The combination of continuous-infusion fluorouracil(Drug information on fluorouracil) (5-FU) with leucovorin and mitomycin(Drug information on mitomycin)-C (Mutamycin) is active and well tolerated. UFT (uracil and tegafur(Drug information on 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 ´ ULN.
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 2.
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.