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Chapter 478gemcitabine can be a relevant consideration for patients with AEGC and problems with the passage of food (and oral medication such as e.g. capecitabine) as a result of obstruction caused by the primary tumor. Therefore, the here employed cisplatin and gemcitabine treatment combination can be considered a reasonable or perhaps even preferred palliative treatment option for AEGC patients with e.g. signs of dysphagia or preexistent neuropathy. This multicenter randomized phase 2 trial was designed to investigate whether supplementation of folic acid and vitamin B12 resulted in an improved clinical outcome in AEGC patients treated with the combination of cisplatin and gemcitabine chemotherapy. Addition of folic acid and vitamin B12 to this chemotherapy backbone did not significantly increase the RR which was 42.1% (n=16) in the vitamin group vs 32.4% (n=12) in the chemotherapy alone group. The difference in RR between the study arms did not meet the prespecified target RR of 50% nor a 15% difference in RR between the two treatment groups. The median OS was not significantly different with or without vitamin suppletion (10.0 months vs 7.7 months). The median TTP was similar in both treatment groups (5.9 months for supplemented patients vs 5.4 months for unsupplemented patients). Baseline characteristics of the patients in both study arms were well balanced. Vitamin supplementation did not result in an apparent decrease in the incidence of grade 3-5 adverse events. As homocysteine levels are inversely related to folate and vitamin B12 consumption, the measured lower concentration of homocysteine in patients receiving concomitant vitamin supplementation is indicative of the biological activity of the employed vitamin supplementation and is in support of adequate patient compliance[28]. Though the use of second line chemotherapy or experimental therapy was not specifically documented in this trial, its use could potentially affect differences in OS between the two study groups. The impact of second line chemotherapy in AEGC was very limited if at all present and is unlikely to substantially confound our data. Our study results contrast with the previously reported beneficial effects observed when folic acid and vitamin B12 were added to the combination of cisplatin and pemetrexed and cisplatin monotherapy[6]. Apart from the fact that a different patient group was studied, both studies also differed in their design as our study