title: Outcome, clinical prognostic factors and genetic predictors of adverse reactions of intermittent combination chemotherapy with docetaxel, estramustine phosphate and carboplatin for castration-resistant prostate cancer.
abstract: OBJECTIVE
  Docetaxel-based chemotherapy is effective in patients with castration-resistant prostate cancer (CRPC). This phase II study assessed the outcome and predictive factors for prognosis and toxicity following intermittent chemotherapy with docetaxel, estramustine phosphate, and carboplatin (DEC) in patients with CRPC.
  
  
  METHODS
  Thirty-five patients were treated with a DEC regimen that consisted of a 28-day cycle of drugs as follows: docetaxel (60 mg/m(2) on day 1), carboplatin (AUC 5 on day 1) and estramustine phosphate (560 mg daily). Treatment was continued intermittently. The end point was to test the effect of DEC on the response rate and overall survival (OS). Statistical correlations between the outcomes and predictive factors, including clinical parameters and 8 single-nucleotide polymorphisms (SNPs) related to drug metabolism, were assessed.
  
  
  RESULTS
  Prostate-specific antigen levels decreased by more than 30% in 65.7% of the patients. The median OS following DEC was 17.8 months, and the median total time of chemotherapy holiday was 7.7 months (range 1.7-35.8). On multivariate analysis, serum lactate dehydrogenase (LDH) was an independent prognostic factor for OS (p = 0.007). On SNP analysis, patients carrying the TT genotype of the ABCB1 C3435T polymorphism showed a significantly more severe leukocytopenia during the first cycle of DEC therapy compared to patients with the CC + CT genotype (p = 0.036).
  
  
  CONCLUSIONS
  Combination chemotherapy with DEC has a potential effect on CRPC with acceptable toxicity. Serum LDH may be a promising predictor of prognosis, and the ABCB1 C3435T polymorphism may be a genetic predictor of the severity of leukocytopenia in patients with CRPC treated with DEC.
authors.affiliation: Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Narita
authors.forename: Norihiko
authors.initials: N
authors.lastname: Tsuchiya
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yuasa
authors.forename: Shinya
authors.initials: S
authors.lastname: Maita
authors.forename: Takashi
authors.initials: T
authors.lastname: Obara
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Numakura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuruta
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Inoue
authors.forename: Yohei
authors.initials: Y
authors.lastname: Horikawa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Satoh
authors.forename: Tomonori
authors.initials: T
authors.lastname: Habuchi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D004961:Estramustine / Q000008:administration & dosage; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D043823:Taxoids; D000077143:Docetaxel; D004961:Estramustine; D016190:Carboplatin; D007770:L-Lactate Dehydrogenase