title: A phase I/II study of oral uracil/tegafur (UFT), leucovorin and irinotecan in patients with advanced colorectal cancer.
abstract: BACKGROUND
  The aim of this study was to determine the maximum tolerated dose (MTD), toxicity profile and response rate of the oral 5-fluorouracil prodrug UFT (tegafur/uracil) and leucovorin (LV) in combination with irinotecan in patients with advanced or metastatic colorectal cancer.
  
  
  METHODS
  Patients with histologically proven advanced or metastatic colorectal adenocarcinoma received first-line chemotherapy comprising UFT 250 mg/m(2)/day and LV 90 mg/day given on days 1 to 14, with escalating doses of irinotecan (200-300 mg/m(2)) administered intravenously on day 1 of a three-weekly cycle. Eligibility criteria were standard. The MTD was defined as the dose at which >33% of six patients experienced a dose-limiting toxicity (DLT) during cycle 1.
  
  
  RESULTS
  A total of 32 patients were studied. Initially, six patients were treated at each of the irinotecan dose levels (200, 250 and 300 mg/m(2)) combined with UFT 250 mg/m(2)/day and LV 90 mg/day. DLTs consisting of grade 3 or 4 diarrhoea and febrile neutropenia were observed in one of 20 patients at 250 mg/m(2) and three of six patients at the 300 mg/m(2) irinotecan dose level. Having defined the MTD, the 250 mg/m(2) dose level was established as the recommended dose (RD) and expanded to 20 patients in whom treatment was generally well tolerated. The overall response rate was 19%, with five patients having a partial response (PR) and 18 stable disease (SD) out of 32 response-evaluable patients.
  
  
  CONCLUSIONS
  UFT and LV can be safely combined with irinotecan. The RDs for future studies are UFT 250 mg/m(2)/day and LV 90 mg/day given on days 1-14, with irinotecan 250 mg/m(2) administered on day 1, every 3 weeks. This combination is well tolerated and active. Further investigation of UFT and LV in combination with irinotecan is warranted in patients with colorectal cancer.
authors.affiliation: Cancer Research UK, Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Glasgow, UK.
authors.forename: H J
authors.initials: HJ
authors.lastname: Mackay
authors.forename: M
authors.initials: M
authors.lastname: Hill
authors.forename: C
authors.initials: C
authors.lastname: Twelves
authors.forename: R
authors.initials: R
authors.lastname: Glasspool
authors.forename: T
authors.initials: T
authors.lastname: Price
authors.forename: S
authors.initials: S
authors.lastname: Campbell
authors.forename: A
authors.initials: A
authors.lastname: Massey
authors.forename: M A
authors.initials: MA
authors.lastname: Macham
authors.forename: M
authors.initials: M
authors.lastname: Uzzel
authors.forename: S M
authors.initials: SM
authors.lastname: Bailey
authors.forename: C
authors.initials: C
authors.lastname: Martin
authors.forename: D
authors.initials: D
authors.lastname: Cunningham
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D018570:Risk Assessment; D016019:Survival Analysis; D005641:Tegafur / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D006113:United Kingdom; D014498:Uracil / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D005641:Tegafur; D014498:Uracil; D000077146:Irinotecan; D002955:Leucovorin; D002166:Camptothecin