title: A randomized phase II trial of mitoxantrone, estramustine and vinorelbine or bcl-2 modulation with 13-cis retinoic acid, interferon and paclitaxel in patients with metastatic castrate-resistant prostate cancer: ECOG 3899.
abstract: BACKGROUND
  To test the hypothesis that modulation of Bcl-2 with 13-cis retinoic acid (CRA)/interferon-alpha2b (IFN) with paclitaxel (TAX), or mitoxantrone, estramustine and vinorelbine (MEV) will have clinical activity in men with metastatic castrate-resistant prostate cancer (CRPC).
  
  
  METHODS
  70 patients were treated with either MEV (Arm A) in a 3-week cycle or CRA/IFN/TAX with an 8-week cycle (Arm B). Patients were assessed for response, toxicity, quality of life (QOL), and the effect of treatment on Bcl-2 levels in peripheral blood mononuclear cells (PBMC).
  
  
  RESULTS
  The PSA response rates were 50% and 23%, measurable disease response rates (CR+PR) 14% and 15%, and median overall survival 19.4 months and 13.9 months on Arm A and Arm B respectively. Transient grade 4 neutropenia occurred in 18 and 2 patients, and grade 3 to 4 thrombosis in 7 patients and 1 patient in Arm A and Arm B respectively. Patients on Arm B reported a clinically significant decline in QOL between baseline and week 9/10 (.71 s.d.), and a significantly lower level of QOL than Arm A (p = 0.01). As hypothesized, Bcl-2 levels decreased with CRA/IFN therapy only in Arm B (p = 0.03).
  
  
  CONCLUSIONS
  Treatment with MEV was well tolerated and demonstrated clinical activity in patients with CRPC. Given the adverse effect of CRA/IFN/TAX on QOL, the study of other novel agents that target Bcl-2 family proteins is warranted. The feasibility of measuring Bcl-2 protein in a cooperative group setting is hypothesis generating and supports further study as a marker for Bcl-2 targeted therapy.
  
  
  BACKGROUND
  
  
  
  BACKGROUND
  CDR0000067865.
authors.affiliation: Department of Medicine, The Cancer Institute of New Jersey, UMDNJ-RWJMS, New Brunswick NJ, USA. dipaolrs@umdnj.edu
authors.forename: Robert S
authors.initials: RS
authors.lastname: DiPaola
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Chen
authors.forename: Mark
authors.initials: M
authors.lastname: Stein
authors.forename: David
authors.initials: D
authors.lastname: Vaughn
authors.forename: Linda
authors.initials: L
authors.lastname: Patrick-Miller
authors.forename: Michael
authors.initials: M
authors.lastname: Carducci
authors.forename: Bruce
authors.initials: B
authors.lastname: Roth
authors.forename: Eileen
authors.initials: E
authors.lastname: White
authors.forename: George
authors.initials: G
authors.lastname: Wilding
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D004961:Estramustine / Q000627:therapeutic use*; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D015474:Isotretinoin / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000627:therapeutic use*; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011788:Quality of Life; D015996:Survival Rate; D013723:Teratogens; D016896:Treatment Outcome; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000077235:Vinorelbine
chemical_list: D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013723:Teratogens; D004961:Estramustine; D014747:Vinblastine; D007372:Interferons; D008942:Mitoxantrone; D015474:Isotretinoin; D017239:Paclitaxel; D000077235:Vinorelbine