title: Role of sorafenib in overcoming resistance of chemotherapy-failure castration-resistant prostate cancer.
abstract: BACKGROUND
  Sorafenib promotes apoptosis through downstream pathways that can be deregulated in CRPC. We hypothesized that sorafenib could overcome chemotherapy resistance in CRPC.
  
  
  METHODS
  Eligible patients were those whose disease had progressed during chemotherapy (docetaxel or mitoxantrone) or within 12 weeks of stopping either. Patients then continued or resumed their last chemotherapy regimen with the addition of sorafenib 400 mg twice daily. Patients received a maximum of 6 cycles of chemotherapy/sorafenib followed by sorafenib alone until disease progression. The primary end point was combination safety. Secondary end points were overall response, percentage of SD, and time to progression (TTP).
  
  
  RESULTS
  Twenty-two patients (21 evaluable) were enrolled (16 patients with Gleason score ≥ 7). Median age was 68 years (range, 59-83 years). Median prostate-specific antigen (PSA) was 142 ng/dL (range, 13.6-9584). Visceral and bone disease were present combined in 9 patients (41%). Ten patients (47.6%) showed biochemical response (19% with > 50% PSA decline) and 16 patients (76%) achieved radiographic stability (according to Response Evaluation Criteria for Solid Tumors) after starting sorafenib for a median duration of 6 months (range, 4-12 months). Grade 3/4 nonhematologic toxicities were fatigue (n = 7, 32%), palmar-plantar erythrodysesthesia (n = 4, 18%). Dose reduction of sorafenib occurred at least once in 15 patients (68%) because of palmar-plantar erythrodysesthesia (22%) and fatigue (22%). With a median follow-up of 19 months (range, 3-46 months), median overall survival was 8 months. TTP according to PSA level was 3 months and TTP according to imaging studies and/or clinically was 6 months. Median number of treatment cycles given was 6 (range, 1-10).
  
  
  CONCLUSIONS
  Sorafenib can be combined safely with chemotherapy and in some patients overcomes chemotherapy resistance.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Advocate Lutheran General Hospital, Park Ridge, IL.
authors.forename: Andrew
authors.initials: A
authors.lastname: Meyer
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Advocate Lutheran General Hospital, Park Ridge, IL.
authors.forename: Peter
authors.initials: P
authors.lastname: Cygan
authors.affiliation: Oncology Specialists, SC, Park Ridge, IL.
authors.forename: Kathy
authors.initials: K
authors.lastname: Tolzien
authors.affiliation: Oncology Specialists, SC, Park Ridge, IL.
authors.forename: Angel G
authors.initials: AG
authors.lastname: Galvez
authors.affiliation: Oncology Specialists, SC, Park Ridge, IL.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Bitran
authors.affiliation: Oncology Specialists, SC, Park Ridge, IL; Division of Hematology and Oncology, Department of Medicine, Advocate Lutheran General Hospital, Park Ridge, IL.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Lestingi
authors.affiliation: Department of Medicine, Section of Hematology and Oncology, The University of Chicago, Chicago, IL. Electronic address: cnabhan@medicine.bsd.uchicago.edu.
authors.forename: Chadi
authors.initials: C
authors.lastname: Nabhan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000401:mortality; D000077157:Sorafenib; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage; D017211:Treatment Failure
chemical_list: D010671:Phenylurea Compounds; D043823:Taxoids; D000077143:Docetaxel; D009536:Niacinamide; D000077157:Sorafenib; D008942:Mitoxantrone
keywords: Hormone-refractory; Nexavaar; Refractory disease; Resistance