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Vitamin B12 and folic acid in advanced oesophageal and gastric cancer754Pharmacokinetic monitoring and assessment of potential prognostic parameters.Following vitamin supplementation, homocysteine levels were lower in supplemented patients vs unsupplemented patients (mean 6.9 %u00b1 1.6 %u00b5M; range 6.2%u00b17.2 vs. 12.5 %u00b1 4.0 %u00b5M; range 11.7%u00b113.4; p%u00a0<%u00a00.001) as shown in figure 3. This difference was expected since homocysteine levels are inversely related to folate and vitamin B12 consumption. Compared to pre-randomization levels, vitamin supplementation decreased homocysteine levels in supplemented patients while homocysteine increased when patients were randomized to the unsupplemented arm. This illustrates compliance to the allocated treatment arm.The maximum concentration (Cmax) of gemcitabine was identical for patients in both treatment groups (n%u00a0 =%u00a0 20; Cmax 53.4 %u00b1 18.6 (mean %u00b1 SEM) %u00b5M for supplemented vs. 53.2 %u00b1 15.0 %u00b5M for unsupplemented pts). However, vitamin supplementation did change gemcitabine pharmacokinetics. For example, supplementation resulted in increased levels of the gemcitabine metabolite dFdU (Fig. 3; p<0.05), and in addition also resulted in an increase in the formation of the active metabolite of gemcitabine dFdCTP (peak levels at 30 min 255 %u00b1 190 vs 133 %u00b1 93 pmol/106 cells and at 90 min 298 %u00b1 245 vs 226 %u00b1 101 pmol/106 cells; p>0.1), though these results were not statistically significant. Vitamin supplementation led to a small, but not statistically significant, increase in total cisplatin levels (total platinum 15.7 %u00b1 2.7 %u00b5M in the vitamin group vs 14.8 %u00b1 1.4 %u00b5M for patients without vitamin supplementation), and a significant increase in free (non-protein bound) platinum levels: 4.7 %u00b1 1.7 %u00b5M in the vitamin group vs. 3.6 %u00b1%u00a00.7 %u00b5M without vitamin supplementation (p<0.05). Genetic polymorphisms in the folate metabolizing enzyme MTHFR 677C>T were measured in 20 patients while polymorphisms in the gemcitabine metabolizing enzyme CDA 79A>C were measured in 37 patients. For the CDA gene, neither the OS (p=0.56; Log-rank; Mantel-Cox test), TTP (p=0.61; Log-rank; Mantel-Cox test) nor the RR (p=0.46, ANOVA test) differed significantly between the patients with the AA, CC or AC variant, although analyzed patient numbers may be too small to formally rule out smaller differences (table 3). Similarly, the incidence of grade 3 toxicity of any cause was not statistically significantly different between patients with either of the three polymorphisms (p=0.9).The OS (p=0.90 Log-rank; MantelCox test), TTP (p=0.89 Log-rank; Mantel-Cox test) and RR (p= 0.42 ANOVA test) were not significantly different for patients with a TT, CC or CT MTHFR 677. Again numbers may be considered too small for a reliable comparison. Grade 3 toxicity of any cause was equally distributed between the different polymorphisms.