Predictors of survival and toxicity in patients on adjuvant therapy with 5-fluorouracil for colorectal cancer

Abstract

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'UTR and 3'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=7.32; P<0.0001); (b) high-5FU clearance predicted poorer DFS (HR=1.96; P=0.041) and OS (HR=3.37; P=0.011); (c) advanced age was associated with shorter DFS (HR=3.34; P=0.0008) and OS (HR=2.66; P=0.024); (d) the C/C genotype of the MTHFR C677T polymorphism was protective against grade 3-4 toxicity (P=0.040); (e) none of the TYMS polymorphisms could explain 5FU toxicity or clinical outcome.

Figure 1

Mean cumulative 5FU dose administered, as percentage of initially planned dose, in each 5FU clearance quartile. Bars represent standard errors. Four patients who stopped therapy because of disease progression were excluded from analysis.

Figure 2

Disease-free (A) and overall survival (OS) plots (B) of patients stratified in four groups according to age (< or ⩾65 years) and 5FU clearance (< or ⩾0.017 mgl⁻¹Kg⁻¹). Open circles indicate censored data points. Log-rank test was significant for both disease-free survival (DFS) (P=0.0012) and overall survival (OS) (P=0.0036).