A combination of the agents UFT and calcium
folinate is known as Orzel. UFT is an oral anticancer drug composed
of a fixed molar ratio (4:1) of uracil and tegafur. In vivo, tegafur,
acting as a prodrug, is metabolized to release the antineoplastic
agent 5-fluorouracil (5-FU). Uracil is combined with tegafur to act
as a competitive inhibitor of dihydropyrimidine dehydrogenase, the
primary catabolic enzyme for 5-FU.[1-3] Competitive inhibition of
dihydropyrimidine dehydrogenase by uracil results in elevated and
sustained concentrations of 5-FU, which is derived from tegafur, in
the plasma and higher intratumoral exposure to cytotoxic 5-FU
anabolites as compared with tegafur administered alone.[4,5]
Administration of calcium folinate along with UFT may provide
additional antitumor efficacy, comparable with the efficacy
previously demonstrated with intravenous 5-FU plus calcium folinate regimens.
The ability of repeated doses of UFT to provide consistently low
concentrations of 5-FU in the plasma suggests that UFT could be an
important compound for the treatment of gastrointestinal
malignancies. In addition to promising efficacy data, there is a
wealth of clinical experience demonstrating a highly acceptable
safety profile for UFT. The dose-limiting side effect associated with
UFT when administered in protracted schedules is diarrhea.
With demonstrated improvement in local control and possibly in
survival, rectal cancer patients have been routinely treated with a
combination of 5-FU and radiotherapy, given either before or after
surgery. Based on encouraging results of preoperative
chemoradiation trials,[10-12] and the potential for sphincter
preservation, preoperative chemoradiation is used at The University
of Texas M. D. Anderson Cancer Center for patients with rectal
neoplasms (T3 and T4, nodal involvement, or both).
Pharmacokinetic trials comparing 5-FU levels attained from UFT to
those observed with low-dose protracted intravenous infusions have
demonstrated a similar area under the curve, with higher 5-FU peak
levels associated with UFT administration. Protracted intravenous
and bolus 5-FU administration, both in combination with pelvic
radiotherapy, have been compared, with the conclusion that protracted
intravenous 5-FU infusions provide superior survival, and local and
distant control of disease. Nevertheless, protracted intravenous
infusions are associated with the expense of central venous catheter
insertion, infusion pump maintenance, and the cost associated with
treatment complications (line infections, thrombosis, slippage). An
oral delivery system allowing protracted 5-FU delivery would be
advantageous from a patient comfort, expense, and safety viewpoint.
A large, randomized trial comparing UFT plus oral calcium folinate to
intravenous 5-FU plus calcium folinate in previously untreated
metastatic colorectal cancer demonstrated equivalent survival with
clinically significant safety advantages to the UFT plus oral calcium
Although UFT plus oral calcium folinate has been administered to a
large number of patients, relatively limited information regarding
the combination of this agent with radiotherapy is currently
available. The primary goal of our present trial is to investigate
the antitumor efficacy and safety of a preoperative regimen of UFT
plus oral calcium folinate combined with radiotherapy in patients
with rectal cancer. The use of UFT plus oral calcium folinate in this
setting might prove to be a less toxic and more cost-effective and
convenient treatment for patients with rectal cancer than protracted
intravenous 5-FU infusions or bolus 5-FU plus calcium folinate.
Patients must have a histologically confirmed diagnosis of rectal
cancer for which chemotherapy and pelvic irradiation are indicated,
such as patients with endoscopic evidence of T3 and T4 lesions, nodal
involvement, or both. Patients also must be able to tolerate major
surgery. Other eligibility criteria include age over 18 years; an
Eastern Cooperative Oncology Group performance status of 0 to 2;
normal renal, hepatic, and hematologic function; and a life
expectancy > 3 months. Patients with distant metastasis or prior
malignancies other than localized, treated nonmelanoma skin cancer
and cervical cancer are ineligible. In addition, women who are
pregnant or nursing and patients who have undergone a major surgical
procedure within 3 weeks before enrollment are ineligible. Patients
must sign an informed consent form indicating that they are aware of
the investigational nature of the study.
Prior to entering the study, all patients are required to have a
complete medical history and physical examination, including
documentation of the presumed stage of disease, performance status,
and concurrent nonmalignant diseases and prior treatments. Baseline
laboratory studies include a complete blood count with differential
and platelet count, electrocardiogram, chest x-ray, electrolytes,
carcinoembryonic antigen level, SMA-12, and urinalysis. Prior to each
treatment course, physical examination and laboratory tests are
repeated. A complete blood count is obtained weekly during each
course. Patients found to have metastatic disease after enrollment
are removed from the study but are considered evaluable for toxicity.
Each group of three patients receives an escalating dose of oral UFT
(starting at 250 mg/m²/day) and a fixed dose of oral calcium
folinate (90 mg/day), both administered in three divided doses daily
for 5 consecutive days. Table 1
shows the UFT dose-escalation schedule. Radiotherapy is given to the
pelvis at 180 cGy/day once a day on the same 5 days that UFT and
calcium folinate are administered. The patient then rests for 2 days.
This 7-day cycle (5 days of treatment, 2 days of rest) is repeated
four additional times for a total of 5 weeks of treatment. Over the 5
weeks, 4,500 cGy of radiation is administered. Surgical resection is
performed 4 to 6 weeks after this combination of chemotherapy and
radiotherapy. Four weeks later, all patients receive fixed doses of
UFT (300 mg/m²/day) and calcium folinate (90 mg/day) three times
a day for 28 consecutive days, followed by a 7-day rest period, as
previously recommended. This 35-day cycle is repeated for a total
of four cycles. At level 0, the postoperative dose of UFT is limited
to 250 mg/m²/day. UFT and calcium folinate are administered in
100-mg capsules and 15-mg tablets, respectively. Because the
available capsule dose of UFT is 100 mg (based on tegafur), the total
daily dosage is approximated to the nearest 100 mg. If the number of
capsules per day cannot be evenly distributed between the three daily
doses, the greater capsule count is administered in the morning and
afternoon, and the lower number is taken in the evening. Patients are
instructed to take UFT and calcium folinate 1 hour after meals.
Patients are contacted by telephone at weekly intervals by a research
nurse to monitor therapy-related toxicity. Patient compliance is
verified at the end of each cycle by verifying the remaining
medication and by reviewing patient diaries. Standard antiemetic
therapy is prescribed as required. Prophylactic antidiarrheal drugs
are not allowed. However, if grade ³
2 diarrhea develops, brief courses of antidiarrheals can be used for
symptomatic relief. Weekly toxicity notations are made and are graded
as per the National Cancer Institute Common Toxicity Criteria. The
days when treatment is withheld because of toxic effects are counted
as treatment days and are not made up. Therapy is withheld upon
development of diarrhea, mucositis, stomatitis, and any other
nonhematologic toxicity with a Common Toxicity Criteria grade ³
2. Therapy is resumed when the toxic event and associated symptoms
are completely resolved. Before initiation of subsequent cycles of
UFT plus oral calcium folinate, all nonhematologic toxicities must be
Common Toxicity Criteria grade £ 1.
Dosage modifications of UFT at the start of a new cycle are based on
the worst Common Toxicity Criteria grade nonhematologic toxicity
encountered during the preceding cycle of chemotherapy or the nadir
granulocyte and platelet counts during the preceding cycle of therapy.
A minimum of three patients must be enrolled in each cohort before
dose escalation is allowed. If one patient has grade ³
3 toxicity, three more patients are entered at the same dose level.
If two of six patients have grade ³ 3
toxicity, the escalation continues; but if three of six patients have
grade ³ 3 toxicity, the next cohort
is entered at a lower dose level. If no additional dose-limiting
toxicity is observed in the patients treated at the reduced level,
this dose is recommended as the maximum tolerated dose.
Eleven patients have been entered in this trial. Dose escalations to
UFT 350 mg/m²/day have been performed. Diarrhea is the
predominant toxicity at this dose level, but is adequately controlled
with the use of conventional antidiarrheal agents, allowing
completion of pelvic irradiation and UFT plus oral calcium folinate
administration on schedule.
This trial demonstrates that even with pelvic radiotherapy
administration, adequate daily doses of UFT can be administered. When
given at this dose level, UFT can achieve 5-FU plasma levels similar
to those achieved with protracted infusions of intravenous 5-FU,
which are commonly used with pelvic irradiation. This intermittent
schedule of UFT plus oral calcium folinate (5 days of treatment
followed by 2 days of rest) allows for a normal tissue rest period
and for greater tolerability with a higher daily dose of UFT. Dose
escalations of UFT plus oral calcium folinate will continue in this trial.
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