Predicting 5-fluorouracil toxicity in colorectal cancer patients from peripheral blood cell telomere length: a multivariate analysis

Abstract

Background: Identifying various pretreatment factors that predict chemotherapy-induced toxicity in colorectal cancer (CRC) patients undergoing treatment for their disease is crucial to optimising patient care.

Methods: Seventy-three patients received adjuvant 5-fluorouracil (5FU)/leucovorin using either the Mayo Clinic (n=42) or a weekly schedule (n=31) and evaluated for clinical toxicity. Pretreatment blood analysis included measures of plasma uracil and dihydrouracil, peripheral blood mononuclear cell (PBMNC) telomere length (TL), standard biochemistry and cell differential analysis. On the first day of treatment 5FU-pharmacokinetic variables of area under the curve, half life and clearance were also measured. These variables together with age and gender were used in univariate and multivariate analysis as predictors of clinical toxicity.

Results: For the Mayo schedule the primary toxicities were neutropenia (69%), mucositis (58%) and leukopenia (46%), with 70% of patients presenting with haematological toxicity ≥grade 1 (neutropenia and/or leukopenia). Multivariate analysis showed that haematological toxicity was predicted by short TL, high platelet lymphocyte ratio (PLR) and low neutrophil count (R(2)=0.38, P<0.0006), whereas mucositis was predicted by age, TL and PLR (R(2)=0.34, P<0.001). For the weekly schedule diarrhoea predominated (16%), with female gender as the only predictive factor. Although measures of uracil metabolism correlated well with 5FU metabolism (r=0.45-0.49), they did not indicate abnormal pyrimidine metabolism in this cohort and not surprisingly failed to predict for 5FU toxicity.

Conclusion: Short TL of PBMNC and an increased PLR were strong predictors of mucositis and haematological toxicity in CRC patients undergoing 5FU treatment in the adjuvant setting.

Figure 1

Association between 5FU-induced clinical toxicity and specific pre-treatment blood parameters in patients receiving the Mayo Schedule of chemotherapy. A smaller BSA (P=0.01) and an increase in PLR (P=0.005) strongly associates with the induction and severity of leukopenia (A, B). Induction and severity of mucositis strongly associates with younger patients (P=0.017) (C). Lower WBC (P=0.006) and lower ANC (P=0.008) strongly associates with induction of haematological toxicity (D, E). Short TL in PBMNCs strongly associates (P=0.003) with induction of haematological toxicity (F). Haematological toxicity is defined as grade 1 or greater leukopenia and/or neutropenia (shaded circles represent grades 3 and 4). The solid bar represents the median value.