title: Phase III study of mitomycin-C with protracted venous infusion or circadian-timed infusion of 5-fluorouracil in advanced colorectal carcinoma.
abstract: The combination of protracted venous infusion (PVI) fluorouracil (5-FU) and mitomycin-C has previously been shown to be superior to PVI 5-FU alone in terms of response rate and failure-free survival. This study explores the effect of dose intensification by circadian timing of 5-FU in this combination on response, toxicity, and survival. Patients with advanced colorectal carcinoma were randomized to receive PVI 5-FU 300 mg/m2 daily or circadian-timed infusion (CTI) of 5-FU, beginning at 600 mg/m2 and subsequently reduced to 450 mg/m2, delivered as a flat-rate infusion from 10:15 PM to 9:45 AM. Both groups received mitomycin-C at a dose of 7 mg/m2 given every 6 weeks. From April 1996 to August 1998, 320 patients were randomized, including 263 with metastatic disease and 21 with circumferential margin involvement. The overall response rate for the PVI 5-FU group was 38%, compared with 30.3% for the CTI group (P = 0.176). There was no statistically significant difference in terms of failure-free survival (8.0 months vs. 9.9 months; P = 0.131) or overall survival (15.8 months vs. 16.3 months; P = 0.275) between the treatment groups. There were no differences in global quality of life. Grade 3/4 diarrhea occurred significantly more frequently with CTI 5-FU (6.5% vs. 19.8%; P < 0.001); a nonsignificant trend toward increased incidences of grade 3/4 infection and palmar plantar erythema were observed with CTI 5-FU. This study confirms the high response rate and overall survival figures for the combination of PVI 5-FU and mitomycin-C in colorectal cancer. However, dose intensification of 5-FU using a circadian-timed, flat-rate infusion did not lead to improved response or survival.
authors.affiliation: Gastrointestinal Unit, Royal Marsden Hospital, London, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Price
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Ross
authors.forename: Tamas
authors.initials: T
authors.lastname: Hickish
authors.forename: Diana
authors.initials: D
authors.lastname: Tait
authors.forename: Andy R
authors.initials: AR
authors.lastname: Norman
authors.forename: Hugo E R
authors.initials: HE
authors.lastname: Ford
authors.forename: Gary
authors.initials: G
authors.lastname: Middleton
authors.forename: Kate
authors.initials: K
authors.lastname: Sumpter
authors.forename: Mark
authors.initials: M
authors.lastname: Hill
authors.forename: Jacqui
authors.initials: J
authors.lastname: Oates
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002940:Circadian Rhythm; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D007262:Infusions, Intravenous; D016685:Mitomycin / Q000008:administration & dosage*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D016685:Mitomycin; D005472:Fluorouracil