title: 5-fluorouracil administered as a 48-hour chronomodulated infusion in combination with leucovorin and cisplatin: a randomized phase II study in metastatic colorectal cancer.
abstract: OBJECTIVE
  The primary objective of this trial was to determine the objective response of two regimens with CDDP administered every 2 weeks immediately before or after an 'optimal' 48-hour chronomodulated infusion of 5-fluorouracil (5-FU) modulated with leucovorin (LV) in metastatic colorectal cancer patients. Secondary endpoints were toxicity, 5-FU and its metabolites, plasma pharmacokinetics and progression-free and overall survival.
  
  
  METHODS
  Metastatic colorectal cancer patients with measurable disease who were chemotherapy-naive or pretreated only with a 5-FU-bolus-based chemotherapy were eligible for this study. The study was designed as a randomized phase II clinical trial.
  
  
  RESULTS
  Eighty-three patients were entered into the study. Forty-two were randomized to CDDP given before 5-FU and 41 to CDDP given after 5-FU. Patient characteristics were similar among the two groups. Toxicities were also similar among the two arms and the most frequent WHO grade III-IV toxicities were stomatitis (14%) and neutropenia (39-50%). Plasma pharmacokinetic profiles of 5-FU and 5-FUH2 were not significantly affected by the sequence of CDDP and 5-FU administration. Antitumor activity was similar in the two arms and was very promising both in pretreated patients (response rate 29%; 95% confidence interval 15-46%) and in chemotherapy-naive patients (response rate 56%, complete response 9%, 95% confidence interval 40-71%). Median survival of the patients with and without pretreatment was 12 and 16 months, respectively.
  
  
  CONCLUSIONS
  These results do not suggest a sequence dependence of the synergism between CDDP and 5-FU. However, they challenge the need of oxaliplatin to improve 5-FU/LV activity in advanced colorectal cancer. In fact, our results with an 'optimal' 5-FU dose and scheduling are very similar to those obtained with oxaliplatin plus 5-FU/LV. However, only a randomized phase III study will be able to give an answer to the hypotheses raised by this study.
authors.affiliation: U.O. Oncologia Medica, Presidio Ospedaliero di Livorno, Livorno, Italy. a.falcone@do.med.unipi.it
authors.forename: A
authors.initials: A
authors.lastname: Falcone
authors.forename: G
authors.initials: G
authors.lastname: Allegrini
authors.forename: G
authors.initials: G
authors.lastname: Masi
authors.forename: M
authors.initials: M
authors.lastname: Lencioni
authors.forename: E
authors.initials: E
authors.lastname: Pfanner
authors.forename: I
authors.initials: I
authors.lastname: Brunetti
authors.forename: R
authors.initials: R
authors.lastname: Danesi
authors.forename: G
authors.initials: G
authors.lastname: Bocci
authors.forename: M
authors.initials: M
authors.lastname: Del Tacca
authors.forename: P
authors.initials: P
authors.lastname: Conte
mesh_terms: D000206:Actuarial Analysis; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D002945:Cisplatin; D002955:Leucovorin; D005472:Fluorouracil