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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.