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.