A PHASE-I TRIAL OF IMMEDIATE POSTOPERATIVE INTRAPERITONEAL FLOXURIDINE AND LEUCOVORIN PLUS SYSTEMIC 5-FLUOROURACIL AND LEVAMISOLE AFTER RESECTION OF HIGH-RISK COLON-CANCER

Background. The purpose of this study was to evaluate the toxicity of immediate postoperative intraperitoneal (IP) floxuridine (FUdR) and le ucovorin (LV) after resection of high risk colon cancer, and to determ ine the appropriate dose of intravenous fluorouracil (FU) plus levamis ole during concurrent intraperitoneal therapy. Methods. The authors co nducted a tertiary referral Comprehensive Cancer Center Phase I Trial in patients with resected colon cancer at high risk for recurrence. Af ter resection of all gross disease, intraperitoneal treatment was admi nistered twice daily for 3 days every 2 weeks for three cycles (Days 1 -3, 15-17, 29-31). Intravenous FU daily for 5 days was administered on days 29-33 concurrently with the third cycle of intraperitoneal thera py. Fluorouracil doses during the last cycle of intraperitoneal therap y were escalated; intraperitoneal FUdR and LV doses and weekly intrave nous FU doses (starting on Day 58) were fixed. Results. Twenty-six pat ients with resected high risk colon cancer were treated. Three had Duk es' B2, 16 Dukes' C, and 7 Dukes' D (M1) resected tumors. Intraperiton eal therapy was well tolerated with no increase in operative morbidity and no operative mortality. Two patients had greater than or equal to Grade 3+ toxicity during IP therapy alone. There were no treatment re lated deaths. During concurrent intraperitoneal and intravenous chemot herapy, the maximum tolerated dose of FU was 300 mg/m(2)/day for 5 day s. The recommended dose for Phase II or III trials is 200 mg/m(2)/day for 5 consecutive days. Pharmacokinetic analysis indicated that using the doses used in this trial, measurable systemic concentrations of FU dR and LV were obtained during IP therapy. This may have contributed t o observed toxicity with intravenous FU doses of 300-400 mg/m(2). With a median duration of follow-up of 18 months, four patients had recurr ence of disease. No peritoneal recurrences have been noted to date. Co nclusions. Immediate postoperative IP FUdR and LV are well tolerated a fter resection of high risk colon cancer. The recommended dose of intr avenous FU beginning on Day 29 (concurrent with the last dose of IP th erapy) is 5FU 200 mg/m(2) for 5 consecutive days. The remaining year o f adjuvant fluorouracil and levamisole can be administered with standa rd dose attenuation. Although follow-up is short, the lack of recurren t peritoneal metastases is encouraging. Additional trials with this ap proach are warranted in patients with high risk colorectal cancer.