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The present study aimed at investigating whether the simultaneous evaluation of pharmacokinetic, pharmacogenetic and demographic factors could improve prediction on toxicity and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil (5FU)/leucovorin therapy. One hundred and thirty consecutive, B2 and C Duke's stage colorectal cancer patients were prospectively enrolled. 5FU pharmacokinetics was evaluated at the first cycle. Thymidylate synthase (TYMS) 5 0 UTR and 3 0 UTR polymorphisms and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms were assessed in peripheral leukocytes. Univariate and multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity, disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that: (a) low 5FU clearance was an independent predictive factor for severe toxicity (OR ¼ 7.32; Po0.0001); (b) high-5FU clearance predicted poorer DFS (HR ¼ 1.96; P ¼ 0.041) and OS (HR ¼ 3.37; P ¼ 0.011); (c) advanced age was associated with shorter DFS (HR ¼ 3.34; P ¼ 0.0008) and OS (HR ¼ 2.66; P ¼ 0.024); (d) the C/C genotype of the MTHFR C677T polymorphism was protective against grade 3 -4 toxicity (P ¼ 0.040); (e) none of the TYMS polymorphisms could explain 5FU toxicity or clinical outcome.

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