title: Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors.
abstract: OBJECTIVE
  To investigate the side effects, determine the maximum-tolerated dose (MTD), and study the pharmacokinetics of S-1, an oral fluoropyrimidine-based antineoplastic agent consisting of the fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate.
  
  
  METHODS
  Patients with advanced solid tumors received S-1 bid for 28 days, followed by 1 week of rest. 5-FU pharmacokinetics were investigated after a single initial dose of S-1 during the first 24 hours and weekly thereafter.
  
  
  RESULTS
  Twenty-eight patients received S-1 at the four consecutive dose levels of 25, 45, 35, and 40 mg/m(2). The MTD was initially found at 45 mg/m(2), with diarrhea as the dose-limiting toxicity (DLT). Diarrhea was also the DLT at the dose of 40 mg/m(2), which was the MTD for patients exposed to extensive prior chemotherapy. Other toxicities were generally mild. Two patients had a reduction of more than 50% in tumor dimension. Plasma pharmacokinetics of 5-FU were linear; at the highest S-1 dose level, 5-FU plasma peak concentrations reached 1 to 2 micromol/L, and the half-life of 5-FU was 3 to 4 hours. A statistically significant relationship was observed between the severity of diarrhea and pharmacokinetic parameters of 5-FU.
  
  
  CONCLUSIONS
  The recommended dose of S-1 in chemotherapy-naive or minimally chemotherapy-exposed patients is 40 mg/m(2) bid on 28 consecutive days, every 5 weeks. In heavily pretreated patients, the recommended dose is 35 mg/m(2) bid. Phase II trials are warranted in tumors known to be responsive to 5-FU treatment.
authors.affiliation: University Hospital Vrije Universiteit, Netherlands Cancer Institute, and NDDO Oncology, Amsterdam, the Netherlands. dr.vangroeningen@azvu.nl
authors.forename: C J
authors.initials: CJ
authors.lastname: van Groeningen
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
authors.forename: J H
authors.initials: JH
authors.lastname: Schornagel
authors.forename: H
authors.initials: H
authors.lastname: Gall
authors.forename: P
authors.initials: P
authors.lastname: Noordhuis
authors.forename: M J
authors.initials: MJ
authors.lastname: de Vries
authors.forename: S L
authors.initials: SL
authors.lastname: Turner
authors.forename: M S
authors.initials: MS
authors.lastname: Swart
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: A R
authors.initials: AR
authors.lastname: Hanauske
authors.forename: G
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010094:Oxonic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005641:Tegafur / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid