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.
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.
Focan
C
C
Les Cliniques Saint-Joseph, Liege, Belgium. christian.focan@skynet.be
Levi
F
F
Kreutz
F
F
Focan-Henrard
D
D
Lobelle
J P
JP
Adam
R
R
Dallemagne
B
B
Jehaes
C
C
Markiewicz
S
S
Weerts
J
J
Bismuth
H
H
Jasmin
C
C
Misset
J L
JL
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
D005467:Floxuridine; D005472:Fluorouracil