title: Fluorouracil modulation in colorectal cancer: lack of improvement with N -phosphonoacetyl- l -aspartic acid or oral leucovorin or interferon, but enhanced therapeutic index with weekly 24-hour infusion schedule--an Eastern Cooperative Oncology Group/Cancer and Leukemia Group B Study.
abstract: OBJECTIVE
  To investigate mechanism-directed regimens in maximizing the efficacy of fluorouracil (5-FU) in advanced colorected cancer.
  
  
  METHODS
  Based on promising phase II data, a randomized comparison of various methods for the biochemical modulation of 5-FU was undertaken in patients with advanced colorectal cancer. The control group received single-agent 5-FU as a 24-hour infusion weekly. Patients (N = 1,120) with no prior chemotherapy for metastatic disease were randomized to one of the following arms: arm A, 5-FU 2,600 mg/m2 by 24-hour infusion, weekly; arm B, N-phosphonoacetyl-l-aspartic acid 250 mg/m2 day l, 5-FU 2,600 mg/m2 by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m2 with oral leucovorin (LV) 125 mg/m2 hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m2 with intravenous (IV) LV 600 mg/m2, weekly; arm E, 5-FU 750 mg/m2/d IV by continuous infusion for 5 days, then 750 mg/m2 weekly, and recombinant interferon alfa-2a 9 million units subcutaneously three times weekly. Median follow-up was 4.8 years.
  
  
  RESULTS
  Of the 1,098 assessable patients, 57% had measurable disease. The toxicity of all the regimens was tolerable. Grade 4 or worse toxicity occurred in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significantly (P <.001) the 24-hour infusion arms. Median survival (months) by arm was A, 14.8; B, 11.9; C, 13.5; D, 13.6; and E, 15.2. These survival durations did not differ significantly.
  
  
  CONCLUSIONS
  We conclude that a weekly infusion regimen of 5-FU is significantly less toxic than and as effective as 5-FU bolus regimens modulated by either LV or interferon in patients with metastatic colorectal cancer.
authors.affiliation: University of Pennsylvania Cancer Center, Philadelphia, PA 19104, USA. podwyer@mail.edu.upenn.edu
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.forename: J
authors.initials: J
authors.lastname: Manola
authors.forename: F H
authors.initials: FH
authors.lastname: Valone
authors.forename: L M
authors.initials: LM
authors.lastname: Ryan
authors.forename: J D
authors.initials: JD
authors.lastname: Hines
authors.forename: S
authors.initials: S
authors.lastname: Wadler
authors.forename: D G
authors.initials: DG
authors.lastname: Haller
authors.forename: S G
authors.initials: SG
authors.lastname: Arbuck
authors.forename: L M
authors.initials: LM
authors.lastname: Weiner
authors.forename: R J
authors.initials: RJ
authors.lastname: Mayer
authors.forename: A B
authors.initials: AB
authors.lastname: Benson
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001224:Aspartic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007262:Infusions, Intravenous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D002955:Leucovorin / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D010746:Phosphonoacetic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D011379:Prognosis; D011994:Recombinant Proteins
chemical_list: D000970:Antineoplastic Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D001224:Aspartic Acid; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D002955:Leucovorin; D005472:Fluorouracil