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

Abstract

AimsTo evaluate UFT and cyclophosphamide (CTX) based metronomic chemotherapy plus celecoxib (CXB) for the treatment of patients with heavily pre-treated advanced gastrointestinal malignancies.MethodsThirty-eight patients received 500 mg/mq2 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-FUH2, 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.ResultsSeventeen 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 Cmax 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.ConclusionMetronomic 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.

Metastatic breast cancer patients treated with low-dose metronomic chemotherapy with cyclophosphamide and celecoxib: clinical outcomes and biomarkers of response

“…Indeed, other clinical MCT trials evaluated TSP-1 levels without finding a consistent behavior. Hence, it does not seems to be a useful biomarker, at least for MCT treatments [37][38][39][40].…”

Effect of celecoxib plus standard chemotherapy on serum levels of vascular endothelial growth factor and cyclooxygenase-2 in patients with gastric cancer

“…The synergistic effects of celecoxib and 5-fluorouracil, cisplatin, or etoposide were previously demonstrated in the BGC-823 gastric cancer cell line (13). Similarly, celecoxib was shown to synergistically inhibit tumor growth, angiogenesis and metastasis in patients with esophageal cancer when combined with other chemotherapeutic agents (14). However, the clinical value of celecoxib in the management of patients with gastric cancer has not been clearly determined.…”

Metronomic chemotherapy regimens in oncology

“…Одновременно снижалась экспрессия маркера стволовых клеток CD133 в пери-ферических мононуклеарах. В то же время значимых различий в динамике VEGF-A и vVE-C среди боль-ных в зависимости от ответа на метрономную тера-пию отмечено не было [104].…”