title: Randomized multicenter phase II trial of bolus plus infusional fluorouracil/leucovorin compared with fluorouracil/leucovorin plus oxaliplatin as third-line treatment of patients with advanced colorectal cancer.
abstract: OBJECTIVE
  The addition of oxaliplatin to fluorouracil (FU) and leucovorin (LV) improves the outcome of patients with colorectal cancer (CRC). This multicenter study evaluated FU/LV with or without oxaliplatin in patients with metastatic CRC after disease progression on sequential fluoropyrimidine and irinotecan.
  
  
  METHODS
  Two hundred fourteen patients were randomly assigned to receive LV 200 mg/m2 intravenously (IV) and FU 400 mg/m2 IV bolus, followed by FU 600 mg/m2 IV over 22 hours on days 1 and 2, every 2 weeks (LV5FU2); or LV and FU as described, plus oxaliplatin 85 mg/m2 IV over 2 hours on day 1 of the schedule (FOLFOX4). The primary end point was overall response.
  
  
  RESULTS
  Baseline characteristics were similar in the two treatment arms. Objective response (complete + partial) rates for LV5FU2 versus FOLFOX4 were 2% v 13% (P = .0027), respectively. Median time to disease progression was 2.4 v 4.8 months (P < .0001), and median survival was 11.4 v 9.9 months (P = .20) for LV5FU2 and FOLFOX4, respectively. Among the 72 patients who crossed over from LV5FU2 to FOLFOX4, 6% responded. Symptomatic improvement was significantly better for patients in the FOLFOX4 arm (32% v 18% for LV5FU2, P = .05). Grade 3/4 toxicities for LV5FU2 and FOLFOX4 were neutropenia (13% and 42%, respectively), diarrhea (6% and 16%, respectively), and overall neuropathy (0% and 6%, respectively).
  
  
  CONCLUSIONS
  In patients with metastatic CRC, the FOLFOX4 regimen was superior to LV5FU2 with a higher response rate and time to disease progression. FOLFOX4 is an effective regimen even after disease progression on two previous chemotherapy regimens with fluoropyrimidines and irinotecan.
authors.affiliation: Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. kemenyn@mskcc.org
authors.forename: Nancy
authors.initials: N
authors.lastname: Kemeny
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Garay
authors.forename: Jayne
authors.initials: J
authors.lastname: Gurtler
authors.forename: Howard
authors.initials: H
authors.lastname: Hochster
authors.forename: Peter
authors.initials: P
authors.lastname: Kennedy
authors.forename: Al
authors.initials: A
authors.lastname: Benson
authors.forename: Debra Schwab
authors.initials: DS
authors.lastname: Brandt
authors.forename: Jonathan
authors.initials: J
authors.lastname: Polikoff
authors.forename: Michael
authors.initials: M
authors.lastname: Wertheim
authors.forename: Grace
authors.initials: G
authors.lastname: Shumaker
authors.forename: Doreen
authors.initials: D
authors.lastname: Hallman
authors.forename: Brent
authors.initials: B
authors.lastname: Burger
authors.forename: Sunil
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D011336:Probability; D011379:Prognosis; D020551:Pulse Therapy, Drug; D012016:Reference Values; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil