A community-based multicenter trial of pharmacokinetically guided 5-fluorouracil dosing for personalized colorectal cancer therapy

Abstract

Background: Pharmacokinetically guided (PK-guided) versus body surface area-based 5-fluorouracil (5-FU) dosing results in higher response rates and better tolerability. A paucity of data exists on PK-guided 5-FU dosing in the community setting.

Patients and methods: Seventy colorectal cancer patients, from one academic and five community cancer centers, received the mFOLFOX6 regimen (5-FU 2,400 mg/m(2) over 46 hours every 2 weeks) with or without bevacizumab at cycle 1. The 5-FU continuous-infusion dose was adjusted for cycles 2-4 using a PK-guided algorithm to achieve a literature-based target area under the concentration-time curve (AUC). The primary objective was to demonstrate that PK-guided 5-FU dosing improves the ability to achieve a target AUC within four cycles of therapy. The secondary objective was to demonstrate reduced incidence of 5-FU-related toxicities.

Results: At cycles 1 and 4, 27.7% and 46.8% of patients achieved the target AUC (20-25 mg × hour/L), respectively (odds ratio [OR]: 2.20; p = .046). Significantly more patients were within range at cycle 4 compared with a literature rate of 20% (p < .0001). Patients had significantly higher odds of not being underdosed at cycle 4 versus cycle 1 (OR: 2.29; p = .037). The odds of a patient being within range increased by 30% at each subsequent cycle (OR: 1.30; p = .03). Less grade 3/4 mucositis and diarrhea were observed compared with historical data (1.9% vs 16% and 5.6% vs 12%, respectively); however, rates of grade 3/4 neutropenia were similar (33% vs 25%-50%).

Conclusion: PK-guided 5-FU dosing resulted in significantly fewer underdosed patients and less gastrointestinal toxicity and allows for the application of personalized colorectal cancer therapy in the community setting.

Trial registration: ClinicalTrials.gov NCT01164215.

Keywords: Colorectal; Community; Dosing; Fluorouracil; Personalized; Pharmacokinetic.

Figure 1.

CONSORT diagram. ^aSample drawn after pump finished infusing, sample not analyzed secondary to labeling issues; patient given hydration via peripheral line and sample drawn without wasting, thus diluted; omission of stabilizing agent and/or blood sample hemolyzed. In addition, three of these patients had protocol violations such as per-protocol dose adjustment not made. ^bAll four patients completed two cycles of PK-guided 5-FU prior to being removed. Abbreviations: 5-FU, 5-fluorouracil; mFOLFOX6, modified FOLFOX regimen (5-FU, leucovorin, oxaliplatin); PK, pharmacokinetic.

Figure 2.

Percentage of patients below, within and above the prespecified area under the concentration-time curve (AUC) threshold at each cycle. (A): Significantly more patients were within range and significantly less were underdosed at cycle 4 compared with cycle 1 (p < .05). The percentages are reflective of the total number of independent patient samples at each cycle (i.e., patients with an AUC >25 mg × h/L at cycle 1 are not necessarily the same patients with an AUC >25 mg × h/L at cycle 4). ^aNumber of patients with an evaluable blood sample for AUC analysis at each cycle. (B): Cumulative percentage of patients achieving the target AUC at each cycle. ^aNumber of patients with an evaluable blood sample for AUC analysis at each cycle. Abbreviation: C, cycle.

Figure 3.

Rates of toxicity at each area under the concentration-time curve (AUC) range during the cycle at which toxicity occurred. ^aA significantly higher incidence of grade 3/4 neutropenia was observed in cycles during which AUC was >25 mg × h/L compared with cycles during which AUC was <20 mg × hour/L (21.6% vs. 8.1%; p = .05). ^bSignificantly higher rates of any grade 3/4 toxicity (e.g., neutropenia, diarrhea, mucositis, fatigue, nausea or vomiting) were noted in patients with an AUC >25 mg × h/L compared with AUC <20 mg × h/L (32.4% vs. 12.8%, respectively; p = .007).