title: Phase I/II study of first-line irinotecan combined with 5-fluorouracil and folinic acid Mayo Clinic schedule in patients with advanced colorectal cancer.
abstract: BACKGROUND
  This multicentre phase I/II study was designed to determine the maximum tolerated dose of irinotecan when combined with 5-fluorouracil and folinic acid according to the Mayo Clinic schedule and to evaluate the activity of this combination as first-line therapy in patients with advanced colorectal cancer.
  
  
  METHODS
  Sixty-three patients received irinotecan (250 or 300 mg/m2, 30- to 90-minute intravenous infusion on day 1), immediately followed by folinic acid (20 mg/m2/day) and 5-fluorouracil (425 mg/m2, 15-minute bolus infusion) days 1 to 5, every four weeks.
  
  
  RESULTS
  Diarrhoea was dose limiting at 300 mg/m2 irinotecan in combination with 5-fluorouracil and folinic acid, and this was determined to be the maximum tolerated dose. Grade 3-4 neutropenia was the most frequently reported toxicity. The recommended dose of irinotecan for the phase II part of the study was 250 mg/m2. The response rate for the evaluable patient population was 36% (13/36), and 44% (16 patients) had stable disease (including 19% of minor response). For the intention-to-treat population, the response rate was 29% (14/49) and 35% (17 patients) stable disease (including 14% of minor response). The median time to progression was 7.0 months and the median survival was 12.0 months. Grade 3-4 non-haematological drug-related toxicities included delayed diarrhoea, stomatitis, fatigue, and nausea/vomiting. There were three deaths due to septic shock that were possibly or probably treatment-related.
  
  
  CONCLUSIONS
  This regimen of irinotecan in combination with the Mayo Clinic schedule of bolus 5-fluorouracil/folinic acid every four weeks showed activity as first-line therapy in patients with advanced colorectal cancer. In keeping with other published results of studies using bolus 5-fluorouracil combined with irinotecan, the use of this regimen is limited by a relatively high rate of grade 3-4 neutropenia, and the combination of irinotecan and infusional 5-fluorouracil / folinic acid should remain the regimen of first choice.
authors.affiliation: Hospital Barmherzige Schwestern vom heiligen Kreuz, Griesskirchner Strasse 42, 4600 Wels, Austria. thomas.kuehr@khwels.at
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuehr
authors.forename: Paul
authors.initials: P
authors.lastname: Ruff
authors.forename: Bernardo L
authors.initials: BL
authors.lastname: Rapoport
authors.forename: Stephen
authors.initials: S
authors.lastname: Falk
authors.forename: Francis
authors.initials: F
authors.lastname: Daniel
authors.forename: Conrad
authors.initials: C
authors.lastname: Jacobs
authors.forename: Neville
authors.initials: N
authors.lastname: Davidson
authors.forename: Josef
authors.initials: J
authors.lastname: Thaler
authors.forename: Blandine
authors.initials: B
authors.lastname: Boussard
authors.forename: James
authors.initials: J
authors.lastname: Carmichael
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D003967:Diarrhea / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D012772:Shock, Septic / Q000139:chemically induced; D013280:Stomatitis / Q000139:chemically induced; D015996:Survival Rate
chemical_list: D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin