title: Diethylstilbestrol and docetaxel: a Phase II study of tubulin active agents in patients with metastatic, androgen-independent prostate cancer.
abstract: BACKGROUND
  The addition of diethylstilbestrol to docetaxel modified tubulin composition and improved the response of prostate cancer to chemotherapy in preclinical models. An attempt was made to recapitulate the observations in a clinical trial.
  
  
  METHODS
  Twenty-nine patients with progressive, metastatic, chemotherapy-naive androgen-independent prostate cancer were treated with diethylstilbestrol 1 mg daily and 5 mg on the day before docetaxel and docetaxel 36 mg/m(2) intravenously weekly for 3 weeks of a 4-week cycle. Prophylactic anticoagulation was used in all patients. Patients were assessed by prostate-specific antigen (PSA) monthly and computed tomography (CT) and bone scans every 3 cycles. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria and PSA decline by >50% maintained for 4 weeks were used to assess activity.
  
  
  RESULTS
  The median age was 68 years (range, 56-84 years), Southwest Oncology Group performance status 0 (score range, 0-2), alkaline phosphatase 120 U/L (range, 49-523), hemoglobin (Hgb) 12.6 g/dL (range, 9.2-16.3), PSA 66 ng/dL (range, 4-1962). The median number of cycles administered was 6. Soft tissue metastases were present in 51% of patients and bone metastases in 93%. Twenty-nine patients are evaluable for response. Of these, 20 patients (69%, 95% confidence interval [CI], 49%-85%) had a PSA decline of >50% and the PSA declined by >90% in 12 patients (41%, 95% CI, 23.1%-58.9%). Of 15 patients with measurable disease, 6 (40%, 95% CI, 23.5%-61%) had a partial response. Median time to progression was 6 months (range, 3-19 months). Fifteen patients (51%) suffered grade 3/4 toxicity. Two patients died of causes unrelated to therapy and another died from a steroid-induced ulcer. Six patients developed thrombosis and of those tested 75% had Factor V mutations. Pretreatment PSA, performance status, Hgb, and alkaline phosphatase had no impact on the likelihood of response.
  
  
  CONCLUSIONS
  The combination of diethylstilbestrol and docetaxel produces a significant level of activity, measured by PSA decline and measurable disease response rate, and except for venous thrombosis the toxicity appears similar to that seen with docetaxel plus prednisone. These results suggest that tubulin modulation with diethylstilbestrol may improve the therapeutic efficacy of docetaxel and the combination is worthy of further study.
authors.affiliation: Department of Medicine, Veterans Affairs Puget Sound Health Care System (VAPSHCS), and University of Washington School of Medicine, Seattle, WA 98108, USA. rbmontgo@u.washington.edu
authors.forename: R Bruce
authors.initials: RB
authors.lastname: Montgomery
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.forename: Daniel
authors.initials: D
authors.lastname: Lin
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Ryan
authors.forename: Mark
authors.initials: M
authors.lastname: Garzotto
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Beer
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003967:Diarrhea / Q000139:chemically induced; D004054:Diethylstilbestrol / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000009:adverse effects; D020246:Venous Thrombosis / Q000139:chemically induced
chemical_list: D050257:Tubulin Modulators; D004054:Diethylstilbestrol; D017430:Prostate-Specific Antigen; D017239:Paclitaxel