Extremely prolonged continuous intraperitoneal infusion of cytosine arabinoside

Intraperitoneal administration of ara-C produces a peritoneal/plasma concentration ratio of 330-1,000: In principle, optimal tumor-cell kill should be obtained when high ara-C concentrations ar maintained in the environment of the tumor for very long periods of time. A phase 1 study was undertaken to determine the maximum tolerated dose of ara-C that could be given as a continuous i.p. infusion for 3 weeks. A total of 14 patients with refractory malignancies were given 28 courses in the outpatient setting. Ara-C infusions were given using a portable programmable pump (Pancreatec Provider Model 2000). No significant side effects were observed in patients receiving 30 mg/m2 per day (five courses) or 40 mg/m2 per day x 21 days (seven courses). However, at a dose of 60 mg/m2 per day, although 10/16 courses were tolerated for at least 1 week, only 3/16 attempted courses could be continued for the full 3 weeks. The dose-limiting toxicity was chemical peritonitis, which occurred during 7/16 courses at this dose level and required termination of therapy in 4 courses. Myelosuppression was also observed at this dose. There was a large variation in the ara-C and ara-U peritoneal concentrations both within and between patients. The mean peritoneal ara-C concentration increased nonlinearly with ara-C dose whereas the mean ara-U concentration decreased. This study establishes the feasibility and safety of giving a cell-cycle-specific drug intraperitoneally over an extremely prolonged period. For subsequent studies a dose of 40 mg/m2 per day for 21 days is recommended.