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Chapter 464AbstractPurpose: Preclinical research and prior clinical observations demonstrated reduced toxicity and suggested enhanced efficacy of cisplatin due to folic acid and vitamin B12 suppletion. In this randomized phase 2 trial, we evaluated the addition of folic acid and vitamin B12 to first-line palliative cisplatin and gemcitabine in patients with advanced esophagogastric cancer (AEGC). %u00a0Methods: Patients with AEGC were randomized to gemcitabine 1250 mg/m2 (i.v. days 1, 8) and cisplatin 80 mg/m2 (i.v. day 1) q 3 weeks with or without folic acid (450 %u03bcg/day p.o.) and vitamin B12 (1000 %u03bcg i.m. q 9 weeks). The primary endpoint was response rate (RR). Secondary endpoints included overall survival (OS), time to progression (TTP), toxicity, and exploratory biomarker analyses. Cisplatin sensitivity and intracellular platinum levels were determined in adenocarcinoma cell lines cultured under high and low folate conditions in vitro.Results: Adenocarcinoma cells cultured in medium with high folate levels were more sensitive to cisplatin and this was associated with increased intracellular platinum levels. In the randomized phase 2 clinical trial, which ran from October 2004 to September 2013, treatment was initiated in 78 of 82 randomized pts, 39 in each study arm. The RR was similar; 42.1% for supplemented patients vs. 32.4% for unsupplemented patients; p=0.4. Median OS and TTP were 10.0 and 5.9 months for supplemented vs 7.7 and 5.4 months for unsupplemented patients (OS, p=0.9; TTP, p=0.9). Plasma homocysteine was lower in the supplemented group (n = 20,%u00a0 6.9 %u00b1 1.6 (mean %u00b1 standard error of mean, SEM) %u00b5M;%u00a0 vs. 12.5 %u00b1 4.0 %u00b5M; p < 0.001). There was no significant difference in the Cmax of gemcitabine and cisplatin in the two treatment groups. Conclusion: Folic acid and vitamin B12 supplementation do not improve the RR, PFS or OS of cisplatin and gemcitabine in patients with AEGC.