Clinical and pharmacodynamic evaluation of metronomic cyclophosphamide, celecoxib, and dexamethasone in advanced hormone-refractory prostate cancer.
OBJECTIVE
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.


METHODS
Twenty-eight patients (68% docetaxel-resistant) received 500 mg/m2 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 > or =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.


CONCLUSIONS
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.
Fontana
Andrea
A
Division of Medical Oncology, Azienda USL 6 of Livorno, Italy.
Galli
Luca
L
Fioravanti
Anna
A
Orlandi
Paola
P
Galli
Costanza
C
Landi
Lorenza
L
Bursi
Simona
S
Allegrini
Giacomo
G
Fontana
Eloise
E
Di Marsico
Roberta
R
Antonuzzo
Andrea
A
D'Arcangelo
Manolo
M
Danesi
Romano
R
Del Tacca
Mario
M
Falcone
Alfredo
A
Bocci
Guido
G
D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000097:blood / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology*; D015820:Cadherins / Q000097:blood / Q000187:drug effects; D000068579:Celecoxib; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D019700:Thrombospondin 1 / Q000097:blood / Q000187:drug effects / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000187:drug effects / Q000378:metabolism*; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D000068579:Celecoxib; D003520:Cyclophosphamide; D003907:Dexamethasone; D017430:Prostate-Specific Antigen; D011720:Pyrazoles; D013449:Sulfonamides; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5