title: Outpatient weekly high-dose continuous-infusion 5-fluorouracil plus oral leucovorin in advanced colorectal cancer. A phase II trial. Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD).
abstract: BACKGROUND
  In a previous phase I-II trial we showed that the maximum tolerable dose (MTD) of 5-fluorouracil (5-FU) in a weekly 48-hour continuous infusion (CI) was 3.5 g/m2. In a subsequent confirmative phase II trial with 85 evaluable patients, a 38.5% response rate was obtained, and a median survival of 12 months. These data were comparable to those achieved by biochemical modulation of 5-FU with leucovorin. On this basis we attempted to modulate high-dose 5-FU (3 g/m2) with oral leucovorin (LV) but the regimen was too toxic and the dose had to be reduced. A new phase II trial with 2 g/m2/week plus oral leucovorin was planned.
  
  
  METHODS
  From July 1992 to June 1994, 110 previously untreated patients with advanced, measurable colorectal cancer were included in a multicenter study. The patients received, on an outpatient basis, 5-FU 2 g/m2 by continuous infusion for 48 hours once a week until progression or the appearance of toxic effects. Oral leucovorin (60 mg every six hours) was also given during the 5-FU infusion.
  
  
  RESULTS
  Patients received a median dose intensity of 5-FU of 1.6 g/m2/week (range 0.9-2). Three complete responses and 36 partial responses were observed. The overall response rate was 37.5% (95% CI, 28% to 46.8%), the median time to progression 7.4 months and median survival 14.5 months. W.H.O. grade 3 diarrhea occurred in 27 patients (24.5%); grade 3 mucositis was observed in 9 (8.1%) patients and grade 4 in one. Grade 3 nausea and vomiting was reported in 13 (11.7%) patients, while grade 3 hand-foot syndrome was detected in only 5 (4.5%). Grade 4 leukopenia occurred in one patient and grade 3-4 thrombocytopenia in two.
  
  
  CONCLUSIONS
  Oral leucovorin modulation of weekly 48-hour continuous infusion of 5-FU at 2 g/m2 is an active regimen, with diarrhea and mucositis as the main limiting toxic effects. Its antitumor activity does not seem superior to that obtained with a weekly 48-hour continuous infusion of 5-FU alone at a dose of 3.5 g/m2.
authors.affiliation: Medical Oncology Department, University Hospital, Cordoba, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Aranda
authors.forename: A
authors.initials: A
authors.lastname: Cervantes
authors.forename: A
authors.initials: A
authors.lastname: Carrato
authors.forename: C
authors.initials: C
authors.lastname: Fernández-Martos
authors.forename: A
authors.initials: A
authors.lastname: Antón-Torres
authors.forename: T
authors.initials: T
authors.lastname: Massutí
authors.forename: I
authors.initials: I
authors.lastname: Barneto
authors.forename: J
authors.initials: J
authors.lastname: García-Conde
authors.forename: J M
authors.initials: JM
authors.lastname: Barón
authors.forename: E
authors.initials: E
authors.lastname: Díaz-Rubio
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis
chemical_list: D002955:Leucovorin; D005472:Fluorouracil