Investigating the utilization of pharmacokinetic-guided fluorouracil in colorectal cancer.

Abstract

e13109 Background: Fluorouracil (FU) has remained the cornerstone of colorectal cancer (CRC) therapy for > 40 years; however, recent evidence suggests inter-individual pharmacokinetic (PK) variability in response. Methods: A total of 58 CRC patients from 6 academic and community sites received mFOLFOX6 (FU 2400 mg/m2 over 46 hours every 2 weeks) +/- bevacizumab. FU doses for cycles 2-4 were adjusted based on an algorithm to target an AUC of 20-25 mg*h/L. Peripheral blood was obtained 2-46 hours post beginning of infusion (BOI) and AUCs were determined using an immune-based assay (OnDose). The primary objective of this study is to describe the feasibility of PK-guided FU in clinical practice using descriptive statistics with a secondary objective of toxicity assessment. Results: Mean AUC post cycle 1 in evaluable patients (n=39) was 19.8 +/- 6.3 mg*h/L (range 7-38) with 31% within, 51% under, and 18% over the AUC target. Based on cycle 1 results, the mean dose estimated to achieve AUC 20-25 mg*h/L would be 2,505 +/- 304 mg/m2 (range 2,040-3,600). For cycle 1, the mean AUC at 2 and 18-24 hours post BOI was 17.5 +/- 6.9 and 21.6 +/- 6.3, respectively. Of 58 patients, 19 were not evaluable due to logistical issues such as sampling errors, dosage deviation from protocol, no stabilizing agent added to sample, or the patient was unable to return to clinic for sampling. Three hospitalizations due to serious adverse events occurred, with 2 at AUCs > 30. See the table for toxicities. Conclusions: Significant heterogeneity is noted in FU AUC with BSA-based dosing, with the majority of patients below the protocol-specified AUC threshold. Although FU should be at steady-state 2 hours post BOI until the end of infusion, a difference in AUC was seen between samples taken at 2 and 18-24 hours. With little study withdrawal observed after initial patient enrollment, appropriate logistical training can allow for individualization of FU in the front-line, community setting for the treatment of CRC; however, larger clinical trials are needed to define the clinical utility of PK-guided FU. [Table: see text]