Clinical and Pharmacodynamic Evaluation of Metronomic Cyclophosphamide, Celecoxib, and Dexamethasone in Advanced Hormone-refract

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Clin Cancer Res. 2009 Jul 21.

Clinical
and Pharmacodynamic Evaluation of Metronomic Cyclophosphamide,
Celecoxib, and Dexamethasone in Advanced Hormone-refractory Prostate
Cancer.

 
Fontana A, Galli L, Fioravanti A, Orlandi P, Galli C, Landi L, Bursi S, Allegrini G, Fontana E, Di Marsico R, Antonuzzo A, D'Arcangelo M, Danesi R, Del Tacca M, Falcone A, Bocci G.
Authors'
Affiliations: Division of Medical Oncology, Azienda USL 6 of Livorno,
Division of Pharmacology and Chemotherapy, Department of Internal
Medicine, and Department of Oncology, Transplants and New Technologies
in Medicine, University of Pisa, Division of Medical Oncology, Azienda
USL 5, Pisa, Pontedera, and Division of Medical Oncology, Azienda USL
2, Lucca, Italy.
 
PURPOSE: The aims of the
present study were to evaluate the clinical activity and the
pharmacodynamic profile of the novel schedule of a single i.v. standard
dose of cyclophosphamide (CTX) immediately followed by an oral
metronomic CTX regimen with celecoxib (CXB) and dexamethasone (DEX) in
advanced hormone-refractory prostate cancer patients.
EXPERIMENTAL
DESIGN:
Twenty-eight patients (68% docetaxel-resistant) received 500
mg/m(2) CTX i.v. bolus on day 1 and, from day 2, 50 mg/day CTX p.o.
plus 200 mg/twice a day CXB p.o. and 1 mg/day DEX p.o. until disease
progression. Plasma vascular endothelial growth factor (VEGF) and
thrombospondin-1 were detected by ELISA, and real-time reverse
transcription-PCR of VEGF and thrombospondin-1 gene expression on
peripheral blood mononuclear cell and of VE-cadherin (VE-C) in blood
samples was done.
RESULTS: A confirmed prostate-specific antigen
decrease of >/=50% from baseline was observed in 9 of 28 patients
(32%). Median progression-free survival and overall survival were 3
months (95% confidence interval, 2.2-4.2 months) and 21 months (95%
confidence interval, 12.4-29.4 months), respectively. Toxicity was mild
and no grade 3 to 4 toxicities occurred. A significant relationship was
found between plasma VEGF and prostate-specific antigen values (r =
0.4223; P < 0.001). VEGF levels significantly increased in
nonresponders, whereas the responder patients maintained significantly
lower levels of VE-C gene expression after the beginning of the
treatment if compared with nonresponder ones.
CONCLUSION: Metronomic
CTX plus CXB and DEX showed favorable toxicity and activity profile in
patients. VE-C gene expression and VEGF levels represent potentially
useful pharmacodynamic markers for the clinical response.