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Harada et al. J Cancer Metastasis Treat 2018;4:18  I  http://dx.doi.org/10.20517/2394-4722.2017.74                           Page 5 of 10

               5-FU-based and cisplatin-based combinations were considered as an acceptable standard therapy according
               to trial in Asia . Then, capecitabine, which is an oral fluoropyrimidine, and oxaliplatin, which is third-
                            [32]
               generation diaminocyclohexane platinum compound, were developed. A phase III in Germany showed
               that the combination of fluorouracil, leucovorin, and oxaliplatin improved median PFS compared with
               fluorouracil, leucovorin, and cisplatin (5.8 months vs. 3.9 months), but not siginificant . The REAL-2 trial
                                                                                        [33]
               demonstrated possible replacement of 5-FU into capecitabine or cisplatin into oxaliplatin . These results
                                                                                            [34]
               have led to trend toward preference of capecitabine plus cisplatin or capecitabine plus oxaliplatin in the USA.

               S-1, which is oral fluoropyrimidine preferred in Japan, was reported to be similarly effective for survival with
               a better toxicity compared with infusional fluorouracil in West [35,36] . However, dose of S-1 administered each
                                   2
               time in West (25 mg/m ) is lower than that in Asia (40-60 mg/body) . Thus, more evidence is needed to get
                                                                        [37]
               acceptance for S-1 in the USA.
               DCF was evaluated in a randomized study, V-325 in 2006 [38,39] . It showed that median OS of DCF was
               significantly longer than CF (9.2 months vs. 8.6 months; P = 0.02), but DCF produced more toxicity [38,39] .
               Several modified DCF regimens demonstrated the efficacy and the safety [40-42] . Thus, the original DCF is not
               recommended, and modified DCF is still one of the option in specific cases.


               Second/third line therapy
               For second line therapy, ramucirumab (an anti-VEGFR2 monoclonal antibody) is the only molecular-targeted
               drug with a confirmed minimal survival benefit in a global phase 3 trial. The REGARD trial compared
               ramucirumab and placebo, and showed that median OS in ramucirumab group was better than that in
               placebo group (5.2 months vs. 3.8 months) . The RAINBOW trial compared paclitaxel with and without
                                                    [43]
               ramucirumab, and showed that OS in ramucirumab plus paclitaxel was significantly longer than in placebo
               plus paclitaxel (median 9.6 months vs. 7.4 months) . Ramucirumab plus paclitaxel is the preferred regimen
                                                         [44]
               in the second line setting. Docetaxel, irinotecan and paclitaxel have significantly prolong OS compared to
               best supportive care, but all these trials were flawed [45-47] .


               Immune checkpoint blockade has received global attention in recent years [48-50] . Keynote-059 assessed efficacy
               and safety of pembrolizumab, programmed death-1 (PD-1) inhibitor, monotherapy showed that overall response
               rate (ORR) was 11.2% and median duration of response (DOR) was 8.1 months in all cohort . ORR was
                                                                                               [51]
               higher in PD-1 ligand (PD-L1) positive patients than PD-L1 negative patients (15.5% vs. 5.5%). Checkmate 032
               assessed the combination of two checkpoint inhibitors, nivolumab (PD-1 inhibitor) and ipilimumab (cytotoxic
               T-lymphocyte-associated protein 4 inhibitor), and showed that ORR for combination therapy in PD-L1 positive
               patients was 40%, which was higher than nivolumab monotherapy . Interestingly, among 7 patients with high
                                                                     [52]
               microsatellite instability (MSI-H) tumors in Keynote-059, ORR was 57% and the CR rate was 14.3%. Given this
               result, the FDA has approved pembrolizumab for the treatment of patients with PD-L1 positive GAC who have
               received 2 or more lines of chemotherapy. Pembro is also approved for MSI-H tumor patients. Therefore, now
               we have to consider all 3 biomarkers for gastroesophageal adenocarcinoma patients (Her2, PD-L1, and MSI).



               PERSPECTIVE FOR TARGETED THERAPY AND IMMUNOTHERAPY
               Targeted therapies against stem cells
               Cancer stem cells possess the capacity to self-renew and to cause the heterogeneous lineages of cancer cells.
               Several makers and pathways related to gastric cancer stemness have been identified . Cancer stem cells
                                                                                        [53]
               are resistant to several chemotherapy, and thus targeting cancer stem cells is a potential therapy to overcome
               treatment resistance. Two stemness related pathways, Hedgehog and signal transducer and activator of
               transcription 3 (STAT3) pathway, were assessed in clinical trials so far. Vismodegib, which inhibit Hedgehog
               signals by binding smoothened (SMO), in combination with FOLFOX was assessed in phase 2, but did not
               benefit PFS (11.5 months vs. 9.3 months; P = 0.34) . Moreover, BRIGHTER study assessed napabucasin,
                                                           [54]
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