title: Biochemical modulation of 5-fluorouracil with methotrexate in advanced colorectal cancer patients pretreated with adjuvant 5-fluorouracil and leucovorin.
abstract: OBJECTIVE
  5-fluoracil (5-FU) remains the standard treatment in advanced colorectal cancer patients. An increasing number of recurring patients, however, have already received this drug as adjuvant after surgery. An attempt to increase 5-FU cytotoxicity through biochemical modulation is justified in this setting. In our study, a combination regimen of methotrexate followed by 5-FU, with leucovorin rescue, was employed.
  
  
  METHODS
  Patients were required to have symptomatic, measurable, inoperable lesions from colorectal cancer, recurring after adequate radical surgery of the primary tumor and adjuvant 5-FU + leucovorin concluded at least 3 months before recurrence. Patients received methotrexate. 250 mg/m2 as a 2-hour i.v. infusion, followed by two doses of 5-FU, 500 mg/m2 as i.v. bolus 1 hour and 21 hours after the end of methotrexate infusion. Leucovorin rescue, 15 mg orally every six hours for 7 times, was started 1 hour after the second 5-FU dose. The cycle was repeated every 2 weeks.
  
  
  RESULTS
  Twenty-two patients entered the trial, and 21 were evaluable. An objective response was observed in one patient (4.8%), 7 patients (33.3%) obtained tumor regression < 50% or disease stabilization. Thirteen patients (61.9%) progressed. Median survival in the whole group was 11 months. Subjective responses were observed in 7 patients (33.3%). Toxicity was mild.
  
  
  CONCLUSIONS
  Biochemical modulation with methotrexate does not seem a satisfactory means of increasing 5-FU activity, when the patient has been previously exposed to 5-FU plus leucovorin. On the other hand, any possible advantages in terms of quality and prolongation of life with this schedule were obtained at the cost of very acceptable toxicity.
authors.affiliation: U.O. Oncologia Medica, Ospedale S. Andrea, La Spezia, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Pronzato
authors.forename: F
authors.initials: F
authors.lastname: Vaira
authors.forename: A
authors.initials: A
authors.lastname: Vigani
authors.forename: P
authors.initials: P
authors.lastname: Losardo
authors.forename: G
authors.initials: G
authors.lastname: Bertelli
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D010166:Palliative Care; D016019:Survival Analysis; D017211:Treatment Failure
chemical_list: D002955:Leucovorin; D005472:Fluorouracil; D008727:Methotrexate