Review Article5-Fluorouracil Response Prediction and Blood Level–Guided Therapy in Oncology: Existing Evidence Fundamentally Supports InstigationChavani, Ottiniel PGDipMLSc, MMLScAuthor Information Toxicology, The Department of Biochemistry, Canterbury Health Laboratories, Christchurch, New Zealand. Correspondence: Ottiniel Chavani, PGDipMLSc, MMLSc, Toxicology, Canterbury Health Laboratories, P O Box 151, Christchurch 8140, New Zealand (e-mail: [email protected]). The author declares no conflict of interest. Therapeutic Drug Monitoring: October 2020 - Volume 42 - Issue 5 - p 660-664 doi: 10.1097/FTD.0000000000000788 Buy Metrics Abstract 5-Fluorouracil (5-FU) response prediction and therapeutic drug monitoring (TDM) are required to minimize toxicity while preserving efficacy. Conventional 5-FU dose normalization uses body surface area. It is characterized by up to 100-fold interindividual variability of pharmacokinetic (PK) parameters, and typically >50% of patients have plasma 5-FU concentrations outside the optimal range. This underscores the need for a different dose rationalization paradigm, hence there is a case for 5-FU TDM. An association between 5-FU PK parameters and efficacy/toxicity has been established. It is believed that 5-FU response is enhanced and toxicity is reduced by PK management of its dosing. The area under the concentration–time curve is the most relevant PK parameter associated with 5-FU efficacy/toxicity, and optimal therapeutic windows have been proposed. Currently, there is no universally applied a priori test for predicting 5-FU response and identifying individuals with an elevated risk of toxicity. The following two-step strategy: prediction of response/toxicity and TDM for subsequent doses seems plausible. Approximately 80% of 5-FU is degraded in a three-step sequential metabolic pathway. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme. Its deficiency can cause toxicity with standard 5-FU doses. DPD also metabolizes uracil (U) into 5,6-dihydrouracil (UH2). The UH2/U ratio is an index of DPD activity and a credible biomarker of response and toxicity. This article outlines the UH2/U ratio as a parameter for 5-FU response/toxicity prediction and highlights key studies emphasizing the value of 5-FU TDM. Broad application of 5-FU response/toxicity prediction and blood level–guided therapy remains unmet, despite ever-increasing clinical interest. Considered collectively, existing evidence is compelling and fundamentally supports universal instigation of response/toxicity prediction and TDM. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.