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 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.

Preliminary observations indicate variable patterns of plasma 5-fluorouracil (5-FU) levels during dose optimization of infusional 5-FU in colorectal cancer patients

“…Low 5-FU clearance has been shown to be a predictor of severe toxicity. 36 This research problem is significant given the current practice that doses given to patients are only reduced when toxic side-effects have been experienced. These side-effects can be avoided with the understanding that 5-FU-based chemotherapy may decrease the ability of patients to metabolize/clear 5-FU.…”

Effective inhibition of colon cancer cell growth with MgAl-layered double hydroxide (LDH) loaded 5-FU and PI3K/mTOR dual inhibitor BEZ-235 through apoptotic pathways

“…33,34 Fluorouracil is very toxic to normal cells and causes severe side effects at the therapeutic dosage, including damage to bone marrow, the gastrointestinal tract, and skin. 35,36 To reduce side effects, its dose must be decreased through combinational application with other drugs or drug delivery systems. In this study, we used LDH to lower the dose of 5-FU, at which higher cytotoxicity to cancer cells still remained.…”

Combinations of Polymorphisms in Genes Involved in the 5-Fluorouracil Metabolism Pathway Are Associated with Gastrointestinal Toxicity in Chemotherapy-Treated Colorectal Cancer Patients

“…Many of the genes that encode proteins involved in 5-FU metabolism contain polymorphisms that change their enzymatic activity or expression levels. Several studies have implicated genetic polymorphisms in thymidylate synthase (TYMS), methylene tetrahydrofolate reductase (MTHFR), and DPYD as risk factors for severe toxicity (3,4,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and a few studies have also implicated orotate phosphoribosyl transferase (OPRT) and VEGFA polymorphisms (15,17,20). The results have been contradictory, probably due to treatment differences, different patient populations, inadequate statistical analyses, and chance findings.…”

“…Reproducibility was checked by regenotyping 10% of the samples, which showed a 100% agreement. TYMS was genotyped using RFLP methods as described previously (19). The greater number of failed genotyping…”

“…This cohort consisted of prospectively collected patients from Italy (19 (18). DNA was isolated from formalin-fixed paraffin-embedded (FFPE) tumor specimens, containing at least 50% tumor tissue.…”