title: Schedule specific biochemical modulation of 5-fluorouracil in advanced colorectal cancer: a randomized study. GISCAD, IOR and collaborating centers.
abstract: BACKGROUND
  We have recently suggested that bolus 5-fluorouracil (5-FU) may work via a RNA directed mechanism while continuous infusion 5-FU may kill cells via a thymidylate synthase related pathway. It may thus be possible to selectively modulate each schedule biochemically. We have compared an alternating regimen of bolus and continuous infusion 5-FU, selectively modulated for the schedule of administration, with modulated bolus 5-FU in advanced colorectal cancer patients.
  
  
  METHODS
  Two hundred fourteen patients from nineteen Italian centers were randomized to the control arm consisting of biweekly cycles of MTX, 200 mg/m2 on day 1, followed by bolus 5-FU 600 mg/m2 on day 2 and 6-S-leucovorin rescue, or to the experimental arm consisting of two biweekly cycles of the same regimen as in the control arm alternated to three weeks of continuous infusion 5-FU (200 mg/m2 day) + weekly bolus 6-S-leucovorin, 20 mg/m2.
  
  
  RESULTS
  Nine CR and twenty-seven PR were obtained on one hundred eleven evaluable patients treated in experimental arm (RR = 32%, 95% confidence interval (95% CI): 24%-42%), while two CR and eleven PR were observed among one hundred three evaluable patients in control arm (RR = 13%, 95% CI: 7%-21%). WHO grade 3-4 toxicity occurred in 13% of cycles of experimental arm and in 8% of cycles in control arm. The PFS was significantly longer in experimental arm (6.2 vs. 4.3 months, odds ratio 0.66, P = 0.003), while the overall survival was similar in both arms (14.8 months in experimental arm vs. 14.1 months in control arm); quality of life was similar as well. Eighty percent of patients receiving second-line chemotherapy in control arm were treated with continuous infusion 5-FU.
  
  
  CONCLUSIONS
  Alternating, schedule-specific biochemical modulation of FU is more active than MTX --> 5-FU as first-line treatment of advanced colorectal cancer. However, the overall survival was similar suggesting that alternating bolus and infusional 5-FU upfront may be as effective as giving them in sequence as first- and second-line treatment.
authors.affiliation: University of Udine, Department of Medical Oncology, Italy. sobrero@uniud.it
authors.forename: A
authors.initials: A
authors.lastname: Sobrero
authors.forename: A
authors.initials: A
authors.lastname: Zaniboni
authors.forename: G L
authors.initials: GL
authors.lastname: Frassineti
authors.forename: C
authors.initials: C
authors.lastname: Aschele
authors.forename: A
authors.initials: A
authors.lastname: Guglielmi
authors.forename: R
authors.initials: R
authors.lastname: Giuliani
authors.forename: A
authors.initials: A
authors.lastname: Ravaioli
authors.forename: C
authors.initials: C
authors.lastname: Lanfranco
authors.forename: C
authors.initials: C
authors.lastname: Caroti
authors.forename: E
authors.initials: E
authors.lastname: Arnoldi
authors.forename: S
authors.initials: S
authors.lastname: Barni
authors.forename: L
authors.initials: L
authors.lastname: Gallo
authors.forename: M A
authors.initials: MA
authors.lastname: Pessi
authors.forename: D
authors.initials: D
authors.lastname: Turci
authors.forename: E
authors.initials: E
authors.lastname: Cortesi
authors.forename: F
authors.initials: F
authors.lastname: Grossi
authors.forename: L
authors.initials: L
authors.lastname: Frontini
authors.forename: E
authors.initials: E
authors.lastname: Piazza
authors.forename: P
authors.initials: P
authors.lastname: Bruzzi
authors.forename: R
authors.initials: R
authors.lastname: Labianca
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D003231:Conjunctivitis / Q000139:chemically induced; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D015993:Life Tables; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D010349:Patient Compliance; D011788:Quality of Life; D016879:Salvage Therapy; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D005472:Fluorouracil; D008727:Methotrexate