title: A randomized phase IIb presurgical study of finasteride vs. low-dose flutamide vs. placebo in men with prostate cancer. Efficacy monitored by karyometry.
abstract: OBJECTIVE
  Presurgical, window of opportunity trials have been proposed as a model to assess the activity of preventive and therapeutic interventions in a cost-effective manner in prostate cancer (CaP). The aim of the study was to explore karyometry as a method for monitoring the efficacy of intervention with preventive agents in patients with CaP.
  
  
  METHODS
  The material used in this investigation was from the 2F study, i.e., an Italian prospective randomized phase IIb presurgical study of finasteride vs. low-dose flutamide vs. placebo in men with CaP. Image analysis was performed in 16 cases treated with finasteride, 24 with flutamide, and 20 with placebo. For all these cases, CaP and normal looking secretory epithelium were present in the pretreatment biopsies as well as the post-treatment ex-vivo biopsies obtained from the radical prostatectomy specimens.
  
  
  RESULTS
  To establish a direction of nuclear change from normal to malignancy, i.e., the so-called line of progression, a discriminant function was derived with the normal looking epithelium in the pretreatment biopsies as one endpoint, and the CaP in the pretreatment biopsies as the other. The discriminant function was then applied to the post-treatment groups. The increase in relative nuclear area was the dominant feature. In the placebo group, 15 out of 20 CaP (75%) cases had a higher discriminant function score at the end of study, with a significant increase of the mean score by 90%. The flutamide treated CaP cases had increased discriminant function scores in 19 out of 24 cases (79%) and an increase of the mean score by 43%; the 5 cases with lower scores involved only minor reductions. In contrast, the finasteride treated CaP cases had increased discriminant function scores for 8 out of 16 cases (50%), but the increase in the mean score was by only 8%.
  
  
  CONCLUSIONS
  This exploratory study establishes that karyometric monitoring can track the results of subtle nuclear changes induced by preventive interventions in men with CaP, thus allowing assessment of agent activity in a cost-effective manner.
authors.affiliation: Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy. r.montironi@univpm.it
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Montironi
authors.forename: Peter H
authors.initials: PH
authors.lastname: Bartels
authors.forename: Andrea
authors.initials: A
authors.lastname: DeCensi
authors.forename: Matteo
authors.initials: M
authors.lastname: Puntoni
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Hurle
authors.forename: Ottavio
authors.initials: O
authors.lastname: Decobelli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Carmignani
authors.forename: Roberta
authors.initials: R
authors.lastname: Mazzucchelli
authors.forename: Hubert G
authors.initials: HG
authors.lastname: Bartels
authors.forename: David S
authors.initials: DS
authors.lastname: Alberts
authors.forename: Massimo
authors.initials: M
authors.lastname: Maffezzini
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D000368:Aged; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003362:Cost-Benefit Analysis; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D018120:Finasteride / Q000008:administration & dosage / Q000627:therapeutic use*; D005485:Flutamide / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007620:Karyometry; D008297:Male; D008875:Middle Aged; D057234:Preoperative Period; D011446:Prospective Studies; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000191:economics / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D018120:Finasteride; D005485:Flutamide