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Most patients with gastric or gastroesophageal junction (GEJ) cancer are diagnosed with inoperable advanced or metastatic disease. In these cases, chemotherapy is the only treatment demonstrating survival benefit. The present study compares clinicopathologic characteristics and survival outcomes for patients with advanced esophageal, GEJ, and gastric adenocarcinoma treated with first-line chemotherapy [epirubicin-cisplatin-5-fluorouracil (ECF), epirubicin-cisplatin-capecitabine (ECX), or etoposide-leucovorin-5-fluorouracil (ELF)] or best supportive care (BSC) at our institution with those for historical controls. Methods We retrospectively reviewed medical information for 401 patients with newly diagnosed advanced esophageal, GEJ, or gastric adenocarcinoma treated with first-line chemotherapy (ECF, ECX, or ELF) or BSC from January 1, 2004, through December 31, 2010. Descriptive statistics were used to compare the data collected with data for historical control patients. Results Of the study patients, 93% were diagnosed with metastatic disease (n = 374), and 63% received BSC only (n = 251). The main reasons that patients received BSC only included poor Eastern Cooperative Oncology Group performance status (55%), patient decision (31%), and comorbidities (14%). Of the remaining patients, 98 (24%) received ECF or ECX and 52 (13%) received ELF as first-line treatment. Median overall survival was significantly longer in patients treated with ECF or ECX or with ELF than in those receiving BSC (12.7 months vs. 12.7 months vs. 5.5 months respectively). Chemotherapy also significantly reduced the risk of death (64% reduction with ECF or ECX, 58% with ELF). Conclusions We confirmed the substantial overall survival benefit of combination chemotherapy compared with BSC, with better survival in our patient population than in historical controls. However, novel treatment options are still warranted to improve outcomes in this patient population. [ABSTRACT FROM AUTHOR]