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Chapter 468advanced esophagogastric cancer treated with the combination of gemcitabine and cisplatin. Secondary endpoints were assessment of time to progression (TTP), defined as the time from randomization to progression and overall survival (OS), defined as the time from randomization to death. Further secondary objectives included the assessment of plasma homocysteine concentrations as an indication for plasma folic acid homeostasis. Moreover we investigated the effect of folate supplementation on plasma pharmacokinetics of cisplatin (total and free unbound), gemcitabine, the gemcitabin degradation product 2%u2019,2%u2019-difluoro2%u2019-deoxyuridine (dFdU) and, in white blood cells (WBC), its active metabolite gemcitabine-triphosphate (dFdCTP). We also determined polymorphisms in the genes encoding methylenetetrahydrofolate reductase (MTHFR), which may affect folate homeostasis[11], and cytidine deaminase (CDA), that catalyzes the deamination of gemcitabine to dFdU[18]. Toxicity evaluation, dose adjustments and response assessmentTreatment toxicity was rated according to CTC version 2.0 (CTCAE v2.0 Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 2.0, DCTD, NCI, NIH, DHHS (http://ctep.cancer.gov). All serious adverse events (SAE) were collected from registration until 30 days after the last protocol treatment administration. Criteria for chemotherapy administration on day 1 of each cycle was delayed one week in case of neutropenia (absolute neutrophil count (ANC) of < 1.5 x 109/L) or thrombopenia (platelets < 100 x 109/L), renal toxicity (creatinine > 120 %u03bcmol/L, and/or creatinine clearance < 60 ml/min) or any non-haematological toxicity above CTC grade 1 or baseline. Gemcitabine was reduced on day 8 with 25% or 50% in case of grade 2 or 3 neutropenia or grade 1 or 2 thrombopenia, respectively. Platelets < 50 x 109/L or neutrophils < 0.5 x 109/L were reason to omit gemcitabine on day 8. The dose of gemcitabine was reduced 50% in case of grade 3 non-haematological toxicity (except emesis) and discontinued in case of grade 4 AE%u2019s. The doses of gemcitabine and cisplatin were reduced with 25% after a two week treatment delay due to toxicity, neutropenic fever, grade 4 neutropenia and/or thrombopenia lasting over one week or thrombopenia associated with bleeding. Cisplatin was reduced or discontinued in case of grade %u22652 peripheral neuropathy or grade %u22652 renal toxicity or other grade %u22653 non-haematological toxicity (except emesis). No dose escalations were allowed. Unacceptable toxicity was defined as failure to recover from side effects after a treatment delay of a maximum of 3 weeks, requirement of a third dose