title: Clinical, pharmacokinetic and pharmacodynamic evaluations of metronomic UFT and cyclophosphamide plus celecoxib in patients with advanced refractory gastrointestinal cancers.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Medical Oncology, Pontedera, Pisa, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Allegrini
authors.forename: Teresa
authors.initials: T
authors.lastname: Di Desidero
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Barletta
authors.forename: Anna
authors.initials: A
authors.lastname: Fioravanti
authors.forename: Paola
authors.initials: P
authors.lastname: Orlandi
authors.forename: Bastianina
authors.initials: B
authors.lastname: Canu
authors.forename: Silvio
authors.initials: S
authors.lastname: Chericoni
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.forename: Antonello
authors.initials: A
authors.lastname: Di Paolo
authors.forename: Gianluca
authors.initials: G
authors.lastname: Masi
authors.forename: Andrea
authors.initials: A
authors.lastname: Fontana
authors.forename: Sara
authors.initials: S
authors.lastname: Lucchesi
authors.forename: Giada
authors.initials: G
authors.lastname: Arrighi
authors.forename: Mario
authors.initials: M
authors.lastname: Giusiani
authors.forename: Andrea
authors.initials: A
authors.lastname: Ciarlo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Brandi
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.forename: Guido
authors.initials: G
authors.lastname: Bocci
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068579:Celecoxib; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005641:Tegafur / Q000008:administration & dosage / Q000493:pharmacokinetics; D014498:Uracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D011720:Pyrazoles; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D005641:Tegafur; D014498:Uracil; D003520:Cyclophosphamide; D000068579:Celecoxib