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

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.

Keywords: 5-FU; GI cancer; adverse event; pharmacokinetics; therapeutic drug monitoring.

Figure 1. Differences between the highest and lowest concentration/dose ratios among 3 cycles for each patient (delta ratios)

Figure 2. Relationship between 5-FU plasma concentration and 5-FU continuous infusion dose at cycle 1

Figure 3. Percentage of patients with 5-FU AUC values below, within or above the therapeutic range for each cycle (black columns: cycle 1, white columns: cycle 2, dotted columns: cycle 3)

Figure 4. Percentage of patients developing grade I/II or III/IV toxicity according to the AUC range (black columns: below or within the therapeutic range, white columns: above the therapeutic range)

Figure 5. Relative risks of grade I/II and III/IV diarrhea, hand-food syndrome, neutropenia and mucositis in patients below or within the AUC range versus overexposed patients

RR > 1 reflects higher incidence in the overexposed group, while RR < 1 represents higher incidence in patients below or within the AUC target. RR = Relative Risk, CI = Confidence Interval, NS = Not Significant, I/II = grade I/II, III/IV = grade III/IV.

Figure 6. Progression-Free Survival (PFS) of metastatic colon cancer patients in first or second line

Dash line: patients with at least one AUC below the target during the 3 first cycles. Black line: patients always within or higher than target during the 3 first cycles.