Many cancer patients prefer to be treated with orally administered
anticancer agents when efficacy equal to other means of
administration can be maintained. Oral agents are suitable for
postoperative, adjuvant chemotherapy of colorectal cancer in terms of
patient convenience and cost. Oral fluoropyrimidines have been
widely used in Japan, and their efficacy has been demonstrated by
One of the newer drugs in this class, UFT (uracil and tegafur) is
conventionally administered at a daily dose of 400 mg. A response
rate of 25% has been reported for UFT alone and of 42% when in
combination with oral leucovorin (a combination being developed under
the trade name Orzel) in advanced colorectal cancer. We designed a
new, dose-intensive, oral, weekday-on/weekend-off UFT schedule of 600
mg for 5 days followed by 2 drug-free days. This amounts to a similar
weekly dose as the conventional daily administration schedule of UFT
at 400 mg.
As a preliminary step to a clinical trial, we compared the tumor
response and survival effects of the weekday-on/weekend-off schedule
with the conventional daily schedule in a cancer-bearing rat model. A
pharmacologic study was also conducted in humans to investigate the
effect of the 2 drug-free days in this schedule. Compliance and
feasibility are other important factors in adjuvant chemotherapy,
especially with oral anticancer agents, because treatment continues
for a long period. Noncompliance by a significant number of patients
could invalidate the results of a clinical trial. We therefore
evaluated compliance and feasibility of this new UFT schedule for 1
year as adjuvant chemotherapy for colorectal cancer before proceeding
to a phase III study.
Experimental Study in Rats
In this experiment, 4-week-old male Donryu rats were subcutaneously
inoculated with 1 × 105 Yoshida sarcoma cells. The 21
rats were then divided into three groups. The weekday-on/weekend-off
group received UFT three times a day at a single dose of 20 mg/kg for
5 days and did not receive it on the last 2 days of the week. The
conventional daily schedule group received UFT twice daily at a
single dose of 20 mg/kg for 7 consecutive days. Each 7-day period was
one treatment cycle, which was repeated three times. The third group
was a control group.
Pharmacologic Study in Humans
The effect of 2 drug-free days in the weekday-on/weekend-off schedule
for patients with colorectal cancer was studied by measuring
fluorouracil (5-FU) concentrations in both the plasma and tumor
during those days. Apportioned into three groups, all 24 patients
were administered UFT 600 mg/day for 5 days. The final dose was
administered 2 hours before surgery in the first group, 24 hours
before surgery in the second group, and 48 hours before surgery in
the third group.
Compliance Study in an Adjuvant Setting
A 1-year clinical trial of the weekday-on/weekend-off schedule of UFT
as adjuvant chemotherapy for colorectal cancer evaluated compliance
and feasibility. For this study, 91 patients from 11 institutions
participating in the UFT Compliance Study Group, Kanagawa, Japan,
were registered between March 1995 and July 1997. Patients were 15 to
75 years of age, had a body weight of at least 40 kg, had undergone
potentially curative resection for surgical stage II or III
colorectal cancer, had a performance status of 0 to 2, and were not
being scheduled for radiation.
Beginning 2 weeks after surgery, patients were given oral UFT 600
mg/day divided into three doses, Monday through Friday for 1 year.
Compliance was investigated by physician interview and patient
self-report, and the results compared with the prescribed dose.
Feasibility was evaluated on the basis of two indices: relative
performance (RP), which is the ratio of the total dose actually taken
to the total dose planned, and individual dose intensity (IDI), which
is the ratio of the dose actually taken to the dose planned during a
The difference between RP and IDI lies in the handling of the
censored cases. Relative performance is a feasibility index that
includes adverse reactions, recurrence, and all other cases of
discontinuation, whereas IDI focuses only on discontinuation because
of adverse reactions to the drug in the study. Because IDI is
calculated for each period, it can be evaluated at any point in time.
This gauge was effective for patients who stopped taking UFT for
reasons other than adverse reactions. In such cases, IDI was
calculated at the time the patients stopped taking UFT, and these
patients were regarded as censored cases thereafter.
Experimental Study in Rats
Survival rates in the three groups are shown in Figure
1. All seven rats in the control group died by day 26, whereas
survivors were observed until day 51 in the conventional daily
schedule group and until day 60 in the weekday-on/weekend-off
schedule group. There was a significant survival effect in both
treated groups compared with the control (P = .0023 and P
= .0035, respectively). The weekday-on/weekend-off schedule group
showed a better survival effect than the conventional daily schedule
group (P = .031).
Body weight increase was slightly suppressed at the end of one course
in both groups treated with UFT as compared with the control group.
However, the body weight increase in the weekday-on/weekend-off group
and in the control group became equal on day 20. Food consumption was
reduced in the weekday-on/weekend-off group on day 4, but had
returned to the control level by day 8 (the second day off the drug),
and exceeded food consumption by the conventional daily schedule group.
Pharmacologic Study in Humans
After the final dose of UFT, the 5-FU concentrations in plasma were
23 ± 12 ng/mL at 2 hours; at 24 hours they were 7 ± 3
ng/mL; at 48 hours they were 6 ± 3 ng/mL. The 5-FU
concentrations in the tumor were 113 ± 45 ng/g at 2 hours, 54
± 20 ng/g at 24 hours, and 54 ± 35 ng/g at 48 hours.
Compliance Study in an Adjuvant Setting
Of the 91 patients, 87 were evaluable. There were 30 cases (35%) in
which UFT was discontinued and not restarted, and in 18 of these (21%
of the series) the drug was stopped because of adverse reactions. UFT
was also stopped due to disease recurrence (7 patients), change of
physician (2), surgical complications (1), patient request
unassociated with adverse reactions (1), and failure to follow up
(1). There were 17 patients (20%) who stopped taking the drug
temporarily, and 11 patients (12.6%) whose dose was reduced.
The overall rate of occurrence of adverse reactions was 35%, and the
principal adverse reactions were upper gastrointestinal symptoms and
signs, including anorexia, nausea and vomiting, and liver
dysfunction. All of the adverse reactions except in one patient were
World Health Organization grade 1 or 2. One patient had grade 3
anorexia and diarrhea and recovered, after discontinuing the drug, by
day 14. No serious adverse reactions were observed.
The RP and IDI values calculated for the 87 patients are shown in Table
1 and Table 2. The mean RP
value was 0.72. The mean IDI was 0.94 at 3 months and 0.83, 0.79, and
0.76 at 6, 9, and 12 months, respectively, with a mean overall value
of 0.80. The IDI value at the time of discontinuation was used for
the 12 cases.
The experimental study in the tumor-bearing rat model revealed that
the weekday-on/weekend-off schedule for oral UFT provided
significantly higher antitumor activity and a better survival effect
than the conventional daily administration schedule, even though the
weekly doses were almost the same. Moreover, based on the results for
body weight increase and food consumption, adverse reactions were
judged to be almost the same on both schedules.
In a previous study in Donryu rats,  plasma 5-FU concentrations
were measured after administration of a single 20-mg/kg oral dose of
UFT, and the duration of 5-FU concentrations maintained at a level of ³
50 ng/mL (T50) and ³ 75
ng/mL (T75) were calculated. The T50 1-week
values on the weekday-on/weekend-off schedule and the conventional
daily schedule were 65.5 hours and 37.5 hours, respectively, and the
T75 1-week values were 16.3 hours and 10.5 hours, respectively. These
differences appeared to have an influence on antitumor activity and
survival effect. The area under the concentration-time curve per week
on both schedules was almost the same, and this may be why toxicity
Because drug metabolism has been reported to differ considerably from
species to species, the 5-FU concentrations were measured in
clinical cases to investigate the effect of the 2 drug-free days. The
5-FU concentration in the tumor was well maintained with the
weekday-on/weekend-off schedule during the 2 drug-free days, but the
5-FU concentration in plasma declined markedly by 24 hours after the
final dose. These results suggest no loss of antitumor activity after
2 drug-free days in the weekday-on/weekend-off schedule, and the
adverse reactions may resolve after the 2 days off the drug.
The mean RP value was 0.72, meaning 72% of the total dose of UFT
planned in the protocol was given. The mean value of the other index
of feasibility, IDI, tended to decrease as the dosage period grew
longer. However, the overall mean value was 0.80, which indicates
that only 20% of the planned dose was not administered because of
adverse reactions. Based on these results, the UFT
weekday-on/weekend-off schedule was judged to have good feasibility.
The results of this study suggest that the novel
weekday-on/weekend-off schedule of UFT can be recommended as one arm
of a randomized controlled study of adjuvant chemotherapy for
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