title: 5-FU split dose; a phase I/II and pharmacokinetic study of a different schedule of the Nordic regimen in advanced colorectal carcinoma.
abstract: OBJECTIVE
  Despite more than four decades of fluoro-pyrimidine treatment in different cancers, the optimal schedule is still not known. The plasma half-life of 5-fluorouracil (5-FU) is extremely short and continuous infusion has gained popularity. In this study we explored whether repeated bolus 5-FU injections could improve the results.
  
  
  METHODS
  Forty-three patients with advanced gastrointestinal carcinoma, where no standard treatment was available, were included in the phase I study. The initial dose of 5-FU was 250 mg/m2 with 30 mg/m2 leucovorin, repeated three hours later. Treatments were repeated every week. Twenty-six patients were recruited in the following phase II after maximal-tolerated dose (MTD) was reached. Plasma was collected for 5-FU pharmacokinetics.
  
  
  RESULTS
  Diarrhoea was the dose-limiting toxicity (DLT), and was reached at 450 mg/m2. One complete and three partial responses (24%) were seen in the phase II study at 400 mg/m2. In addition, several patients had lasting subjective improvements. The treatments were well-tolerated but accumulated toxicity was seen after several months. Dose intensity was 89% after four months of treatment. A great interpatient variability was seen in 5-FU pharmacokinetics. The plasma AUC correlated with the 5-FU dose and toxicity, but not with the tumour response.
  
  
  CONCLUSIONS
  A split of the 5-FU push bolus injection is possible with maintained treatment activity and surprisingly high doses can be tolerated; a weekly dose intensity of 800 mg/m2 could be reached compared with 500 mg/m2 in the standard Nordic FLv schedule.
authors.affiliation: Department of Oncology, Radiology and Clinical Immunology, University of Uppsala, Akademiska Sjukhuset, Uppsala, Sweden. ake.berglund@onkologi.uu.se
authors.forename: Ake
authors.initials: A
authors.lastname: Berglund
authors.forename: Göran
authors.initials: G
authors.lastname: Carlsson
authors.forename: Bengt
authors.initials: B
authors.lastname: Gustavsson
authors.forename: Jan-Erik
authors.initials: JE
authors.lastname: Frödin
authors.forename: Peter
authors.initials: P
authors.lastname: Ragnhammar
authors.forename: Bengt
authors.initials: B
authors.lastname: Glimelius
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil