Diagnostic Assessment Report commissioned by the NIHR HTAProgramme on behalf of the National Institute for Health and CareExcellence – Final report. Fluorouracil plasma monitoring : the My5-FU assay for guiding dose adjustment in patients receiving fluorouracil chemotherapy by continuous infusion

Introduction 5-flourouracil (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 and cost effectiveness of the My5-FU assay for PK dose adjustment to 5-FU therapy. Objectives To systematically review the evidence on: A. the accuracy of the My5-FU assay compared to gold standard methods (High-Performance Liquid Chromatography [HPLC] and Liquid Chromatography-Mass Spectrometry [LC-MS]). B. the effectiveness of My5-FU PK dosing compared to BSA C. the effectiveness of HPLC and/or LC-MS compared with BSA D. the generalizability of published My5-FU and PK studies E. costs of using My5-FU To develop a cost-effectiveness model. Methods We searched MEDLINE, EMBASE, Science Citation Index and other databases between JanuaryApril 2014. Two reviewers independently screened titles and abstracts with arbitration and consensus agreement. We undertook quality assessment. We reconstructed Kaplan-Meier plots for progressionfree survival (PFS) and overall survival (OS) for comparison of BSA and PK dosing. We developed a cost effectiveness model to compare My5-FU with BSA dosing, using PFS, OS and adverse events and costs with a lifetime horizon, from a Health and Personal Social Services (PSS) with a 3.5% discount rate over a 10 year time horizon with a 2-week cycle length. Results 8341 records were identified through electronic searches and 35 and 54 studies were included in the clinical and cost effectiveness reviews, respectively. There was a high correlation between My5-FU, HPLC and LC-MS/MS but upper and lower limits of agreement were -18% to +30%. Quality and quantity of evidence were very weak for PK versus BSA dosing for all cancers with no RCTs using 17 current regimens. Median overall survivals were estimated as 19.6 months (95% CI: 17.0 – 21.0) PK versus 14.6 months (95% CI: 14.1 – 15.3) BSA for 5-FU + FA (folinic acid) and 27.4 months (95% CI: 23.2 – 38.8) PK versus 20.6 months (95% CI: 18.4 – 22.9) BSA for FOLFOX6 in metastatic colorectal cancer. For H&N cancer, two studies of regimens no longer in use were identified. PK versus BSA studies were generalisable to the relevant populations. We developed cost effectiveness models for mCRC and H&N. The base case assumed a cost per My5-FU assay of £61.03. For mCRC for 12 cycles of a FOLFOX regimen, there was a QALY gain of 0.599 with an ICER of £4,148 per QALY. Probabilistic and scenario analyses gave similar results. The CEAC 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 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.