title: A phase I trial of 5-day chronomodulated infusion of 5-fluorouracil and 1-folinic acid in patients with metastatic colorectal cancer.
abstract: The aim of this phase I study was to establish the maximum tolerated dose (MTD) of 5-fluorouracil (5-FU), administered as a 5-day chronomodulated infusion in combination with 1-folinic acid (FA) to ambulatory metastatic colorectal cancer patients. Consecutive cohorts of 6 patients were given 5-FU and FA infusions from 10.00 p.m. to 10.00 a.m. with peak delivery at 4.00 a.m. by means of a multichannel programmable pump. The FA dose was always the same (150 mg/m2/d). For the first cohort, the 5-FU dose level was 600 mg/m2/d at the first course, escalated by 100 mg/m2 for each subsequent cohort. Intrapatient dose was also escalated by 100 mg/m2 if toxicity was less than grade 2. The courses were repeated every 3 weeks. Thirty-four patients (17 previously treated) received a total of 154 courses. Dose-limiting toxicity consisted of stomatitis and diarrhoea. No significant haematological, cutaneous or cardiac toxicity was encountered. The MTD of 5-FU was reached at the fourth level (first course at 900 mg/m2/d equal to 4500 mg/m2/course) with 5-FU increased to 1100 mg/m2/d (5500 mg/m2/course) in 4 patients. The received 5-FU dose intensity (DI) over the first 3 courses at this level was 1318 mg/m2/week. Thirty-three patients were assessed for response. An objective response was achieved in 1 out of the 13 previously-treated and in 8 out of the 20 previously-untreated patients. The chronomodulated infusion of 5-FU at a dose of 900 mg/m2/d, together with FA at 150 mg/m2/d for 5 days, was safely delivered to out-patients with metastatic colorectal cancer. The low toxic profile and activity of this regimen in previously untreated patients deserves further exploration for the treatment of 5-FU-sensitive tumours.
authors.affiliation: Service of Complementary Medical Oncology, Regina Elena Cancer Institute, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Garufi
authors.forename: F
authors.initials: F
authors.lastname: Lévi
authors.forename: A M
authors.initials: AM
authors.lastname: Aschelter
authors.forename: R
authors.initials: R
authors.lastname: Pace
authors.forename: S
authors.initials: S
authors.lastname: Giunta
authors.forename: C
authors.initials: C
authors.lastname: Nisticò
authors.forename: D A
authors.initials: DA
authors.lastname: Gallà
authors.forename: G F
authors.initials: GF
authors.lastname: Silecchia
authors.forename: F
authors.initials: F
authors.lastname: Franchi
authors.forename: C
authors.initials: C
authors.lastname: Narduzzi
authors.forename: E
authors.initials: E
authors.lastname: Terzoli
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary*; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D005472:Fluorouracil