title: A dose-finding study of irinotecan (CPT-11) plus a four-day continuous 5-fluorouracil infusion in advanced colorectal cancer.
abstract: OBJECTIVE
  Irinotecan (CPT-11) has shown considerable activity in colorectal cancer, and its combination with 5-fluorouracil (5-FU) represents an attractive approach. A phase I study was conducted to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of CPT-11 in combination with a continuous infusion of 5-FU for 4 days.
  
  
  METHODS
  Forty-two patients with histologically confirmed metastatic colorectal cancer who had not received prior treatment for advanced disease were enrolled. The patients' median age was 64 years; 26 (62%) patients were men, and the performance status (WHO) was 0 in 26 (62%) patients, 1 in 15 (36%) and 2 in 1 (2%). Twenty-two (52%) patients had 2 or more metastatic sites. CPT-11 (starting dose 200 mg/m(2)) was administered as a 30-min intravenous infusion with increments of 50 mg/m(2) on day 4. 5-FU (starting dose 400 mg/m(2)) was administered as a 4-day continuous intravenous infusion with increments of 50 mg/m(2) on days 1-4. Treatment was repeated every 4 weeks.
  
  
  RESULTS
  The MTD of the combination was found to be 600 mg/m(2) for 5-FU and 350 mg/m(2) for CPT-11. Neutropenia, febrile neutropenia and delayed diarrhea were the DLTs. Grade 3/4 neutropenia was observed in 22 (13%) out of 169 administered treatment cycles, febrile neutropenia in 7 (4%) and grade 3/4 diarrhea in 20 (12%). Other toxicities were mild. Among 36 patients evaluable for response, partial response was achieved in 8 (22%), stable disease in 12 (33%) and progressive disease in 16 (44%) patients. Responses were mostly seen at the higher dose levels.
  
  
  CONCLUSIONS
  The combination of a 4-day continuous infusion of 5-FU followed by CPT-11 represents an active and well-tolerated regimen for patients with colorectal cancer. This regimen merits further evaluation in phase II studies.
authors.affiliation: Department of Medical Oncology, School of Medicine, University General Hospital of Heraklion, Heraklion, Crete, Greece.
authors.forename: S
authors.initials: S
authors.lastname: Kakolyris
authors.forename: J
authors.initials: J
authors.lastname: Souglakos
authors.forename: C
authors.initials: C
authors.lastname: Kouroussis
authors.forename: N
authors.initials: N
authors.lastname: Androulakis
authors.forename: D
authors.initials: D
authors.lastname: Mavroudis
authors.forename: K
authors.initials: K
authors.lastname: Kalbakis
authors.forename: A
authors.initials: A
authors.lastname: Kotsakis
authors.forename: N
authors.initials: N
authors.lastname: Vardakis
authors.forename: M
authors.initials: M
authors.lastname: Koukourakis
authors.forename: J
authors.initials: J
authors.lastname: Romanos
authors.forename: V
authors.initials: V
authors.lastname: Georgoulias
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged
chemical_list: D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin