Original Article

Yonago Acta medica 2015;58:77–80

Changes in Standard Treatments and Postoperative Outcomes for Advanced
Gastric Cancer at One Institute over an 11-Year Period
A.T.M. Abdul Kader, Kozo Miyatani, Seigo Takaya, Tomoyuki Matsunaga, Yoji Fukumoto, Tomohiro Osaki, Hiroaki Saito,
Shinji Otani, Toshiro Wakatsuki and Masahide Ikeguchi
Division of Surgical Oncology, Department of Surgery, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504,
Japan

ABSTRACT

Gastric cancer (GC) is the fourth most common malignancy worldwide1 and the second leading cause ofcancer-related death, with the highest mortality rates
reported in East Asia including Japan, Korea and China;
approximately 60% of gastric cancers in the world are
diagnosed in this area.2 Early detection and curative surgery can improve survival of loco-regional GC but thesurvival rates of advanced or recurrent GC remain low.
Surgery is the main modality for the treatment ofresectable GC. Surgical technique is the most importantfactor for patients’ outcome and has progressed rapidly
in recent years with newly developed operative apparatus. Furthermore, tegafur and uracil (UFT) and its
derived anticancer drug, fluoropyrimidine S (S-1) reportedly to have survival benefits for patients with curatively
operated advanced GC as adjuvant chemotherapy (ADJ),
as shown in large randomized studies in Japan.3, 4 Thus,
from 2007, fluoropyrimidine-based therapy has beenused as standard ADJ for stage II–III GC.5
However, the improvement of GC patients’ survival
from single institutions has not been widely discussed.
In the present study, we selected patients with stage II–
III GC who were treated over an 11-year period (1998–2008) and we followed these patients at least 5 years.
We divided these patients into two sub-groups (Group
A, who were treated between 1998 and 2002; and GroupB, who were treated between 2003 and 2008) and compared clinicopathological characteristics and prognoses
between the two groups.

Background Reportedly, the recently established post-

operative adjuvant chemotherapies (ADJs) with tegafur
and uracil (UFT) or fluoropyrimidine S (S-1) show better survival than surgery alone in patients with advanced
gastric cancer (GC). We analyzed chronological changes
in postoperative prognosis of patients with advanced GC
in our institute, and investigated the efficacy of ADJ inpatients with stage II–III GC.
Methods Of 143 patients with stage II–III GC who
underwent curative gastrectomy at Tottori University
Hospital between 1998 and 2008, three died with operative complications within 1 month after surgery. The
remaining 140 patients were followed to the end of 2013.
We compared disease-free survival (DFS) and clinicopathological differences between 82 patients who underwent gastrectomy during 1998–2002 (Group A) and 58
patients who underwent gastrectomy during 2003–2008(Group B).
Results Operative quality, as represented by numberof dissected lymph nodes, was similar in both groups,
but the recurrence rate of Group A (51.2%) was higher
than in Group B (37.9%, P = 0.12) and the 5-year DFS
rate of Group B (62.3%) was higher than that of GroupA (50.2%, P = 0.095). In stage II, the 5-year DFS rateof patients in Group B (73.3%) was similar to GroupA (77%), but at tumor stage III, the 5-year DFS rate ofpatients in Group B increased to 48.7%, compared with33.1% of Group A. Between 2003 and 2008, S-1 was
widely used as ADJ for stage II–III GC.
Conclusion Postoperative ADJ with S-1 improved
DFS of patients with stage III gastric cancer.

MATERIALS AND METHODSPatients

Between 1998 and 2008, 143 patients with stage II–III
GC underwent curative gastrectomy with D2 or more
extensive lymph node dissection for adenocarcinoma of
the stomach. Three patients died with operative complications within 1 month after surgery. We excluded
these three patients and we enrolled the remaining 140
patients for this study. All 140 patients (average age:62.7 years; range 34–89 years) had pathological stage
II–III gastric adenocarcinomas.6 Clinicopathologicalcharacteristics of the patients were described accordingwith the Japanese Classification of Gastric Carcinoma.6

Key words

adjuvant chemotherapy; gastric cancer;
S-1; tegafur and uracil

Corresponding author: A.T.M. Abdul Kaderkaderatm@yahoo.com
Received 2015 February 17
Accepted 2015 March 20
Abbreviations: ADJ, adjuvant chemotherapy; DFS, disease-free survival; GC, gastric cancer; S-1, fluoropyrimidine S; UFT, tegafur anduracil77

A. Kader et al.

pared using the chi-squair test for independence, Fisher’s
exact probability test, and the Mann-Whitney U test.
Disease-free survival (DFS) was defined as time fromdate of registration to date of detection of progressive
disease, death, or treatment discontinuation. Survival
curves were estimated using the Kaplan-Meier method,and differences were analyzed using the stratified logrank test. P value < 0.05 was regarded as statisticallysignificant.

All patients provided informed consent for the treatment
including ADJ. The study design was approved by the
Ethics Review Board of Tottori University. We divided
the patients into two sub-groups (Group A, who weretreated between 1998 and 2002; and Group B, who weretreated between 2003 and 2008). All patients were followed at our hospital or at our affiliated hospital till theend of 2013.
ADJ
DFS was defined as the time from the date of registration to the date of detection of progressive disease,
death, or treatment discontinuation. The recurrence sites
were detected by clinical findings, enhanced computed
tomography (CT), or magnetic resonance imaging (MRI).
Between 1998 and 2008, ADJ was applied to 36 patients(40%) of Group A, and 34 patients (24%) of Group B. Of
Group A patients, 30 (21.4%) received UFT and 6 (4.9%),
S-1. While in Group B, 5 patients (3.6%) were treatedwith UFT and 29 patients (20.7%), S-1. Before 2001,
UFT (300–600 mg/day) was mainly used; UFT-based
ADJ was applied for a total of 35 patients. By 2002, S-1
began to be used as ADJ for advanced GC; S-1 (80 mg/m2) was given for a total of 35 patients. A summary of
ADJ is listed in Table 1.

RESULTS
Table 1 shows the clinicopathological differences between Group A (82 patients who were treated between
1998 and 2002) and Group B (58 patients who weretreated between 2003 and 2008). Patients in Group A
tended to be at more advanced stages, although not significantly different. However, operative quality (numberof dissected lymph nodes) did not differ between thegroups. ADJ was administered to a larger percentage ofGroup B patients. The main ADJs for patients in GroupA were UFT-based, but S-1 was the main adjuvant drugin Group B.
The recurrence rate of Group A (51.2%) was higher
than that of Group B (37.9%, P = 0.12). Major sites ofmetastases were the lymph node in 14.6%/15.5% (GroupA/B) patients, peritoneum in 23.1%/12.0% patients, liverin 7.3%/10.3% patients, lung in 4.8/3.9% patients andothers in 4.8%/3.4% patients. Sites of metastases are
summarized in Table 2. The 5-year DFS rate of GroupA (50.2%) was lower than that of Group B (62.3%, P =0.095, Fig. 1), but not significantly different for both recurrence and DFS.

Table 1. Patients’ characteristics
Group A Group B P valuen82

Age (mean, SD)

67.5 (11.4) 66.9 (12)0.934

Sex (male/female)

58/24

36/22

0.282

Histological type (well differen51/31
tiated/poorly differentiated)

27/31

0.301

Tumor stage (II/III)

32/50

32/26

0.059

46/1/35

25/3/30

0.166

Gastrectomy (Total/proximal/
distal)Dissected number of lymph
nodes (mean, SD)

58

35.5 (19.5) 38.9 (18.1)

0.156

Adjuvant chemotherapy (yes/no) 36/46

34/24

0.086

Chemotherapy (UFT-based/S-1) 30/6

5/29

< 0.001

Recurrence (yes/no)

22/36

0.12

42/40

Table 2. Sites of metastasis
Group A Group B P value
Metastatic sites
0.665
Lymph nodes
129Peritoneum
19
7
Liver
6
6
Lung
4
2
Others4
2
Recurrence (yes/no)
42/40
22/36
0.12

We also analyzed the survival effect of ADJ for
these 140 patients. The 5-year DFS rate of 70 patients
who received ADJ (54%) was close to that of 70 patients
without ADJ (57%, P = 0.904). The 5-year DFS of the 35
patients treated with S-1 (62.2%) was better than that of
35 patients treated with UFT-based chemotherapy (45%)
but not significantly different (P = 0.208). For patientswith stage III disease, 5-year DFS of 22 patients treatedwith UFT-based ADJ (30.3%) was close to that of 36

Group A patients underwent gastrectomies during 1998–2002 andGroup B patients, during 2003–2008. UFT, tegafur and uracil.

Statistical analysis

The terminology used in this study conforms to the Japanese Classification of Gastric Carcinoma, 3rd English
edition.6 Differences between two parameters were com78

Clinical changes in gastric cancer

patients without chemotherapy, but increased to 46.6%
in 18 patients treated with S-1. This difference was not
significant (P = 0.654).
Subgroup analysis

DFS rates in eligible patients were analyzed according to
the disease stage (Japanese Classification, 14th edition)and histological type. Kaplan-Meier estimates of DFS
are shown according to disease stage. Among patientswith stage II disease, 5-year DFS rates were very closein the 2 groups (Fig. 2); but, for those with stage III disease, 5 year DFS for Group B was better than for GroupA (Fig. 3).

Time After Surgery (Months)
Fig. 1. Disease-free survival for the 58 patients in Group B (whounderwent gastrectomies during 2003–2008; solid line) was better
than that of the 82 patients in Group A (who underwent gastrectomies during 1998–2002; dotted line), but not significantly different (P = 0.095).

Time After Surgery (Months)

Time After Surgery (Months)

Fig. 2. Disease-free survival for the 32 patients in Group B withstage II (who underwent gastrectomies during 2003–2008; solidline) was better than that of the 32 patients in Group A with stage
II (who underwent gastrectomies during 1998–2002; dotted line),
but not significantly different (P = 0.903).

Fig. 3. Disease-free survival for the 50 patients in Group B withstage III (who underwent gastrectomies during 2003–2008; solidline) was better than that of the 26 patients in Group A with stage
III (who underwent gastrectomies during 1998–2002; dotted line),
but not significantly different (P = 0.350).

79

A. Kader et al.

DISCUSSIONAs ADJ has become more sophisticated, the survival ofpatients with operable advanced GC has improved. In
the present study, we analyzed changes in outcome as
standard treatments for advanced GC have changed. We
found that DFS for patients treated between 2003 and2008 was longer than that of patients treated between
1998 and 2002. The quality of surgery for advanced GC(as represented by the number of dissected lymph nodes)
did not change between the 2 periods. The prognostic
improvement was most conspicuous in patients withstage III disease who were treated with S-1 ADJ.
The UFT has been used as adjuvant drug for advanced GC for a long time in Japan. Even though oursample size was small, the effectiveness of UFT as ADJ
for GC was confirmed.3 However, since S-1 has become
widely used in this clinical context, the situation haschanged completely. S-1 was developed as an oral anticancer agent that combines tegafur (a prodrug of fluorouracil) with 5-chloro-2,4-dihydropyrimidine and potassium oxonate at a molar ratio of 1:0.4:1 (Taiho Pharmaceutical, Tokyo, Japan).7 The Adjuvant Chemotherapy
Trial of S-1 for Gastric Cancer (ACTS-GC) confirmedthat oral S-1 administration for 1 year significantly improved DFS in patients with stage II–III GC after curative surgery.4 From 2007 on, oral S-1 administration for
1 year has therefore been recognized as the standard
postoperative ADJ for advanced GC in Japan,5 and has
been widely used in that setting since 2002.
In this study, a small amount of cancer cells remained after gastrectomy in stage II. S-1 and UFT wereeffective in killing the cancer cells in this stage. In stage
III, S-1 was effective but UFT (serosa-negative, locallyadvanced) was not effective in killing cancer cells because a small amount of cancer cells remained. So, DFS
for S-1 was better than that of UFT in stage III whereas
it was close in stage II.
We had little data for our patients. In the ACTSGC trail, 5-year DFS rates for S-1 were 65.4%.8 Survival
rates of S-1 ADJ in the present study were close to the
ACTS-GC trail.
No randomized study comparing UFT versus S-1 as
ADJ for patients with stage II–III GC has been conduct-

ed in Japan. This study is limited by its small sample
size, retrospective design and single-institution cohort.
In our hospital, procedures for GC are performed by
specialists in GC treatment. Although surgical quality
was not changed, the prognosis of patients with stage III
GC improved in more recently treated patients. These
data indicate the usefulness of S-1 as ADJ for these patients.
The authors declare no conflict of interest.

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