5-FU therapeutic monitoring with dose adjustment leads to an improved therapeutic index in head and neck cancer

Abstract

Summary This 4 year study reports on a pharmacokinetic study for the widely used regimen of cis-platin plus continuous 5-day 5-FU as first-line chemotherapy of head and neck cancer, and the benefit of such data for real-time therapy management. Pharmacokinetic analysis of 177 cycles for 77 patients from a group of 89 patients (group 1; 228 cycles) revealed that both the time-concentration product (AUC) for the entire cycle and the half-cycle AUC (AUCO3days) were predictive of cycle toxicity. Real-time analysis of individual AUCO-3 days was used to decide whether to reduce the dose during the second half of the cycle for a total of 249 cycles (81 patients; group 2). The dose in the second half of the course was reduced in 40% of the group 2 courses. There was a statistical difference in complete response rates between group 1 (31%) and group 2 (47%), (0.02<P<0.05) and a statistically significant reduction was observed in the incidence of toxic cycles (>grade 2, group 1= 20% versus group 2 = 12.4%; 0.02 <P <0.05). Pharmacokinetic follow-up of these patients has proved to be an objective means to improve therapeutic index significantly.In addition to the digestive tract, where its efficacy remains limited (Buroker et al., 1985), chemotherapy by 5-FU is used for other disease sites. In squamous cell carcinoma of the head and neck very high response rates have been observed when the drug is combined with cisplatin (CDDP) (Thyss et al., 1986b;Amrein & Weitzman, 1985;Kish et al., 1982). This combination protocol is accompanied by a significant incidence of toxicity (Amrein & Weitzman, 1985) that is often acceptable but sometimes severe, depending on the dose (Merlano et al., 1987) or the specific site (Kies et al., 1987).One of the major objectives of clinical pharmacokinetics is to improve the therapeutic index on an individual patient basis. For a limited population of head and neck carcinoma patients treated by CDDP-5-FU, we previously showed that the digestive tract and/or haematological tolerance was linked to the degree of total body exposure to the drug during the cycle (C xT, area under curve, AUC) (Thyss et al., 1986a).The first part of the present study extends and confirms this result on a larger population. In the second stage, data obtained were used for a prospective study in an attempt to improve the therapeutic index. Evaluation of response and toxicity Response was evaluated by the same physician 10 days after completion of the last chemotherapy course. Clinical response was defined using the product of two perpendicular lesion diameters. Complete response (CR) corresponded to disappearance of all clinically visible or palpable lesions; partial response (PR) was defined as tumour regression of over 50%; no response (NR) corresponded to tumour regression of 50% or less, stable disease or progressive disease. For the patients who underwent surgery after chemotherapy, the histological response was evaluated by examining the surgical specimen. Haematological and digestive tract toxicities were evaluated u...

Therapeutic drug monitoring of 5-fluorouracil

“…Santini et al determined the 5-FU AUC in 170 patients with squamous cell carcinoma of head and neck receiving first-line chemotherapy with cisplatin and continuous 5-day infusion of 5-FU [31]. In 81 patients (arm 2), 5-FU AUC during the first 3 days (AUC 0–3 days ) was analyzed in real-time to decide whether to reduce the dose of 5-FU during the second half of the cycle.…”

5-fluorouracil steady state pharmacokinetics and outcome in patients receiving protracted venous infusion for advanced colorectal cancer

“…Relationships between 5FU exposure and outcome have been reported for patients with head and neck cancer. Santini et al reported 2 sequential cohorts of patients in whom dose modification was made based on 5FU exposure (Santini et al, 1989). Santini suggested an increase in therapeutic index as patients appeared to suffer less toxicity and the complete response rate was also improved.…”

Individualization of 5-Fluorouracil in the Treatment of Colorectal Cancer

“…Interestingly, toxicity because of 5-FU exposure is not increased by the addition of other drugs in the regimen. Dose-adjustment strategies based on fluorouracil AUC have been reported for some fluorouracil-containing regimens, such as weekly 8-hour continuous intravenous infusion with intravenous bolus folinic acid 200 mg/m 2 , [60] long-term 5-fluorouracil continuous intravenous infusion with or without cisplatin [69] and a bimonthly regimen consisting of intravenous folinic acid 200 mg/m 2 /day over 2 hours followed by a fluorouracil intravenous bolus 400 mg/m 2 /day and a continuous fluorouracil intravenous infusion 600 mg/m 2 /day over the next 22 hours on two consecutive days (2000 mg/m 2 per cycle, called LV5FU2-regimen) [61].…”

“…Measures of systemic exposure towards fluorouracil (AUC, steady-state plasma concentration [Css], peak plasma concentration [Cmax]) have been correlated with the incidence of toxicity, tumour response and survival [59,60,65,68,69]. Most studies suggest that improved responses occurred in patients with a mean fluorouracil AUC be in the range of 24-30 AUC units (mg·h/L; Table 1) [58,59,[61][62][63], A number of studies have demonstrated that the target AUC for 5-FU is the same regardless of tumour type, administration schedule, and drug combination.…”

“…For continuous infusions, no limited sampling strategies based on predictions of AUC values have been published, but nomograms and charts for dose adjustments based on steady-state fluorouracil concentrations were developed. Plasma sampling was done at 8:00 am and 5:00 pm every day during a 3-day infusion, [69] or every 4th and 8th hour during a 6-day infusion [59,62]. The nomograms were presented as graphs or tables, and related dose decrements or increments to plasma concentration estimates made during the preceding cycle of therapy.…”