Cancer Therapy Vol 4, 135-142, 2006
The usefulness of oral TS-1 treatment for potentially
curable gastric cancer patients with intraperitoneal free cancer cells
Research Article
Yutaka Yonemura1,*, Yoshio Endou2, Etsurou
Bando1, Taiichi Kawamura1, Gorou Tsukiyama1,
Shouji Takahashi1, Naoko Sakamoto5, Kiyoshi Tone6,
Kimihide Kusafuka6, Ichirou Itoh6, Masashi Kimura7,
Masakazu Fukushima3, Takuma Sasaki4, Narikazu Boku8
1Peritoneal Dissemination Program, Shizuoka Cancer
Center, Shizuoka, Japan
2Department of Experimental Therapeutics, Cancer
Research Institute, Kanazawa University, Kanazawa, Japan
3Cancer Research Laboratory and Institute for
Pathogenic Biochemistry in Medicine, Taiho Pharmaceutical Co., Ltd, Japan
4Deaprtment of Pharmacology, Aichi-Gakuin University,
Aichi, Japan
5Department of Surgery, Self Defence Force Fuji
Hospital, Shizuoka, Japan
6Department of Pathology, Shizuoka Cancer Center,
Shizuoka, Japan
7Department
of Pharmacology, Shizuoka Cancer Center, Shizuoka, Japan
8Department of Medical Oncology, Shizuoka Cancer
Center, Shizuoka, Japan
__________________________________________________________________________________
*Correspondence: Dr. Yutaka
Yonemura, Peritoneal Dissemination Program, 1007 Shimo-nagakubo,
Nagaizumi-machi, Suntou-gun, Shizuoka, 411-8777, Japan; Phone: 81-55-989-5235;
Fax: 81-55-989-5634; E-mail: y.yonemura@scchr.jp
Key words: Gastric
cancer, peritoneal dissemination, TS-1, S-1, lavage cytology
Abbreviations:
5-chloro-2, 4-dihydroxypyridine, (CDHP); 5-fluorouracil, (5-FU); area under the
curve, (AUC); orotate phosphoribosytransferase, (ORPT); oxonate, (Oxo); platinum,
(Pt)
Received: 16 January 2006; Revised: 24 January 2006
Accepted: 30 January 2006; electronically published: March
2006
Summary
Prognosis of
patients with positive peritoneal wash cytology (Cy1) but no macroscopic
peritoneal dissemination (P0) is very poor. We assessed the effects of TS-1, a
novel oral derivatives of 5-fluorouracil, as a postoperative chemotherapy for
these patients. Positive cytology by peritoneal washing was found in 101
potentially curable gastric cancer patients with peritoneal free cancer cells
(P0/Cy1 status). After radical gastrectomy, 35 patients were treated with oral
TS-1 (80mg/m2) for 28 consecutive days and 14 day rest, and the
schedule was repeated every 6 weeks (TS-1 group). The other 66 patients did not
receive any chemotherapy (Control group). A total of 220 courses were
administered with a median of 7 courses and the range from 2 to 25 courses. The
patients of TS-1 group survived significantly longer than that of Control group
(P<0.0001). Two year survival rates of Control group and TS-1 group were 9%
and 53%, respectively. Recurrence was not found in 15 (43%) for TS-1 group and
3 (5%) for Control group. Peritoneal recurrences of TS-1 treatment and Control
group were found in 11 (31%) and 34 (52%) patients (P<0.05). Cox
proportional hazard model showed TS-1 treatment as an independent prognostic
factor, and the relative risk by TS-1 treatment was 0.17-fold lower than that
of Control group. Major adverse reactions included myelosuppression and
gastrointestinal toxicities, but they were generally mild and no
treatment-related deaths. TS-1 treatment is safe and effective as a
postoperative chemothrapy for patients with P0/Cy1 status.
I. Introduction
Prognosis of patients with advanced gastric cancer is
still poor, because many patients with T3 and T4 tumor died of peritoneal
dissemination even after curative resection (Chu et al, 1989). More than 30% of
potentially curable gastric cancer patients show positive lavaged cytology by
peritoneal washing (Band et al, 1999), and almost all the patients died of
peritoneal recurrence (Band et al, 1999). Accordingly, the patients are grouped
as P0/Cy1 in the Japanese rules of gastric cancer (Japanese Research Society
for Gastric Cancer, 2004). P0 means no macroscopic peritoneal dissemination and
Cy1 is the status showing positive cytology by the peritoneal washing which is
recommended to be done just after laparotomy (Japanese Research Society for
Gastric Cancer, 2004). Because the prognosis of the patients with P0/Cy1 status
is very poor as that of patients with established peritoneal dissemination,
these patients are classified as staged 4 (Japanese Research Society for
Gastric Cancer, 1995). However, no standard treatment for the
patients with P0/Cy1 status is proposed in the guidelines (Japanese Research
Society for Gastric Cancer, 2004).
Intravenous 5FU infusion (Cullinan
et al, 1985) or in combination with other anticancer drugs, FAM
(MacDonald et al, 1980), FAMTX (Wils et al, 1991) have been used for chemotherapy of advanced gastric
cancer. However, there has been no report to study the efficacy of systemic
chemotherapy on patients with P0Cy1 status (MacDonald et al, 1980; Cullinan
et al, 1985;
Wils et al, 1991).
TS-1 is a new oral fluorinated pyrimidine agent, which
contains tegaful, 5-chloro-2, 4-dihydroxypyridine (CDHP) and potassium oxonate
(Oxo) in a molar ratio of 1:0.4:1 (Shirasaka et al, 1996). Dihydropyridine dehydrogenase DPD, which are found
in a high concentration in the liver, rapidly degrade 5-fluorouracil (5-FU).
CDHP is a specific inhibitor of DPD and the inhibition of the 5-FU by CDHP is
very important for the efficacy of 5-FU. In the experimental model, high and
constant 5-FU concentrations were maintained by continuous infusion of 5FU in
combination with CDHP (Tatsumi et al, 1987). However, in the model, diarrhea
due to 5FU is a severe dose-limiting factor.
Oxo is an inhibitor of orotate
phosphoribosytransferase (ORPT) and acts as a protector against 5-FU-induced GI
toxicity without loss of antitumor activity (Shirasaka
et al, 1996). Accordingly, TS-1 might be more effective in the
treatment of cancer patients than continuous infusion of 5-FU from the point of
anti-tumor potency and toxicity.
Because prolonged exposure is desirable from the view
of anti-tumor mechanisms of 5-FU, oral administration of TS-1 is certainly the
most appealing rout of administration, as compared with intravenous infusion of
5-FU (Van Groeningen et al, 2000). Hirata et al reported that plasma
concentrations of 5-FU for 4-week consecutive administration of TS-1 maintained
the concentrations enough to kill cancer cells during the treatment period
(Hirata et al, 1999).
In the present study, the
effect of oral TS-1 was studied on the survival of patients diagnosed as
P0/Cy1.
II.
Materials and methods
A. Patients
During the last 5 years from
September, 26, 2000 to December, 23, 2005, 1039 patients with gastric cancer
underwent curative resection at Shizuoka Cancer Center and Kanazawa university
hospital. Just after laparotomy, peritoneal cavity was inspected and palpated
and the findings of the status of T-grade, N-grade, peritoneal dissemination
and liver metastasis were recorded. Then, 200 ml of physiological saline was
injected into the peritoneal cavity, and peritoneal washings were collected
from the left subdiaphragmatic space and DouglasÕ pouch and heparin was used as
an anticoagulant. The fluid was centrifuged 5 min at 1500 rpm, and the
cytospins were obtained with Auto Smea CF-12D (Sakura Seiki Co., Ltd., Tokyo
Japan). Five slides per on person were prepared and two and one were stained
with Papanicolau method and Alcian Blue staining. The other two were fixed 10
minutes in cold absolute acetone for immunocytochemistry.
The monoclonal antibodies
used in the study were anti-human carcinoembryonic antigen (TAKARA Bio INC.,
Tokyo, Japan) and anti-human epithelial antigen (DAKO, Copenhagen, Denmark).
Immunocytochemical staining of cytospins was performed by means of a sensitive
streptoavidin, biotin immunohistoperoxidase method (LSAB KIT, DAKO). The enzyme
activity was developed using 3-amino 9-ethyl carbazole as chromogen substrate.
The immunocytochemical
findings were evaluated independently by two investigators with no knowledge of
the cytopathologic diagnosis. Peritoneal washings were considered as positive
when at least one of the five slides showed cells compatible with cancer cells
(Benevolo et al, 1998).
Among 1039 potentially
curable patients, 114 patients showed positive cytology. The incidences of
positive cytology in T1, T2, T3, and T4 tumors were 0.2 % (1/411), 8.3%
(34/409), 38.9% (70/180) and 23.1% (9/35), respectively. The 114 patients
underwent subtotal or total gastrectomy with D1+a or D2 dissection.
Thirty-five patients (TS-1 group) were received oral TS-1 treatment after
gastrectomy and the 66 patients were not treated with any chemotherapy (Control
group). The other 13 patients were treated with systemic chemotherapy except
TS-1 therapy. All the patients were
received informed consent about the regimens, which are considered to be
effective for gastric cancer from the medical oncologists. The medical
oncologists explained the results of clinical trials of the regimens, schedule,
effective rates and the precise adverse effects after chemotherapy. The
selection of the regimen was made by the patients.
Eligibility for TS-1
treatment required adequate organ functions: hemoglobin >=9.0 gr/dl, WBC
>=4000-12000; platelets>= 100000/ml, AST and ALT <=100 IU/ml, serum
alkaline phosphatase within twice the normal upper limit, bilirubin
<=1.5mg/dl; creatinine within upper normal limit; and informed consent from
the patients.
Among
13 patients who
were treated
with systemic chemotherapy except TS-1 therapy,
.MTX/5-FU
therapy was done in 6 patients, and the other patients selected the CPT-11/MMC
in two, TS-1/CDDP in two, CPT-11/CDDP in two, and 5FU/Taxol in one.
B. Drugs
The patients were assigned on
the basis of body surface area to receive one of the following doses twice a
daily, after breakfast and dinner.: body surface area < 1.25 m2,
40 mg; < 1.5 m2, 50 mg; >=1.5 m2, 60 mg. TS-1
(Taiho Pharmacoceutical Co., Ltd., Tokyo, Japan) was administered at the
respective dose for 28 days, followed by a 2-week rest. This schedule was
repeated every 6 weeks until the occurrence of recurrence, unacceptable
toxicities or patientsÕ refusal. Compliance was assessed by patient interviews
with each investigator, with a schedule calendar with regular monitoring.
C. Statistical analyses
Survival was calculated by
the method of Kaplan-Meier, and Cox proportional hazard model was used for the
multivariate analyses using SPSS software (SPSS¨ Version
10.1,
Chicago, Illinois, USA). Results are presented as the mean plus or minus the standard
deviation of the mean. The chi-squared test and StudentÕs-t test were used to analyze data. Differences associated with a P value
of 0.05 or less were considered to be statistically significant.
III. Results
Clinicopathologic factors of the two groups were shown
in Table 1. There was no statistical
difference in macroscopic type, wall invasion, lymph node metastasis and
histologic type between Control and TS-1 group (Table 1).
Operation
methods of both groups were listed in Table
2. D2 dissection was done in 55 (83%) and 25 (71%) of Control and TS-1
group, respectively. Combined resection of spleen was performed in 7 (11%), and
6 (17%) of Control and TS-1 group.
TS-1 was administered during day 25 and day 56 after
operation. TS-1 administration was started from 4, 6 and 8 weeks after
operation in 22 (63%), 9 (26%) and 4 (11%) patients. A total of 220 courses
were administered to the 35 patients in TS-1 Group with a median of 7 courses and
the range from 2 to 25 courses. All the 35 patients received TS-1 as
outpatients, but three patients were treated as inpatients due to interstitial
pneumonia, and severe general malaise. Two patients required dose reduction
from 120mg/day to 100mg/day, and from 100mg/day to 80mg/day due to adverse
reactions.
Survival curves of the two groups were shown in Figure 1. The patients of TS-1 group
survived significantly longer than that of Control group (P<0.0001). Two
year survival rates of Control group and TS-1 group were 9% and 53%,
respectively. The mean days between operation and recurrence were 372 (±63)
days for TS-1 group, but was 220 (±221) days for Control group (P<0.05).
Recurrence was not found in 15 (43%) for TS-1 group and 3 (5%) for Control
group. Recurrence sites after TS-1 treatment were 11, 5, 2 and 1 in the
peritoneum, lymph nodes, bone and liver, respectively. In Control group, 34,
10, 8 and 5 patients had recurrences in peritoneum, lymph nodes, liver and
bone.
In
contrast, lymph node metastasis or local recurrence might be prevented by
extended gastrectomy. Accordingly, peritoneal recurrence must be more important
prognostic factor than T or N grade in patients with P0/Cy1 status. TS-1 may
inhibit the growth of peritoneal
dissemination.
Many good clinical responses in patients with advanced
gastric cancer by TS-1 therapy have been reported (Sakata et al, 1998; Abe et al,
2003). However, the outcome was markedly poorer in the patients with
established peritoneal dissemination than in those with lymph node or liver
metastasis (Abe et al, 2003). One of the reasons why the peritoneal
dissemination resists against systemic administration of anticancer drugs is
the poor penetration of drugs into the peritoneal cavity. Accordingly, only a
small amount of drugs reaches the peritoneal cavity after intravenous
administration, because drug distribution is limited due to the peritoneal
blood barrier (Sugarbaker et al, 1993; Jacquet and Sugarbaker, 1996). In
contrast, IP
chemotherapy offers potential therapeutic advantages over systemic chemotherapy
by generating high IP concentrations of
drugs (Los et al, 1989; Markman, 1991). Los et al, reported that the area under the curve
(AUC) for bound and free platinum (Pt) in the peritoneal cavity after IP
treatment of cisplatinum is 6 times higher than the AUCs in the peritoneal
cavity after IV treatment in rats (Los et al, 1989; Markman, 1991). However,
the problem of IP chemotherapy is the rapid clearance of drugs from the
peritoneal cavity, and the intermittent administration of drugs does not allow
the exposure of anti-cancer drugs to the peritoneal cancer tissue for a long
period.
In addition, even distribution of anti-cancer drugs in
the peritoneal cavity can not be obtained due to adhesion after gastrectomy.
So far, there was no report to confirm the efficacy of
anti-cancer drugs for the prevention of peritoneal recurrence in the patients
with peritoneal free cancer cells. Yamagata et al reported the effects of TS-1
on patients with peritoneal dissemination from gastric cancer, but the number
of patients is only 7 (Yamagata et al, 2004). The present study clearly showed
the effect of TS-1 on the survival improvement of patients with P0/Cy1 status.
In the experimental peritoneal dissemination models,
5-FU concentrations in ascites after oral administration of TS-1 were
significant high levels of around 300-500 ng/ml at 1-6 hours (Mori et al, 2003;
Yonemura et al, 2005). In contrast, 5-FU levels in ascites after oral
administration of 5-FU was almost nil (Mori et al, 2003; Yamagata et al, 2004).
TS-1 contains CDHP, which exhibits a very high activity in inhibiting DPD. DPD
in a high concentration in the peritoneal mononuclear cells, degrades 5-FU, but
CDHP concentration in ascites showed high level from 30 min. after oral
administration of TS-1 (Yonemura et al, 2005). As a result, CDHP inhibit the
rapid degradation of 5-FU by DPD in the ascites. Accordingly, high and constant
5-FU concentrations were maintained in the ascites (Mori et al, 2003; Yonemura et
al, 2005). Furthermore, Mori et al reported in 2003 that 5-FU concentrations in
the experimental peritoneal dissemination were significantly higher than in the
levels of ascites 1 hour after oral TS-1 administration, and maintained at
significant high levels even after 8 hours (Mori et al, 2003).
Hirata et al reported the plasma concentrations of
5-FU after TS-1 administration for advanced gastric cancer patients ranged
between 3 ng/ml to 128ng/ml, and the levels maintained during the treatment
period of 28 days. The 5-FU concentrations in the ascites after 120mg/day of oral
TS-1 ranged from 30 to 80 ng/ml, and the levels maintained during the treated
period (Iiduka et al, 2002). Furthermore, CDHP levels in ascites of human
gastric cancer patients also maintained at enough levels to inhibit DPD
activities (Iiduka et al, 2002).
The high concentrations and long exposure duration of
5-FU in the peritoneal cavity after TS-1 may be effective against peritoneal
free cancer cells. Furthermore, high concentrations of CDHP may also prevent
5-FU degradation in the peritoneal cavity.
In addition, the regimen is safe, because of the
absence of any grade 4 toxicities. However, TS-1 related toxicities developed
during 1st and 2nd coursed, because patients did not
fully recover from operation. TS-1 treatment could be started from 6 weeks
after operation in nine (26%) of 35 patients. However, tumor growth may occur
during the postoperative weeks before TS-1 administration. Earlier start of
TS-1 administration should be recommended, but the recovery after operation is
not enough in some patients. We are now trying to treat the patients by early
postoperative intraperitoneal chemotherapy before TS-1 therapy (Yu et al, 2001;
Yonemura et al, 2003).
Prognosis of patients with P0/Cy1 status is similar to
the prognosis of those who underwent palliative resection (Wu et al, 1997). Accordingly,
Wu proposed that gastrectomy without additional lymphadenectomy is recommended
for the patients with P0/Cy1 status. As shown in the present paper, TS-1 is
effective to improve the survival and to control peritoneal recurrence for
patients with P0/Cy1 status. From these studies, the dissection of lymph node
metastases may be important to improve the survival in patients with P0/Cy1
status.
TS-1 treatment is safe and
effective as a postoperative chemotherapy for patients with P0/Cy1 status, and
radical gastrectomy plus postoperative TS-1 therapy are recommended for the
patients.
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