This open-label phase I trial has been designed to determine the safety of UFT (uracil and tegafur in a 4:1 molar combination) and leucovorin (LV), both given orally three times daily concurrently with fixed doses of pelvic radiotherapy, and to determine the safety of this regimen after pelvic radiotherapy (RT), chemotherapy, and surgery.
The trial, which will provide data regarding the feasibility of preoperative oral UFT/LV chemotherapy given during radiotherapy, and oral UFT/LV chemotherapy given following surgery in the treatment of patients with rectal cancer, is anticipated to serve as a pilot trial to develop an investigational treatment arm for a randomized phase II trial of preoperative treatment of patients with rectal cancer.
At our institution, standard treatment for patients with rectal neoplasms (stages T3, T4, and/or N > 1) is a preoperative continuous infusion of fluorouracil (5-FU) with radiation therapy, followed by four courses of 5-FU/LV postoperatively. Data suggest that oral UFT/LV may offer a well-tolerated, fully oral treatment option that could be more convenient for patients.
The present study has two major objectives: to determine the maximum tolerated dose and dose-limiting toxicities of oral UFT plus LV when given three times daily, 5 days per week, during full-dose radiotherapy in patients with rectal cancer and to determine the maximum tolerated dose and dose-limiting toxicities of oral UFT/LV when given daily for 28 days following full-dose radiotherapy, chemotherapy, and surgery in patients with rectal cancer.
This open-label phase I trial to determine the safety of oral UFT and LV, given orally three times daily during pelvic radiotherapy and after radiotherapy, chemotherapy, and surgery, will evaluate whether this combination represents a less expensive, less toxic regimen than standard treatment, eg, preoperative continuous-infusion 5-FU with radiotherapy, followed by four postoperative courses of 5-FU/LV. Because oral UFT avoids the use of central intravenous lines and ambulatory infusion pumps and has been associated with less mucositis and neutropenia than intravenous 5-FU, it is more convenient for patients to receive. 5-FU generated by UFT has a similar area under the concentration-time curve to that of a protracted, low-dose 5-FU intravenous infusion. Data suggest that UFT and LV may offer a well-tolerated, fully oral treatment option with efficacy comparable to standard parenteral regimens.
Eligible patients are required to meet the following criteria: Patients must have biopsy-proven rectal cancer for which preoperative treatment with chemotherapy and pelvic radiotherapy is indicated. This includes patients with endoscopic evidence of T3 and T4 lesions and/or nodal involvement (N > 1 disease). No evidence of distant metastasis is allowed. Patients must be 18 years of age or older and have a Zubrod performance status score of 0-2, with a life expectancy of at least 3 months. Additionally, patients must be able to tolerate a major operation, with possible abdominoperineal resection. Patients must be free of significant nausea and vomiting. Adequate absolute granulocyte count, platelet count, liver function tests, and renal function tests are also required, and eligible patients must be willing and able to provide written informed consent.
Patients with distant metastatic disease and those with medical or psychiatric conditions that, in the opinion of the investigator, would constitute a contraindication to the patients participation in this trial or with prior malignancy (except appropriately treated localized epithelial skin or cervical cancer) are excluded from participation in the study. Additional exclusion criteria include pregnancy or lactation. Sexually active, fertile patients are required to use effective birth control. Patients who have received prior radiation to the pelvis and/or prior chemotherapy are ineligible.
Radiation beginning on day 1, week 1, will be given to the pelvis once daily, 5 days per week at 180 cGy/day over 5 weeks, for a total of 4,500 cGy. Coincident with the start of radiotherapy, treatment with UFT and LV will begin. The starting dose of UFT for the first cohort of patients will be 250 mg/m2/day, given in three divided doses, each accompanied by 30 mg LV. This is one dose below the starting dose used in current UFT protocols (Pazdur, 300 mg/m2/day). UFT and LV will be taken on the same days (15) that radiotherapy is given each week (Figure 1).
Surgery will be performed 4 to 6 weeks after completion of chemoradiotherapy. Four to 6 weeks after surgery, adjuvant therapy consisting of four courses of UFT plus oral LV will be administered. A course of UFT plus oral LV will consist of 28 consecutive days of drug administration, followed by a weeks rest. The dose of LV will remain fixed at 90 mg/day (30 mg tid). The starting postsurgical dose of UFT for the first cohort of patients will be 250 mg/m2/day, increasing in increments of 50 mg/m2 (Table 1).
The primary purpose of this phase I trial is to determine the maximum tolerated dose and dose-limiting toxicity of UFT plus oral LV given during radiotherapy. The safety of this combination administered orally, daily for 28 consecutive days every 35 days following surgery, will also be defined. Groups of three to six patients will be tested at each dose level to achieve this end. Up to 12 patients will be treated at one dose level below the maximum tolerated dose in each stage to better assess the regimens cumulative toxicity.
It is estimated that approximately 30 patients will need to be evaluated to determine the maximum tolerated dose and the recommended phase II dose. Allowing for follow-up time, the study duration is expected to be 12 to 15 months. Descriptive statistics will be employed in the analysis of all safety and laboratory observations in this study.