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Chapter 6114Part two: oesophageal and gastric cancerSystemic therapy and miRNAs. In chapter 4 we describe the results of a multicenter randomized open label phase 2 trial that aimed to improve the RR of palliative first-line chemotherapy for patients with advanced oesophageal cancer (EC) and gastric cancer (GC) by adding folic acid and vitamin B12 to the (at the time) commonly used schedule of cisplatin in combination with gemcitabine (24, 25). The rationale of this study consisted of an effect of the folate environment to cisplatin sensitivity of human cancer cell lines (26, 27) and the efficacy and toxicity benefits that were published after the addition of folic acid and vitamin B12 in a phase III study of pemetrexed in combination with cisplatin versus cisplatin in patients with a malignant mesothelioma as described in the introduction of this thesis (28). In the pemetrexed trial, a limited number of patients received chemotherapy without vitamin supplementation (in both the cisplatin and pemetrexed-cisplatin arm), and there was no randomization between those who received vitamin supplementation and those who did not. We first studied the sensitivity of adenocarcinoma cell lines for cisplatin under high and low folate conditions in the preclinical part of our study. It appeared that adenocarcinoma cells that were grown under high folate conditions were more sensitive to cisplatin and the intracellular platinum accumulation was higher in these cells, providing further support for the clinical part of the study in chapter 4. Patients with a histologically or cytologically confirmed metastatic or locally advanced EC (both squamous cell, ESCC or esophageal adenocarcinoma, EAC) or GC were included in this study. In the clinical part of the study a total of 82 patients were randomized from 2004 until 2013 between palliative treatment with cisplatin in combination with gemcitabine with or without folic acid and vitamin B12 suppletion. Vitamin suppletion did not result in a statistically significantly different RR (42.1% vs. 32.4%; p = 0.4). The median OS and time to progression (TTP) were 10.0 and 5.9 months, respectively, with chemotherapy and vitamin supplementation, compared to 7.7 and 5.4 months, respectively, with chemotherapy alone (OS, p = 0.9; TTP, p = 0.9). No difference in the plasma concentration of cisplatin and gemcitabine in the two treatment groups was observed, supporting the lack of a response benefit. The observation of lower plasma homocysteine levels in the supplemented group was interpreted as evidence of compliance with vitamin B12 and folic acid supplementation in the experimental group, since homocysteine is metabolized by folic acid and vitamin B12 metabolism (29). The different findings of the study in