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

• Published in: Angiogenesis (London) 2012-06, Vol.15 (2), p.275-286
• Main Authors: Allegrini, Giacomo, Di Desidero, Teresa, Barletta, Maria Teresa, Fioravanti, Anna, Orlandi, Paola, Canu, Bastianina, Chericoni, Silvio, Loupakis, Fotios, Di Paolo, Antonello, Masi, Gianluca, Fontana, Andrea, Lucchesi, Sara, Arrighi, Giada, Giusiani, Mario, Ciarlo, Andrea, Brandi, Giovanni, Danesi, Romano, Kerbel, Robert S., Falcone, Alfredo, Bocci, Guido
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Blood and lymphatic vessels; Cancer Research; Cardiology; Cardiology. Vascular system; Cardiovascular system; Celecoxib; Cell Biology; Cyclophosphamide - administration & dosage; Cyclophosphamide - pharmacokinetics; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Female; Gastrointestinal Neoplasms - blood; Gastrointestinal Neoplasms - drug therapy; Humans; Male; Medical sciences; Middle Aged; Oncology; Ophthalmology; Original Paper; Pharmacology. Drug treatments; Pyrazoles - administration & dosage; Pyrazoles - pharmacokinetics; Sulfonamides - administration & dosage; Sulfonamides - pharmacokinetics; Tegafur - administration & dosage; Tegafur - pharmacokinetics; Uracil - administration & dosage; Uracil - pharmacokinetics; Vascular Endothelial Growth Factor A - blood; Vasodilator agents. Cerebral vasodilators
• ISSN: 0969-6970; 1573-7209
• DOI: 10.1007/s10456-012-9260-6

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.