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disease of this tumor should include survival benefit with symptom relief, and systemic chemotherapy is a
[8]
major treatment option for those cases . Treatments for advanced EGJ adenocarcinoma has been developed
as a type of advanced gastric cancer, and many clinical trials were conducted targeting both EGJ and
gastric adenocarcinoma. Recent comprehensive molecular analysis for upper GI cancers reveals molecular
differences between EGJ and gastric adenocarcinoma [9,10] . Here, we update recent evidences of treatments for
advanced EGJ adenocarcinoma, and discuss future perspective.

CYTOTOXIC AGENTS (FOR HER2-NEGATIVE TUMORS)
Fluoropyrimidine (ftorafur, S-1, or capecitabine), platinum (cisplatin, or oxaliplatin), irinotecan, and
taxanes (paclitaxel, or docetaxel) are globally used for metastatic disease of EGJ adenocarcinoma. In
addition, trastuzumab is a humanized monoclonal antibody that selectively binds with high affinity to the
extracellular domain of the human epidermal growth factor receptor, and approved for tumors with HER2+
[protein overexpression by immunohistochemistry (IHC) or gene amplification by in situ hybridization
(FISH)] EGJ adenocarcinoma. Considering chemotherapeutic managements, tumor HER2 status is a
valuable information for adding trastuzumab to cytotoxic agents. As a first-line therapy, there is no widely
accepted first-line standard regimen for advanced EGJ adenocarcinoma.

In the USA and Europe, fluorouracil and platinum-based agents (CF) or docetaxel, fluorouracil, and
cisplatin (DCF) is widely used regimen based on the clinical trial. In 2006, the V-325 study group showed no
superiority between DCF and DC (docetaxel and cisplatin) in OS. Median OS was 9.6 months for DCF, and
10.5 months for DC. The incidence of hematologic toxicities was high, but it was comparable between DCF
and DC. Grade 3 or 4 neutropenia was the most common in hematologic toxicity; it occurred in 86% in the
patients with DCF, and 87% in DC cases, although non-hematologic toxicities of DCF had a higher incidence
[11]
than that of DC .

In Europe, epirubicin, cisplatin, and fluorouracil (ECF), epirubicin, cisplatin, and capecitabine (ECX),
epirubicin, oxaliplatin, and fluorouracil (EOF), or epirubicin, oxaliplatin, and capecitabine (EOX) is a
major regimen for advanced EGJ or stomach adenocarcinoma. The REAL-2 trial assessed above-mentioned
four regimens with different three-drug combination, and showed median OS of 9.9 months with ECF,
9.9 months with ECX, 9.3 months with EOF, and 11.2 months with EOX, respectively. One-year-survival
rates were 37.7%, 40.8%, 40.4%, and 46.8%. The trial showed capecitabine and oxaliplatin were as effective as
[12]
fluorouracil and cisplatin .
In Asia, the recommended first-line treatment is S-1 plus cisplatin (SP) or capecitabine plus cisplatin (XP). In
the SPIRITS trial [phase III, including advanced gastric adenocarcinoma (n = 298)], OS was better in patients
treated with SP than with S-1 alone. Median OS was 13.0 months [interquartile range (IQR) 7.6-21.9] in those
assigned to SP compared with 11.0 months (IQR 5.6-19.8) in those assigned to S-1 alone [hazard ratio (HR)
0.77; 95% CI 0.61-0.98; P = 0.04]. Progression-free survival (PFS) was significantly longer in those assigned to
SP than S-1 alone [median PFS 6.0 months (3.3-12.9) for SP vs. 4.0 months (2.1-6.8) for S-1 alone; P < 0.0001].
The trial showed more grade 3 or 4 adverse events including leucopenia, neutropenia, anemia, nausea, and
[13]
anorexia, in patients assigned to SP than in patients assigned to S-1 alone . However, the incidence of EGJ
cancer remains low in Japan, and this clinical trial included only gastric cancer patients. Therefore, the
standard treatment for EGJ cancer has not yet been established in Japan and patients with EGJ cancer are
usually treated based on the evidence for gastric cancer.

MOLECULARLY TARGETED DRUG
In the first decade of this century, molecularly targeted drugs have been developed for advanced EGJ
adenocarcinoma [Table 1]. To date, trastuzumab and ramucirumab are the only molecularly targeted drugs