Phase I study of a combination of s-1 and weekly paclitaxel in patients with advanced or recurrent gastric cancer.
OBJECTIVE
A phase I study of weekly intravenous paclitaxel combined with a fixed dose of S-1, a dihydropyrimidine-dehydrogenase-inhibitory oral fluoropyrimidine, was conducted for patients with advanced or recurrent gastric cancer (ARGC). Endpoints of this study were to examine the toxicity profile OF this regimen and to determine the recommended dose (rd) of paclitaxel.


METHODS
S-1 was fixed at a dose of 80 mg/m(2) per day and was administered for 2 weeks (days 1--14) followed by a 2-week rest. Two dose levels of paclitaxel (level 1: 60 mg/m(2), level 0: 50 mg/m(2)) were studied. Paclitaxel was infused over 1 h on days 1, 8, and 15. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of paclitaxel in some patients. Fifteen patients were enrolled (6 patients in level 1, and 9 patients in level 0). Dose-limiting toxicities were defined as grade 4 hematological (including grade 3 febrile neutropenia) and grade 3 non-hematological (except anorexia, nausea, vomiting and depilation) toxicities.


RESULTS
Three of 6 patients in level 1 developed grade 4 neutropenia or grade 3 febrile neutropenia, and 1 of them also showed grade 3 diarrhea, which settled the maximum-tolerated dose at this level. At level 0, 2 of 9 patients developed grade 4 neutropenia or grade 3 febrile neutropenia, and the RD of paclitaxel for this protocol was set at this level. Pharmacologic studies demonstrated the persistence of significant serum paclitaxel levels over 24 h after drug administration at both levels. Objective responses according to Response Evaluation Criteria in Solid Tumors were observed in 3 of 6 patients who had measurable disease.


CONCLUSIONS
A combination of S-1 and weekly paclitaxel was feasible and well tolerated, and is suggested to produce a worthwhile response in ARGC. These results warrant further investigation, and a phase II study has already been started.
Ueda
Yuji
Y
Department of Surgery, Division of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. yueda@koto.kpu-m.ac.jp
Yamagishi
Hisakazu
H
Ichikawa
Daisuke
D
Morii
Jun
J
Koizumi
Kinya
K
Kakihara
Naoki
N
Shimotsuma
Masataka
M
Takenaka
Atsushi
A
Yamashita
Tetsuro
T
Kurioka
Hideaki
H
Nishiyama
Masahiko
M
Morita
Satoshi
S
Nakamura
Kanae
K
Sakamoto
Junichi
J
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy*; D010094:Oxonic Acid / Q000008:administration & dosage*; D017239:Paclitaxel / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D005641:Tegafur / Q000008:administration & dosage*; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D017239:Paclitaxel