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 combination with a fixed systemic administration of 5-fluorouracil (5-FU) in patients with advanced 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-FU infused over 5 days. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of paclitaxel.


RESULTS
Eighteen patients received combination therapy at four dose levels of weekly Taxol, ranging from 60 to 90 mg/m2/week. Dose-limiting toxicities > grade 3 were observed at the 90 mg/m2/week dose level. Toxicities included anemia, neutropenia, thrombocytopenia, nausea and alopecia. Two episodes of grade 4 neutropenia occurred in two of the three patients receiving 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/m2/week of paclitaxel for 3 weeks plus 600 mg/m2/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 on these findings, the recommended dose and schedule for phase II study of combination chemotherapy is paclitaxel 80 mg/m2/week x 3 over 4 weeks, and continuous 5-FU 600 mg/m2/day x 5 days every 4 weeks.
Kondo
Ken
K
Department of Surgery, Nagoya National Hospital, 1-1, San-nomaru 4-chome, Naka-ku, Nagoya 460-0001, Japan. kkondnnh@ce.mbn.or.jp
Kobayashi
Michiya
M
Kojima
Hiroshi
H
Hirabayashi
Naoki
N
Kataoka
Masato
M
Araki
Kyoujiro
K
Matsui
Takanori
T
Takiyama
Wataru
W
Miyashita
Yumi
Y
Nakazato
Hiroaki
H
Nakao
Akimasa
A
Sakamoto
Junichi
J
D000328:Adult; D000368:Aged; D000505:Alopecia / Q000139:chemically induced; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D015996:Survival Rate
D017239:Paclitaxel; D005472:Fluorouracil