title: Fluorouracil plasma monitoring: systematic review and economic evaluation of the My5-FU assay for guiding dose adjustment in patients receiving fluorouracil chemotherapy by continuous infusion.
abstract: BACKGROUND
  5-Fluorouracil (5-FU) is a chemotherapy used in colorectal, head and neck (H&N) and other cancers. Dose adjustment is based on body surface area (BSA) but wide variations occur. Pharmacokinetic (PK) dosing is suggested to bring plasma levels into the therapeutic range to promote fewer side effects and better patient outcomes. We investigated the clinical effectiveness and cost-effectiveness of the My5-FU assay for PK dose adjustment to 5-FU therapy.
  
  
  OBJECTIVE
  To systematically review the evidence on the accuracy of the My5-FU assay compared with gold standard methods [high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS)]; the effectiveness of My5-FU PK dosing compared with BSA; the effectiveness of HPLC and/or LC-MS compared with BSA; the generalisability of published My5-FU and PK studies; costs of using My5-FU; to develop a cost-effectiveness model.
  
  
  METHODS
  We searched MEDLINE, EMBASE, Science Citation Index and other databases between January and April 2014.
  
  
  METHODS
  Two reviewers independently screened titles and abstracts with arbitration and consensus agreement. We undertook quality assessment. We reconstructed Kaplan-Meier plots for progression-free survival (PFS) and overall survival (OS) for comparison of BSA and PK dosing. We developed a Markov model to compare My5-FU with BSA dosing which modelled PFS, OS and adverse events, using a 2-week cycle over a 20 year time horizon with a 3.5% discount rate. Health impacts were evaluated from the patient perspective, while costs were evaluated from the NHS and Personal Social Services perspective.
  
  
  RESULTS
  A total of 8341 records were identified through electronic searches and 35 and 54 studies were included in the clinical effectiveness and cost-effectiveness reviews respectively. There was a high apparent correlation between My5-FU, HPLC and LC-MS/mass spectrometer but upper and lower limits of agreement were -18% to 30%. Median OS were estimated as 19.6 [95% confidence interval (CI) 17.0 to 21.0] months for PK versus 14.6 (95% CI 14.1 to 15.3) months for BSA for 5-FU+folinic acid (FA); and 27.4 (95% CI 23.2 to 38.8) months for PK versus 20.6 (95% CI 18.4 to 22.9) months for BSA for FOLFOX6 in metastatic colorectal cancer (mCRC). PK versus BSA studies were generalisable to the relevant populations. We developed cost-effectiveness models for mCRC and H&N cancer. The base case assumed a cost per My5-FU assay of £ 61.03. For mCRC for 12 cycles of a oxaliplatin in combination with 5-fluorouracil and FA (FOLFOX) regimen, there was a quality-adjusted life-year (QALY) gain of 0.599 with an incremental cost-effectiveness ratio of £ 4148 per QALY. Probabilistic and scenario analyses gave similar results. The cost-effectiveness acceptability curve showed My5-FU to be 100% cost-effective at a threshold of £ 20,000 per QALY. For H&N cancer, again, given caveats about the poor evidence base, we also estimated that My5-FU is likely to be cost-effective at a threshold of £ 20,000 per QALY.
  
  
  CONCLUSIONS
  Quality and quantity of evidence were very weak for PK versus BSA dosing for all cancers with no randomised controlled trials (RCTs) using current regimens. For H&N cancer, two studies of regimens no longer in use were identified.
  
  
  CONCLUSIONS
  Using a linked evidence approach, My5-FU appears to be cost-effective at a willingness to pay of £ 20,000 per QALY for both mCRC and H&N cancer. Considerable uncertainties remain about evidence quality and practical implementation. RCTs are needed of PK versus BSA dosing in relevant cancers.
authors.affiliation: Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Karoline
authors.initials: K
authors.lastname: Freeman
authors.affiliation: Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Connock
authors.affiliation: McMDC Ltd, Glasgow, UK.
authors.forename: Ewen
authors.initials: E
authors.lastname: Cummins
authors.affiliation: Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Tara
authors.initials: T
authors.lastname: Gurung
authors.affiliation: Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Taylor-Phillips
authors.affiliation: Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Court
authors.affiliation: The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Saunders
authors.affiliation: Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Aileen
authors.initials: A
authors.lastname: Clarke
authors.affiliation: Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Sutcliffe
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy; D003362:Cost-Benefit Analysis; D016903:Drug Monitoring / Q000191:economics / Q000379:methods*; D005472:Fluorouracil / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007118:Immunoassay / Q000191:economics*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D053758:Nanoparticles; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D019057:Quality-Adjusted Life Years; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D005472:Fluorouracil