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Table 1. Results of trials with chemotherapy for metastatic gastric cancer in Japan
Authors, year Regimen Patients (n) OS (months) HR
Koizumi et al. , 2008 S-1 + cisplatine 148 13.0 0.77 (0.61-0.98)
[8]
S-1 150 11.0 1
Yamada et al. [33] , 2015 S-1 234 11.4 0.83 (0.68-1.00)
Cisplatine + irinotecan 236 12.3 0.82 (0.68-0.99)
5-FU continuous infusion 234 10.8 1
Koizumi et al. [34] , 2014 S-1 + docetaxel 314 12.5 0.84 (0.71-0.99)
S-1 321 10.8 1
Boku et al. [35] , 2009 S-1 234 11.4 0.83 (0.68-1.00)
Cisplatine + irinotecan 236 12.3 0.82 (0.68-0.99)
5-FU continuous infusion 234 10.8 1
Narahara et al. [36] , 2011 S-1 + irinotecan 155 12.8 0.93
S-1 160 10.5 1
Hironaka et al. [44] , 2013 Weekly paclitaxel 108 9.5 1.13 (0.86-1.49)
Weekly irinotecan 111 8.4 1
Shitara et al. [45] , 2017 Tri-weekly nab-paclitaxel 247 10.3 1.06 (0.87-1.31)
Weekly nab-paclitaxel 246 11.1 0.97 (0.76-1.23)
Weekly paclitaxel 248 1.06 1
OS: overall survival; HR: hazard ratio; 5-FU: 5-fluorouracil

and drugs targeting specific molecular pathways, have achieved an increase in the response rate, it is
difficult to cure metastatic GC with chemotherapy alone. The current goals of treatment, therefore, are to
relieve GC-related symptoms and to prolong survival. The median survival time achieved in clinical trials
for metastatic or recurrent GC remains between 6 and 13 months , although it has been proven that
[6-8]
chemotherapy prolongs survival when compared with the best supportive care (BSC) [9,10] . Recently, it has
been reported that curative resection may be performed for patients with liver metastasis, para-aortic lymph
node metastasis, or positive peritoneal cytology, especially when chemotherapy has been effective [11-19] . In
this review, we summarize the publications and guidelines that have focused on recent progress in the
treatment of metastatic GC in Japan.

TREATMENT STRATEGY FOR METASTATIC GC
The main treatment for metastatic GC is chemotherapy. Table 1 shows the representative trials for metastatic
or recurrent GC in Japan. The first chemotherapeutic agent of choice against metastatic GC was 5-fluorouracil
(5-FU), which was used either alone or in combination with various agents. In Japan, 5-FU as a key drug for
GC was replaced by S-1 (tegafur-gimestat-otastat potassium), based on favorable results in trials involving
Japanese patients [8,20] . Thereafter, trials focused on identifying the best combination regimen using S-1.
Recently, many drugs designed to target the molecular pathways involved in the development or progression
of cancer have been studied for metastatic GC [21-31] [Table 2]. In patients with GC overexpressing human
epidermal growth factor receptor 2 (HER2), the addition of trastuzumab, an antibody targeting HER2,
to the first-line cytotoxic drug regimens significantly prolonged the survival of patients . Therefore, the
[21]
presence or absence of HER2 overexpression is the first branch point when selecting the treatment regimen.
The recommended treatment algorithm for patients of metastatic GC in the 5th edition of the Japanese
Gastric Cancer Treatment Guideline is shown in Figure 1. Recommendation A indicates that the regimen is
strongly recommended based on the certain evidence while recommendation B suggests that the regimen is
weakly recommended because of insufficient evidence. Figure 2 demonstrates the alternative algorithm for
patients who are unfit for the standard treatment due to comorbidities or social situations.

HER2-negative advanced GC
In Japan, the first choice of chemotherapy for metastatic GC is S-1 and cisplatin (SP), according to the results
of a phase III trial (SPIRITS trial ). This trial showed that patients treated with SP had significantly better
[8]
overall survival (OS) than those treated with S-1 alone, with a median OS of 13 vs. 11 months (P = 0.04).
Progression-free survival (PFS) was also significantly longer in patients treated with SP than in those treated