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UFT in the Treatment of Colorectal and Breast Cancer

UFT in the Treatment of Colorectal and Breast Cancer

ABSTRACT: UFT and leucovorin (Orzel) is a combination of tegafur and uracil in a molar ratio of 1:4. Tegafur, a prodrug of 5-fluorouracil (5-FU), is converted to 5-FU by the hepatic cytochrome P450 pathway, whereas uracil enhances the half-life of converted 5-FU leading to prolonged exposure and higher intracellular concentration of 5-FU by inhibiting dihydropyrimidine dehydrogenase (DPD), a rate-limiting enzyme in 5-fluorouracil catabolism. UFT has broad antitumor activity against colorectal and breast cancer, and has been studied extensively worldwide. Trials conducted in the United States have mainly focused on the combination of UFT and leucovorin (Orzel). Compared with an intravenous 5-fluorouracil plus leucovorin regimen in advanced colorectal cancer treatment, UFT plus leucovorin appears to have equivalent antitumor efficacy with less toxicity. UFT may also provide a more convenient protracted treatment method with fewer complications, compared to intravenous programs. The application for FDA approval of UFT with leucovorin as a first-line treatment regimen for advanced colorectal cancer is pending. Administered as a single agent or in combination with other chemotherapy agents and hormones, UFT may also be effective in treating breast cancer, either as a primary adjuvant treatment or as palliative treatment for metastatic disease. [ONCOLOGY 15(Suppl 2):49-56, 2001]

Introduction

Breast cancer is the most common malignancy in women in
the United States and second only to lung cancer as a cause of cancer death.
Based on American Cancer Society estimates, there were 180,300 new cases of
breast cancer and 43,900 deaths from breast cancer in 1998 in the United States
alone. Colorectal cancer is the third leading cause of cancer mortality both in
male and females in the United States, with an estimated 131,600 new cases and
55,500 deaths in 1998.[1]

The pyrimidine analogue 5-fluorouracil (5-FU) has been a
mainstay of chemotherapy for breast cancer, colorectal cancer, and other
malignancies for more than 30 years since its initial synthesis by Heidelberger.
Combination regimens such as CAF (cyclophosphamide, doxorubicin [adriamycin],
and 5-FU) and CMF (cyclophosphamide, methotrexate and 5-FU) are among the
standard therapies for breast cancer. 5-FU is the most widely prescribed therapy
for the treatment of advanced colorectal cancer and, combined with leucovorin,
is the only currently recommended regimen for use as adjuvant therapy.

5-FU and UFT

An understanding of the mechanism of action of 5-FU has resulted
in significant therapeutic advances in the past 10 years, including synergy with
leucovorin and low-dose continuous infusion for improving both the antitumor
activity and the toxicity profile.

The cytotoxic effects of 5-FU are a result of interference with
both RNA and DNA structure and function. 5-FU is converted intracellularly to
FdUMP (5-fluoro-2’-deoxyuridine monophosphate) and FUTP (5-fluorouridine
triphosphate). FUTP is incorporated into RNA as a fraudulent base causing errors
during RNA processing.[2] FdUMP binds to thymidylate synthetase (TS) with
greater affinity than the natural substrate and inhibits production of thymidine
monophosphate (dTMP), and thus DNA synthesis.[3] 5-FU is catabolized rapidly in
the liver by dihydropyrimidine dehydrogenase (DPD) and subsequently excreted in
the urine as a-fluoro--alanine (FBAL).[4] Dihydro- pyrimidine dehydrogenase
is the initial rate-limiting enzymatic step in the catabolism of
pyrimidines,[5,6] and is widely distributed in many tissues, including the
liver, lung, gastrointestinal tract, kidney, and many tumors.[7] DPD occupies an
important position in the overall metabolism of 5-FU, converting over 85% of
clinically administered 5-FU to 5-FUH2, then FBAL. There is a broad variation in
DPD activity from person to person, which is partly responsible for great
variation in the t1/2 and bioavailability of 5-FU.[8] DPD activity in the
intestinal mucosa and liver also contributes to the limited and erratic
bioavailability of orally administered 5-FU, and clearance of the drug. The
variable DPD activity level of different tumors may contribute to the variable
tumor response to 5-FU. In addition, elevated levels of DPD in many tumors after
5-FU treatment may contribute to the development of drug resistance.[9]

When the value of low-dose continuous infusion of 5-FU was
confirmed,[10] it was recognized that the requirement for surgically-implanted
venous access and need for a constant-infusion pump may impose serious financial
and quality of life constraints. Accordingly, the potential for oral
administration as a substitute for continuous exposure of fluoropyrimidines has
been re-examined.

The oral chemotherapy agent UFT is a combination of uracil and
tegafur in 4:1 molar ratio. Tegafur (1-[2-tetra hydrofuranyl]-5-FU, ftorafur,
BMS-200604) acts as a prodrug of 5-FU, being rapidly and completely absorbed
after oral administration, and slowly metabolized by cytochrome P450.[11-13]
Uracil is a normal substrate for DPD, which competitively inhibits the
metabolism of 5-FU, thereby reducing 5-FU clearance and increasing plasma and
intratumor 5-FU concentration.[14] In preclinical studies, the antitumor
activity of tegafur is enhanced by co-administration of uracil and this effect
is maximized at a uracil:tegafur molar ratio of 4:1. The ratio of 5-FU in tumor
tissue compared with plasma or normal tissue is enhanced.[15,16]

In a further effect to maximize the therapeutic efficacy of
tegafur, UFT in the United States has been developed in combination with oral
leucovorin (calcium folinate), a derivative of tetrahydrofolic acid. Leucovorin
increases the reduced folate concentration, stabilizing the FdUMP-TS complex and
therefore further enhancing 5-FU effects to mimic the biochemical modulation of
5-FU with leucovorin.[17]

Phase I studies of UFT in the United States have examined two
schedules: 5 days of drug administration repeated every 21 days, and 28 days
repeated every 35 days. The daily dose of UFT is given in 3 daily doses, every 8
hours.[18,19] Granulocytopenia is dose-limiting with the 5-day schedule, while
diarrhea is the principal toxicity seen with 28-day dosing. The dose of 350-400
mg/m2/day in a 28-day schedule has been recommended for phase II trials as a
single agent. Further phase I studies have concentrated on UFT plus leucovorin
(Orzel). Four large institutions in the United States conducted similar phase I
trials of UFT plus leucovorin on 14-day and 28-day schedules, at 8 hour
intervals (Table 1).[18-22] Diarrhea, nausea, and vomiting are dose-limiting.
These investigators have recommended a UFT dose of 350 mg/m2/day with various
doses of leucovorin (15-150 mg/day) for further combination studies.

UFT in Colorectal
Cancer Treatment

Phase II Studies of UFT in Colorectal Cancer

Starting in 1993, several phase II trials of UFT
(tegafur/uracil) and leucovorin have been conducted in the United States. All
patients enrolled in these trials had measurable diseases and no prior
chemotherapy for metastatic colorectal cancer.

With the initial regimen of UFT 350 mg/m2/d and leucovorin 150
mg/d, five of the first seven patients at the M. D. Anderson Cancer Center
developed grade 3 diarrhea. Subsequently, 39 patients were treated with UFT at
300 mg/m2/d and leucovorin at 150 mg/d.[23] The lower dose was associated with
less grade 3 diarrhea. No significant neutropenia, thrombocytopenia, hand-foot
syndrome, mucositis, or alopecia was seen. Another phase II trial at the
University of Southern California and Memorial Sloan-Kettering Cancer Center
treated 21 patients with advanced colorectal cancer with UFT 350 mg/m2/d plus 15
mg/d of leucovorin.[22] The toxic effects of these two doses of UFT are
presented in Table 2.

One complete response (CR) and 15 partial responses (PR) were
achieved in the 39 patients treated with the 300 mg/m2/d regimen; the median
survival was 16 months. The overall response rates of these phase II trials
ranged from 26% to 44% (Table 3).

Subsequent trials of UFT and leucovorin have used a leucovorin
dose of 75 or 90 mg/d (25 mg or 30 mg every 8 hours), because of the saturable
oral absorption of leucovorin when the dose exceeds 25 mg.[24]

A phase II trial of UFT and leucovorin was conducted in Europe
with UFT at 390 mg/m2/d and leucovorin (either 30 mg/day oral for 14 days or 500
mg/m2 IV on day 1) in 75 advanced colorectal cancer patients. This regimen
resulted in an overall response rate of 39%.[25] The patients in the phase II
studies from Europe and the United States are compared in Table
4
.

In Spain, the Oncopaz clinical trial evaluated UFT plus
leucovorin in elderly patients with advanced colorectal cancer (median age 74
years).[26] They observed an overall response rate of 29%, with diarrhea as the
major toxicity. UFT plus leucovorin was felt to be both well-tolerated and
feasible as outpatient treatment for elderly patients.

The efficacy of UFT with leucovorin was demonstrated in a
separate phase II study in patients with metastatic rectal carcinoma.[27]
Patients were treated with UFT at 600 mg/m2/d and leucovorin at 90 mg/d for 14
days in a 28-day schedule. Of the 52 evaluable patients, 50% had liver
metastases, and 62% had received treatment for advanced disease prior to the
trial. Overall response was 70% in patients without previous chemotherapy, and
22% in patients who had had previous treatment. The median time to progression
for all patients was 8.2 months, but was 19.6 months in patients without prior
chemotherapy.

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