title: Continuous delivery of venous 5-fluorouracil and arterial 5-fluorodeoxyuridine for hepatic metastases from colorectal cancer: feasibility and tolerance in a randomized phase II trial comparing flat versus chronomodulated infusion.
abstract: High-dose chemotherapy combining regional hepatic artery infusion (HAI) of fluorodeoxyuridine (HAI FUDR) and systemic venous infusion of 5-fluorouracil (i.v. 5-FU) was delivered against liver metastases from colorectal cancer. The hypothesis that chronomodulation of delivery rate along the 24 h time scale would improve the tolerable doses of both drugs was tested. Combined HAI FUDR (80 mg/m2/day) and i.v. 5-FU (1200 mg/m2/day) were administered for five consecutive days every 3 weeks, either as a constant rate infusion (schedule A, 27 patients) or as chronotherapy (schedule B, 29 patients). This latter regimen consisted of a sinusoidal modulation of the delivery rate over the 24 h scale with a maximum at 16:00 for FUDR and 4:00 for 5-FU. Intrapatient dose escalation up to the individual maximum tolerated doses (MTD) was planned for both drugs in the absence of any previous grade 3 or 4 toxicity. All patients had metastatic colorectal cancer, with adjuvant or palliative chemotherapy given to six patients (22%) on schedule A and 12 patients on schedule B (41%). Severe stomatitis occurred in 71% of the patients and was dose limiting. No hepatic toxicity was encountered. Dose reductions of 5-FU and/or FUDR were required for 17 of 27 patients on schedule A (63%) as compared to 11 of 29 patients on schedule B (38%), following reaching the individual MTD (p<0.05). Over the first six cycles, patients on schedule B received higher doses (mg/m2/cycle; FUDR: 522 +/- 85 versus 499 +/- 50, p=0.004 and 5-FU: 5393 +/- 962 versus 5136 +/- 963, p=0.009) and higher dose intensities (mg/m2/week; FUDR: 164 +/- 46 versus 151 +/- 52, p=0.018 and 5-FU: 1652 +/- 478 versus 1553 +/- 535, p<0.041) of both drugs than patients on schedule A. As a result the number of courses with doses of 5-FU above 1200 mg/m2/day and/or FUDR above 110 mg/m2/day was larger in group B than in group A (5-FU, A: 67 of 268, 25% versus B: 133 of 321, 41% and FUDR, A: 86 of 268, 32% versus B: 155 of 321, 48%; p<0.001). Objective responses were observed in 13 patients on schedule A (48%) and 11 patients on schedule B (38%). The results support the need for further exploration of chronotherapy of colorectal cancer liver metastases with combined arterial and venous fluoropyrimidine chemotherapy.
authors.affiliation: Les Cliniques Saint-Joseph, Liege, Belgium. christian.focan@skynet.be
authors.forename: C
authors.initials: C
authors.lastname: Focan
authors.forename: F
authors.initials: F
authors.lastname: Levi
authors.forename: F
authors.initials: F
authors.lastname: Kreutz
authors.forename: D
authors.initials: D
authors.lastname: Focan-Henrard
authors.forename: J P
authors.initials: JP
authors.lastname: Lobelle
authors.forename: R
authors.initials: R
authors.lastname: Adam
authors.forename: B
authors.initials: B
authors.lastname: Dallemagne
authors.forename: C
authors.initials: C
authors.lastname: Jehaes
authors.forename: S
authors.initials: S
authors.lastname: Markiewicz
authors.forename: J
authors.initials: J
authors.lastname: Weerts
authors.forename: H
authors.initials: H
authors.lastname: Bismuth
authors.forename: C
authors.initials: C
authors.lastname: Jasmin
authors.forename: J L
authors.initials: JL
authors.lastname: Misset
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001683:Biological Clocks; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004334:Drug Administration Schedule; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage* / Q000009:adverse effects; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D012004:Rectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D013280:Stomatitis / Q000139:chemically induced
chemical_list: D005467:Floxuridine; D005472:Fluorouracil