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Page 4 of 9                                    Eto et al. J Cancer Metastasis Treat 2018;4:23  I  http://dx.doi.org/10.20517/2394-4722.2017.73

               Capecitabine and cisplatin (Cape/CDDP) combination is one of the standard first-line regimens for patients
               with metastatic or recurrent GC worldwide. Cape/CDDP has been employed as a control regimen in
               global phase III trials, including the ToGA  and AVAGAST trials . The subset analyses of the Japanese
                                                                        [24]
                                                    [21]
               participants in these trials have shown safety and efficacy of this regimen; therefore, Cape/CDDP is a first-
               line treatment choice for Japanese patients.

               The REAL-2 trial  evaluated whether fluorouracil could be replaced with capecitabine, and cisplatin
                               [32]
               replaced with oxaliplatin, in the epirubicin, 5-FU and cisplatin (ECF) regimen. This trial demonstrated that
               capecitabine and oxaliplatin are as effective as 5-FU and cisplatin, respectively, in patients with previously
               untreated esophagogastric cancer. Cisplatin causes renal toxicity and intravenous hydration is required to
               decrease the toxicity. Oxaliplatin does not require hydration and can be administered in an outpatient clinic.
               In Japan, the combination of S-1 plus oxaliplatin (SOX) appears to be as effective as SP for metastatic GC,
               with a favorable safety profile .
                                        [33]
               The superiority of a combination of S-1 and docetaxel (DTX) to S-1 monotherapy as first-line treatment was
               evaluated in the START trial  which included Japanese and Korean patients with metastatic or recurrent
                                        [34]
               GC. Although the initial survival analysis failed to demonstrate superiority after clarifying the outcomes
               of censored cases, a reanalysis demonstrated the efficacy of this regimen [OS 12.5 vs. 10.8 months, hazard
               ratio (HR) 0.84, 95% CI: 0.71-0.99, P = 0.032]. Therefore, S-1/DTX can be selected as an alternative to SP,
               Cape/CDDP, or SOX. Both irinotecan (CPT-11) plus cisplatin and S-1 plus CPT-11 combinations failed
               to demonstrate survival benefit over 5-FU alone or S-1 alone, and are not recommended as a first-line
               regimen [35,36] .

               Regarding triplet regimens, the V325 trial  demonstrated survival benefits of docetaxel, cisplatin, and 5-FU
                                                  [37]
               (DCF) over cisplatin and 5-FU (CF), although grade 3 or 4 toxicities were more frequent with DCF than CF.
               In Japan, a triplet regimen consisting of S-1, cisplatin and docetaxel is currently being evaluated in a phase
               III trial, JCOG1013, based on the favorable results of a phase II trial in Japan [38-40] .


               Based on these findings, the Japanese guidelines recommend SP or Cape/CDDP as first-line treatment
               of HER2-negative metastatic GC, and SOX, CapeOX, FOLFOX, FP and S-1/DTX are recommended as
               alternatives.


               HER2-positive advanced GC
               The ToGA trial showed that trastuzumab combined with conventional chemotherapy provided a significant
               survival advantage compared with chemotherapy alone in patients with HER2 positive metastatic or recurrent
               GC . A total of 584 patients who had HER2-positive advanced GC or gastroesophageal junction cancer were
                  [21]
               randomly assigned to chemotherapy (consisting of CF or Cape/CDDP) with or without trastuzumab. The addition
               of trastuzumab significantly improved OS from 11.1 to 13.8 months (P = 0.0046), as compared with chemotherapy
               alone. In addition, PFS increased from 5.5 to 6.7 months (HR 0.7, 95% CI: 0.59-0.85, P = 0.0002). In the subgroup
               analysis, the survival benefit was more evident in the group of patients who had immunohistochemistry
               (IHC) 3+ or IHC 2+/fluorescent in-situ hybridization (FISH)-positive tumors than in the others. The addition
               of trastuzumab increased survival from 11.8 to 16.0 months (HR 0.65, 95% CI: 0.51-0.83, P = 0.036) among
               this cohort. Therefore, trastuzumab is recommended for patients with IHC 3+ or IHC 2+/FISH positive
               tumors. A phase II trial to explore the efficacy and toxicity of trastuzumab combined with triweekly SP enrolled
               a total of 56 patients . The response rate and the disease control rate were 68% (95% CI: 54%-80%) and 94% (95% CI:
                               [41]
               84%-99%), respectively. The median OS and PFS were 16.0 and 7.8 months, respectively. Major grade 3 or 4
               adverse events included neutropenia (36%), anorexia (23%), and anemia (15%). Although the study was not
               a randomized controlled trial, SP plus trastuzumab is considered to be a first-line chemotherapy choice for
               HER2-positive metastatic GC in Japan.
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