The combination of continuous-infusion fluorouracil (5-FU) with
leucovorin and mitomycin-C (Mutamycin) is active and well
tolerated. UFT (uracil and tegafur) plus oral leucovorin (a
combination being developed under the trade name Orzel) may be an
attractive alternative to continuous-infusion 5-FU because daily
administration of three doses of UFT results in comparable
concentrations of 5-FU in the plasma. UFT combined with mitomycin-C
was found to be active and safe in the treatment of advanced
colorectal cancer in the only study reported to date. It is,
therefore, of interest to investigate the combination of UFT plus
leucovorin with mitomycin-C in a larger group of previously untreated
patients with metastatic colorectal cancer.
The primary objective of this study was to determine the response
rate to UFT plus leucovorin when administered in combination with
mitomycin-C. Secondary objectives were to determine the
progression-free survival and evaluate the type, frequency, and
severity of side effects.
To be eligible for the study, patients had to have histologically
confirmed metastatic colorectal adenocarcinoma and at least one
bidimensionally measurable lesion located outside of previously
irradiated fields. (The diameter of the indicator lesion(s) had to be ³
1.5 cm. Lesions were assessed by physical examination, computed
tomography (CT) scan/ultrasound, and/or x-ray). Eligible patients
completed any prior adjuvant treatment ³
12 months prior to study enrollment; they demonstrated a chronologic
age of ³ 18 years and a physiologic
age of £ 80 years. Other eligibility
criteria for patients were (1) an Eastern Cooperative Oncology
Group/World Health Organization performance status 0 to 2; (2) a life
expectancy ³ 3 months; (3) an
absolute neutrophil count ³ 1.5 ´ 109/L
and platelet count ³ 100 ´ 109/L;
(4) liver function test values as follows: bilirubin £
1.25 ´ upper limit of normal (ULN) (£ 1.5 ´
ULN in case of liver metastases), and alanine aminotransferase £
2.0 ´ ULN ( £
5 ´ in case of liver metastases); and
(5) serum creatinine £ 1.25 ´
Women of childbearing age must have tested negative on a serum or
urine pregnancy test (minimum sensitivity 25 µL of b-HCG) within
72 hours prior to initiating study medication. All patients had to
provide written consent according to local ethics committee requirements.
Patients not eligible for the study included those who had (1) any
type of prior treatment for metastatic disease with the exception of
radiotherapy to treat locally symptomatic disease; (2) known brain
metastases, regardless of prior treatment; (3) previous or another
concomitant malignancy, with the exception of adequately treated
basal cell skin cancer or in situ cervical cancer; (4) inability to
follow the treatment and evaluation schedule; (5) any other condition
or therapy that, in the investigators opinion, may pose a risk
to the patient or interfere with the study objectives; (6) pregnancy
or active nursing, or childbearing potential and not using adequate
methods of birth control; and (7) active infections or other serious
underlying medical condition that would impair their ability to
receive protocol treatment.
The treatment schedule is outlined in Table
1. The dose of UFT for the first six patients will be 250
mg/m²/d. If only one of six patients develops grade 3-4
hematologic and/or nonhematologic toxicity, except for alopecia,
during the first course, subsequent patients will be treated with UFT
300 mg/m²/d. A detailed dosing regimen is presented in Table
During treatment days 1 to 28: if granulocytes are < 1.0 ´ 109/L
or platelets are < 50 ´ 109/L,
UFT plus leucovorin therapy will be suspended until granulocytes are ³
1.5 ´ 109/L and platelets
are ³ 100 ´ 109/L.
Therapy can then be resumed at one lower dose level. Missed doses
will be skipped and treatment should not be extended beyond 28 days
from the start of the therapy.
UFT plus leucovorin will be suspended for Common Toxicities Criteria
toxicity grade greater than 2, except for nausea, vomiting, and
alopecia. When toxicity subsides to baseline or grade 1, therapy will
be resumed at one lower dose level. Treatment should be discontinued
after day 28, regardless of the number of days that it was interrupted.
Patients whose treatment was interrupted for less than 2 weeks due to
toxicity will be retreated on an adjusted dose level. The dose level
should be adjusted based on the highest grade of toxicity observed
during the previous course (Table 3).
Table 4 outlines the testing
and evaluation protocol designed for this study.
Simons two-stage phase II minimax design will be
used to assess sample size and power. For the first stage, 42 response-evaluable
patients will be entered. If eight or fewer patients respond, the
study will stop further accrual. If more than eight patients entered
into the first stage achieve a response, an additional 35
response-evaluable patients will be accrued. If at least 22 of the 77
response-evaluable patients respond to the combination, thus
producing a response rate of 35%, the treatment will be considered of
further clinical interest.
In conclusion, the present study should provide a solid basis for the
decision on a phase III trial.
1. Ross P, Norman A, Cunningham D, et al: A prospective randomized
trial of protracted venous infusion 5-fluorouracil with or without
mitomycin-C in advanced colorectal cancer. Ann Oncol 8:995-1001, 1997.
2. Ikeda E, Kodaira S, Teramoto T, et al: Optimal dosage of UFT + MMC
combination chemotherapy for advanced colorectal cancer: phase I/II
study of combination chemotherapy of MMC with 2-week intervals and
intermittent UFT administrationStudy Group of UFTM Therapy for
Advanced Colorectal Cancer. Gan To Kagaku Ryoho 23: 1291-1298, 1998.