title: Docetaxel plus oral metronomic cyclophosphamide: a phase II study with pharmacodynamic and pharmacogenetic analyses in castration-resistant prostate cancer patients.
abstract: BACKGROUND
  Docetaxel plus prednisone is currently the standard first-line treatment in metastatic castration-resistant prostate cancer (mCRPC). The aim of this study was to assess the clinical activity and pharmacodynamic/pharmacogenetic profile of docetaxel plus prednisone in combination with metronomic cyclophosphamide in mCRPC patients.
  
  
  METHODS
  Forty-one chemotherapy-naive patients received docetaxel (60 mg/m(2) intravenously every 3 weeks up to 12 cycles) and, from day 2, prednisone 10 mg/day, celecoxib 400 mg/day, and metronomic cyclophosphamide 50 mg/day, continuously. Plasma VEGF and bFGF were detected by ELISA. Real-time PCR-SNP analysis of VEGF gene was performed using an ABI PRISM 7900HT SDS and TaqMan SNP genotyping.
  
  
  RESULTS
  Eighty-seven percent of patients were free of progression at 6 months. A decrease in prostate-specific antigen ≥50% was observed in 82% of 39 evaluable patients, with a median time to progression of 12.3 months. Grade 3 adverse events were neutropenia (5%), thrombocytopenia, diarrhea, and stomatitis (2.5%). Median PFS and OS were 14.9 months (95% CI, 9.2-15.3 months) and 33.3 months (95% CI, 23-35.6 months), respectively. Of 11 patients (28%) with evaluable disease, 5 (44%) achieved a complete response, 2 (11%) a partial response, and 2 (11%) stable disease, whereas 2 showed disease progression. The -1154A/G VEGF polymorphism, plasma VEGF, and bFGF after the first cycle of chemotherapy may represent useful pharmacodynamic markers to predict better outcomes.
  
  
  CONCLUSIONS
  The combination of docetaxel and oral metronomic chemotherapy is effective and well tolerated in mCRPC patients and may deserve further evaluation.
authors.affiliation: Oncology Unit 2, University Hospital of Pisa, Pisa, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Derosa
authors.forename: Luca
authors.initials: L
authors.lastname: Galli
authors.forename: Paola
authors.initials: P
authors.lastname: Orlandi
authors.forename: Anna
authors.initials: A
authors.lastname: Fioravanti
authors.forename: Teresa
authors.initials: T
authors.lastname: Di Desidero
authors.forename: Andrea
authors.initials: A
authors.lastname: Fontana
authors.forename: Andrea
authors.initials: A
authors.lastname: Antonuzzo
authors.forename: Elisa
authors.initials: E
authors.lastname: Biasco
authors.forename: Azzurra
authors.initials: A
authors.lastname: Farnesi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Marconcini
authors.forename: Giulio
authors.initials: G
authors.lastname: Francia
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.forename: Guido
authors.initials: G
authors.lastname: Bocci
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D059250:Administration, Metronomic; D000284:Administration, Oral; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D018450:Disease Progression; D000077143:Docetaxel; D006801:Humans; D008297:Male; D008875:Middle Aged; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D003520:Cyclophosphamide
keywords: cyclophosphamide; docetaxel; metronomic chemotherapy; pharmacodynamic markers; pharmacogenetics; prostate cancer