Phase I evaluation of continuous 5-fluorouracil infusion followed by weekly paclitaxel in patients with advanced or recurrent gastric cancer.

Objective: We conducted a phase I trial of escalating doses of weekly paclitaxel (Taxol) in combinationwithafixedsystemicadministrationof5-fluorouracil(5-FU)inpatientswithadvanced or metastatic gastric cancer. Methods: Patients with advanced or recurrent gastric cancer were treated with escalating doses of weekly paclitaxel as a 60 min intravenous (i.v.) infusion, along with a fixed dose of continuous 5-FUinfusedover5days.Plasmasamplingwasperformedtocharacterizethe pharmacokinetics and pharmacodynamics of paclitaxel. Results: Eighteen patients received combination therapy at four dose levels of weekly Taxol, ranging from 60 to 90 mg/m 2 /week. Dose-limiting toxicities >grade 3 were observed at the 90 mg/m 2 /week dose level. Toxicities included anemia, neutropenia, thrombocytopenia, nausea andalopecia.Twoepisodesofgrade4neutropeniaoccurredintwoofthethreepatientsreceiving this dose. At each dose level, pharmacological studies documented the persistence of significant serum paclitaxel levels over 24 h after drug administration. The maximum tolerated dose (MTD) for this regimen was 90 mg/m 2 /week of paclitaxel for 3 weeks plus 600 mg/m 2 /day of continuous 5-FU for 5 days. Conclusions: The combination of weekly paclitaxel and 5-FU demonstrated an acceptable toxicity profile and feasible pharmacokinetic results suggesting its practical applicability. Based onthesefindings,therecommendeddoseandscheduleforphaseIIstudyofcombinationchemotherapy is paclitaxel 80 mg/m 2 /week · 3 over 4 weeks, and continuous 5-FU 600 mg/m 2 /day · 5 days every 4 weeks.