Constant intraperitoneal 5-fluorouracil infusion through a totally implanted system

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Abstract
Five-day continuous i.p. infusions of 5-fluorouracil (FU) were injected into 5 patients as part of a phase I clinical study. They received 20 courses through a totally implanted catheter/injection port system. In each course a 2-3 log FU concentration differential in favor of the peritoneal cavity was achieved and maintained. Steady-state venous plasma FU concentrations averaged 0.34 .mu.M, whereas steady-state i.p. FU concentrations averaged 697 .mu.M. Mean total body clearance (TBC) in these patients was 18.4 l/min and mean permeability-area (PA) product for diffusion from the peritoneum was 13.7 ml/min. Mean TBC of 20 l/min with i.p. FU infusion was observed in 1 patient who also received a 24-h i.v. FU infusion for comparison. The TBC during the later infusion was 5.9 l/min. In this patient, calculations indicate 75% extraction of drug during the passage from the peritoneum to the systemic circulation, presumably representing in large part hepatic extraction of FU taken into the portal venous circulation. I.p. constant infusion and bolus kinetics were compared in 1 patient. TBC for the i.p. bolus was 14.3 l/min, which was .apprx. 1/2 of the TBC of 29.5 l/min determined during the 5-day constant i.p. infusion. Constant i.p. infusion of FU (1 gm/day) can provide an improved regional advantage over bolus i.p. FU because of an increased TBC. Toxicity was acceptable in all courses. Dose limiting toxicity was regional, namely moderate chemical peritonitis seen in 2 patients on repeated courses. The only patient with measurable disease had an objective response in hepatic metastases from gastric cancer. The implanted device was well tolerated and facilitated peritoneal fluid sampling.