Prostate Cancer, Prostatic Intraepithelial Neoplasia
Conditions
Keywords
Prostate Cancer, Prostatic Intraepithelial Neoplasia, Chemoprevention, Flutamide, Finasteride, Biomarkers, drug response, Karyometry
Brief summary
Pre-surgical, window-of-opportunity trials provide a suitable model to assess the activity of preventive interventions in a cost-effective manner using tissue biomarkers as surrogate endpoints. Finasteride has been shown to reduce prostate cancer development in a large phase III trial, and flutamide has a well-known anticancer effect in advanced prostate cancer at the dose of 750 mg/day.
Detailed description
In this randomized, phase IIB, double blind, placebo controlled, multicenter, pre-surgical, window-of-opportunity trial we compared the effects of finasteride (5 mg/day) versus low-dose flutamide (250 mg/day) or placebo on tissue biomarkers in patients with prostate cancer who were candidate to radical surgery. Specifically, the effects of both drugs on the change in epithelial cell nuclear area in prostate cancer tissue between pre- and post-treatment biopsies was evaluated (primary endpoint). Moreover, the changes of the proliferation marker Ki-67 and of karyometric parameters in benign, dysplastic (HG-PIN) and malignant tissues were evaluated (secondary endpoints). Additional endpoints include the changes of serum PSA and testosterone, assessment of toxicity, overall survival, recurrence-free survival and event-free (recurrence + death) survival. Patients with intracapsular biopsy proven prostate cancer were randomized to either flutamide, 250 mg/day, or finasteride, 5 mg/day, or placebo for 4-6 weeks before radical prostatectomy. Blood samples were taken before and after treatment. At surgery, end-of-study ex-vivo biopsies were obtained from the prostatectomy specimens to assess the treatment changes in nuclear area (primary endpoint), Ki-67, topoisomerase-II-α and a 20-feature karyometric discrimant function in normal, high-grade PIN and malignant tissue. After surgery patients were followed up for at least 15 years to assess recurrence and/or mortality. We also plan to follow-up patients by telephone interview to assess their vital status for up to 20 years.
Interventions
DRUGFlutamide
1 tablet daily until the day before surgery
DRUGFinasteride
1 tablet daily until the day before surgery
OTHERPlacebo
1 tablet daily until the day before surgery
Sponsors
Universita degli Studi di Genova
Cliniche Humanitas Gavazzeni
Università Politecnica delle Marche
European Institute of Oncology
University of Arizona
Ente Ospedaliero Ospedali Galliera
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The drugs and placebo were purchased through the Galliera Hospital Pharmacy, encapsulated to preserve blinding, then packaged and labelled for the study under GMP.
Intervention model description
The study was a prospective, randomized, phase IIB, placebo controlled, double-blind, pre-surgical trial of Finasteride 5 mg day versus Flutamide 250 mg day versus placebo in men with PCa. Patients with a biopsy proven, clinically intracapsular prostate cancer who were candidate to radical retropubic prostatectomy were enrolled in four different institutions in Northern Italy. Different biopsy criteria according to each contributing centre were acceptable provided that a minimum of 8 cores were evaluable. Patients were randomized to receive either flutamide, 250 mg/day orally, or finasteride, 5 mg/day orally, or oral placebo in a double-blind manner beginning 4 to 6 weeks before surgery.
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients aged \> 18 years * Patients with a biopsy proven, clinically intracapsular PCa who are candidates to radical retropubic prostatectomy * ECOG performance status ≤ 2 * Satisfactory hematological and biochemical functions: * Platelets ≥100 x 10\^9/L * AST and ALT in the normal range * Able to understand and sign an informed consent
Exclusion criteria
* Previous hormone treatment during the 8 weeks before enrollment * Neurologic and psychiatric diseases precluding patient participation in the study * Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing or participating in the study and/or comply with the study procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of Nuclear area size | 4-6 weeks (baseline and at the end of the study biopsy) | The study primary endpoint is the change of epithelial cell nuclear area in prostate cancer tissue and HG-PIN tissue between pre- and post-treatment measure in the two active treatment arms (Finasteride or Flutamide) compared with the placebo arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change Kariometry value | 4-6 weeks (baseline and at the end of the study biopsy) | Changes in karyometric features in normal HG-PIN and prostate cancer cells in the three arms. |
| Serum biomarkers values | 4-6 weeks (on blood samples at baseline and the day before surgery) | Changes in total PSA, free PSA and testosterone concentrations after treatment in the three arms. |
| Adverse Events | 4-6 weeks (during the treatment) | Toxicity is assessed using the National Cancer Institute-Common Terminology Criteria for Adverse Events (version 3, 2003). |
| Change of ki-67 value | 4-6 weeks (baseline and at the end of the study biopsy) | Changes of Ki-67 labeling index in normal, HG-PIN and prostate cancer cells in the three arms. |
| Comparison of Event free survival | up to 20 years | Comparison of Event free survival among arms will be assessed by the Kaplan Meier actuarial survival curves and analyzed by the log-rank test and the Cox proportional hazard model for multivariate analyses. Vital status and medical condition will be assessed by telephone interview and clinical visit. |
| Comparison of Overall Survival | up to 20 years | Comparison of Overall Survival among arms will be assessed by the Kaplan Meier actuarial survival curves and analyzed by the log-rank test and the Cox proportional hazard model for multivariate analyses. Vital status and medical condition will be assessed by telephone interview and clinical visit. |
| Recurrence-free survival | up to 20 years | Comparison of Recurrence-free survival among arms will be assessed by the Kaplan Meier actuarial survival curves and analyzed by the log-rank test and the Cox proportional hazard model for multivariate analyses. Vital status and medical condition will be assessed by telephone interview and clinical visit. |
Countries
Italy
Outcome results
None listed