Determining the maximum tolerated frequency (MTF) of intraperitoneal fluorouracil/folinic acid (FU/FA) administered with adjuvant intravenous FU/FA in patients with colorectal and upper GI tumours

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Abstract
3668 Background: Intraperitoneal (IP) FU/FA may confer a survival advantage when added to IV adjuvant therapy in patients (pts) with colorectal cancer (Br J Cancer 77:1349, 1998). The aims of this study were to determine the MTF and pharmacokinetics (PK) of IP FU/FA when added to weekly IV FU/FA. Methods: Pts were recruited after complete resection of GI cancers where there was peritoneal involvement, after which a peritoneal port was implanted for IP treatment and PK sampling. Pts received IV FU/FA (400/20 mg/m2) weekly for 24 wks. IP FU/FA, (400/20 mg/m2) in 1500ml of 4% icodextrin, was given with increasing frequency from 4-weekly to weekly in successive cohorts, with weekly monitoring of toxicity. IP and plasma FU PK was investigated in 11 pts. Results: 57 pts were registered, of whom 53 had ports inserted. 44 (37 colorectal, 7 other) pts received 1 or more IP treatments (299 in total), but 3 withdrew early due to port failure, leaving 41 evaluable for MTF. IP FU/FA was tolerable with 4, 3 or 2-weekly IP dosing, but not with weekly dosing, with 11/13, 7/8, 10/13 and 0/7 pts respectively completing treatment without IP dose modifications. Good fluid distribution was observed by ultrasound in 41/42 pts at baseline, and in 26/27 pts after 5–13 (median 8) IP treatments. FU AUC in IP fluid was 1148 ± 567 μg/ml.hr, compared to 1.12 ± 0.61 μg/ml.hr in plasma after IP treatment alone, giving an IP/plasma ratio of >1000. Following IV and IP treatment plasma FU AUC was 11.5 ± 2.4 μg/ml.hr, with an IP/plasma ratio of 100. Systemic FU bioavailability after IP FU was 11.1 ± 6.6%. 3½ years after the end of accrual, 41% of pts have relapsed. Peritoneal relapse has occurred in 3/24 (12.5%) pts who received ≥ 7 IP doses, and in 7/20 (35%) who received ≤ 6 (χ2 p=0.06). Conclusions: The addition of IP FU/FA every 2 weeks to a standard IV regimen is safe, tolerable and practical and results in a 100-fold higher local exposure to FU than is achieved with standard IV therapy. A more reliable peritoneal administration system would improve the feasibility of this promising therapeutic approach.

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