Cancer, Prostate Cancer
Conditions
Keywords
cancer, pre-operative surgery, prostate, prostatectomy, radiation
Brief summary
This is a randomized trial comparing the effect of oral simvastatin versus placebo on targets of the mevalonate pathway in men undergoing a prostatectomy as planned management for prostate cancer. Observed tissue effects will be correlated with changes in serum cholesterol and low-density lipoprotein.
Detailed description
Prostate cancer patients that have chosen to undergo a prostatectomy as their primary treatment option will be recruited to this trial. Forty-four subjects will be randomized to either placebo or simvastatin (40 mg po/day) for 4 weeks prior to surgery. Serum samples will be obtained at baseline and immediately prior to prostatectomy. At prostatectomy, cancerous and benign prostate tissue will be microdissected and cryopreserved. Archival prostatectomy tissues will be used to construct tissue microarrays containing matched benign and malignant sections. The effect of HMG-CoA reductase inhibition on lipid raft cholesterol content and targets of prenylation will be determined. The incidence of apoptosis will be determined along with protein levels of mediators of apoptosis. Lastly the effect of statin therapy on cellular markers of proliferation will be determined. Previously, we studied the effect of statin use on the risk of prostate cancer detection in a case-control study at the Portland VA Medical Center. Statin use was associated with a 62% reduction in cancer odds-risk (OR = 0.38, 95% CI 0.21-0.69). Although these epidemiologic and laboratory findings have generated enthusiasm for the study of statins in prostate cancer, no studies have examined the biologic effects of statins on prostate cancer in humans. Hypothesis: Statin therapy prior to prostatectomy will successfully target the mevalonate pathway in the human prostate and this intervention will favorably alter tumor biomarker status.
Interventions
DRUGSimvastatin
40 mg of simvastatin
OTHERPlacebo
placebo
Sponsors
Oregon Health and Science University
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SCREENING
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed prostatic adenocarcinoma with Gleason 5 to 7 (3+4 = 7 accepted, not 4 + 3 = 7) * Radical prostatectomy chosen as primary treatment for prostate cancer * Age 18 years or older * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Exclusion criteria
* Other preoperative or prior treatment directed at prostate cancer (i.e., Radiation, hormonal therapy, cryotherapy) * Significant active medical illness which in the opinion of the investigator would preclude protocol treatment * History of or active liver disease or abnormal results of the baseline liver function test (\> 2 x normal) * Current use of: * simvastatin * lovastatin * other HMG-CoA inhibitors * lipid-lowering agents * Amiodarone * Cholestyramine * Cholestyramine and colestipol (bile acid sequestrants) * Clofibrate and fenofibrate * Cyclosporine * CYP3A4 inhibitors * Danazol * Diltiazem * Gemfibrozil * Niacin ( 1 g/day) * Verapamil and Warfarin * Known allergy or sensitivity to ingredients in simvastatin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Measure the Effect of Pre-operative Simvastatin Versus Placebo on the Mevalonate Pathway Synthesis and Target Activation in Benign and Malignant Prostate Tissue. | 5 years | Measure the effect of pre-operative simvastatin versus placebo on the mevalonate pathway synthesis and target activation in benign and malignant prostate tissue using Androgen Receptor (AR) antibody. AR was measured in tissue obtained at the time of prostatectomy in both benign and malignant tissues. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Compare the Effect of Pre-operative Simvastatin Versus Placebo on Prostate Cancer Cell Apoptosis and Its Mediators in Men Undergoing Planned Prostatectomy. | 2 years | Compare the effect of pre-operative simvastatin versus placebo on prostate cancer cell apoptosis and its mediators in men undergoing planned prostatectomy. Apoptosis was measured by calculating the percent of Ki67 cellular staining. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Simvastatin Participants were randomized into the Simvastatin arm of this trial. | 20 |
| Placebo Participants were randomized into the placebo arm of this trial. | 16 |
| Total | 36 |
Baseline characteristics
| Characteristic | Placebo | Simvastatin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 4 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 16 Participants | 28 Participants |
| Age, Continuous | 60.75 Years | 60.4 Years | 60.56 Years |
| Region of Enrollment United States | 16 participants | 20 participants | 36 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 16 Participants | 20 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 20 | 0 / 16 |
| serious Total, serious adverse events | 11 / 20 | 3 / 16 |
Outcome results
Primary
Measure the Effect of Pre-operative Simvastatin Versus Placebo on the Mevalonate Pathway Synthesis and Target Activation in Benign and Malignant Prostate Tissue.
Measure the effect of pre-operative simvastatin versus placebo on the mevalonate pathway synthesis and target activation in benign and malignant prostate tissue using Androgen Receptor (AR) antibody. AR was measured in tissue obtained at the time of prostatectomy in both benign and malignant tissues.
Time frame: 5 years
Population: We enrolled a total of 42 subjects, 36 completed this study. Of the 36 subjects who completed this study, only 26 subjects had tissue available for this analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Simvastatin | Measure the Effect of Pre-operative Simvastatin Versus Placebo on the Mevalonate Pathway Synthesis and Target Activation in Benign and Malignant Prostate Tissue. | 168.6666667 Percentage of cells |
| Placebo | Measure the Effect of Pre-operative Simvastatin Versus Placebo on the Mevalonate Pathway Synthesis and Target Activation in Benign and Malignant Prostate Tissue. | 182.7272727 Percentage of cells |
Secondary
Compare the Effect of Pre-operative Simvastatin Versus Placebo on Prostate Cancer Cell Apoptosis and Its Mediators in Men Undergoing Planned Prostatectomy.
Compare the effect of pre-operative simvastatin versus placebo on prostate cancer cell apoptosis and its mediators in men undergoing planned prostatectomy. Apoptosis was measured by calculating the percent of Ki67 cellular staining.
Time frame: 2 years
Population: We enrolled a total of 42 subjects, 36 completed this study. Of the 36 subjects who completed this study, only 26 subjects had tissue available for this analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Simvastatin | Compare the Effect of Pre-operative Simvastatin Versus Placebo on Prostate Cancer Cell Apoptosis and Its Mediators in Men Undergoing Planned Prostatectomy. | 7.53333 Percentage of cells |
| Placebo | Compare the Effect of Pre-operative Simvastatin Versus Placebo on Prostate Cancer Cell Apoptosis and Its Mediators in Men Undergoing Planned Prostatectomy. | 6 Percentage of cells |