The combination of 5-fluorouracil (5-FU) and
radiotherapy appears to be more effective than radiotherapy alone in
the treatment of pancreatic cancer. Continuous admini- stration of
5-FU may be superior to bolus treatment in rectal cancer and appears
to be promising in pancreatic cancer and other tumor types. Available
data suggest that uracil and tegafur (in a molar ratio of 4:1 [UFT])
plus oral calcium folinate (Orzel) offers a well-tolerated, fully
oral treatment option with efficacy comparable to that of standard
5-FU parenteral regimens.[1,2] Patient acceptance of a noninjected
treatment option is likely to be high because this approach frees the
patient from the constraints of frequent doctor visits for treatment
administration and from the anxiety and discomfort associated with
injections. Furthermore, the cost of an oral regimen is expected to
be lower than the more labor- and equipment-intensive parenteral
treatments, both in terms of direct cost of treatment administration
and the indirect cost of lost work days for patients and their
families due to treatment visits.
With these benefits in mind, we initiated a phase I study to evaluate
the feasibility and safety of administering UFT plus oral calcium
folinate in combination with radiotherapy for the treatment of
patients with pancreatic cancer.
The clinical benefit of administering 5-FU by infusion rather than
bolus delivery is based on the short serum half-life of this
compound. It is also based on the larger proportion of malignant
cells in human solid tumors that are not undergoing active growth,
and that are not, therefore, affected by cycle-active antimetabolites
at any one point in time. Longer periods of drug administration might
result in a greater percentage of tumor cells exposed to the
cytotoxic agent during a sensitive phase of the growth cycle,
resulting in an enhanced therapeutic effect.
Although the fundamental biochemical mechanism of 5-FU
radiosensitization is not well understood, tissue culture
experiments have clearly shown that there are three basic
prerequisites for 5-FU radiosensitivity: 1) 5-FU must be present
after each x-ray exposure; 2) the 5-FU concentration must be
sufficient to be cytotoxic from the drug alone; and 3) the duration
of 5-FU exposure must be at least one full cell cycle in length.
Because of the short half-life of 5-FU in man, these prerequisites
can be met only by continuous infusion of 5-FU.
The University of Alabama (UAB) study 9614 was designed to determine
the maximum tolerated dose and dose-limiting toxicity of UFT plus
oral calcium folinate administered three times per day to patients
with pancreatic cancer during full-dose radiotherapy. The maximum
tolerated dose would then be used to define the appropriate dose for
phase II testing. Another goal was to assess the response rate, time
to progression, and survival of patients with measurable disease
treated in this phase I study setting.
In this phase I, single-center, open-label, dose-escalation study,
patients with pancreatic cancer are receiving UFT plus oral calcium
folinate and concurrent radiation. Dose escalation of UFT will be
performed until the maximum tolerated dose is defined. The initial
dose of 150 mg/m²/day of UFT was administered with 90 mg/day of
oral calcium folinate, both divided into three daily doses for 35
days. Radiotherapy started on day 1 and was administered to a total
dose of 45 Gy at 1.8 Gy per day (approximately 5 weeks). UFT doses
are being escalated in cohorts of three to six patients (Table
1). The dose and schedule of oral calcium folinate and
radiotherapy are being kept constant. No dose escalation will be made
during therapy for individual patients.
In the second part of this study, an additional group of six patients
will be treated at the recommended phase II dose, which will be one
level lower than the maximum tolerated dose of UFT plus oral calcium
folinate. This approach will provide some early information on
efficacy and will expand our knowledge of the toxicity profile of
this combined-modality regimen.
A total of 11 patients with a median age of 59 years have been
accrued into this study. The patients have been treated with UFT at
doses of 150 to 300 mg/m²/day. The first three cohorts of
patients (150 mg/m²/day, 200 mg/m²/day, and 250 mg/m²/day)
included three patients at each dose level. Currently, two patients
have completed therapy at dose level 4 (300 mg/m²/day). Overall,
therapy has been well tolerated, and the maximum tolerated dose has
not yet been reached.
1. Pazdur R: Phase I and pharmacokinetic solutions of UFT plus oral
leucovorin. Oncology 11:35-39, 1997.
2. Hoff PM, Pazdur R: UFT plus oral leucovorin: A new oral treatment
for colorectal cancer. The Oncologist 3:155-164, 1998.
3. Byfield JE, Calabro-Jones P, Klisak I, et al: Pharmacologic
requirements for obtaining sensitization of human tumor cells in
vitro to combined 5-fluorouracil of ftorafur and x-rays. Int J Radiat
Oncol Biol Phys 8:1923-1933, 1982.