title: Neutropenia as a potential pharmacodynamic marker for docetaxel-based chemotherapy in men with metastatic castration-resistant prostate cancer.
abstract: BACKGROUND
  Docetaxel clearance appears increased in men who are castrated. Neutropenia in cycle 1 may be a pharmacodynamic marker for docetaxel, which may enable tailored dosing in metastatic castration-resistant prostate cancer (mCRPC).
  
  
  METHODS
  The association of cycle 1 neutropenia with overall survival (OS) was examined post hoc in a randomized phase II trial of 221 men with mCRPC who received docetaxel-prednisone combined with placebo or AT-101 (bcl-2 inhibitor); weekly blood cell counts were performed during the first cycle. Patients from both arms were combined because no outcome and toxicity differences were observed. OS was calculated from randomization by the Kaplan-Meier method, and Cox proportional hazards regression models were used to estimate the association with OS.
  
  
  RESULTS
  The difference in OS between men with day 8 ≥grade 3 neutropenia and those with ≤grade 2 neutropenia was significant after adjusting for trial stratification factors, pain, and performance status (hazard ratio [HR] 0.64; 2P = .048). Results were similar for logarithmic neutrophil counts adjusted for the risk group based on anemia, visceral metastasis, progression by bone scan and pain (HR 1.18; 2P = .07) for stratification factors (HR 1.20; 2P = .052) or both (HR, 1.20; 2P = .046). Men with ≥grade 3 neutropenia and ≥30% prostate-specific antigen level decline by day 90 had improved OS compared with men exhibiting neither (HR 0.51; 2P = .014).
  
  
  CONCLUSIONS
  For patients with mCRPC who received docetaxel, ≥grade 3 neutropenia on day 8 was prognostic for improved OS, which suggests its utility as a pharmacodynamic marker, in this hypothesis-generating analysis. Exploration of dose escalation of docetaxel to attain ≥grade 3 neutropenia on day 8 may be warranted.
authors.affiliation: Department of Oncology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Pond
authors.forename: William R
authors.initials: WR
authors.lastname: Berry
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galsky
authors.forename: Brian A
authors.initials: BA
authors.lastname: Wood
authors.forename: Lance
authors.initials: L
authors.lastname: Leopold
authors.forename: Guru
authors.initials: G
authors.lastname: Sonpavde
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000494:pharmacology; D018572:Disease-Free Survival; D000077143:Docetaxel; D006072:Gossypol / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced*; D011241:Prednisone / Q000008:administration & dosage; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D012189:Retrospective Studies; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage*
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D017430:Prostate-Specific Antigen; D006072:Gossypol; C028178:gossypol acetic acid; D011241:Prednisone