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Page 6 of 10                            Harada et al. J Cancer Metastasis Treat 2018;4:18  I  http://dx.doi.org/10.20517/2394-4722.2017.74

               Table 3. Key trials for gastric or gastro-esophageal junction adenocarcinoma
                Study          Enrolled      Treatment            Survival       HR (95% CI)  P value  Ref.
                               number
                Pre or postoperative treatment
                 INT-0116       281    Surgery → 5-FU/45 Gy   Median OS: 36 months  1.35 (1.09-1.66)  0.005  [6]
                                275    Surgery               Median OS: 27 months
                 ARTIST         228    Surgery → XP          3-year DFS: 74%    -              0.86   [8]
                                230    Surgery → XP/45 Gy    3-year DFS : 78%
                 CRITICS        393    ECC → surgery → ECC   5-year OS: 41%     -              0.99   [9]
                                395    ECC → surgery → ECC/45 Gy  5-year OS: 41%
                 FNCLCC/        113    CF → surgery (n = 113)  5-year rate: 38%  0.69 (0.50-0.95)  0.02  [14]
                 FFCD           111    Surgery (n = 111)     5-year rate: 24%
                 MAGIC          250    ECF → surgery → ECF   5-year rate: 36%   0.75 (0.60-0.93)  0.009  [13]
                                253    Surgery               5-year rate: 23%
                 MRC            446    ECF → surgery         3-year rate: 39%   0.92 (0.79-1.08)  0.30  [15]
                 OEO-5          451    CF → surgery          3-year rate: 42%
                 FLOT4          360    ECF → surgery → ECF   Median OS: 35 months  0.77 (0.63-0.94)  0.012  [17]
                                356    FLOT → surgery → FLOT  Median OS: 50 months
                Targeted therapy
                 ToGA           298    Trastuzumab + XP      Median OS: 13.8 months  0.74 (0.60-0.91)  0.0046  [22]
                                296    Placebo + XP          Median OS: 11.1 months
                 REGARD         238    Ramucirumab           Median OS: 5.2 months  0.78 (0.60-0.99)  0.047  [43]
                                117    Placebo               Median OS: 3.8 months
                 RAINBOW        330    Ramucirumab + paclitaxel  Median OS: 9.6 months  0.81 (0.68-0.96)  0.017  [44]
                                335    Placebo + paclitaxel  Median OS: 7.4 months
               OS: overall survival; DFS: disease free survival; HR: hazard ratio; CI: confidence interval; XP: cisplatin and capecitabine; ECC: epirubicin,
               cisplatin and capecitabine; CF: cisplatin and 5-FU; ECF: epirubicin, cisplatin and 5-FU; FLOT: docetaxel, oxaliplatin, leucovorin, and 5-FU;
               5-FU: 5 fluorouracil

               STAT3 inhibitor, in combination with paclitaxel . Although detail result of this trial is not available as of
                                                        [55]
               this date, napabucasin did not benefit OS . However, these strategies might be effective for tumor with high
                                                  [55]
               expression of stem cell markers . Further research is expected.
                                          [56]
               Immunotherpy
               To enhance immune checkpoint blockade therapy, combination with several agents have been assessed.
               Firstly, DNA methyltransferase inhibitor have been found to upregulate interferon signaling and tumor
               antigen presentation . Therefore, a phase 1/2 study have been evaluating azacitidine in combination with
                                 [57]
               pembrolizumab and epacadostat (NCT02959437). Secondly, because inducible CO-stimulator of T cells
               (ICOS) activate T cell and stimulate an anti-tumor immune response , JTX-2011, an agonist of ICOS, in
                                                                           [58]
               combination with nivolumab is being assessed (NCT02904226).


               TREATMENT FOR PERITONEAL METASTATIC GAC IN THE USA
                                                                                                        [59]
               Recommended therapy for peritoneal metastasis is systemic chemotherapy or best supportive care .
               Hyperthermic intraperitoneal chemoperfusion (HIPEC) is a potential therapy for peritoneal metastases .
                                                                                                       [60]
               Our institution performed phase II study which evaluated neoadjuvant laparoscopic HIPEC (mitomycin
               C 30 mg and cisplatin 200 mg) for GAC patients with peritoneal metastasis . Seven patients (37%) had
                                                                                 [61]
               negative peritoneal cytology after HIPEC, and the median OS from the date of diagnosis of metastatic
               disease  was  30.2 months .  However, performing  only  HIPEC  without  systemic therapy  might  impair
                                     [61]
               control of primary or distant disease. Therefore, further phase II trial of HIPEC (NCT02891447) is ongoing
               in our institution, and this result is expected.



               SUMMARY
               In summary, perioperative chemotherapy or preoperative chemoradiation is recommended for localized
               advanced GAC. Postoperative chemoradiation is option for GAC patients who undergo surgery without
               preoperative treatment [Table 3]. Result of trials comparing preoperative chemotherapy to chemoradiation
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