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The Oncologist, Vol. 3, No. 3, 155-164, June 1998
© 1998 AlphaMed Press

Original Papers

UFT Plus Oral Leucovorin: A New Oral Treatment for Colorectal Cancer

Paulo M. Hoff, Richard Pazdur

Division of Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Correspondence: Richard Pazdur, M.D., Division of Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 92, Houston, Texas 77030, USA. Telephone: 713-792-3634; Fax: 713-745-1827; e-mail: rpazdur{at}notes.mdacc.tmc.edu


   Abstract
Top
 Abstract
Introduction
 Mechanism of Action
 Phase I Trials
 Dose-Ranging Trials
 Phase II Trial
 Pharmacoeconomics
 Discussion
 References
 
UFT is an oral antineoplastic agent that combines the 5-fluorouracil (5-FU) prodrug tegafur with uracil in a 1:4 molar ratio. Uracil is added because it competitively inhibits the degradation of 5-FU, resulting in increased plasma and tumor 5-FU concentrations. Although UFT has been available in Japan since 1984, it has only recently been in clinical development in the United States. Beginning in 1991, phase I/II trials of UFT have been conducted in the United States to establish a maximum tolerated dose, evaluate its pharmacokinetics, and assess its efficacy and safety in advanced colorectal cancer. Pharmacokinetic studies demonstrated that UFT 300 mg/m2/day administered in divided doses every 8 h for 28 days provides an effective oral method of delivering a prolonged exposure to 5-FU. UFT plus oral leucovorin is well tolerated, with diarrhea as the dose-limiting toxicity. Unlike i.v. administered 5-FU, UFT is not associated with significant myelosuppression, mucositis, hand-foot syndrome, or alopecia, and patients have a decreased risk of toxicity-related hospitalization. In a phase II trial in advanced colorectal cancer, UFT plus oral leucovorin produced an objective response rate of 42%, with survival similar to weekly i.v. 5-FU plus leucovorin. The reduced toxicity, efficacy comparable to i.v. 5-FU, and the convenience and cost savings of an orally administered regimen have potential pharmacoeconomic advantages.

Key Words. Colorectal cancer • UFT • 5-fluorouracil • Tegafur • Uracil • Leucovorin


   Introduction
Top
 Abstract
 Introduction
Mechanism of Action
 Phase I Trials
 Dose-Ranging Trials
 Phase II Trial
 Pharmacoeconomics
 Discussion
 References
 
UFT (Taiho Pharmaceutical Ltd.; Tokyo, Japan; BMS-200604, Bristol-Myers Squibb; Princeton, New Jersey) is an oral antineoplastic agent combining tegafur (ftorafur, a prodrug of 5-fluorouracil [5-FU]) and uracil in a 1:4 molar ratio. The development of UFT is based on the pioneering work of Fujii more than 20 years ago and builds on the observation that uracil inhibits the degradation of 5-FU, generated from tegafur [1]. Although UFT has been commercially available in Japan since 1984 and is widely prescribed in that country for the treatment of solid tumors, knowledge and experience with the drug in other countries is relatively limited.

Tegafur was evaluated in the United States in the 1970s by the National Cancer Institute, with most clinical trials using short-duration i.v. dosing schedules that resulted in high peak plasma concentrations of tegafur and 5-FU [2]. Although objective responses were observed in colorectal, breast, and gastric tumors, these administration schedules were complicated by severe diarrhea, mucositis, and central nervous system toxicity [3-5]. Tegafur appeared no more efficacious than i.v. 5-FU, but was associated with significantly more diarrhea and central nervous system toxicity; based on these findings, further development of tegafur in the United States was suspended [4].

In contrast, the Japanese strategy in developing tegafur was to use the drug as an oral agent administered in divided doses over a prolonged period with few interruptions. This approach resulted in moderate efficacy with a mild toxicity profile [6, 7]. In early clinical trials in Japan, investigators observed activity in a variety of tumors (e.g., breast cancer, head and neck tumors, and gastrointestinal cancer) with mild toxicity. The recognition that uracil modulated 5-FU metabolism led to the subsequent development of UFT [1, 8].

Many early Japanese trials did not use conventional toxicity criteria, definitions of maximum-tolerated dose (MTD), dose escalations, and response criteria that have been carefully defined by investigators in the United States over the past two decades [9]. Thus, investigators in the United States initiated conventional phase I trials of UFT in 1990, despite its commercial availability in Japan. These studies also were designed to include leucovorin (folinic acid), a biochemical modulator of i.v. 5-FU that was increasingly prescribed in the United States, but which had not been evaluated in Japan with i.v. 5-FU or UFT [7].

The current development of UFT with leucovorin represents an effort to bridge the drug development philosophies of Japan and the United States. Prolonged UFT oral dosing schedules were based on Japanese trials. Prolonged oral exposure to fluorinated pyrimidines was also consistent with an emerging concept that protracted i.v. 5-FU infusions may be the optimum dosing schedule [10-12]. Based on phase I trial methodology used in the United States, UFT was evaluated at doses approximating an MTD, considering that the optimal dose intensity of prolonged oral dosing must allow for the fewest toxicity-related dose interruptions. In addition, there was extensive experience in the United States with the biochemical modulation of 5-FU by leucovorin, principally administered by the i.v. route [13-15]. This experience, incorporating leucovorin (given orally) to modulate UFT-generated 5-FU, allowed the development of a completely oral treatment regimen.


   Mechanism of Action
Top
 Abstract
 Introduction
 Mechanism of Action
Phase I Trials
 Dose-Ranging Trials
 Phase II Trial
 Pharmacoeconomics
 Discussion
 References
 
Tegafur is a prodrug of 5-FU; it is slowly metabolized to 5-FU via several metabolic pathways, but especially through hepatic microsomal cytochrome P450 [16-18]. Once tegafur is converted to 5-FU, the drug has a metabolism and cytotoxic activity identical to that of i.v. 5-FU (Fig. 1Go).



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  		Figure 1. Metabolism of 5-fluorouracil. 5-FU: 5-fluorouracil; R-1-P: ribose monophosphate; dR-1-P: deoxyribose monophosphate; Pi: phosphate; FUR: fluorouridine; FUMP: fluorouridine monophosphate; FUDP: fluorouridine diphosphate; RNA: ribonucleic acid; PRPP: 5'-phosphoribosyl-1-pyrophosphate; PPi: pyrophosphate inositol; FUdR: fluorodeoxyuridine (floxuridine); FdUMP: 5-fluoro-2'-deoxyuridine monophosphate; FdUDP: 5-fluoro-2'-deoxyuridine diphosphate; FdUTP: 5-fluoro-2'-deoxyuridine triphosphate; dUMP: deoxyuridine-5'-monophosphate; dUTP: deoxyuridine-5'-triphosphate; DNA: deoxyribonucleic acid; 5,10-CH2FH4: 5,10-methylenetetrahydrofolate.

 
The cytotoxic activity of 5-FU is believed to result from its metabolism to two active nucleotides, fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP). FdUMP acts by forming a complex with thymidylate synthase, an integral component of DNA synthesis. The other active metabolite, FUTP, is integrated into cellular RNA and may alter RNA processing and function [7, 19].

In addition to its conversion to these active metabolites, 5-FU is also metabolized to inactive metabolites, primarily by the enzyme dihydropyrimidine dehydrogenase (DPD). Uracil is a natural pyrimidine that is also metabolized by DPD. Thus, when tegafur and uracil are coadministered, uracil competitively binds to DPD, decreasing 5-FU degradation. This results in a more prolonged half-life of 5-FU and its active metabolites than with the administration of tegafur alone, producing an enhancement of the cytotoxic effects of the drug [7]. In preclinical studies, coadministration of tegafur and uracil enhanced the concentration of 5-FU in tumors and resulted in increased antitumor activity [2, 20, 21]. In rats bearing subcutaneous colorectal tumors, UFT demonstrated greater antitumor activity than tegafur alone, and this activity was further increased with leucovorin biomodulation [22]. The higher concentration of 5-FU achieved in tumor tissue with UFT has been confirmed in humans [23-25]. In patients with a variety of solid tumors, the tumor-to-normal-tissue ratio of 5-FU was 4.1:1 in patients receiving UFT compared with a ratio of 1.6:1 in those receiving tegafur alone [23]. The 1:4 molar ratio of tegafur:uracil was determined to be the optimal ratio for the combination [2, 23, 26].

The FdUMP/thymidylate synthase complex that forms after 5-FU administration depends on the presence of adequate concentrations of reduced folate [19, 27-29]. Leucovorin is a derivative of tetrahydrofolic acid, the reduced form of folic acid. The addition of leucovorin increases the intracellular concentration of reduced folates, thus stabilizing the FdUMP/thymidylate synthase enzyme complex, providing the biochemical rationale for adding leucovorin to 5-FU and tegafur chemotherapy regimens. The addition of leucovorin to i.v. 5-FU regimens has been evaluated in a number of clinical trials, and a meta-analysis has demonstrated a significantly higher response rate with the combination compared with the administration of 5-FU alone [30]. This earlier experience provided the basis for the United States experience with UFT.

In the United States, clinical experience with UFT was initiated in 1991. These trials included phase I studies to determine the pharmacokinetics and optimal dosage regimen of UFT with and without oral leucovorin, as well as phase II trials evaluating the efficacy and safety of UFT plus oral leucovorin in the treatment of advanced colorectal cancer.


   Phase I Trials
Top
 Abstract
 Introduction
 Mechanism of Action
 Phase I Trials
Dose-Ranging Trials
 Phase II Trial
 Pharmacoeconomics
 Discussion
 References
 
Pharmacokinetics
In initial phase I studies, the pharmacokinetics of tegafur, 5-FU, and uracil following administration of UFT were evaluated in 21 patients with solid tumors [31]. Two dose-escalation administration schedules were studied: (A) administering 345 mg/m2/d and escalating to 900 mg/m2/d for five days, and (B) administering 160 mg/m2/d and escalating to 450 mg/m2/d for 28 days. The daily dose was given in three divided doses every eight h. At all time points measured, plasma concentrations were highest for tegafur, followed by uracil and 5-FU. Peak plasma concentrations of 5-FU were achieved between approximately 0.5 and two h after a dose and were generally dose-dependent.

Single-Dose and Steady-State Pharmacokinetics
In another study, the single-dose pharmacokinetics following escalating doses of UFT plus oral leucovorin and the steady-state pharmacokinetics of UFT plus oral leucovorin during the 28-day administration schedule were analyzed [32]. One week prior to initiating continuous therapy with UFT and leucovorin, 18 patients with refractory colorectal cancer received a single dose of UFT 100 (n = 6), 200 (n = 6), or 400 mg (n = 6) and leucovorin. One week after this single-dose phase, all patients received oral UFT 300 mg/m2/d plus leucovorin 75 mg/d, both drugs given in divided doses every eight h for 28 days followed by a seven-day rest period.

Single-dose UFT (100 to 400 mg) administration resulted in maximum plasma concentrations and areas under the plasma concentration-time curve (AUC) for uracil, tegafur, and 5-FU that increased with escalating doses of UFT [32]. Steady-state plasma concentration data for tegafur, uracil, and 5-FU showed a consistent peak and trough appearance during each eight-h dosing interval and were similar to single-dose administration; there was no evidence of accumulation. Plasma 5-FU concentrations peaked 0.5-1 h after dosing, with mean peak plasma concentrations ranging from 304 to 403 ng/ml during the 28-day schedule. Mean trough 5-FU concentrations ranged from 31 to 46 ng/ml. Median plasma 5-FU AUC0-8h on days 8, 15, and 28 were 926, 758, and 770 ng/ml•h, respectively. Plasma 5-FU concentrations remained detectable throughout the entire eight-h dosing interval, with relatively low intrapatient variability in plasma 5-FU exposure [32]. Continuous plasma exposure of reduced folates was evident throughout the dosing period with little variation; this schedule provided adequate reduced folate exposure for each dose of UFT given during the 28-day schedule.

Comparison to Protracted 5-FU Infusion
Compared with i.v. bolus schedules of 5-FU, protracted low-dose 5-FU infusions are associated with decreased toxicity and at least comparable efficacy. However, protracted i.v. infusion requires a central venous catheter and portable infusion pump. As many as 30% of patients receiving these regimens have central line complications including infections, line slippage, thrombosis, or septicemia; these complications require line replacement in 11% of patients [33]. An oral treatment regimen that would provide protracted delivery of 5-FU eliminates the need for central venous catheters and infusion pumps. The pharmacokinetics of i.v. 5-FU with oral UFT administered in equimolar dosages were compared in 10 patients [34]. In this study, patients first received a protracted infusion of low-dose 5-FU 250 mg/m2/d over five days, and then after a one-week wash-out period, received UFT 300 mg/m2/d plus oral leucovorin 75 mg/d administered in divided doses every eight h over 28 days. The results are presented in Table 1Go. Following initiation of the protracted 5-FU infusion, plasma 5-FU levels rapidly reached a steady-state concentration (Css) that was maintained for the entire five days. After administration of UFT, the mean peak plasma concentration (Cmax) of 5-FU ranged from 0.30 to 0.35 µg/ml over the first five days of administration. By day 25, the mean Cmax was 0.44 µg/ml. These values exceeded the mean Css produced by the continuous i.v. infusion (0.08 µg/ml). Although the 5-FU AUC was greater for the i.v. infusion on day 1, the AUC values for the two regimens were similar by day 5. The elimination half-life of 5-FU after administration of UFT was 7.2 h. This is considerably longer than the half-life previously reported for i.v. 5-FU (0.21 h) [35].


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  		Table 1. Plasma 5-FU concentrations after oral UFT and continuous infusion of 5-FU [34]
 
These studies indicate that, at equimolar dosages, UFT delivers higher peak plasma 5-FU concentrations with similar systemic 5-FU exposure compared with a low-dose protracted infusion of 5-FU.


   Dose-Ranging Trials
Top
 Abstract
 Introduction
 Mechanism of Action
 Phase I Trials
 Dose-Ranging Trials
Phase II Trial
 Pharmacoeconomics
 Discussion
 References
 
Single-Agent UFT
Between 1990 and 1994, several phase I dose-ranging trials with UFT were conducted (Table 2Go). Initially, UFT was studied as a single agent. Schedules for these studies included five days of dosing repeated every 21 days, and 28 days of dosing repeated every 35 days. The daily UFT dose was divided into three doses administered every eight h. With the five-day schedule, UFT dosages ranging from 360 to 900 mg/m2/d were evaluated [36]. No toxicity was observed at the 360- and 720-mg/m2/d dosage levels; however, at 900 mg/m2/d, grade 4 granulocytopenia was seen in four of five patients. The dose was subsequently de-escalated to 800 mg/m2/d in an additional eight patients. At this dosage, only one patient developed grade 4 granulocytopenia, while an additional two patients experienced grade 3 toxicity (nausea [n = 1], thrombocytopenia [n = 1]). Using the 28-day schedule, dosages of 180 to 450 mg/m2/d were evaluated [36]. No grade 3/4 toxic reactions occurred at the 180-mg/m2/d dosage level. At 450 mg/m2/d, two patients developed grade 4 toxicity (granulocytopenia [n = 1], diarrhea [n = 1]), and grade 3 toxicity occurred in three patients (diarrhea [n = 2], oral mucositis [n = 1]). A subsequent dosage reduction to 400 mg/m2/d produced grade 3/4 diarrhea in three of eight patients.


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  		Table 2. Phase I dose-ranging trials of UFT conducted in the United States
 
These trials demonstrated that single-agent UFT possessed schedule-dependent toxicity differences. The dose-limiting toxicity (DLT) with the five-day schedule was granulocytopenia, which was observed at 900 mg/m2/d; the DLT with the 28-day schedule was diarrhea, which occurred at 400 mg/m2/d. In addition, with the 28-day schedule, a steep dose-toxicity relationship was observed; no patients receiving 360 mg/m2/d developed diarrhea. Grade 3/4 diarrhea generally began during the fourth week of treatment and required prolonged hospitalizations. Grade 2 diarrhea generally resolved within two to three days, allowing patients to resume UFT without dose reduction. Therefore, the recommended phase II dosages of UFT without oral leucovorin were 800 mg/m2/d using the five-day schedule and 360 mg/m2/d with the 28-day schedule. These dosages were well tolerated, and patients did not develop significant neutropenia, oral mucositis, acral erythema (hand-foot syndrome), or diarrhea.

UFT Plus Oral Leucovorin
Two phase I studies to evaluate the addition of oral leucovorin 150 mg/d to UFT using either a 14- or 28-day schedule were performed at the MD Anderson Cancer Center (Table 2Go). With the 14-day schedule, dosages of 400 mg/m2/d administered to six patients produced grade 3 diarrhea (n = 4), vomiting (n = 1), nausea (n = 1), and abdominal cramping (n = 1) [38]. In contrast, among six patients receiving 350 mg/m2/d, there were only two episodes of grade 3 toxicity (diarrhea [n = 1], vomiting [n = 1]). In another study combining UFT and oral leucovorin, UFT dosages ranging from 200 to 400 mg/m2/d for 28 days were evaluated [39]. No grade 3/4 toxicities were observed among nine patients receiving dosages of 300 mg/m2/d or less. Grade 3 diarrhea was dose limiting in two of three patients receiving 400 mg/m2/d and in six of 14 patients receiving 350 mg/m2/d.

Similar to the single-dose results, diarrhea was the DLT at 350-400 mg/m2/d. The shorter treatment duration (14-day) did not allow a significant increase in the UFT starting dose, and diarrhea remained the DLT [38]. Therefore, a UFT dosage of 300 mg/m2/d for 28 days when administered with leucovorin 150 mg/d was recommended for phase II trials [39]; this dosage allowed delivery of a greater UFT dose intensity. Subsequent reduction of the leucovorin dosage to 75 or 90 mg/d (25-30 mg every eight h) was made based on the saturable oral absorption of leucovorin beyond these lower dosages [40].


   Phase II Trial
Top
 Abstract
 Introduction
 Mechanism of Action
 Phase I Trials
 Dose-Ranging Trials
 Phase II Trial
Pharmacoeconomics
 Discussion
 References
 
Between April 1993 and January 1994, 45 patients with advanced metastatic colorectal carcinoma were enrolled in a trial evaluating the efficacy of UFT plus oral leucovorin [41, 42]. These patients had not received prior chemotherapy or biologic therapy, and only three patients had received prior adjuvant therapy. Based on phase I results, the first seven patients received UFT 350 mg/m2/d and leucovorin 150 mg/d in divided doses every eight h for 28 days, followed by a seven-day rest period. However, since five of the first seven patients developed grade 3 diarrhea, the starting dosage for the remaining 38 patients was reduced to 300 mg/m2/d. Patient characteristics for this study are summarized in Table 3Go.


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  		Table 3. Patient characteristics (n = 45) in MD Anderson Cancer Center phase II trial of UFT plus oral leucovorin in the treatment of metastatic colorectal carcinoma [41]
 
The toxicities of the two dosage regimens are summarized in Table 4Go. The 300 mg/m2 regimen was much better tolerated than the 350 mg/m2 regimen, with grade 3 diarrhea occurring in 11% and 71% of these dosage groups, respectively. There was no significant neutropenia, thrombocytopenia, hand-foot syndrome, oral mucositis, or alopecia.


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  		Table 4. Adverse events in patients treated in the MD Anderson Cancer Center phase II trial of UFT plus oral leucovorin [41]
 
In patients receiving 300 mg/m2/d, treatment delays were insignificant. Of 127 courses of treatment at this dosage, only 11 courses in three patients had interruptions of 5 to 10 days and only one course was delayed more than 10 days. In contrast, among the patients receiving 350 mg/m2/d, 17% of courses were delayed between 5 and 10 days, and 20% of courses were delayed for longer than 10 days [41].

There were 15 partial responses (39%) and one complete response (3%) among the 38 patients treated with UFT 300 mg/m2/d [41]. Three of seven patients (43%) receiving 350 mg/m2/d also responded. The overall response rate for the two dosage groups combined was 42% (95% confidence interval: 28%-58%). Sites of response included liver (n = 18), lung (n = 6), and bone (n = 1). Of the 19 responding patients, six developed progressive disease after response durations ranging from 15 to 38 weeks. An analysis of survival data indicates that the survival curve of patients in this trial is similar to that of patients treated with weekly i.v. 5-FU and leucovorin at the MD Anderson Cancer Center (Fig. 2Go) [42].



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  		Figure 2. The survival of patients treated in the phase II trial of UFT plus oral leucovorin is compared to patients treated with an i.v. schedule of weekly 5-FU plus leucovorin (LV) treated at MD Anderson Cancer Center during this same time period (reprinted with permission from [42]).

 
The results of this trial compare favorably with those of other phase II trials conducted in the United States and Europe (Table 5Go) [43-45]. Although these trials evaluated slightly different dosage regimens for both UFT and leucovorin, objective response rates ranged from 25% to 40%, which corroborates the objective response rate observed in the trial described. Together, these results support the ongoing evaluation of UFT and oral leucovorin in phase III clinical trials.


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  		Table 5. Phase II trials evaluating UFT and oral leucovorin in metastatic colorectal and rectal cancer
 
Although these trials were not comparative, the results would compare favorably to those reported with regimens of i.v. 5-FU plus leucovorin [10, 46, 47]. A number of i.v. regimens have been evaluated, but two dosing schedules for 5-FU and leucovorin are commonly used in the United States. The low-dose leucovorin regimen (leucovorin 20 mg/m2/d plus 5-FU 425 mg/m2/d) is used more commonly than the high-dose leucovorin regimen (leucovorin 200 mg/m2/d plus 5-FU 370 mg/m2/d). These intensive-course regimens are administered for five consecutive days and repeated every four to five weeks. Response rates for the low- and high-dose regimens have generally ranged from 26% to 40% in several large studies, with median survival durations of up to 12.7 months [10, 14, 46, 48]. However, in order to attain these response rates, there was a considerable degree of toxicity. The frequencies of severe stomatitis, diarrhea, and leukopenia ranged from 14% to 28%, 12% to 18%, and 20% to 29%, respectively [10, 14, 46, 48]. Toxicity requiring hospitalization was reported in 15% to 21% of patients receiving the low-dose leucovorin schedule [46, 48]. Other regimens, such as i.v. 5-FU and leucovorin administered weekly, also produce severe toxicity such as diarrhea, although stomatitis and myelosuppression tend to be less severe with the weekly regimens than with the intensive-course regimens [10, 46].

The most frequent adverse reactions of UFT plus leucovorin are gastrointestinal; severe (grade 3/4) diarrhea occurred in 10% of patients in phase II trials and completely resolved with treatment discontinuation [41, 43-45]. Severe nausea/vomiting and stomatitis/mucositis occurred in only 4% and 2% of patients, respectively. After the diarrhea stops, patients can usually resume therapy. In comparison, severe diarrhea may occur in up to 27% of patients receiving 5-FU [10, 46]. Although diarrhea can occur with UFT, it usually occurs in the absence of significant neutropenia. Severe myelosuppression occurred in only 1% of patients in phase II trials of UFT plus oral leucovorin [41, 43-45], but may occur in up to 22% of patients receiving i.v. 5-FU [10, 46]. Many of the patients who have significant morbidity or who require hospitalization when receiving i.v. 5-FU and leucovorin have diarrhea concomitantly with neutropenia. These patients have a compromised epithelial membrane and an increased risk of sepsis. Since UFT is not associated with significant neutropenia, this risk is markedly reduced and may be one of the reasons for the substantially lower rate of hospitalizations observed with UFT.


   Pharmacoeconomics
Top
 Abstract
 Introduction
 Mechanism of Action
 Phase I Trials
 Dose-Ranging Trials
 Phase II Trial
 Pharmacoeconomics
Discussion
 References
 
When evaluating the financial impact of a new therapy, pharmacoeconomic analyses should evaluate the effect of the treatment on overall healthcare costs rather than simply compare drug acquisition costs. UFT has properties that have the potential to reduce overall treatment costs. The lower propensity of UFT to cause severe adverse events such as neutropenia and stomatitis should result in decreased toxicity-induced hospitalizations and may be associated with a decreased need for laboratory monitoring. The oral route of administration also means that drug administration costs are reduced, since there is no need for i.v. lines or infusion pumps, and treatment can be administered on an outpatient basis. These advantages should improve patient quality of life.

In a recent pharmacoeconomic evaluation of UFT versus i.v. 5-FU in the treatment of metastatic colorectal cancer in Brazil and Argentina, a panel of experts from each country developed a model that identified clinical practices associated with chemotherapy administration and adverse event management [49]. Practice patterns and clinical events were then evaluated for resource utilization trends. Cost data were derived from a survey of local healthcare institutions. These data were used to calculate the average cost per patient receiving either a six-cycle course of i.v. 5-FU with levamisole and/or leucovorin or a modeled oral UFT plus leucovorin regimen. In Argentina, the oral UFT regimen cost $Arg1,188 ($Arg1.0 = $US1.0, June 1997) less than the i.v. regimen ($Arg12,367 versus $Arg13,555), whereas in Brazil oral UFT cost $Brz335 ($1.0Brz = $US0.93, June 1997) less than i.v. 5-FU ($Brz10,901 versus $Brz11,236). The differences were primarily due to the lower costs for managing adverse events and to lower costs for drug administration with UFT. This study suggests that UFT plus leucovorin is a viable economic alternative to standard i.v. 5-FU in the treatment of metastatic colorectal cancer.


   Discussion
Top
 Abstract
 Introduction
 Mechanism of Action
 Phase I Trials
 Dose-Ranging Trials
 Phase II Trial
 Pharmacoeconomics
 Discussion
References
 
Current experience indicates that UFT plus oral leucovorin provides a convenient, well-tolerated, and effective alternative to i.v. 5-FU/leucovorin for the treatment of advanced colorectal cancer. Pharmacokinetic studies have demonstrated that UFT produces maximum 5-FU plasma concentrations that are greater than those produced by an equimolar dosage of 5-FU administered by continuous infusion. However, the total drug exposure (as measured by AUC) of the two regimens is similar. These data demonstrate that UFT is an effective method for delivering prolonged 5-FU exposure.

At the recommended dosage of 300 mg/m2/d administered every eight h for 28 days in combination with oral leucovorin 25-30 mg every eight h, UFT is well tolerated. The most commonly reported adverse effect is diarrhea; however, severe diarrhea is infrequent and is not associated with significant neutropenia. In contrast to i.v. 5-FU, UFT is not associated with significant myelosuppression, mucositis, hand-foot syndrome, or alopecia. It is also not associated with the central nervous system toxicity observed with i.v. tegafur. This improved tolerability profile means that the rate of drug-toxicity-induced hospitalization is much lower with UFT than with i.v. 5-FU. With i.v. 5-FU, the incidence of toxicity-related hospitalization is approximately 20% to 30%, whereas only one of 100 patients enrolled in phase II trials at MD Anderson Cancer Center was hospitalized for drug-related toxicity. The low toxicity of this regimen also improves compliance. Among those receiving UFT 300 mg/m2/d plus oral leucovorin, only 11 of 127 courses had interruptions of 5 to 10 days and only one course was delayed more than 10 days.

The oral UFT regimen offers a number of advantages (Table 6Go). It may be administered without visits to the hospital or clinic, resulting in decreased cost and increased convenience for the patient. The oral schedule also allows patients to temporarily hold a dose of the drug when adverse events such as grade 2 diarrhea first emerge, preventing the toxicity from becoming severe, and allows the patient to restart the medication after one to two days when the diarrhea resolves. In contrast, when administering i.v. 5-FU on a five-day schedule, the toxicity generally does not appear until after the regimen is complete, making it difficult to prevent the occurrence or minimize the severity of adverse events for that particular course of therapy.


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  		Table 6. Potential advantages of UFT
 
The successful clinical application of an oral treatment regimen such as oral UFT plus leucovorin administered for a prolonged time requires collaboration between the physician, nurse, and patient. The patient must be educated on the importance of compliance and the management of diarrhea, the DLT associated with oral UFT plus leucovorin. Simply eliminating several doses at the onset of early-stage diarrhea can prevent its progression to a serious or life-threatening toxicity which would require hospitalization. At MD Anderson Cancer Center, patients receive written information about the medication and its adverse effects and are contacted weekly by nurses to monitor compliance and toxicity development. Patients are carefully instructed to stop UFT therapy when they develop grade 2 diarrhea. They then contact the physician's office and receive instructions on how to monitor this toxicity and when to restart UFT therapy.

The improved tolerability profile of UFT has potential pharmacoeconomic and quality-of-life implications. The use of UFT should be associated with decreased treatment costs because of the lower propensity for toxicity-induced hospitalization. UFT is also associated with decreased drug administration costs because i.v. lines and pumps are not required, and there is a decreased need for laboratory monitoring. This advantage was demonstrated in a recent study from South America in which the use of UFT plus leucovorin was associated with lower overall treatment costs compared with i.v. 5-FU in patients with metastatic colorectal cancer [49]. The oral route and reduced toxicity should improve overall patient quality of life.

Phase II studies of UFT plus leucovorin for advanced colorectal cancer suggest response rates comparable to those achieved with i.v. 5-FU/leucovorin with better tolerability. These promising results have prompted randomized phase III comparative trials in previously untreated patients with metastatic colorectal cancer (Table 7Go). In addition to traditional end points, particularly survival, these studies will evaluate pharmacoeconomics and quality of life. Adjuvant trials in patients with colon carcinoma or rectal cancer are also ongoing. The NSABP C-06 trial is currently ongoing, comparing UFT and oral leucovorin to a weekly regimen of i.v. 5-FU plus leucovorin in 1,500 patients who have had stage II or III colon cancer resected surgically. UFT plus leucovorin is also being explored as a radiation sensitization agent in the preoperative treatment of rectal cancer [50].


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  		Table 7. Ongoing trials of UFT plus oral leucovorin in the treatment of colorectal cancer
 


   Acknowledgments
 
This work was supported in part by Bristol-Myers Squibb Oncology, Princeton, New Jersey and Taiho Pharmaceutical Ltd., Tokyo, Japan.


   References
Top
 Abstract
 Introduction
 Mechanism of Action
 Phase I Trials
 Dose-Ranging Trials
 Phase II Trial
 Pharmacoeconomics
 Discussion
 References
 

  1. Fujii S, Ikenaka K, Fukushima M et al. Effect of uracil and its derivatives on antitumor activity of 5-fluorouracil 1-(2-tetrahydryofuryl)-5-fluorouracil. Gann 1978;69:763-772.[Medline]
  2. Fujii S, Kitano S, Ikenaka K et al. Studies on coadministration of uracil or cytosine on antitumor activity of FT-207 or 5-FU derivatives. Jpn J Cancer Chemother 1979;6:377-384.
  3. Buroker T, Padilla F, Groppe C et al. Phase II evaluation of ftorafur in previously untreated colorectal cancer: a Southwest Oncology Group study. Cancer 1979;44:48-51.[Medline]
  4. Friedman MA, Ignoffo RJ. A review of the United States clinical experience of the fluoropyridimine, ftorafur (NSC-148958). Cancer Treat Rev 1980;7:205-213.[Medline]
  5. Valdivieso M, Bodey GP, Gottlieb JA et al. Clinical evaluation of ftorafur (pyrimidine-deoxyribose N1-2'-furanidyl-5-fluorouracil). Cancer Res 1976;36:1821-1824.[Abstract/Free Full Text]
  6. Ansfield FJ, Kallas GJ, Singson JP. Phase I-II studies of oral tegafur (ftorafur). J Clin Oncol 1983;1:107-110.[Abstract]
  7. Taguchi T. Clinical application of biochemical modulation in cancer chemotherapy: biochemical modulation of 5-FU. Oncology 1997;54(suppl 1):12-18.
  8. Watanabe H, Yamamoto S, Naito T. Clinical results of oral UFT therapy under cooperative study. Jpn J Cancer Chemother 1980;7:1588-1596.
  9. Pazdur R, Lassere Y, Diaz-Canton E et al. Phase I trial of uracil-tegafur (UFT) plus oral leucovorin: 14-day schedule. Invest New Drugs 1997;15:123-129.[Medline]
  10. Leichman CG, Fleming TR, Muggia FM et al. Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. J Clin Oncol 1995;13:1303-1311.[Abstract]
  11. Lokich JJ, Ahlgren JD, Gullo JJ et al. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal cancer. A Mid-Atlantic Oncology Program study. J Clin Oncol 1989;7:425-432.[Abstract]
  12. The Meta-analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998;16:301-308.[Abstract/Free Full Text]
  13. Arbuck S. Overview of clinical trials using 5-fluorouracil and leucovorin for the treatment of colorectal cancer. Cancer 1989;63(suppl 6):1036-1044.[Medline]
  14. Poon MA, O'Connell MJ, Moertel CG et al. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 1989;7:1407-1417.[Abstract]
  15. Rustum YM. Toxicity and antitumor activity of 5-fluorouracil in combination with leucovorin. Role of dose, schedule, and route of administration of leucovorin. Cancer 1989;63(suppl 6):1013-1017.[Medline]
  16. Au JL-S, Sadée W. Activation of ftorafur [R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil] to 5-fluorouracil and {gamma}-butyrolactone. Cancer Res 1980;40:2814-2819.[Medline]
  17. El Sayed YM, Sadée W. Metabolic activation of ftorafur [R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil]: the microsomal oxidative pathway. Biochem Pharmacol 1982;31:3006-3008.[Medline]
  18. El Sayed YM, Sadée W. Metabolic activation of R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) to 5-fluorouracil by soluble enzymes. Cancer Res 1983;43:4039-4044.[Abstract/Free Full Text]
  19. Lockshin A, Danenberg PV. Biochemical factors affecting the tightness of 5-fluorodeoxyuridylate binding to human thymidylate synthetase. Biochem Pharmacol 1981;30:247-257.[Medline]
  20. Taguchi T, Nakano Y, Jikuya K et al. Effect of uracil on the antitumor activity of ftorafur. Jpn J Cancer Chemother 1978;5:1161-1165.
  21. Saitoh T, Kagaya T, Takebe T et al. The enhancement of the antitumor effect of FT-207 coadministered with uracil on the transplanted ductal adenocarcinoma of the Syrian golden hamster pancreas. Jpn J Cancer Chemother 1982;9:2168-2174.
  22. Rustum YM. Mechanism-based improvement in the therapeutic selectivity of 5-FU prodrug alone and under conditions of metabolic modulation. Oncology 1997;54(suppl 1):7-11.
  23. Fukui T, Imabayashi N, Nishi M et al. Clinical study on the enhancement of drug delivery into tumor tissue by using UFT. Jpn J Cancer Chemother 1980;7:2124-2129.
  24. Tsujimoto T, Sakai S, Murata M et al. Concentrations of 5-FU in the tissue and serum of the patients with head and neck malignant tumors by preoperative administration of UFT. Jpn J Cancer Chemother 1983;10:78-83.
  25. Suemasu K, Nomoto C, Higashi Y. Concentration of 5-FU level in the tissue and blood of the patients with breast cancer by preoperative administration of UFT. Jpn J Cancer Chemother 1982;9:667-671.
  26. Fujii S, Ikenaka K, Fukushima M et al. Effect of coadministration of uracil or cytosine on the antitumor activity of clinical doses of 1-(2-tetrahydro-furyl)-5-fluorouracil and level of 5-fluorouracil in rodents. Gann 1979;70:209-214.[Medline]
  27. Evans RM, Laskin JD, Hakala MT. Effect of excess folates and deoxyinosine on the activity and site of action of 5-fluorouracil. Cancer Res 1981;41:3283-3295.
  28. Houghton JA, Maroda SJ Jr, Phillips JO et al. Biochemical determinants of responsiveness to 5-fluorouracil and its derivatives in xenografts of human colorectal adenocarcinomas in mice. Cancer Res 1981;41:144-149.[Abstract/Free Full Text]
  29. Ullman B, Lee M, Martin DW Jr et al. Cytotoxicity of 5-fluoro-2'deoxyuridine: requirement for reduced folate cofactors and antagonism by methotrexate. Proc Natl Acad Sci USA 1978;75:980-983.[Abstract/Free Full Text]
  30. Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol 1992;10:896-903.[Abstract]
  31. Ho DH, Covington WP, Pazdur R et al. Clinical pharmacology of combined oral uracil and ftorafur. Drug Metab Disp 1992;20:936-940.[Abstract]
  32. Pazdur R, Patt Y, Ajani J et al. Phase II/pharmacology study of UFT (BMS-200604) and leucovorin in refractory colorectal cancer patients (Abstract 959). Proc Am Soc Clin Oncol 1997;16:270a.
  33. Hill M, Norman A, Cunningham D et al. Impact of protracted venous infusion with or without interferon alfa-2b on tumor response, survival and quality of life in advanced cancer. J Clin Oncol 1995;13:2317-2323.[Abstract/Free Full Text]
  34. Pazdur R, Covington WP, Brown NS et al. Comparative steady state pharmacokinetics of oral UFT versus protracted intravenous 5-fluorouracil (FU) (Abstract 1498). Proc Am Soc Clin Oncol 1996;15:474.
  35. Collins JM, Dedrick RL, King FG et al. Nonlinear pharmacokinetic models for 5-fluorouracil in man: intravenous and intraperitoneal routes. Clin Pharmacol Ther 1980;28:235-246.[Medline]
  36. Pazdur R, Lassere Y, Diaz-Canton E et al. Phase I trials of uracil-tegafur (UFT) using 5 and 28 day administration schedules: demonstration of schedule-dependent toxicities. Anti-Cancer Drugs 1996;7:728-733.[Medline]
  37. Muggia F, Wu X, Spicer D et al. Phase I and pharmacokinetic study of oral UFT, a combination of the 5-fluorouracil prodrug tegafur and uracil. Clin Cancer Res 1996;2:1461-1467.[Abstract]
  38. Pazdur R, Rivera E, Diaz-Canton E et al. Phase I trial of UFT (uracil:tegafur) with leucovorin: 14-day schedule (Abstract 1568). Proc Am Soc Clin Oncol 1995;14:482.
  39. Jaiyesimi I, Pazdur R, Rhodes V et al. Phase I study of tegafur plus uracil coadministered with oral leucovorin (Abstract 451). Proc Am Soc Clin Oncol 1994;13:164.
  40. Priest DG, Schmitz JC, Bunni MA et al. Pharmacokinetics of leucovorin metabolites in human plasma as a function of dose administered orally and intravenously. J Natl Cancer Inst 1991;83:1806-1812.[Abstract/Free Full Text]
  41. 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 1994;12:2296-2300.[Abstract/Free Full Text]
  42. Pazdur R. Phase II study of UFT® plus leucovorin in colorectal cancer. Oncology 1997;54(suppl 1):19-23.
  43. González-Barón M, Feliu J, de la Gándara I et al. Efficacy of oral tegafur modulation by uracil and leucovorin in advanced colorectal cancer. a phase II study. Eur J Cancer 1995;31A:2215-2219.
  44. Saltz LB, Leichman CG, Young CW et al. A fixed-ratio combination of uracil and ftorafur (UFT) with low dose leucovorin. Cancer 1995;75:782-785.[Medline]
  45. Sanchiz F, Milla A. Tegafur•uracil (UFT) plus folinic acid in advanced rectal cancer. Jpn J Clin Oncol 1994;24:322-326.[Abstract/Free Full Text]
  46. Buroker TR, O'Connell MJ, Wieand HS et al. Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol 1994;12:14-20.[Abstract]
  47. Petrelli N, Douglass HO Jr, Herrera L et al. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. J Clin Oncol 1989;7:1419-1426.[Abstract]
  48. Poon MA, O'Connell MJ, Wieand HS et al. Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol 1991;9:1967-1972.[Abstract/Free Full Text]
  49. Murad AM, de Andrade CA, Delfino C et al. Pharmacoeconomic evaluation of tegafur-uracil (UFT) vs fluorouracil for the management of colorectal cancer in Brazil and Argentina. Clin Drug Invest 1997;13:90-98.
  50. Diaz-Canton E, Pazdur R. Preoperative combined oral UFT plus leucovorin and radiation therapy for rectal cancer. Oncology 1997;11(suppl 10):58-60.
accepted for publication April 6, 1998.





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