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Table 2. Summary of NCCN guideline for metastatic gastric adenocarcinoma
Line Preferred regimen (recommendation category)
First-line therapy HER2 overexpression Trastsuzumab combination with fluoropyrimidine and cisplatin (1)
Trastsuzumab combination with other chemotherapy agents (2b)
HER2 negative Fluoropyrimidine and cisplatin (1)
Fluoropyrimidine and oxaliplatin (2A)
Paclitaxel withcisplatin or carboplatin (2A)
Docetaxel with cisplatin (2A)
Fluoropyrimidine (2A)
Docetaxel or paclitaxel (2A)
Fluorouracil and irinotecan (2A)
DCF modification (2A)
ECF or ECF modification (2B)
Second-line therapy Ramucirumab and paclitaxel (1)
Paclitaxel (1)
Docetaxel(1)
Irinotecan (1)
Ramucirumab (1)
Fluorouracil and irinotecan (2A)
Irinotecan and cisplatin (2A)
Docetaxel and irinotecan (2B)
DCF: docetaxel, cisplatin, and intravenous 5-FU; ECF: epirubicin, cisplatin, and 5-FU; 5-FU: 5-fluorouracil

paclitaxel-based induction chemotherapy and chemoradiotherapy were also assessed. This trial demonstrated
that pCR rate was 20%, and over 36 months median survival had been estimated . In these trials, laparoscopic
[19]
staging and endoscopic ultrasonography were used for initial staging. Moreover, surgery was a part of
sequential treatment strategy and thus was required to be high quality, such as D2 dissection. Therefore,
this strategy was considered to be limited in some specialized institutions. The RTOG 9904 assessed quality,
survival, and safety of this strategy with 20 institutions and demonstrated its feasibility. In this trial, the pCR
and R0 resection rates were 26% and 77%, respectively. A D2 dissection was performed in 50% of patients .
[20]
Phase III trials to assess the value of preoperative chemoradiation in GAC, TOPGEAR trial, is currently evaluating
the efficacy of adding preoperative chemoradiation to perioperative ECF (MAGIC trial regimen) . The
[21]
CRITICS-II trial started to assess the optimal preoperative regimen by comparing three arms; preoperative
chemotherapy followed by surgery, preoperative chemotherapy and subsequent chemoradiation followed
by surgery, and preoperative chemoradiation followed by surgery (NCT02931890). Results of these trials are
forthcoming.

STANDARD TREATMENT FOR METASTATIC GAC IN THE USA
First line therapy
The recommended first-line therapy for patients with good performance status is a 2-drug combination of
oxaliplatin plus 5-FU or capecitabine [Table 2]. Trastuzumab is added to the first line cytotoxic therapy in
patients with HER2 positive GAC based on the ToGA trial . Irinotecan in the first line setting did not produce
[22]
OS advantage and used only for patients who are unable to tolerate platinum-based chemotherapy [23-25] .
Three-drug combination of docetaxel, cisplatin, and intravenous 5-FU (DCF) or its modification is used by
some but it is discouraged for two reasons: (1) it is toxic and provides marginal OS advantage and (2) it is
better to avoid a taxane in the first line because one would not be able to take advantage of paclitaxel and
ramucirumab in the second line. ECF is not recommended anymore in this situation .
[26]
5-FU alone or in combination with various reagents used to be the key chemotherapeutic agent against
metastatic GAC in the USA; FAM (5-FU, doxorubicin, and mitomycin), and FAMTX (methotrexate,
5-FU and adriamycin) used to be standard treatment [27,28] . EAP (etoposide, adriamycin, and cisplatin) was
temporarily used in the 1990s, but was discontinued due to toxicity . A randomized trial showed that ECF
[29]
was better than FAMTX, however remained controversial [30,31] .