title: Schedule-selective biochemical modulation of 5-fluorouracil: a phase II study in advanced colorectal cancer.
abstract: Based on experimental findings suggesting that 5-fluorouracil (FUra) may have different mechanisms of action depending on the schedule of administration, we generated the hypothesis that biochemical modulation of this fluoropyrimidine should be schedule specific. We thus tested the activity of a hybrid regimen consisting of two biweekly cycles of FUra bolus (600 mg/m2) modulated by pretreatment (24-h interval) with methotrexate (200 mg/m2), alternating with a 3-week continuous infusion of FUra (200 mg/m2/day) modulated by low-dose (6S)leucovorin (20 mg/m2 bolus weekly). Thirty-three consecutive patients with advanced measurable colorectal cancer and no prior therapy for metastatic disease entered the study from February 1992 to August 1993. They were treated with two biweekly cycles of FUra bolus (600 mg/m2) preceded by (24-h interval) methotrexate (200 mg/m2), alternating with a 3-week continuous infusion of FUra (200 mg/m2/day) modulated by low-dose (6S)leucovorin (20 mg/m2 bolus weekly). The median Eastern Cooperative Oncology Group performance status was 1; the liver was the only metastatic site in 17 patients. Treatment outcome was evaluated by computed tomographic scan in all patients, except for two. Three complete and 13 partial responses were obtained among these 33 patients (response rate, 48%; 95% confidence limits, 31-66%). Performance status (Eastern Cooperative Oncology Group) influenced clinical response. The combined complete response and partial response rate was 69%, 33%, and 25% in patients with an Eastern Cooperative Oncology Group performance status of 0, 1, and 2, respectively (chi2, 4.6, P = 0.032, two-tailed Mantel test for trend). After a median follow-up time of 26 months, 10 patients are still alive. The median progression-free survival and overall survival were 9.5 and 20.2 months, respectively. No toxic deaths or grade 4 toxicity occurred. The incidence of grade 3 toxicity per patient in any cycle was: mucositis 6%, diarrhea 3%, and vomiting 3% for the bolus part and 21%, 3%, and 6%, respectively, for the continuous infusion part of the regimen. Hand-foot syndrome occurred in 27% of the patients treated with the continuous infusion regimen.
authors.affiliation: Medical Oncology, Surgical Oncology, and Epidemiology Departments, Istituto Nazionale per la Ricerca sul Cancro, University of Genoa, Viale Benedetto XV, 10 16132 Genova, Italy.
authors.forename: A F
authors.initials: AF
authors.lastname: Sobrero
authors.forename: C
authors.initials: C
authors.lastname: Aschele
authors.forename: A P
authors.initials: AP
authors.lastname: Guglielmi
authors.forename: A M
authors.initials: AM
authors.lastname: Mori
authors.forename: L M
authors.initials: LM
authors.lastname: Tixi
authors.forename: E A
authors.initials: EA
authors.lastname: Bolli
authors.forename: R
authors.initials: R
authors.lastname: Rosso
authors.forename: S
authors.initials: S
authors.lastname: Mammoliti
authors.forename: G A
authors.initials: GA
authors.lastname: Rollandi
authors.forename: S
authors.initials: S
authors.lastname: Bertoglio
mesh_terms: D000328:Adult; D000368:Aged; D000931:Antidotes / Q000008:administration & dosage / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D008875:Middle Aged; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000931:Antidotes; D002955:Leucovorin; D005472:Fluorouracil; D008727:Methotrexate