title: A phase I study of bi-weekly combination therapy with S-1 and docetaxel for advanced or recurrent gastric cancer.
abstract: BACKGROUND
  S-1 is a novel oral fluorouracil antitumor drug that contains a combination of 3 pharmacological agents: tegafur (FT), a 5-fluorouracil (5-FU) prodrug, 5-chloro-2,4-dihydroxypyridine (CDHP), which inhibits the activity of dihydropyrimidine dehydrogenase (DPD), and potassium oxonate (Oxo), which reduces the gastrointestinal toxicity of 5-FU. S-1 and docetaxel have both been identified as effective agents for the treatment of gastric cancer. However, little is known about the effects and/or adverse effects of a combination of these drugs in the treatment of gastric cancer. The aim of this phase I study was to determine the maximum-tolerated dose (MTD) and the recommended dose of docetaxel with a fixed dose of S-1 in patients with advanced or recurrent gastric cancer.
  
  
  METHODS
  Patients with metastatic, recurrent, or unresectable gastric cancer received docetaxel at a starting dose of 25 mg/m2 by i.v. infusion over 1 h on days 1, 15 and 29, and S-1 at the full dose of 80 mg/m2 daily for 4 weeks of every 6 weeks. Nine patients were treated with increasing dosages of docetaxel as follows: (docetaxel/S-1, mg/m2): 25/80 (level 1), 30/80 (level 2) and 35/80 (level 3). All cases were assessable for drug safety and 7 were assessable for response. Colony-stimulating factor (CSF) was not used in this study. The adverse effects of treatment were analyzed according to NCI-CTC, version 2 and the response was assessed according to the Japanese Classification of Gastric Cancer, 13th Ed.
  
  
  RESULTS
  The MTD was reached at the 35/80 mg/m2 dose-level in 3 out of 3 patients. These patients experienced some dose-limiting toxicity (DLT) or grade 3 anemia. The reported DLTs included diarrhea, stomatitis and general fatigue. Due to these results, 3 additional patients were not enrolled at this dose-level. No hematological or non-hematological adverse effects (more severe than grade 2) were observed in any of the level 1 or 2 patients. However, among the level 1 patients, 66.7% developed grade 2 leukocytopenia and 33.3% developed grade 2 neutropenia. Among the level 2 patients, 33.3% developed grade 2 appetite loss, diarrhea and general fatigue. Partial responses were achieved in 3 (42.9%) out of the 7 patients with evaluable lesions. These results indicated that the appropriate doses of the 2 drugs in combination therapy are 30 mg/m2 for docetaxel and 80 mg/m2 for S-1.
  
  
  CONCLUSIONS
  The S-1/docetaxel drug combination showed a good safety profile, with diarrhea and general fatigue being common, but manageable, adverse reactions. Moreover, the responses observed in this study suggest that the drug combination shows a high degree of efficacy in patients with advanced and/or recurrent gastric cancer.
authors.affiliation: Department of Surgery, School of Medicine, Yokohama City University, Japan. rino@med.yokohama-cu.ac.jp
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Rino
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takanashi
authors.forename: Norio
authors.initials: N
authors.lastname: Yukawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Saeki
authors.forename: Hiroo
authors.initials: H
authors.lastname: Wada
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kanari
authors.forename: Roppei
authors.initials: R
authors.lastname: Yamada
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Satoh
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Toshio
authors.initials: T
authors.lastname: Imada
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D000077143:Docetaxel; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D010094:Oxonic Acid / Q000008:administration & dosage / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D005641:Tegafur / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D004338:Drug Combinations; D011725:Pyridines; D043823:Taxoids; C079198:S 1 (combination); D005641:Tegafur; D000077143:Docetaxel; D010094:Oxonic Acid