The optimization of 5-fluorouracil (5FU) dose by pharmacokinetic (PK) monitoring in Asian patients with advanced-stage gastrointestinal (GI) cancer.

Abstract

770 Background: PK guided dose management and systemic plasma levels of 5FU have shown correlation with both reduced toxicity and improved efficacy. However, data for Asian patients are lacking. Levels are highly variable with doses based on body surface area. Methods: Area under the curve (AUC) was estimated using a nanoparticle immunoassay from Saladax Biomedical (My5-FU). Patients with GI cancers receiving de Gramont, FOLFIRI or mFOLFOX6 regimens had 5 PK sampling time points obtained (reduced to 2 samplings after first 15 patients). If target AUC (18-28 mg.h/L) was reached for 2 consecutive cycles, monitoring is performed for alternate cycles. With dose adjustments, PK sampling will be done in the next cycle. Results: 50 patients (33 males, 17 females) enrolled, with 349 PK samplings done, and 291 analyzable. 31 (62%) had mFOLFOX6, 18 (36%) FOLIRI and 1 (2%) de Gramont. Colorectal cancer (76%) and gastric cancer (12%) were the most common cancer types. Median AUC (35 evaluable) was 24.2 in C1, 23.65 in C2 (n=38), 20.6 in C3 (n=38) and 22 mg.hr/L in C4 (n=35). Proportion of patients achieving target AUC were 54.3%, 32%, 39.5% and 51% respectively and did not change significantly despite PK guided doses adjustments (C1 vs. C4 p=0.81, C2 vs. C3 p= 0.63, C2 vs. C4 p=0.085, C3 vs. C4 p=0.31). Higher than expected rate of G3/4 neutropenia (52%) and fewer mucositis (0%) and diarrhea (8%) were observed. Other toxicities (all grades) were fairly consistent with historical data. There were no inter-cycle differences in rates of toxicity, and no relationship with G3/4 toxicities and high AUC levels were observed. Correlation of response rates, efficacy with AUC were omitted due to heterogeneous tumor types. Conclusions: Contrary to past studies, PK guided 5FU did not result in a greater number of patients achieving target AUC in Asian patients. Furthermore, AUC levels of 5FU did not correlate with toxicity. Larger numbers are needed to confirm the clinical utility and benefit of PK guided 5FU in Asian patients. Clinical trial information: NCT00943137.

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

“…Only a single conference abstract failed to show such effects from TDM of 5-FU. 85 Is there evidence that TDM reduces toxicity in patients receiving 5-FU?…”

“…4 However, this AUC target has only an $20% range, which is rather small, especially given the significant intrapatient variability and reported commercial testing experience, potentially resulting in frequent unnecessary dose adjustments. 30 Based on subsequent observational clinical studies and a review of the PK-PD data, the target range was subsequently widened to 20-30 mgÁh/L, and applied to 46-hour infusion schedules of 5-FU, as is now typically used with modern chemotherapy regimens, such as FOLFOX6 or FOLFIRI 16,30,33,85,100 (see also Figure 1). The recommended exposure target range of 20-30 mgÁh/L is not appropriate for 5-FU bolus dosing and infusions of 120 hours and longer.…”

“…Although there was only one randomized controlled clinical trial showing a substantial improvement of the proportion of patients being “within target” from 8% to 94%, there is an overwhelming amount of longitudinal data within cohorts of patients that shows consistent reduction of variability in exposure upon applying TDM. Only a single conference abstract failed to show such effects from TDM of 5‐FU …”

Therapeutic drug monitoring of 5-fluorouracil

“…Soh et al reported on the clinical experience with PK-guided dose adjustment of 5-FU in Asian patients (N = 50) with GI cancers (CRC in 76% and gastric cancer in 12%) receiving LV5FU2 (2%), FOLFIRI (36%), or mFOLFOX6 (62%) chemotherapy [40]. Plasma 5-FU AUC values were determined using an immunoassay, and 5-FU dose adjustments were recommended using a target 5-FU AUC of 18–28 mg•35;h/L.…”

Therapeutic drug monitoring for cytotoxic anticancer drugs: Principles and evidence-based practices

“…When patients frequently cannot receive therapy because of considerable financial burden labeled as “financial toxicity,” cost-effectiveness has now become an even more crucial factor to take into account. There are two studies [conducted by Goldstein (2014) and Soh (2015)] that evaluated the cost-effectiveness of TDM, and it has been observed that 5-FU TDM is economical in the management of both mCRC and SCCHN ( 104 , 105 ). Associated toxicities with 5-FU, such as febrile neutropenia, nausea/vomiting, and diarrhea, can have serious negative clinical and cost effects on patients and the healthcare system.…”