Phase I Study of S-1 Combined with Irinotecan (CPT-11) in Patients
with Advanced Gastric Cancer (OGSG 0002)
Hiroya Takiuchi1, Hiroyuki Narahara2, Toshimasa Tsujinaka3, Masahiro Gotoh1, Sei-ichiro Kawabe1,
Ken-ichi Katsu1, Hiroyasu Iishi2, Masaharu Tatsuta2, Kazumasa Fujitani3, Hiroshi Furukawa4and
Tetsuo Taguchi5for Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG)
1Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka,2Department of
Gastroenterology, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka,3Department of Surgery,
Osaka National Hospital, Osaka,4Department of Surgery, Sakai Municipal Hospital, Sakai, Osaka and
5Japan Society for Cancer Chemotherapy, Osaka, Japan
Received April 13, 2005; accepted July 26, 2005; published online September 1, 2005
pyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended
dose (RD) and dose-limiting toxicities (DLTs) in advanced gastric cancer.
Methods: S-1 was administered orally at 80 mg/m2/day for 21 consecutive days followed by a
the RD, five patients were added to conduct a pharmacokinetic (PK) study.
the criteria of the Japanese Research Society of Gastric Cancer was 58.3% (14/24) and the RR
at the RD was 66.7% (6/9), suggesting promising clinical efficacy. There were no significant
differences between the PK parameters of S-1 on days 10 and 15.
holds promise as an effective regimen for advanced gastric cancer.
Key words: S-1 – irinotecan – combination chemotherapy – pharmacokinetics
Unresectable advanced or recurrent gastric cancer still has
a poor prognosis and chemotherapy is the only reasonable
therapeutic option for these patients (1–3). Consequently,
many combination regimens based on 5-fluorouracil (5-FU)
have been studied clinically to further improve the objective
response rate (RR) and survival for unresectable advanced
gastric cancer. The additive survival advantage yielded by
these combination therapies appears to be marginal, however,
thus no standard regimen has yet been established (4–8).
Thus, there is a need to develop new agents and combination
regimens to achieve greater survival benefit in unresectable
advanced or recurrent gastric cancer.
The new oral fluoropyrimidine S-1 has been commercially
available for patients with gastric cancer in Japan since 1999.
S-1 consists of tegafur (FT) and two modulators, 5-chloro-2,4-
dihydroxypyridine (CDHP) and potassium oxonate (OXO), at
a molar ratio of 1:0.4:1 (9). CDHP is a reversible competitive
inhibitor of dihydropyrimidine dehydrogenase, which is an
enzyme for 5-FU degradation. Therefore, CDHP with FT is
expected to yield prolonged 5-FU concentration in serum and
tumor tissue. OXO is a reversible competitive inhibitor of
for 5-FU phosphoribosylation in the gastrointestinal mucosa.
It is reported that OXO ameliorates gastrointestinal toxicity of
FT by decreasing 5-fluorodeoxyuridine monophosphate pro-
duction in the gastrointestinal mucosa (10). In two late phase II
clinical studies for advanced gastric cancer in Japan, the RR of
S-1 as a single agent was 44.6% (45/101), with a low incidence
of grade 3 or 4 toxicities (11–12). The median survival time
(MST), 1 year survival rate and 2 year survival rate were
244 days, 37 and 17%, respectively. These results warrant
For reprints and all correspondence: Hiroya Takiuchi, Second Department of
Internal Medicine, Osaka Medical College, 2-7 Daigaku Cho, Takatsuki,
Osaka, 569-8686, Japan. E-mail: firstname.lastname@example.org
Jpn J Clin Oncol 2005;35(9)520–525
#2005 Foundation for Promotion of Cancer Research
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