Measurements of 5-FU Plasma Concentrations in Patients with Gastrointestinal Cancer: 5-FU Levels Reflect the 5-FU Dose Applied

Abstract

Introduction: 5-Fluorouracil (5-FU) is the basis of most combination chemotherapies for gastrointestinal tumors. It is generally well tolerated, but side-effects might require dose-adjustment. As adverse events are not specific to the 5-FU component of the chemotherapy-combination, i.e. neutropenia, diarrhea or cardiotoxicity, the knowledge of 5-FU serum levels might help to attribute these side effects to the 5-FU compound. The optimal concentration-range (AUC, area under the curve) has been described to be within 20-25 mgh/l. The aim of this study was to analyse the intra- and interindividual variability of 5-FU AUC-levels in patients with 5-FU infusion therapy. Methods: 230 blood samples were obtained from 31 different gastrointestinal cancer patients (esophagus (8), stomach (10), ileum (1), colorectum (12)) treated with 5-FU-infusional regimes, based on a 24- or 48-hour AIO treatment-schedule. 5-FU plasma concentrations were measured using an immunolinked Elisa assay (Saladax 5-FU PCM<sup>TM</sup>). Intra- and interindividual differences were analysed before (0 h; n = 115), at 2 - 3 hours after the start of infusional 5-FU treatment (n = 19) (early sampling) and towards the end of the infusion (n = 96) (late sampling). Results: Early blood sampling resulted in low 5-FU plasma concentrations (541 ± 127 g/ml) due to saline prefilling (2 - 3 ml) of the Baxter pump. Blood sampling at the later time-point resulted in reproducible values (971 ± 81 ng/ml). 5-FU concentrations were dose-dependent with low intra- and interindividual variability. However, care has to be taken, as the results can be influenced by inaccurate blood sampling: too early or late sampling (when the folfusor-pump is empty), delayed centrifugation of the tube or hemolysis. Conclusions: With critical analysis of the measurements and correct performance of blood sampling, the measurement of 5-FU plasma concentrations with the immunoassay may in the future allow to optimize 5-FU dosing and to identify the cause of toxicity. Changes of 5-FU clearance in long-term therapy still have to be studied

Therapeutic Drug Monitoring in Oncology: International Association of Therapeutic Drug Monitoring and Clinical Toxicology Recommendations for 5‐Fluorouracil Therapy

“…If blood sampling for TDM is planned at the end of the drug infusions, patients should be recalled to the center ∼4 hours before the calculated end of infusion to avoid a substantial proportion of TDM failures as a consequence of empty drug pumps. Electric pumps are preferable compared to elastomeric pumps for patients in which 5‐FU TDM is performed, as they have a higher precision with regard to infusion times, while elastomeric pump balloons are sensitive to pressure, temperature, season, and patient activity …”

“…In reviewing 5‐FU PK data, one needs to consider a number of technical and pharmacological issues as to how the various studies were performed. Variability in infusion pump speed will translate in variability in steady‐state plasma concentrations of 5‐FU, especially with the use of elastomeric pump balloons, which are sensitive to pressure, temperature, season, and patient activity, but also with portable pumps delivering in essence a series of boluses . 5‐FU may also be unstable after collection, as it will continue to be metabolized by even small amounts of dihydropyrimidine dehydrogenase (DPD) present in blood and especially the buffy coat .…”

“…Electric pumps are preferable compared to elastomeric pumps for patients in which 5-FU TDM is performed, as they have a higher precision with regard to infusion times, while elastomeric pump balloons are sensitive to pressure, temperature, season, and patient activity. 11,12 While the time of day of the sampling may have an impact on measured concentration through the known circadian variation of 5-FU metabolism, this impact is variable and appears to be relatively small with a difference between 3 PM to 6 AM mean of 1 20% (95% CI 5 12-28%), comparable to even the residual variation within infusion (CV 5 21%). 36 Any such variability should be accommodated by the AUC target range of 20-30 mgÁh/L, and the sample timing could be standardized for a given patient whenever possible.…”

Notch pathway inhibition targets chemoresistant insulinoma cancer stem cells

“…After testing a set of chemotherapeutics commonly used in the treatment of human INS, we identified 5-FU as the most suitable drug to evaluate the INS cancer cells' chemoresistance. The relative IC 50 values for 5-FU of adherent CM and canINS cells were 5 µM and 0.5 µM, respectively, which reside within, or are lower than the therapeutic plasma dose range of 5-FU (800 ng/mL-2000 ng/mL, 5 µM-15 µM) (Danquechin-dorval & Gesta 1996, Yamada 2003, Blaschke et al 2012. Both CM and canINS CSC-enriched tumourspheres proved to be more resistant to 5-FU treatment compared to adherent cells in cell viability (Fig.…”

Pharmacokinetics of continuous transarterial infusion of 5-fluorouracil in patients with advanced hepatocellular carcinoma

“…The half-life of 5-FU in the human body is 10–20 min ( 47 ). The majority of drugs will reach steady state following 5 half-lives during continuous intravenous administration ( 48 ).…”