The Rationale for Pharmacokinetically Guided 5-FU Monitoring

JNCI | Review 1543 The fluoropyrimidine 5-fluorouracil (5-FU) has been used in daily clinical oncology practice for nearly 50 years, and it has been well established that a good correlation exists between 5-FU plasma levels and the biological effects of 5-FU treatment, both in terms of clinical efficacy and toxicity ( 1 – 6 ). Although 5-FU pharmacokinetic studies using cell-based and physical detection methods have been conducted since the mid-1960s ( 7 – 14 ), the application of 5-FU pharmacokinetic monitoring to clinical practice has become more realistic and practical since 5-FU administration via infusion schedules evolved to become the standard of care over the past 5 – 8 years ( 15 , 16 ). Clinical studies that were conducted during the past 20 years have demonstrated reduced toxicity and improved clinical outcomes with pharmacokinetic dose management. These pharmacokinetically guided studies have identifi ed an optimal target therapeutic range for 5-FU and have recommended dose-adjustment algorithms to bring plasma concentrations into the optimal range ( 17 – 29 ). Recent work has shown that many patients who are currently being treated with 5-FU are not being given the appropriate doses to achieve optimal plasma concentration. Of note, only 20% – 30% of patients are treated in the appropriate dose range, approximately 40% – 60% of patients are being underdosed, and 10% – 20% of patients are overdosed. Studies that have shown associations between 5-FU plasma concentration with toxicity and clinical effi cacy have demonstrated that pharmacokinetically guided dose adjustments substantially improve these biological effects, which are associated with 5-FU therapy. However, 5-FU monitoring has not been widely used, at least not in the United States, and certainly not outside the clinical research setting, given the absence of simple, fast, and inexpensive testing methods for 5-FU monitoring. Recent developments with testing based on liquid chromatography – mass spectrometry (LC-MS/MS) and a nanoparticle antibody – based immunoassay, as discussed later in this review, may facilitate routine monitoring of 5-FU in daily clinical practice ( 12 – 14 ).