5-FU therapeutic drug monitoring as a valuable option to reduce toxicity in patients with gastrointestinal cancer

Abstract

Aims5-FU is used as the main backbone of chemotherapy regimens for patients with colorectal and other gastrointestinal cancers. Despite development of new strategies that allowed enhancing clinical effectiveness and tolerability of 5-FU, 10–30% of patients treated with 5-FU-based regimens experience severe treatment-related toxicity. In our study, we evaluated the 5-FU exposure-toxicity relationship and investigated the efficacy of PK-guided dosing in increasing tolerability of 5-FU-based chemotherapy.Results50.7% of patients required dose adjustments after cycle 1. Percentage of patients within 5-FU AUC range was 49.3%, 66.9%, 61.0% at cycle 1, 2 and 3 respectively (p = 0.002 cycle 1 vs cycle 2). At all 3 cycles, lower incidences of grade I/II toxicities were observed for patients below or within range compared with those above range (19.4% vs 41.3%, p < 0.001 respectively).ConclusionsOur analysis confirms that the use of BSA-guided dosing results in highly variable 5-FU exposure and strongly suggests that PK-guided dosing can improve tolerability of 5-FU based chemotherapy in patients with gastrointestinal cancers, thus supporting 5-FU therapeutic drug monitoring.Methods155 patients with gastrointestinal cancers, who were to receive 5-FU-based regimens were included in our study. At cycle 1, the 5-FU dose was calculated using patient’s Body Surface Area (BSA) method. A blood sample was drawn on Day 2 to measure 5-FU concentration. At cycle 2, the 5-FU dose was adjusted using a PK-guided dosing strategy targeting a plasma AUC range of 18–28 mg·h/L, based on cycle 1 concentration. Assessments of toxicity was performed at the beginning of every cycle.

How can we best monitor 5-FU administration to maximize benefit to risk ratio?

“…Rates of A c c e p t e d M a n u s c r i p t nausea/vomiting, diarrhea or mucositis were significantly lower in the PK-guided group, contrary to neutropenia which were identical in both groups [34,40]. Of note, most of the time, low exposure and good overall tolerance were found in the PK-guided group, explaining the fact that dose was mainly increased [29,35].…”

“…Polymorphism in the gene coding for DPD (DPYD) has already been addressed and has been extensively discussed elsewhere [5,25] but age, gender, disease state and organ dysfunction (particularly liver failure) have also been reported to have an impact on 5-FU pharmacokinetics [26] [27,28]. Absence of correlation between body surface area and 5-FU clearance has been extensively demonstrated [29], [13].…”

“…Several maximal delays between sampling and centrifugation have been proposed. Whereas Boisdron-Celle et al [61] recommended a maximum delay of 2 hours between sampling and centrifugation, Morawska et al[29] proposed to centrifuge the blood sample within 30 min after collection. Indeed, these authors observed a decrease in concentrations of about 25% between samples centrifuged in the hour versus those centrifuged within 30 min after collection.…”

Suivi thérapeutique pharmacologique du 5-fluorouracile : mise au point et recommandations du groupe STP-PT de la SFPT et du GPCO-Unicancer

“…L'incidence des nausées et vomissements, des diarrhées ou des mucites est significativement inférieure dans le bras adapté, ce qui n'est pas le cas de l'incidence de neutropénies, qui reste comparable entre bras adapté et bras standard (27,34). A noter que, lors d'adaptation de posologie en fonction de l'exposition, la posologie est plus souvent augmentée que diminuée, devant un profil de toxicité souvent favorable (14,29).…”

Synthesis, Characterization and Preliminary Anticancer Study of Novel 5-fluorouracil Conjugate with Pyrrolidine Dithiocarbamate as a Mutual Anticancer Prodrug

“…(4)(5)(6) where NF-κB inhibition is independent of its antioxidant property (7) . 5-Fluorouracil (5-FU) the Fluorinated analogue of uracil, one of the commonly used chemotherapy drugs in anticancer therapy, for a variety of human malignancies breast cancer, head, and neck cancer (8) , skin cancer, (9) colorectal and other gastrointestinal cancers (10) . also ovarian and liver cancers (11) .…”