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.
Kirmani
S
S
Department of Medicine, University of California, San Diego, La Jolla 92092.
Zimm
S
S
Cleary
S M
SM
Mowry
J
J
Howell
S B
SB
D000328:Adult; D000368:Aged; D001086:Arabinofuranosyluracil / Q000493:pharmacokinetics; D001202:Ascitic Fluid / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003561:Cytarabine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D015918:Infusion Pumps, Implantable; D007263:Infusions, Parenteral / Q000379:methods; D007970:Leukopenia / Q000139:chemically induced; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D013997:Time Factors
D003561:Cytarabine; D001086:Arabinofuranosyluracil