Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors.
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.
van Groeningen
C J
CJ
University Hospital Vrije Universiteit, Netherlands Cancer Institute, and NDDO Oncology, Amsterdam, the Netherlands. dr.vangroeningen@azvu.nl
Peters
G J
GJ
Schornagel
J H
JH
Gall
H
H
Noordhuis
P
P
de Vries
M J
MJ
Turner
S L
SL
Swart
M S
MS
Pinedo
H M
HM
Hanauske
A R
AR
Giaccone
G
G
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*
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid