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

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. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ML Laboratories PLC