title: A phase I trial of immediate postoperative intraperitoneal floxuridine and leucovorin plus systemic 5-fluorouracil and levamisole after resection of high risk colon cancer.
abstract: BACKGROUND
  The purpose of this study was to evaluate the toxicity of immediate postoperative intraperitoneal (IP) floxuridine (FUdR) and leucovorin (LV) after resection of high risk colon cancer, and to determine the appropriate dose of intravenous fluorouracil (FU) plus levamisole during concurrent intraperitoneal therapy.
  
  
  METHODS
  The authors conducted a tertiary referral Comprehensive Cancer Center Phase I Trial in patients with resected colon cancer at high risk for recurrence. After resection of all gross disease, intraperitoneal treatment was administered 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 therapy. Fluorouracil doses during the last cycle of intraperitoneal therapy were escalated; intraperitoneal FUdR and LV doses and weekly intravenous FU doses (starting on Day 58) were fixed.
  
  
  RESULTS
  Twenty-six patients with resected high risk colon cancer were treated. Three had Dukes' B2, 16 Dukes' C, and 7 Dukes' D (M1) resected tumors. Intraperitoneal therapy was well tolerated with no increase in operative morbidity and no operative mortality. Two patients had > or = Grade 3+ toxicity during IP therapy alone. There were no treatment related deaths. During concurrent intraperitoneal and intravenous chemotherapy, the maximum tolerated dose of FU was 300 mg/m2/day for 5 days. The recommended dose for Phase II or III trials is 200 mg/m2/day for 5 consecutive days. Pharmacokinetic analysis indicated that using the doses used in this trial, measurable systemic concentrations of FUdR and LV were obtained during IP therapy. This may have contributed to observed toxicity with intravenous FU doses of 300-400 mg/m2. With a median duration of follow-up of 18 months, four patients had recurrence of disease. No peritoneal recurrences have been noted to date.
  
  
  CONCLUSIONS
  Immediate postoperative IP FUdR and LV are well tolerated after resection of high risk colon cancer. The recommended dose of intravenous FU beginning on Day 29 (concurrent with the last dose of IP therapy) is 5FU 200 mg/m2 for 5 consecutive days. The remaining year of adjuvant fluorouracil and levamisole can be administered with standard dose attenuation. Although follow-up is short, the lack of recurrent peritoneal metastases is encouraging. Additional trials with this approach are warranted in patients with high risk colorectal cancer.
authors.affiliation: Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
authors.forename: D P
authors.initials: DP
authors.lastname: Kelsen
authors.forename: L
authors.initials: L
authors.lastname: Saltz
authors.forename: A M
authors.initials: AM
authors.lastname: Cohen
authors.forename: T J
authors.initials: TJ
authors.lastname: Yao
authors.forename: W
authors.initials: W
authors.lastname: Enker
authors.forename: W
authors.initials: W
authors.lastname: Tong
authors.forename: Y
authors.initials: Y
authors.lastname: Tao
authors.forename: J R
authors.initials: JR
authors.lastname: Bertino
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000601:surgery*; D003131:Combined Modality Therapy; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D007263:Infusions, Parenteral; D002955:Leucovorin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007978:Levamisole / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D011184:Postoperative Period; D016019:Survival Analysis
chemical_list: D005467:Floxuridine; D007978:Levamisole; D002955:Leucovorin; D005472:Fluorouracil