26. The role of pharmacokinetic monitoring of fluorouracil in the improvement of efficacy and reduction of adverse reactions for patients with advanced gastric cancer

Objective: To retrospectively investigate the relationship between plasma concentration of fluorouracil and its therapeutic efficacy as well as adverse reactions in 70 patients with locally advanced or metastatic gastric cancer, and to determine the role of pharmacokinetic monitoring of fluorouracil in the improvement of efficacy and reduction of adverse reactions of fluorouracil-based chemotherapy.
Methods: Seventy patients with unresectable locally advanced or metastatic gastric cancer were randomly assigned into group A [treated with DCF regimen (docetaxol + cisplatin + fluorouracil), repeated every three weeks for at least four cycles] and group B [treated with DOF regimen (docetaxol + oxaliplatin + fluorouracil), repeated every three weeks for at least four cycles]. The plasma concentration of fluorouracil was detected by high performance liquid chromatography (HPLC) (time for detection: 4-6 AM) after continuous infusion of fluorouracil over 12 h in each cycle. The average values of plasma concentrations in each cycle were calculated, and the factors related to plasma concentration of fluorouracil were screened by stepwise regression. Then all patients were divided into three groups (group l, group 2 and group 3) according to the predictive confidence interval of plasma concentration of fluorouracil, and the average plasma concentrations of fluorouracil in each cycle of these three groups were less than or equal to 25.5 mg/L, 25.6-37.4 mg/L, and more than 37.4 mg/L, respectively. The relationship between plasma concentration of fluorouracil and its therapeutic efficacy as well as adverse reactions was retrospectively analyzed.
Results: Stepwise regression analysis showed that the plasma concentration of fluorouracil was associated with myelosuppression, mucositis, progression-free survival (PFS) and overall survival (OS). The average plasma concentrations of fluorouracil in group l, group 2 and group 3 were 20.73±3.80 mg/L, 31.98±3.10 mg/L and 40.32±3.45 mg/L, respectively (χ²=66.24, P<0.001). As for efficacy, the median PFS and OS of group 2 and group 3 were both significantly higher than those of group l (PFS: 6.00±0.32, 7.50±0.75 and 4.50±0.19 months, χ²=22.09, P<0.001; OS: 13.00±1.58, 12.50±2.66 and 8.50±l.00 months, χ²=32.32, P<0.001). In terms of adverse reaction, the incidence rates of bone marrow suppression and mucositis of group 3 were both higher than those of group 1 and group 2 (P=0.04 and P=0.03).
Conclusions: The patients with advanced gastric cancer receiving fluorouracil-based chemotherapy with an average plasma concentration of fluorouracil maintained within the range of 25.6-37.4 mg/L can obtain better survival and tolerance as well as lower incidence rates of adverse reactions such as myelosuppression (especially grade III/IV) and mucositis, etc.