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

// Katarzyna Morawska 1 , Françoise Goirand 2, 3 , Laurine Marceau 1 , Madeline Devaux 1 , Adèle Cueff 1 , Aurélie Bertaut 1, 3 , Julie Vincent 1 , Leila Bengrine-Lefevre 1 , François Ghiringhelli 1, 3 and Antonin Schmitt 1, 3 1 Centre Georges-François Leclerc, Dijon, France 2 Laboratoire de Pharmacologie/Toxicologie, CHU de Dijon, Dijon, France 3 INSERM U1231, University of Burgundy Franche-Comté, Dijon, France Correspondence to: Antonin Schmitt, email: antonin.schmitt@u-bourgogne.fr Keywords: 5-FU; therapeutic drug monitoring; adverse event; GI cancer; pharmacokinetics Received: September 29, 2017      Accepted: January 23, 2018      Published: January 30, 2018 ABSTRACT Aims: 5-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. Results: 50.7% 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). Conclusions: Our 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. Methods: 155 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.