Treatment Administration Guidelines
UFT was administered orally in three divided daily doses. Vinorelbine
was administered as a 5-minute IV infusion.
- The sequence for cycle 1, days 1, 8, and 15, was UFT first
dose at 7:00 am; vinorelbine 6 hours later at 1:00 pm; UFT second
dose at 3:00 pm; and UFT third dose at 11:00 pm.
- The sequence for cycle 2, days 1, 8, and 15, was vinorelbine
at 7:00 am; UFT first dose at 7:10 am; UFT second dose at 3:10 pm;
and UFT third dose at 11:10 pm.
- For the subsequent cycles, the sequence for days 1, 8, and 15
was UFT first dose at 7:00 am; vinorelbine at the investigators
discretion after the first dose of UFT; UFT second dose at 3:00 pm;
and UFT third dose at 11:00 pm. The third injection of vinorelbine on
day 15 was given for dose levels 1 and 2 and removed for subsequent
Treatment was continued unless there was evidence of disease
progression or unacceptable toxicity, or if patient refusal occurred.
Pretreatment evaluations included medical history; physical
examination and vital signs; WHO performance status; left ventricular
ejection fraction; tumor measurements (chest x-ray, abdominal
computed tomography [CT] scan or ultrasound, and CT scans of all
measurable and/or evaluable lesions); complete blood cell count
(white blood cells, platelets, hemoglobin); blood biochemistry and
urinalysis; liver function tests; and electrocardiogram. During
treatment, hematologic measurements were performed twice weekly.
Tumor measurements were repeated every two cycles, or every cycle if
clinically indicated, in order to assess response.
Patients who had received at least two cycles of therapy were
evaluable for response to treatment according to standard WHO
criteria unless disease progression was noted prior to cycle 2,
in which case the patient was considered to have failed.
The pharmacokinetics of UFT and vinorelbine were evaluated during the
first treatment cycle. For UFT, blood samples were collected before
the first dose on day 1, then 30 minutes and 1, 1.5, 2, 2.5, 4, and 6
hours after the first dose. In addition, samples were collected on
days 8, 15, and 21 as follows: before the first daily dose, then 30
minutes and 1, 1.5, 2, and 6 hours after this dose. For vinorelbine,
blood samples were collected on day 1 before the 5-minute infusion,
which was administered 6 hours after the first dose of UFT, then 5,
10, 20, and 35 minutes and 1:35, 3:35, 6:35, 10:35, and 18 hours
after the start of infusion.
The pharmacokinetics of UFT were also evaluated during the second
treatment cycle. Vinorelbine was infused first, 10 minutes before the
first daily UFT dose. Blood samples were collected at day 1 before
the first dose, and 30 minutes and 1, 1.5, 2, 2.5, 4, and 6 hours
after the first dose. In addition, samples were collected on days 8,
15, and 21, before the first daily dose, then 30 minutes and 1, 1:30,
2, and 6 hours after this dose.
For both drugs, the analysis focused on the area under the plasma
concentration-time curve (AUC) and total plasma clearance. The
half-lives (t½aa, t½bbb,
t½ggg) and volume of distribution at
steady state (Vss) were also estimated.
Patient Characteristics and Treatment Administration
As of September 1, 1999, 22 patients (aged 41 to 70 years) have been
treated with UFT and vinorelbine as second-line cytotoxic treatment
for metastatic breast cancer (Table 3).
Twelve patients had one metastatic site, 8 had two metastatic sites,
and 2 had three metastatic sites.
Because of one patient with dose-limiting toxicity, six patients were
treated at dose level 1. Dose level 2, with six patients enrolled and
three patients with dose-limiting toxicity, was considered the
maximum tolerated dose. The dose-escalation scheme was subsequently
modified, with the removal of the third administration of vinorelbine
on day 15. Three patients have been enrolled at level 3, and three at
level 4 with no dose-limiting toxicity. Level 5, with four patients
enrolled and one patient with dose-limiting toxicity, is currently
A total of 80 cycles of UFT/vinorelbine were administered. At levels
1 and 5, two patients received only one cycle due to toxicity. Six
patients were treated for only two cycles because of early
progressive disease, reported mainly at levels 1 and 2.
Thus far, no episodes of grade 4 hematologic toxicity have been
observed. However, because of grade 2/3 neutropenia at day 15, one
patient at level 1 and three patients at level 2 were unable to take
one of the three vinorelbine doses; one patient at level 5 was also
unable to take one of the two vinorelbine doses (dose-limiting toxicity).
No grade 3/4 nonhematologic toxicities were observed during the first
cycles. In addition, the incidence of grade 3/4 episodes was very low
for subsequent cycles (2% nausea, 4% vomiting, 2% diarrhea, 2%
fatigue). Table 4 illustrates
the overall incidence of nonhematologic toxicities, including nausea
and vomiting, diarrhea, constipation, hand/foot syndrome, fatigue,
stomatitis, and headache.
The pharmacokinetics of UFT and vinorelbine were evaluated in the 12
patients enrolled at levels 1 and 2 (receiving UFT 300 mg/d) and in
five patients treated at levels 3 and 4 (receiving UFT 400 mg/d). At
levels 1 and 2, the mean area under the concentration- time curve (AUC0-6
h) of 5-FU was 0.68 ± 0.53 µmol/L ´
h, and at levels 3 and 4, 4.39 ± 3.91 µmol/L ´
h. Thus, the increase of the AUC0-6 h of 5-FU was more
than dose-proportional. For the five patients who developed a dose-limiting
toxicity at day 15 (inability to give the vinorelbine dose because
of grade 2/3 neutropenia), the AUC0-6 h values of 5-FU
were significantly higher (P < .01) than noted for the
other patients. The removal of one administration of vinorelbine at
dose levels 3 and 4 has allowed for increased UFT dosage and AUC0-6
h of 5-FU, with no dose-limiting toxicity reported for these
patients. No pharmacokinetic interaction between UFT and vinorelbine
was observed (Table 5).
Eighteen patients were evaluable for antitumor response. One had a
complete response obtained after three cycles and four had partial
responses. Four of five responses were observed at dose level 3 and
higher. Seven patients experienced stable disease and disease
progressed in the remaining six patients after two cycles.
We reported the preliminary results of this ongoing study, that is
currently enrolling patients at dose level 5. With vinorelbine
administered at days 1, 8, and 15, the maximum tolerated dose was
reached at level 2 (UFT 300 mg/d, days 1 through 21, vinorelbine 20
mg/m²). At levels 1 and 2, four patients with dose-limiting
toxicities were reported: one patient at level 1 and three patients
at level 2 were unable to receive one of the three vinorelbine doses
because of grade 2/3 neutropenia at day 15. In addition, at dose
level 2 one of these three patients was unable to receive full doses
of UFT for > 3 of 21 days.
The removal of one administration of vinorelbine at dose levels 3 and
4 has allowed for increased UFT dosage (400 mg/d on days 1 through
21) with no dose-limiting toxicity reported for six patients. Dose
level 5 is currently being studied (UFT at 500 mg/d on days 1 through
21, vinorelbine at 25 mg/m² on days 1 and 8).
Twenty-two patients received UFT plus leucovorin and vinorelbine as
second-line cytotoxic treatment for advanced disease. Eighteen
patients were evaluable for antitumor response. One patient had a
complete response obtained after three cycles, four had partial
responses. The responses were mainly observed at dose levels 3 and above.
Comparing dose levels 1 and 2 with levels 3 and 4, the increase of
the AUC0-6 h of 5-FU was more than dose-proportional. For
the four patients who developed a dose-limiting toxicity at day 15,
the AUC0-6 h values of 5-FU were significantly higher than
noted for the other patients. The removal of one administration of
vinorelbine at dose levels 3 and 4 has allowed for increased UFT
dosage and AUC0-6 h of 5-FU, with no dose-limiting
toxicity reported. No pharmacokinetic interaction between UFT and
vinorelbine was observed.
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