title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Oncology, Calvary Mater Newcastle Hospital, Hunter Regional Mail Centre, Locked Bag No 7, Waratah, NSW 2310, Australia.
authors.forename: M B
authors.initials: MB
authors.lastname: Garg
authors.forename: L F
authors.initials: LF
authors.lastname: Lincz
authors.forename: K
authors.initials: K
authors.lastname: Adler
authors.forename: F E
authors.initials: FE
authors.lastname: Scorgie
authors.forename: S P
authors.initials: SP
authors.lastname: Ackland
authors.forename: J A
authors.initials: JA
authors.lastname: Sakoff
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000648:ultrastructure*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016615:Telomere / Q000378:metabolism* / Q000473:pathology
chemical_list: D002955:Leucovorin; D005472:Fluorouracil