Clinical, pharmacokinetic and pharmacodynamic evaluations of metronomic UFT and cyclophosphamide plus celecoxib in patients with advanced refractory gastrointestinal cancers

Abstract

Aims: To evaluate UFT and cyclophosphamide (CTX) based metronomic chemotherapy plus celecoxib (CXB) for the treatment of patients with heavily pre-treated advanced gastrointestinal malignancies.

Methods: Thirty-eight patients received 500 mg/mq(2) CTX i.v bolus on day 1 and, from day 2, 50 mg/day CTX p.o. plus 100 mg/twice a day UFT p.o. and 200 mg/twice a day CXB p.o. Tegafur, 5-FU, 5-FUH(2), GHB and uracil pharmacokinetics were assessed. Plasma vascular endothelial growth factor (VEGF), soluble VE-cadherin (sVE-C) and thrombospondin-1 (TSP-1) levels were detected by ELISA and real-time PCR of CD133 gene expression on peripheral blood mononuclear cell was also performed.

Results: Seventeen patients (45%) obtained stable disease (SD) with a median duration of 5.8 ms (range, 4.2-7.4). Median progression free survival (PFS) and overall survival (OS) were 2.7 ms (95% CI, 1.6-3.9 ms) and 7.1 ms (95% CI, 4.3-9.9 ms), respectively. No toxicities of grade >1 were observed. Pharmacokinetics of 27 patients (13/14, SD/progressive disease, PD) after the first treatment of UFT revealed that 5-FU AUC and C(max) values greater than 1.313 h × μg/ml and 0.501 μg/ml, respectively, were statistically correlated with stabilization of disease and prolonged PFS/OS. VEGF and sVE-C plasma levels were greater in the PD group when compared to SD group. CD133 expression increased only in the PD patients.

Conclusion: Metronomic UFT and CTX with CXB in heavily pre-treated gastrointestinal patients were well tolerated and associated with interesting activity. Potential predictive pharmacokinetic parameters and pharmacodynamic biomarkers have been found.

Fig. 1

Progression free survival (a) and overall survival (b) curves calculated by the Kaplan–Meier method from the first day of the metronomic CTX, UFT and CXB schedule

Fig. 2

Plasma levels of Tegafur, 5-fluorouracil (5-FU), 5-fluoro-5,6-dihydrouracil (5-FUH2), Uracil and gamma-hydroxybutyric acid (GHB) in 13 stable disease (SD) patients and 14 progressive disease (PD) patients at day 1, 28 and 56, receiving the metronomic CTX, UFT and CXB schedule. Points mean; bars Standard Deviation. *P < 0.05 PD versus SD; ^# P < 0.01 PD versus SD

Fig. 3

PFS according to 5-FU AUC (a) and C_max (b) cutoff values obtained by a ROC analysis (see “Results” section of the text) and OS according to 5-FU AUC (c) and C_max (d) values at day 1 of treatment of patients administered with the metronomic CTX, UFT and CXB schedule

Fig. 4

VEGF (a) and sVE-C (b) plasma level profiles of patients (n = 35) administered with the metronomic CTX, UFT and CXB schedule. Points mean; bars SD. The data are presented as percentage of the concentration at day 0 (before the beginning of the metronomic treatment) of each individual patient. *P < 0.05 PD versus SD. PD progressive disease, SD stable disease

Fig. 5

TSP-1 AUCs of patients (n = 35) administered with the metronomic CTX, UFT and CXB schedule (a). Mean ± SD; *P < 0.01 progressive disease (PD) versus stable disease (SD). CD133 gene expression in PBMC of patients administered with the metronomic CTX, UFT and CXB schedule (b). Points mean, bars SD. The data are presented as percentage of at day 0 (before the beginning of the metronomic treatment) of each single patient