Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors

Cees J. van Groeningen, Godefridus J. Peters, Jan H. Schornagel, Helen Gall, Paul Noordhuis, Martin J. de Vries, Sue L. Turner, Martha S. Swart, Herbert M. Pinedo, Axel R. Hanauske, Giuseppe Giaccone

Research output: Contribution to journalArticlepeer-review

136 Scopus citations


Purpose: To investigate the side effects, determine the maximum-tolerated dose (MTD), and study the pharmacokinetics of S-1, an oral flouropyrimidine-based antineoplastic agent consisting of the fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2,4-dihydroxypryridine and potassium oxanate. Patients and 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/m2. The MTD was initially found at 45 mg/m2, with diarrhea as the dose- limiting toxicity (DLT). Diarrhea was also the DL at the dose of 40 mg/m2, 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 dimensional. Plasma pharmacokinetics of 5-FU were linear; at the highest S-1 dose level, 5-FU plasma peak concentrations reached 1 to 2 μmol/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. Conclusion: The recommended dose of 5-1 in chemotherapy-naive or minimally chemotherapy-exposed patients is 40 mg/m2 bid on 28 consecutive days, every 5 weeks. In heavily pretreated patients, the recommended dose is 35 mg/m2 bid. Phase II trials are warranted in tumors known to be responsive to 5-FU treatment. (C) 2000 by American Society of Clinical Oncology.

Original languageEnglish (US)
Pages (from-to)2772-2779
Number of pages8
JournalJournal of Clinical Oncology
Issue number14
StatePublished - Jul 2000
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


Dive into the research topics of 'Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors'. Together they form a unique fingerprint.

Cite this