European Journal of Cancer 65 (2016) 164e171

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Original Research

Randomised phase III study of S-1 alone versus
S-1 plus lentinan for unresectable or recurrent
gastric cancer (JFMC36-0701)*
Shigefumi Yoshino a,*, Kazuhiro Nishikawa b,1, Satoshi Morita c,
Tsuyoshi Takahashi d, Koichiro Sakata e, Jiro Nagao f, Hiroshi Nemoto g,
Nozomu Murakami h, Takeru Matsuda i, Hiroyasu Hasegawa j,
Ryoichi Shimizu k, Takaki Yoshikawa l, Hiroyuki Osanai m,
Motohiro Imano n, Hiroshi Naitoh o, Akiyoshi Tanaka p, Takashi Tajiri q,
Akira Gochi r, Michinari Suzuki s, Junichi Sakamoto t, Shigetoyo Saji t,
Masaaki Oka uaDepartment of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Ube, Japan
Department of Surgery, Osaka National Hospital, Osaka, Japanc
Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japand
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japane
Department of Digestive Surgery, Shimonoseki Medical Center, Shimonoseki, Japanf
Department of Surgery, Toho University Omori Medical Center, Tokyo, Japang
Department of Gastroenterological and General Surgery, School of Medicine, Showa University Fujigaoka Hospital,
Yokohama, Japanh
Department of Palliative Care and Surgery, Koseiren Takaoka Hospital, Takaoka, Japani
Department of Surgery, National Hospital Organization Kobe Medical Center, Kobe, Japanj
Department of Surgery, Tokuyama Central Hospital, Shunan, Japank
Department of Surgery, Ogori Daiichi General Hospital, Yamaguchi, Japanl
Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japanm
Department of Surgery, Sapporo Geka Kinen Hospital, Sapporo, Japann
Department of Surgery, Kinki University Faculty of Medicine, Osakasayama, Japano
Department of Surgery, Japan Community Health Care Organization Gunma Chuo Hospital, Maebashi, Japanp
Department of Surgery, Mine City Hospital, Mine, Japanq
Nippon Medical School, Tokyo, Japanr
Digestive Tract Surgery, Okayama University Hospital, Okayama, Japans
Department of Surgery, Shunan City Shinnanyo Hospital, Shunan, Japant
Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo, Japanu
Yamaguchi University, Yamaguchi, Japanb*

Dr. Kazuhiro Nishikawa presented in part at European Cancer Congress 2015 (25e29 September 2015, Vienna, Austria).
* Corresponding author: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, 1-1-1
Minami-Kogushi Ube, Yamaguchi, 755-8505, Japan. Tel.: þ81 836 22 2264; fax: þ81 836 22 2263.
E-mail address: sigefumi@yamaguchi-u.ac.jp (S. Yoshino).
1
The second author Kazuhiro Nishikawa contributed equally to the first author.
http://dx.doi.org/10.1016/j.ejca.2016.06.012
0959-8049/ª 2016 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

S. Yoshino et al. / European Journal of Cancer 65 (2016) 164e171

165

Received 18 February 2016; received in revised form 17 May 2016; accepted 16 June 2016
Available online 5 August 2016

KEYWORDS
Lentinan;
S-1;
Gastric cancer;
Quality of life;
Biomarker;
Phase III study

Abstract Background: Lentinan (LNT) is a purified b-1, 3-glucan that augments immune responses. The present study was conducted to assess the efficacy of LNT in combination with S1 as a first-line treatment for unresectable or recurrent gastric cancer.
Patients and methods: Eligible patients were randomly assigned to receive S-1 alone or S-1 plus
LNT. The primary end-point was overall survival (OS). Secondary end-points were time-totreatment failure (TTF), overall response rate (ORR), safety, quality of life (QOL), andbiomarker. The percentages of LNT-binding monocytes in peripheral blood prior to treatment
were analysed for the biomarker assessment.
Results: One hundred and fifty-four and 155 patients were randomly assigned to receive S-1
alone or S-1 plus LNT, respectively. The median OS was 13.8 and 9.9 months (P Z 0.208),
the median TTF was 4.3 and 2.6 months (P < 0.001), the ORR was 22.3% and 18.7% for
the S-1 and S-1 plus LNT groups, respectively. The incidences of haematologic and non-haematologic adverse events were similar, and no significant changes in QOL scores wereobserved during the treatment in both groups. In a subpopulation of patients with LNTbinding monocytes 2%, patients who received more than two cycles of chemotherapy showeda longer survival time in the S-1 plus LNT group.
Conclusions: OS did not improve and TTF was significantly worse in the S-1 plus LNT groupas compared with the S-1-only group. This study showed no efficacy of LNT when combinedwith S-1 treatment in patients with unresectable or recurrent gastric cancer.
Clinical trial registration ID number: UMIN 000000574.
ª 2016 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction
Lentinan (LNT) is a purified b-1, 3-glucan with b-1, six
branches obtained from Lentinus edodes, an edible
mushroom cultivated in Japan [1]. LNT augments immune responses and increases host resistance against
murine and human tumours [2]. LNT promotes Tcelledependent immunopotentiation and functions as amaturation factor for lymphoid cells [3]. We previously
determined that the initial step of immunomodulation by
LNT may be its binding to monocytes [4]. In cancer patients, LNT-bound macrophages may produce IL-12
followed by the induction of a T helper (Th) 1 response,
which mediates cellular immunity, and may induce
downregulation of Th2 responses [5]. In patients withadvanced gastric cancer, cellular immunity is decreased
and Th2-dominant status develops [6]; so, it is important
to enhance the cellular immunity and alleviate the Th2dominant condition. Ochiai et al. [7]reported that an increase in the number of cytotoxic T cells in peripheral
blood was found in the chemotherapy plus LNT group ascompared with chemotherapy-alone group in a controlled
randomised study in advanced gastric cancer.
A cooperative clinical study group in Japan has performed a phase III clinical trial of LNT that revealed thatLNT prolonged survival when patients with advanced
gastric cancer were treated in combination with tegafur[8]. Recently, an individual patient data meta-analysis ofchemoimmunotherapy using LNT was performed in 650
patients with unresectable or recurrent gastric cancer infive trials. This meta-analysis revealed that LNT significantly prolonged the overall survival (OS) in advanced
gastric cancer patients who were treated in combination
with tegafur or other fluoropyrimidines [9]. However, allfive clinical studies included in the analysis were performed in the 1980s, and S-1, which was developed in the
1990s, was not used in these trials.
S-1 was designed to enhance the anti-cancer activityof tegafur by combining it with two modulating substances: gimeracil to inhibit dihydropyrimidine dehydrogenase and potassium oxonate to reduce
gastrointestinal toxicities [10]. The JCOG9912 trial,
which was designed to assess whether S-1 alone was asgood as 5-fluorouracil alone, revealed that S-1 was notinferior to 5-fluorouracil [11]. S-1 is the most widelyused drug for the treatment of unresectable or recurrent gastric cancer in Japan. It is reported that themedian survival time (MST) of 400 d was in a pilot
study of S-1 combined with LNT in advance gastriccancer [12]. It is of great interest that LNT may also
have a synergistic effect with this new type of fluoropyrimidine S-1. Therefore, we conducted a randomised phase III study of S-1 alone versus S-1 plus LNTin advanced or recurrent gastric cancer to assess the166

S. Yoshino et al. / European Journal of Cancer 65 (2016) 164e171

efficacy of LNT (JFMC36-0701, UMIN Clinical Trial
ID 000000574).
2. Patients and methods
2.1. Patients
Eligibility criteria included histologically proven, unresectable or recurrent gastric cancer; measurable lesion if
gastrectomy was performed; age 20 years (no upper age
limit); an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0e2; no previous chemotherapy or immunotherapy; no adjuvant chemotherapy
with S-1; oral intake capability, adequate haematologic,
renal, and hepatic function; and an expected survival ofat least 3 months. Exclusion criteria were as follows:
pregnant or breast-feeding women, clinically significant
cardiovascular disease, gastrointestinal bleeding, central
nervous system metastases, and ascites and thoracic effusions necessitating paracentesis. This study was performed in accordance with the principles of Good
Clinical Practice and the ethical standards laid down in
the Declaration of Helsinki. The study protocol wasapproved by each site’s ethics committee, and written
informed consent was obtained from each patient.
2.2. Study design
This study was a prospective, multicentre, randomised,open-label phase III clinical trial conducted at 97 centres
in Japan. S-1 monotherapy was selected for the control
arm because the SPIRITS trial had not finished yet
when this study started [13]. Patients were centrally
randomised to receive treatment with S-1 alone or S-1
plus LNT at a 1:1 ratio, stratified by ECOG PS (0/1
versus 2), disease status (unresectable versus recurrent),
and the institution.
2.3. Treatment
S-1 was given orally twice daily for the first 4 weeks of a
6-week cycle. The dose of S-1 administered was calculated according to the patient’s body surface area asfollows: less than 1.25 m2, 40 mg; 1.25e1.5 m2, 50 mg;
and greater than 1.5 m2, 60 mg. LNT was given as an
intravenous infusion of 2 mg/body every week. Treatment for both groups was continued until one of thefollowing occurred: progressive disease, unacceptabletoxicity, withdrawal of consent by the patient, or
termination of treatment by the attending physician.
2.4. Efficacy and safety assessments
The primary end-point was OS, defined as time fromdate of randomization to date of death from any cause.
Secondary end-points were time-to-treatment failure(TTF), overall response rate (ORR), safety, quality oflife (QOL) score, and biomarker level. TTF was definedas the time from randomization to treatment discontinuation for any reason, including disease progression,
treatment toxicity, patient preference, physician’s decision, or death. Measurable lesions were assessed every
month during initial four cycles by computed tomography scan according to RECIST version 1.0 [14] byprincipal investigators at each participating centre until
onset of progressive disease. Adverse events were gradedaccording to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.
Clinical and laboratory assessments were performed atscreening and on days 1, 15, and 29 of each cycle. S-1
was withheld at grade 3 haematological toxicities orgrade 2 non-haematological toxicities and reintroduced
after recovery of toxicities at grade 1. S-1 was reduced at
any grade 3 toxicities. Treatment could be withheld for
up to 4 weeks.
2.5. QOL assessment
The self-administered, 40-item Functional Assessmentof Cancer Therapy-Biological Response Modifier [15]was used to assess participants’ overall QOL. Patientswere asked to complete the QOL assessment at five time
points: baseline (before treatment), at 4 and 6 weeks
after treatment (during the first chemotherapy cycle)
and at 10 and 12 weeks after treatment (during thesecond chemotherapy cycle). The QOL assessment was
not obligatory in this study; so, the data were collectedfrom the patients who agreed to participate in the QOL
assessment.
2.6. Biomarker assessment
LNT-binding monocytes were assessed by using fluorescein-labelled LNT [16]. Briefly, peripheral blood obtained from patients prior to the treatment was
incubated with fluorescein-labelled LNT at 37  C for
75 min, and phycoerythrin-labelled anti-CD14 antibody(CALTAG) was added during the last 30 min. The
percentage of LNT-binding CD14þ monocytes wasmeasured with a fluorescence-activated cell sorter(FACS Calibur, Becton Dickinson).
2.7. Statistical analysis
In the phase II study of S-1 treatment in patients withadvanced gastric cancer who had not received previous
chemotherapy, the MST was 244 d [17]. In a pilot studyof S-1 combined with LNT, the MST was 400 d [12]. On
the basis of these findings, we assumed MST would be 8months in the S-1 group and 12 months in the S-1 plus
LNT group. The required number of events was estimated as 284 with a 2-sided a value of 0.05 and a powerof 90% to detect differences in survival on completion offollow-up between the S-1 and the S-1 plus LNT group.

S. Yoshino et al. / European Journal of Cancer 65 (2016) 164e171

Baseline patient characteristics were compared byusing Pearson’s chi-square test, except for age, which wascompared by using ManneWhitney’s U test. OS and
TTF were compared by using log-rank tests stratified byrandomization factors and KaplaneMeier estimates.
Cox proportional hazards models stratified by the
randomization factors estimated hazard ratios (HRs)and 95% confidence intervals (CIs). For the biomarker
assessment, we performed the weighted log-rank testwith the HarringtoneFleming class of weights [18]. P
values less than 0.05 were considered statistically significant. Statistical analyses were performed by using SAS
version 9.2 and version 9.4 (SAS Institute, Cary, NC).
3. Results
3.1. Patients and treatment exposure
Between February 2007 and June 2010, 309 patients wereenrolled (Fig. 1). Fourteen patients were excluded fromthe analysis; so, the full analysis set comprised 295 patients, and OS was analysed in these patients. Six patientswere excluded from the full analysis set population. The
safety population comprised 289 patients, and the safety,
response, TTF, and QOL were analysed in this safety
population. Table 1 shows baseline patient characteristics, which were well balanced between the treatmentgroups. However, the proportion of patients with serum
albumin less than 3.0 g/dl was significantly higher in the
S-1 plus LNT group as compared to the S-1 group,

167

Table 1
Patient characteristics.
S-1 (n Z 146)

S-1 þ LNT (n Z 149)

n (%)

n (%)

Sex
Men
107 (73.3)
Women
39 (26.7)
Age (years)
Median (range)
74 (32e94)
ECOG PS0102 (69.9)
1
39 (26.7)
2
5 (3.4)
Serum albumin (g/dl)
3.0
108 (74.0)
3.0>
17 (11.6)
Unknown
21 (14.4)
Disease status
Unresectable
126 (86.3)
Recurrent
20 (13.7)
Primary lesion
Present
96 (65.8)
Resected
50 (34.2)
Measurable lesions
Yes
94 (64.4)
No
52 (35.6)
Histology
Intestinal type
57 (39.0)
Diffuse type
77 (52.8)
Unknown
12 (8.2)

101 (67.8)
48 (32.2)

0.31

73 (44e93)

0.97

107 (71.8)
34 (22.8)8 (5.4)0.57

104 (69.8)
32 (21.5)
13 (8.7)

0.04

126 (84.6)
23 (15.4)

0.74

94 (63.1)
55 (36.9)

0.72

96 (64.4)
53 (35.6)

0.99

76 (51.0)
65 (43.6)
8 (5.4)

0.10

LNT, lentinan; ECOG PS, Eastern Cooperative Oncology Group
performance status.

309 patients enrolled

Assigned to S-1(n=154)8 patients excluded
5 no measurable lesion after gastrectomy
1 previous chemotherapy
1 double cancers
1 concurrent immunotherapy

Full Analysis Set(n=146)
4 patients excluded
3 not treated
1 unknown treatment situation

Assigned to S-1+LNT(n=155)6 patients excluded
2 no measurable lesion after gastrectomy
1 previous chemotherapy
1 gastrointestinal bleeding
1 treatment start before registration
1 no case report form

Full Analysis Set(n=149)2 patients excluded
2 not treated

Safety population(n=142)P

Safety population(n=147)

Fig. 1. CONSORT diagram.

168

S. Yoshino et al. / European Journal of Cancer 65 (2016) 164e171

whereas an ECOG PS was well balanced between the twogroups.
Patients in the S-1 group received a median of threecycles of S-1 (range, 1e38), and patients in the S-1 plus
LNT group received a median of two cycles of S-1(range, 1e19) and 22 treatments with LNT (range,
1e104). In the S-1 group, the S-1 doses were reduced in
17.8% of patients. In the S-1 plus LNT group, 19.5% of
patients had dose reductions.
3.2. Efficacy
All follow-up assessments were completed by 30th
June 2012, which was 48 months after the enrolment of
the last patient. The median OS was 13.8 months (95%CI, 11.8e15.8) and 9.9 months (95% CI, 7.9e12.0) for
the S-1 group and S-1 plus LNT group, respectively,
with an HR of 1.169 (95% CI, 0.916e1.493, P Z 0.208)(Fig. 2).
The reasons for treatment discontinuation are progressive disease in 79 and 74 patients, clinical nonefficacy in 8 and 15 patients, adverse events in 18 and 29
patients, withdrew consent in 15 and 13 patients, indications for surgery in 2 and 3 patients, death in 2 and 4
patients, and others in 16 and 10 patients in the S-1
group and the S-1 plus LNT group, respectively. Median TTF was 4.3 months (95% CI, 3.8e4.7) and 2.6
months (95% CI, 2.2e3.0) for the S-1 group and S-1 plus
LNT group, respectively, with an HR of 1.540 (95% CI,
1.210e1.961, P < 0.001) (Fig. 2).
Objective response was evaluable by the investigatorsin the 190 patients (65.7%) with measurable disease atbaseline. The ORR was 22.3% in the S-1 group
including complete response (CR) in one patient andpartial response (PR) in 19 patients. The ORR was
18.7% in the S-1 plus LNT group including CR in one

A

3.3. Safety
The incidence of adverse events during treatment issummarised in Table 2. The incidences of haematologic
and non-haematologic adverse events were similar inboth groups. Only one patient died as a result of neutropenia related to protocol treatment in the S-1 plus
LNT group. The proportions of patients who terminated treatment because of intolerable adverse events

Table 2
Haematologic and non-haematologic adverse events.
S-1 (n Z 142)

S-1 þ LNT(n Z 147)

All grades, Grade 3 or All grades, Grade 3n (%)
4, n (%)
n (%)
or 4, n (%)
Leucopenia
65 (45.8)
Neutropenia
73 (51.4)
Anaemia
72 (50.7)
Thrombocytopaenia 63 (44.4)
Febrile neutropenia
1 (0.7)
Anorexia
52 (36.6)
Nausea22 (15.5)
Vomiting
14 (9.9)
Diarrhoea
24 (16.9)
Fatigue43 (30.3)
Stomatitis
24 (16.9)
Pigmentation
36 (25.4)Rash0Lacrimation
18 (12.7)
Handefoot syndrome 12 (8.5)
Creatinine elevation 17 (12.0)
Hyponatremia
31 (21.8)

6 (4.2)17 (12.0)
7 (4.9)1 (0.7)1 (0.7)
12 (8.5)
01 (0.7)1 (0.7)5 (3.5)1 (0.7)00
4 (2.8)1 (0.7)0
7 (4.9)69 (46.9)
68 (46.3)
75 (51.0)64 (46.3)
075 (51.0)
35 (23.8)
19 (12.9)
28 (19.0)
52 (35.4)
28 (19.0)
38 (25.9)
3 (2.0)14 (9.5)
11 (7.5)
14 (9.5)
27 (18.4)

12 (8.2)
16 (10.9)
12 (8.2)
6 (4.1)0
19 (12.9)
5 (3.4)2 (1.4)6 (4.1)13 (8.8)
3 (2.0)01 (0.7)00
1 (0.7)7 (4.8)

LNT, lentinan.

B
Median

13.8M
9.9M

HR (95% CI)
1.17 (0.92-1.50)

nMedianHR (95% CI)

P

S-1
142
S-1 + LNT 147

4.3M
2.6M

1.54 (1.21-1.96)<0.001P
0.208

Probability of TTF

n

S-1
146
S-1 + LNT 149

Probability of OS
Number at risk
S-1
146 113
S-1 + LNT 149 108

patient and PR in 17 patients. There was no statisticaldifference in the ORR between the two groups.

Months
80
59

46
40

31
25

14
8

7
6

4
3

3
3

0
2

0
1

Number at risk
S-1
142
S-1 + LNT 147

Months
38
27

13
5

5
2

2
1

2
0

1
0

1
0

1
0

Fig. 2. KaplaneMeier curves for OS in the full analysis set population (A) and TTF in safety population (B). OS, overall survival; TTF,
time-to-treatment failure; LNT, lentinan; HR, hazard ratio; CI, confidence interval.

S. Yoshino et al. / European Journal of Cancer 65 (2016) 164e171

were similar: 13.1% in the S-1 group and 19.9% in the S1 plus LNT group.

169

S-1 group (HarringtoneFleming method, r1 Z 0 andr2 Z 0.5, P Z 0.0491; r1 Z 0 and r2 Z 1, P Z 0.0171)(Fig. 4).

3.4. QOL analysis
One hundred and nine (76.8%) patients in the S-1 groupand 117 (79.6%) patients in the S-1 plus LNT groupcompleted a baseline QOL assessment. Fig. 3 shows thebaseline scores and changes in the mean scores for theoverall QOL scale of each group. No significant changes
were observed at 4, 6, 10, and 12 weeks after chemotherapy as compared with baseline in both the S-1 andS-1 plus LNT groups.
3.5. Biomarker assessment

This study showed no efficacy of LNT administration
combined with S-1 treatment in patients with unresectable or recurrent gastric cancer. OS did not improve in
the S-1 plus LNT group as compared with the S-1-onlygroup. However, TTF was significantly worse in the S-1
plus LNT group. Although the patient characteristics
were well balanced between the groups, the proportionof patients with low serum albumin was significantly
higher in the S-1 plus LNT group. Hypoalbuminemia is
an independent prognostic factor for OS in patients withadvanced gastric cancer who receive chemotherapy[19,20]. Therefore, it is speculated that the unexpectedhigh proportion of enrolment of patients with hypoalbuminemia in the S-1 plus LNT group caused theworse TTF as compared to the S-1 group.
In the present study, MST was 13.5 months in the S-1
group and 10.9 months in the S-1 plus LNT group,
respectively. In previous phase III clinical trials in patients with advanced gastric cancer, the median survivalof 10.5, 11.0, and 11.4 months was reported for S-1
treatment by Narahara et al. [21], Koizumi et al. [13],and Boku et al. [11], respectively. The MST for S-1
treatment in our study was almost the same as those inthese three previous studies. However, patients analysedin these three studies were 75 years of age or younger.
According to the Surveillance, Epidemiology, and End

QOL score

The percentages of LNT-binding cells in total CD14þ
monocytes showed individual variations ranging from
0.03% to 38.7% (median, 2.0%) among 309 patients.
Patients were divided into an LNT high-binding population with at least 2.0% of monocytes bound to LNT
and an LNT low-binding population with less than 2.0%
of monocytes bound to LNT.
In patients who received more than two cycles ofchemotherapy, OS was similar in both the S-1 and S-1
plus LNT groups in the LNT low-binding population.
However, in the LNT high-binding population, somepatients showed a longer survival time in the S-1 plus
LNT group as compared to the S-1 group. The 3-year
survival rate of the S-1 group was 3.1%, whereas that of
the S-1 plus LNT group was 24.1%. A longer OS wasobserved in the S-1 plus LNT group as compared to the

4. Discussion

S-1
S-1 + LNT

Number of patients
S-1
S-1 + LNT

Pre-treatment

4W

6W

10W

12W

109
117

102
101

104
93

84
63

78
62

Fig. 3. Changes in QOL score during treatment. QOL was assessed by FACT-BRM. Maximum score is 160 points, and values are
expressed as mean  standard deviation. QOL, quality of life; FACT-BRM, Functional Assessment of Cancer Therapy-Biological
Response Modifier; LNT, lentinan.

170

S. Yoshino et al. / European Journal of Cancer 65 (2016) 164e171
A

B

S-1
(n=44)
S-1 + LNT (n=33)

Probability of OS

Probability of OS

S-1(n=64)
S-1 + LNT (n=34)

MonthsNumber at risk
S-1
64
S-1 + LNT 34

54
30

39
16

22
12

15
7

8
2

3
2

3
0

Months30

Number at risk
S-1
44
S-1 + LNT 33

39
32

30
22

16
14

9
10

3
4

1
3

0
2

0
2

0
1

0
1

Fig. 4. KaplaneMeier curves of OS according to the percentages of LNT-binding monocytes in patients who received more than two
cycles of treatment. OS in LNT low-binding population (A) and LNT high-binding population (B). The weighted log-rank test with theHarringtoneFleming class of weights were performed in LNT high-binding population and resulted in, r1 Z 0 and r2 Z 0.5, P Z 0.0491;
r1 Z 0 and r2 Z 1, P Z 0.0171. OS, overall survival; LNT, lentinan.

Results data from the United States of America [22],35.7% of patients with gastric cancer were diagnosed
over 75 years of age. Half of the patients enrolled in thisstudy were over the age of 73; so, the efficacy of S-1
treatment for elderly patients with gastric cancer could
be suggested in this study.
QOL is impaired in patients with advanced gastriccancer [23]; so, it is important to maintain the QOL
during the cancer treatment. An improvement of QOL
was showed in patients with gastric cancer who
received chemotherapy [24]. However, some authors
reported no improvement of QOL during cancer
treatment [25,26]. No significant changes were observed
during treatment with either S-1 alone or S-1 plus LNT
as compared with before treatment. LNT had no efficacy to improve the QOL in patients with advanced
gastric cancer.
LNT-binding monocytes were analysed for thebiomarker assessment. In the LNT high-binding population, patients who received more than two cycles ofchemotherapy showed a longer survival time in the S-1
plus LNT group as compared with in the S-1 group. In
chemotherapy, it is important to select patients who arepromising candidates for responding to treatment.
Hazama et al. [27] reported the importance of
biomarker exploration for selecting patients with abetter treatment outcome in chemotherapy with vaccine treatment for advanced colorectal cancer. The
percentages of LNT-binding monocytes could be oneof the biomarker for predicting the long survivors inpatients with advanced gastric cancer who received S-1
treatment with LNT.
In conclusion, the present study showed no efficacy of
LNT administration combined with S-1 treatment inpatients with unresectable or recurrent gastric cancer.

Disclosure
S. Yoshino has received personal fees from MSD,
Taiho and Chugai, outside the submitted work. K.
Nishikawa has received personal fees from Taiho, Ajinomoto, Yakult and Chugai, outside the submitted
work. S. Morita has received personal fees from Taiho,
outside the submitted work. T. Takahashi has received
grants from SBI pharma, outside the submitted work. T.
Yoshikawa has received personal fees from Taiho,
outside the submitted work. The other authors havedeclared no conflicts of interest.

Acknowledgements
We thank the investigators from the institutions who
enrolled patients for this trial. Furthermore, we deeply
appreciate all patients who participated in the trial. This
work was supported by The Japanese Foundation for
Multidisciplinary Treatment of Cancer.

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