In a step toward a clinical trial, the tumor response and survival of a weekday-on/weekend-off schedule of UFT was compared with its conventional daily schedule in a cancer-bearing rat model. The dose-intensive schedule-600 mg of UFT for 5 days followed by 2 drug-free days-amounts to a weekly dose similar to the conventional schedule of 400 mg/day. The weekday-on/weekend-off schedule provided increased survival and significantly greater antitumor activity than the conventional daily schedule, with no difference in adverse reactions.
ABSTRACT: In a step toward a clinical trial, the tumor response and survival of a weekday-on/weekend-off schedule of UFT was compared with its conventional daily schedule in a cancer-bearing rat model. The dose-intensive schedule-600 mg of UFT for 5 days followed by 2 drug-free days-amounts to a weekly dose similar to the conventional schedule of 400 mg/day. The weekday-on/weekend-off schedule provided increased survival and significantly greater antitumor activity than the conventional daily schedule, with no difference in adverse reactions. A study was also conducted in human subjects to measure fluorouracil (5-FU) concentrations that identified the pharmacokinetic activity during the 2 drug-free days of the weekday-on/weekend-off schedule. The plasma 5-FU concentration declined markedly after 24 hours, but the concentration in the tumor remained at a relatively high level after 2 days off the drug. A one-year clinical study evaluated the compliance and toxicity of the weekday-on/weekend-off UFT schedule as adjuvant chemotherapy for colorectal cancer. Based on the findings of all these studies, the weekday-on/weekend-off schedule for UFT as adjuvant chemotherapy for colorectal cancer can be recommended for a clinical trial. [ONCOLOGY 14(Suppl 9):87-90, 2000]
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 meta-analysis.
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 given period.[9,10]
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 was similar.
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 colorectal cancer.
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