were seen among eight patients treated with UFT 350 mg/m2 with high-dose leucovorin.
A phase I study performed at Memorial Sloan-Kettering Cancer Center and the University of Southern California used low-dose leucovorin (15 mg/day) in the same schedule as in The M.D. Anderson study. Dose-limiting toxicity was observed at 350mg/m2, with diarrhea the most common toxicity noted. Other toxicities included sepsis, stomatitis, and mild myelosuppression. A phase II study performed at Memorial Sloan-Kettering Cancer Center, using a UFT dose of 350 mg/m2, reported a response rate of 25% in 21 patients.
In view of the interesting activity and low toxicity of UFT in combination with leucovorin, a phase III study has been set up to compare UFT plus low-dose leucovorin with a conventional regimen of 5-day modulated 5-FU.
This open-label, randomized phase III trial has been designed to compare UFT plus low-dose leucovorin with 5-day bolus-modulated 5-FU. The study end points are time to progression, survival, toxicity of treatment, quality of life, and symptom control. In addition, the pharmacoeconomics of therapy are being evaluated.
To identify 288 disease-progression events, 362 patients will be recruited. This number of patients gives the study 80% power to detect a hazard ratio of 1.40 between the two treatments. Recruitment was completed by July 1997. Figure 1 shows projected vs actual accrual in May 1997.
Patients randomized to the investigational arm will receive UFT 300 mg/m2/day divided into three equal daily doses for 28 days, followed by 1 week of rest. In addition, these patients will receive leucovorin 90 mg divided into three equal daily doses for 28 days. Patients receiving the control treatment will receive 5-FU 425 mg/m2/day plus leucovorin 20 mg/m2/day for 5 days every 35 days.
Patients will be assessed for tumor response and symptoms at every cycle, with computed tomography scans performed every two cycles. Symptom evaluation includes assessment of pain, analgesic use, weight loss, and performance status. An estimation of medical time required by patients in both arms of the study, including primary care and specialist treatment, will be made as part of a pharmacoeconomic evaluation. In responding patients, computed tomography scans will be repeated 5 weeks later to confirm response.
Patients with histologically confirmed metastatic colorectal adenocarcinoma, with bidimensionally measurable disease or evaluable disease located outside previously irradiated fields (all measurements
³ 1.5 cm) are considered eligible to participate in this study. Subjects are between 18 and 75 years of age, have an Eastern Cooperative Oncology Group performance status score of 0 to 2, and have completed any prior colorectal adjuvant treatment at least 6 months prior to enrollment.
In addition, eligible patients have a granulocyte count
³ 2,000/mm3, platelet count
³ 100,000/mm3, total bilirubin
£ 1.5 × upper limit of normal, and creatinine levels
´ upper limit of normal. No serious concurrent uncontrolled medical disorder or prior malignancies were allowed, and all patients gave their informed consent.
As outlined in Table 1, 47 centers in 15 countries had enrolled a total of 302 patients by May 1997. Of this total, 46 patients had received prior adjuvant chemotherapy, and 256 were chemotherapy naive. Patients were generally of good performance status, with 173 patients at grade 0 and 129 patients at grade 1 or 2. Recruitment was completed July 1997.
Modulated 5-FU remains the standard therapy for colorectal carcinoma. Infusional regimens appear to have benefits over bolus schedules, in terms of both efficacy and toxicity. However, delivery of continuous-infusion 5-FU has been known to result in problems, particularly relating to Hickman line complications.
UFT, which uses a tegafur and uracil combination, represents an interesting new development that results in increased tumor concentrations of 5-FU in preclinical models. The multiple daily dosing and good bioavailability of this product enables us to evaluate a prolonged-exposure treatment that is easy to administer. Early clinical studies using UFT combined with either low- or high-dose leucovorin have reported good activity with a very acceptable toxicity profile.
Therefore, a UFT plus low-dose leucovorin schedule was chosen for comparison with standard therapy comprising a 5-day bolus schedule of 5-FU plus low-dose leucovorin. The multicenter, multinational study recruitment of 362 patients has now been completed and is awaiting analysis. The primary end point of this study is to compare time to progression between the two treatments, looking for a 40% improvement in time to progression in the UFT/leucovorin-treated group.
UFT represents an interesting new product for the treatment of colorectal cancer and a range of other malignancies sensitive to 5-FU. Data from a number of randomized clinical trials comparing UFT/leucovorin with standard therapy are eagerly awaited to identify the potential therapeutic role of the newer regimen.
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9. Bristol-Myers Squibb: Data on file.
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