Finasteride Group Research Articles

Abstract B97: Combination chemoprevention and underlying mechanisms of finasteride with NSAIDs using in vitro and in vivo models (Pten-/-) for prostate cancer

Abstract B97 Background The Prostate Cancer Prevention Trial (PCPT) in a total of 1,626 men demonstrated that finasteride, a 5α reductase inhibitor reduces prostate cancer risk by 24.8%, and however, it was associated with a risk of small increase in high-Gleason grade tumors. This suggests that although finasteride is a potential chemopreventive agent, prostate cancer risk factors are not limited its target. To enhance the efficacy of finasteride, earlier studies have successfully used the combination with flutamide for the treatment of advanced disease. Based on our successful attempts in testing the chemopreventive effects of NSAIDs in combination against prostate cancer, in this study, we tested the efficacy of finasteride with anti-inflammatory agents at low doses in preclinical models to synergistically decrease prostate cancer incidence. Methods To accomplish our goals, we examined the effects of finasteride individually and in combination with celecoxib or aspirin using in vitro and in vivo models. We used murine prostate cancer cells (CaP8) deleted for Pten-/- and human benign prostate hyperplastic epithelial cells (BPH1). The cells were pretreated for 24 h with testosterone before incubating with different doses of finasteride (15μM) or aspirin (40μM) or celecoxib (40μM) individually and in combination (half of each of the single dose) for 48 h. Effect on cell growth, cell cycle, apoptosis, molecular targets AR, AKT, Cyclin D1, COX-2 and serum PGE2 levels were analyzed with MTT, flow cytometry, Western blot and ELISA assays. To determine in vivo efficacy, four week old PTEN/KO mice (an immune-competent, orthotopic model) were administered (n=5/group) orally with finasteride (15mg/kg bw) or celecoxib (200 mg/kg bw) or aspirin (200 mg/kg bw) individually or in combinations with half of the single dose for a period of six weeks. Histopathological analysis of the DL prostate tissues was performed to determine the effect on the incidence of mPIN or adenocarcinoma stages. Specific immunohistochemical staining was performed to detect the molecular targets. Results Findings from MTT assays showed inhibition of CaP8 cell (Pten-/-) growth by 56% (P<0.001) with finasteride in combination with aspirin in contrast to the effect (32%) exerted by finasteride alone. A similar effect (53%) was observed in celecoxib treated cells. Cell cycle analysis revealed G1 arrest with a decline in the “S” phase in all the treatments. Human BPH1 cells showed a significant inhibitory effect (65%) with finasteride in combination with aspirin, in contrast to the effect (25%) with finasteride alone. Histological determination of tumor incidence of mPIN showed a decrease by 5 fold in the group of mice that received dietary administration of finasteride in combination with aspirin or celecoxib after six 6 weeks in contrast to the mice that received finastride or aspirin alone (P<0.001). Serum levels of PGE2 were reduced significantly in the finasteride and celecoxib combination group. Significance changes due to the treatment effect on tumor incidence and molecular targets will be discussed. Conclusion Finasteride in combination with anti-inflammatory agents, aspirin or celecoxib at low doses, synergistically prevents prostate cancer in preclinical models. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B97.

Abstract CN01-02: The Prostate Cancer Prevention Trial: An update on pathology

Abstract CN01-02 The Prostate Cancer Prevention Trial (PCPT), sponsored by the National Cancer Institute and coordinated by the Southwest Oncology Group, was the first large-scale phase III chemoprevention trial for prostate cancer. The study randomized over 18,000 men to receive either finasteride (5 mg/day) or placebo and followed them with annual examinations and prostate-specific antigen (PSA) measurements. Biopsies of the prostate were obtained during the study if clinically indicated and also at the end of the study regardless of exam or PSA findings. The PCPT was designed to answer a single question: could finasteride, a selective type 1 5α-reductase inhibitor (5ARI), prevent the diagnosis of prostate cancer in men taking the drug versus placebo over a seven year period. In this aspect, the PCPT was a success. The study found a 24.8% reduction in the seven-year period-prevalence of prostate cancer in the finasteride group compared with placebo.1 However, the secondary findings of the study raised two critical concerns that reduced enthusiasm for the use of 5ARI’s for prostate cancer prevention. The first concern revolved around the nature of the cancers that were “ prevented” in the trial. A unique aspect in the design of the PCPT was the end-of-study biopsy, performed regardless of digital rectal exam (DRE) findings or PSA level. Since almost half of the cancers diagnosed in the PCPT were in men with PSA values ≤4.0 ng/ml and a normal DRE, the concern was that finasteride may have only prevented clinically “insignificant” tumors that would otherwise have not been diagnosed and thus would have little value for impacting prostate cancer as a whole. Pathological criteria have been proposed to identify potentially insignificant tumors on prostate needle biopsy.2,3 When applied to biopsies from the PCPT, it was revealed that 75% of the cancers diagnosed in the PCPT including those at end-of-study met the most commonly used criteria for defining clinically significant tumor.4 This figure is similar to observed rates of insignificant disease of up to 31% in men undergoing radical prostatectomy in previously published studies.3,5 The second and more serious concern was the possibility that finasteride might selectively induce high-grade tumors: the number of men diagnosed with high-grade (Gleason score 7-10) tumors was increased in the finasteride group compared with placebo (6.4% vs. 5.1%, respectively, p<0.005). Subsequent analyses of the data collected during the PCPT do not support this contention but point to an alternative explanation for this apparent increase in high-grade cancer: improved cancer detection. The findings can be summarized as follows: 1) the cumulative proportional incidence of high-grade disease did not exhibit a time-dependent increase in the hazard ratio with prolonged exposure to the drug. 2) pathological analysis of the tumors in the PCPT did not find that high-grade tumors were larger or more advanced in the finasteride arm compared with placebo as would be expected if finasteride potentiated their growth.6 3) finasteride improved the sensitivity and specificity for PSA for detection of cancer overall and high-grade cancer specifically.7 4) finasteride improved the sensitivity of DRE for detection of cancer.8 5) finasteride significantly reduced prostate volume and improved the sensitivity and negative predictive values for prostate biopsy for detecting high-grade cancer.6 Statistical modeling adjusted for biases in prostate cancer detection have estimated that finasteride may actually reduce the risk of high grade disease in addition to its overall reduction in risk of prostate cancer.9,10 These new analyses demonstrate a more favorable risk:benefit ratio for the use of finasteride as a chemopreventive agent for prostate cancer. The interpretation issues exemplified by the PCPT emphasize an important problem regarding the design of chemoprevention trials that target the androgen axis: how to optimally detect and grade prostate cancer when the agents employed effect our current means of diagnosis. In order for an individual to be diagnosed with cancer on biopsy, two things must happen: 1) there must be an indication for biopsy (ie. an elevated PSA or abnormal DRE) and 2) the needle must strike the tumor when inserted into the prostate. The effects of finasteride on PSA performance (possibly due to the ability of finasteride to suppress PSA being produced by the benign prostate to a greater degree than that produced by cancer) and biopsy performance (due to shrinkage of the prostate) have impacts on both of these factors. Finasteride apparently inhibited low-grade cancer to a greater degree than high-grade cancer in the PCPT leaving high-grade foci to be impacted more by increased detection. This may or may not be due to increased expression of Type 1 5α-reductase in high-grade cancer.11 Whether dutasteride, a dual type 1 and 2 5ARI, has similar effects in the REDUCE trial remains to be seen.12 Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN01-02.

Androgens and prostate cancer risk

Androgens have been implicated in prostate tumourigenesis. However, no association between circulating levels of androgens and prostate cancer risk was found in a recent large pooled analysis of prospective studies. A decreased risk of prostate cancer among men treated with finasteride, a 5 alpha-reductase inhibitor which reduces levels of dihydrotestosterone, was observed in the Prostate Cancer Prevention Trial (PCPT), a large clinical trial. In the PCPT, a higher number of high-grade tumours was found in the finasteride group than in the control group; the reason for this finding is still unclear. Treatment of symptoms of late-onset hypogonadism - such as decreased muscle and bone mass and decreased cognition and libido - has become more prevalent with the advent of new forms of administration of testosterone replacement therapy. One small placebo-controlled study showed no increase in incidence of prostate cancer after 6 months of testosterone therapy, but data on the safety of testosterone replacement therapy remain limited.

Reduced intraoperative bleeding during transurethral resection of the prostate: Evaluation of finasteride, vascular endothelial growth factor, and CD34

Finasteride is an antiandrogen that inhibits 5-α-reductase, an enzyme that converts testosterone to dihydrotestosterone. Finasteride significantly reduces intraoperative bleeding when 10 mg/d is administered for 60 days before transurethral resection of the prostate. Our double-blind, randomized, placebo-controlled study evaluated 200 patients with benign prostatic hyperplasia who underwent transurethral resection of the prostate. We compared a placebo group (n = 100) with a group (n = 100) administered 5 mg of finasteride twice a day for 8 weeks. We intended to demonstrate the mechanisms and effects of finasteride compared with those of vascular endothelial growth factor, and to evaluate CD34, an immunohistochemical marker of blood vessel density in the prostate. Our results indicated a lower average microvascular density and vascular endothelial growth factor index for hypertrophic prostate in the finasteride group than in the placebo group.

Pathologic Characteristics of Cancers Detected in the Prostate Cancer Prevention Trial: Implications for Prostate Cancer Detection and Chemoprevention

The Prostate Cancer Prevention Trial (PCPT) showed a risk of prostate cancer at prostate-specific antigen (PSA) <4.0 ng/mL and that prostate cancer risk is reduced by finasteride. A major concern about early detection by PSA and prevention by finasteride is that they may involve biologically inconsequential tumors. We reviewed the pathologic characteristics of prostate biopsies from men in the placebo and finasteride groups of the PCPT. We examined tumor pathology characteristics stratified by level of PSA for men in the placebo group who underwent radical prostatectomy. Seventy-five percent of all cancers and 62% of Gleason score <or=6 cancers in the PCPT met the biopsy criteria for clinically significant tumors. Surrogate measures for tumor volume (number of cores positive, percent cores positive, linear extent, and bilaterality) and risk of perineural invasion were lower in men who received finasteride. The PSA-associated risks of insignificant cancer were 51.7% (PSA, 0-1.0 ng/mL), 33.7% (1.1-2.5 ng/mL), 17.8% (2.6-4.0 ng/mL), and 11.7% (4.1-10 ng/mL). Conversely, the risks of high-grade (Gleason score >or=7) tumors for the same PSA strata were 15.6%, 37.9%, 49.1%, and 52.4%, respectively. These data highlight the dilemma of PSA when used for screening: Lower cutoff levels increase detection of insignificant disease, but cure is more likely, whereas higher cutoff levels make detection of significant cancer more likely, but cure is less likely. Therefore, the effectiveness of finasteride in preventing prostate cancer, including Gleason score <or=6 cancer, with meaningful rates of significant disease in the PCPT suggests that cutoff values for PSA screening should be individualized and that men undergoing screening should be informed of the opportunity to reduce their risk of disease with finasteride.

The REDUCE trial: chemoprevention in prostate cancer using a dual 5α-reductase inhibitor, dutasteride

Dutasteride, a dual 5α-reductase inhibitor, is used in the treatment of benign prostatic hyperplasia (BPH). It reduces serum prostate-specific antigen levels by approximately 50% at 6 months and total prostate volume by 25% after 2 years. Randomized placebo-controlled trials in BPH patients have shown the efficacy of dutasteride in symptomatic relief, improvements in quality of life and peak urinary flow rate. Side effects occurring with dutasteride are decreased libido, erectile dysfunction, ejaculation disorders and gynecomastia. Preliminary data from placebo-controlled BPH trials have shown a decrease in the detection of prostate cancer in patients treated with dutasteride, although these studies were not designed to look at this issue. Dutasteride differs from finasteride in that it inhibits both isoenzymes of 5α-reductase, type I and type II. The landmark Prostate Cancer Prevention Trial at the end of the 7-year study demonstrated a 24.8% reduction in the incidence of prostate cancer in the finasteride group compared with placebo. However, a 25.5% increase in the prevalence of high-grade Gleason tumors has been observed, the clinical significance of which has been debated. Preliminary data suggest a decrease in prostate cancer incidence in dutasteride-treated patients and demonstrate type I αreductase enzyme expression in prostate cancer. As a result, dutasteride is being investigated for prostate cancer prevention in the ongoing Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, which is discussed here.

Le point de vue du pathologiste concernant l’étude PCPT

The PCPT (Prostate Cancer Prevention Trial) trial which compared 5 mg/d of finastéride to placebo in men over 55 years old showed that active treatment reduced the incidence of prostate cancer from 24.4 to 18.4%. Paradoxically, the incidence of high grade cancers (Gleason score > or = 7) was higher in the finasteride group (6.4%) than in the placebo group (5.1%). Histological interpretation of the radical prostatectomy specimens showed an overestimation of Gleason score on biopsy both in the finasteride and placebo group. The high grade cancers on total prostatectomy specimens were not more aggressive in the finasteride arm than in the placebo arm. There is no argument to suggest that long term finasteride may promote the development of highly aggressive cancer. Urologists must clearly be aware that finasteride treatment may result in morphological changes in order to inform the pathologist that this drug is being taken. If a prostate cancer with a Gleason score > or = 7 is diagnosed in a treated patient, the pathologist will perform a double reading of the slides to confirm the score.

L’étude PCPT

The PCPT trial is the first phase III trial with the principal objective of examining the hypothesis that the use of chemoprevention could prevent the development of prostate cancer. This is a large scale randomised clinical trial comparing finasteride (5-alpha reductase inhibitor) to placebo. A total of 18,882 men aged 55 years old or above with unremarkable rectal examination and serum PSA below 3 ng/ml were randomised between daily treatment with 5 mg of finasteride or placebo for 7 years. The incidence of prostate cancer diagnosed by biopsy was 24.4% in the placebo group compared to 18.4% in the finasteride group. The incidence of high Gleason grade cancers (7-10) in the finasteride group (6.4%) appeared to be higher than in the placebo group (5.1%) although it was subsequently shown that these results were not significant. Sexual adverse effects were more common in the finasteride group and urinary symptoms were more common in the placebo group than in the finasteride group. The volumes of prostates treated with finasteride were reduced by 24% compared to the placebo arm. It does not therefore appear at present appropriate to give finasteride to prevent the development of prostate cancer until more detailed results are available about the nature of the cancers which may possibly have been detected or avoided.

Effect of Finasteride Treatment on Suburethral Prostatic Microvessel Density in Patients with Hematuria Related to Benign Prostate Hyperplasia

Introduction: In the present study we evaluated the effect of short-term finasteride treatment on microvessel density (MVD)which is an indicator of prostatic angiogenesis in patients with hematuria secondary to benign prostatic hyperplasia (BPH). Materials and Methods: 30 patients who were candidates for BPH surgery were prospectively included in the study. All patients had history of gross hematuria and evaluated by ultrasonography and cystoscopy. The patients were randomized two groups before surgery. The treatment group consisted of 13 patients who were given 5 mg finasteride daily for 4 weeks before surgery. The control group consisted of 17 patients who did not receive finasteride before surgery. During surgery, resected suburethral and hyperplastic prostate specimens were sent for histopathologic MVD determination separately. Results: Mean MVD in the suburethral portion of prostate was significantly lower in patients treated with finasteride when compared with controls (9.08 ± 5.6 and 13.94 ± 5.90, respectively, p < 0.05). Mean MVD for the hyperplastic portion of prostate was similar for the finasteride and control groups (14.21 ± 7.10 and 19.75 ± 9.73, respectively, p > 0.05). Conclusion: The potential role of finasteride on hematuria related to BPH may be the suppressive effect on MVDin the suburethral tissue of prostate.

The Effect of Doxazosin, Finasteride and Combination Therapy on Nocturia in Men With Benign Prostatic Hyperplasia

We evaluated the effectiveness of single or combination drug therapy on nocturia in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. A total of 3,047 men with lower urinary tract symptoms/benign prostatic hyperplasia enrolled in the Medical Therapy of Prostatic Symptoms trial were randomly assigned to receive doxazosin alone, finasteride alone, combination therapy or placebo. Treatment effectiveness was assessed according to intent to treat by mean reduction in self-reported nightly nocturia at 1 and 4 years. A subgroup analysis by age (younger than 70 vs 70 years old or older) was also performed. Of the men 2,583 reported 1 or more episodes of nocturia and finished 12 or more months of the trial. Mean nocturia was similar in all groups at baseline. Mean nocturia was reduced at 1 year by 0.35, 0.40, 0.54 and 0.58 in the placebo, finasteride, doxazosin and combination groups, respectively. Reductions with doxazosin and combination therapy were statistically greater than with placebo (p <0.05). At 4 years nocturia was also significantly reduced in patients treated with doxazosin and combination therapy (p <0.05 vs placebo). In men older than 70 years (495) all drugs significantly reduced nocturia at 1 year (finasteride 0.29, doxazosin 0.46 and combination 0.42) compared to placebo (0.11, p <0.05). Doxazosin and combination therapy reduced nocturia more than placebo, but the net benefit of active drug compared to placebo was often modest with a net difference of less than 0.20 fewer nightly nocturia episodes at 1 and 4 years. Findings in men 70 years old or older were similar, with an even smaller effect observed for finasteride.

Detection Bias Due to the Effect of Finasteride on Prostate Volume: A Modeling Approach for Analysis of the Prostate Cancer Prevention Trial

The Prostate Cancer Prevention Trial (PCPT) demonstrated a 24.8% reduction in the 7-year prevalence of prostate cancer among patients treated with finasteride (5 mg daily) compared with that among patients treated with placebo; however, a 25.5% increase in the prevalence of high-Gleason grade tumors was observed, the clinical significance of which is unknown. One hypothesized explanation for this increase is that finasteride reduced prostate volume, leading to detection of more high-grade tumors due to increased sampling density. This possibility was investigated in an observational reanalysis of the PCPT data, with adjustment for sampling density. A logistic model for the association of high-grade (Gleason score 7-10) prostate cancer with baseline covariates and/or baseline covariates plus prostate volume and number of cores obtained at biopsy was developed using the placebo group (n = 4775) of the PCPT. This model was then applied to the finasteride group (n = 5123) to compare the predicted and observed numbers of high-grade tumors in that group. In a second approach, odds ratios (ORs) for prostate cancer in the finasteride versus placebo groups calculated from binary and polytomous logistic regression models that contained or excluded covariates for gland volume and number of needle cores were compared. Median prostate volume was 25% lower in the finasteride group (median = 25.1 cm3) than in the placebo group (median = 33.5 cm3). The logistic model developed in the placebo group showed that the likelihood of detection of high-grade prostate cancer decreased as volume increased (for each 10 cm3 increase in prostate volume, OR = 0.81, 95% confidence interval [CI] = 0.74 to 0.90). Based on this model, 239 high-grade prostate cancers were predicted in the finasteride group, whereas 243 were observed, a non-statistically significant difference. Among all participants, the odds ratios for high-grade cancer in the finasteride versus placebo groups decreased from 1.27 (95% CI = 1.05 to 1.54) with adjustment for baseline covariates to 1.03 (95% CI = 0.84 to 1.26) following additional adjustment for gland volume and number of biopsy cores in binary outcome models and from 1.14 (95% CI = 0.94 to 1.38) to 0.88 (95% CI = 0.72 to 1.09) following these adjustments in the polytomous models. Although analyses using postrandomization data require cautious interpretation, these results suggest that sampling density bias alone could explain the excess of high-grade cancers among the finasteride-assigned participants in the PCPT.

Finasteride and High-Grade Prostate Cancer in the Prostate Cancer Prevention Trial

The Prostate Cancer Prevention Trial (PCPT) reported a decreased incidence of prostate cancer overall but an increase in the incidence of high-grade prostate cancer with finasteride compared with placebo. We assessed whether the increased high-grade prostate cancer associated with finasteride in the PCPT was due to finasteride's potential effects on tumor morphology or prostate size. Prostate biopsies with Gleason score 8-10 (n = 90, finasteride; n = 52, placebo) were examined histologically for hormonal effects, and those with Gleason score 7-10 (n = 282, finasteride; n = 244, placebo) were examined for pathologic surrogates of disease extent. Prostate volumes were measured at biopsy. Samples from radical prostatectomies (n = 222, finasteride; n = 306, placebo) were examined for tumor grade and extent, and, where possible, grades at biopsy and prostatectomy were compared between the groups. Logistic regression was used to analyze differences between treatment groups with respect to pathologic criteria. All statistical tests were two-sided. Degenerative hormonal changes in high-grade biopsies were equivalent between the finasteride and placebo groups, but prostate volumes were lower in the finasteride group (median = 25.1 versus 34.4 cm3, P<.001). Pathologic surrogates for tumor extent were lower with finasteride than with placebo, including mean percentage of positive cores (34% versus 38%, P = .016), mean tumor linear extent (greatest [4.4 versus 4.8 mm, P = .19] and aggregate [7.6 versus 9.2 mm, P = .13]), bilaterality (22.8% versus 30.6%, P = .046), and perineural invasion (14.2% versus 20.3%, P = .07). Among patients who had prostatectomy, the finasteride-associated increase in high-grade disease (Gleason score > or = 7) at biopsy (42.7% finasteride versus 25.4% placebo, P<.001) was diminished at prostatectomy (46.4% finasteride versus 38.6% placebo, P = .10). Biopsy identified a greater proportion of patients with high-grade disease present at prostatectomy in the finasteride group than in the placebo group (69.7% versus 50.5%, P = .01). The rate of upgrading (from low-grade cancer at biopsy to high-grade cancer at prostatectomy) and pathologic stage at prostatectomy were similar in both groups. Effects of finasteride on prostate volume and selective inhibition of low-grade cancer, rather than effects on tumor morphology, may have contributed to the increase in high-grade cancers with finasteride in the PCPT. Although induction of high-grade cancer cannot be excluded, the results suggest that high-grade cancer was detected earlier and was less extensive in the finasteride group than in the placebo group.

Prediction of Prostate Cancer for Patients Receiving Finasteride: Results From the Prostate Cancer Prevention Trial

Using data from men in the finasteride group of the Prostate Cancer Prevention Trial (PCPT), we evaluated the impact of prostate-specific antigen (PSA) and other risk factors on the risk of prostate cancer. Four thousand four hundred forty men in the finasteride group of the PCPT underwent prostate biopsy, had at least one PSA and a digital rectal exam (DRE) during the year before biopsy, had at least two PSA values from the 3 years before biopsy, and were on finasteride at the time of PSA evaluation. Logistic regression was conducted using the variables age, race, family history of prostate cancer, PSA, PSA velocity, and DRE adjusting for history of prior prostate biopsy. Six hundred forty-nine (14.6%) of 4,440 men were diagnosed with prostate cancer; 250 had Gleason 7 or higher cancer. Factors associated with an increased risk of prostate cancer included high PSA value and a rising PSA (24.9% risk for PSA value of 1.0 ng/mL and 24.8% risk for a rising PSA), family history of prostate cancer, abnormal DRE result, African American race, and older age. Factors associated with an increased risk of Gleason 7 or higher grade prostate cancer included PSA, abnormal DRE, and older age. A prior negative biopsy was associated with decreased risk of prostate cancer and high-grade prostate cancer. Risk factors for prostate cancer on biopsy for men receiving finasteride include PSA, DRE, age, race, family history, and history of a prior negative biopsy. With the exception of the approximate reduction of PSA by half with finasteride, the impact of these risk factors is similar to men who do not receive finasteride.

Finasteride Decreases the Risk of Prostatic Intraepithelial Neoplasia

High grade prostatic intraepithelial neoplasia is likely a premalignant lesion of the prostate. Decreasing the frequency of high grade PIN may decrease the risk of prostate cancer. In the Prostate Cancer Prevention Trial we evaluated the impact of finasteride on the risk of a needle biopsy diagnosis of high grade prostatic intraepithelial neoplasia. The Prostate Cancer Prevention Trial was a randomized, placebo controlled clinical trial that enrolled 18,882 men without evidence of prostate cancer, prostate specific antigen less than 3.0 ng/ml and normal digital rectal examination, and randomized them to 5 mg finasteride daily or placebo. Subjects were followed for 7 years with biopsy recommended for prostate specific antigen greater than 4.0 ng/ml, adjusted in the finasteride group to achieve an equal number of biopsy recommendations or for abnormal digital rectal examination. All cancer-free subjects were recommended to undergo biopsy after 7 years on study. We evaluated the diagnosis of high grade prostatic intraepithelial neoplasia with or without concomitant prostate cancer in these 2 study groups. The number of men evaluable for high grade prostatic intraepithelial neoplasia was 4,568 in the finasteride group and 4,886 in the placebo group. High grade prostatic intraepithelial neoplasia alone was diagnosed in 276 men (6.0%) in the finasteride group vs 347 (7.1%) in the placebo group (RR 0.85, 95% CI 0.73-0.99, p=0.04). High grade prostatic intraepithelial neoplasia accompanied by prostate cancer was diagnosed in 144 men (3.2%) in the finasteride group vs 223 (4.6%) in the placebo group (RR 0.69, 95% CI 0.56-0.85, p=0.0004). Finasteride significantly decreased the overall risk of high grade prostatic intraepithelial neoplasia (alone and with cancer) from 570 cases (11.7%) in the placebo group to 420 (9.2%) in the finasteride group (HR 0.79, 95% CI 0.70-0.89, p<0.001). Finasteride significantly decreased the risk of high grade PIN. This observation may explain how finasteride decreased prostate cancer in the Prostate Cancer Prevention Trial, supporting the notion that high grade prostatic intraepithelial neoplasia is a premalignant lesion of the prostate, and it provides new information relevant to the consideration of finasteride for prostate cancer prevention.

Finasteride Improves the Sensitivity of Digital Rectal Examination for Prostate Cancer Detection

Men undergoing screening for prostate cancer are recommended to undergo digital rectal examination and prostate specific antigen measurement. We previously presented data from the Prostate Cancer Prevention Trial indicating that finasteride improves the performance characteristics of prostate specific antigen for cancer detection. In the current study we report the impact of finasteride on digital rectal examination sensitivity and specificity. We examined the sensitivity and specificity of digital rectal examination in Prostate Cancer Prevention Trial subjects receiving finasteride or placebo who underwent prostate biopsy, had prostate specific antigen measurement and digital rectal examination within 1 year before biopsy and were on treatment at biopsy. Of 9,423 men in the finasteride group 4,579 and 5,112 of 9,459 in the placebo group met study evaluation requirements. Of 4,579 men in the finasteride group 695, including 264 with Gleason 7 or greater and 81 with Gleason 8 or greater, and 1,111 of 5,112 in the placebo group, including 240 with Gleason 7 or greater and 55 with Gleason 8 or greater, were diagnosed with prostate cancer. In men in the placebo and finasteride groups digital rectal examination sensitivity was greater for detecting higher grade tumors. The sensitivity of digital rectal examination was significantly greater for cancer detection in men receiving finasteride than placebo (21.3% vs 16.7%, p=0.015). Digital rectal examination sensitivity was also greater for detecting high grade (Gleason 7 or greater and 8 or greater) cancers in men receiving finasteride but this did not attain statistical significance. Digital rectal examination specificity was similar in men receiving finasteride or placebo. Finasteride significantly improves prostate cancer detection with digital rectal examination.

A Review of Phase III Clinical Trials of Prostate Cancer Chemoprevention

Prostate cancer is an excellent target for chemoprevention strategies; given its late age of onset, any delay in carcinogenesis would lead to a reduction in its incidence. This article reviews all the completed and on-going phase III trials in prostate cancer chemoprevention. All phase III trials of prostate cancer chemoprevention were identified within a Medline search using the keywords 'clinical trial, prostate cancer, chemoprevention'. In 2003, the Prostate Cancer Prevention Trial (PCPT) became the first phase III clinical trial of prostate cancer prevention. This landmark study was terminated early due to the 24.8% reduction of prostate cancer prevalence over a 7-year period in those men taking the 5alpha-reductase inhibitor, finasteride. This article reviews the PCPT and the interpretation of the excess high-grade prostate cancer (HGPC) cases in the finasteride group. The lack of relationship between cumulative dose and the HGPC cases, and the possible sampling error of biopsies due to gland volume reduction in the finasteride group refutes the suggestion that this is a genuine increase in HGPC cases. The other on-going phase III clinical trials of prostate cancer chemoprevention - the REDUCE study using dutasteride, and the SELECT study using vitamin E and selenium - are also reviewed. At present, finasteride remains the only intervention shown in long-term prospective phase III clinical trials to reduce the incidence of prostate cancer. Until we have the results of trials using alternative agents including the on-going REDUCE and SELECT trials, the advice given to men interested in prostate cancer prevention must include discussion of the results of the PCPT. The increased rate of HGPC in the finasteride group continues to generate debate; however, finasteride may still be suitable for prostate cancer prevention, particularly in men with lower urinary tract symptoms.

Effect of finasteride on the sensitivity of PSA for detecting prostate cancer: Thompson IM, Chi C, Ankerst DP, Goodman PJ, Tangen CM, Lippman SM, Lucia MS, Parnes HL, Coltman CA Jr, Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, TX

In the Prostate Cancer Prevention Trial (PCPT), men receiving finasteride had a 24.8% lower risk of prostate cancer than men receiving placebo but a higher risk of high-grade cancer. We examined the impact of finasteride on the sensitivity and area under the receiver operating characteristic curve (AUC) of prostate-specific antigen (PSA) for detecting prostate cancer. We studied men in the placebo and finasteride groups of the PCPT who had a prostate biopsy and concurrent PSA tests during the 7-year study. We compared the placebo and finasteride groups for sensitivity and AUC of PSA for the detection of all prostate cancer, of Gleason grade 7 or higher prostate cancer, and of Gleason grade 8 or higher prostate cancer. All statistical tests were two-sided. Of 5112 men in the placebo group, prostate cancer was detected in 1111. Gleason tumor grade was available for 1100 men, of whom 240 had grade 7 or higher and 55 had grade 8 or higher. Of 4579 men in the finasteride group, 695 had prostate cancer. Gleason grade was available for 686 men, of whom 264 had grade 7 or higher and 81 had grade 8 or higher. The AUC of PSA for all outcomes was greater for the finasteride group than the placebo group. For detecting prostate cancer versus no cancer, the AUCs were 0.757 and 0.681, respectively (P < .001); for detecting Gleason grade > or = 7 versus < or = 6 or no cancer, the AUCs were 0.838 and 0.781, respectively (P = .003); and for detecting Gleason grade > or = 8 versus < or = 7 or no cancer, the AUCs were 0.886 and 0.824, respectively (P = .071). The sensitivity of PSA was higher for men in the finasteride group than in the placebo group at all PSA cutoffs matched by specificity. PSA had statistically significantly better sensitivity and AUC for detecting prostate cancer in the finasteride arm of the PCPT than in the placebo arm. This bias would be expected to contribute to greater detection of all grades of prostate cancer with finasteride.

Dynamic Contrast Enhanced Magnetic Resonance Imaging as a Biological Marker to Noninvasively Assess the Effect of Finasteride on Prostatic Suburethral Microcirculation

We assessed dynamic contrast enhanced magnetic resonance imaging as a biological marker of in vivo changes in microcirculation in the prostatic suburethral region. A total of 12 male beagle dogs with spontaneous benign prostatic hyperplasia were randomly allocated to 1 control group and 1 finasteride (Merck and Co., Whitehouse Station, New Jersey) treated group. Two baseline dynamic contrast enhanced magnetic resonance imaging examinations and 3 followups were performed to assess prostate microcirculation. Treatment duration was 3 months. The pharmacokinetic parameters evaluated in prostatic suburethral areas were the maximum enhancement ratio in AU, time to maximum signal enhancement in minutes, amplitude in AU and the exchange rate constant in minutes(-1). After completion of the therapeutic regimen time to maximum signal enhancement was significantly longer in the finasteride group than in controls (p < 0.01). Amplitude and the exchange rate constant decreased 39% and 34%, respectively, in the finasteride group at the end of treatment, which significantly differed from results in the control group (p < 0.05). Dynamic contrast enhanced magnetic resonance imaging is capable of noninvasively assessing the prostatic microcirculation changes induced by finasteride. Pharmacokinetic parameters show considerable promise to be biomarkers for the development of benign prostatic hyperplasia drugs such as 5alpha-reductase inhibitors by the in vivo monitoring of microvascular changes. A relevant clinical application could be the pretreatment assessment of finasteride effectiveness to decrease perioperative bleeding at transurethral prostate resection and in treatment for hematuria.

Effect of Finasteride on the Sensitivity of PSA for Detecting Prostate Cancer

In the Prostate Cancer Prevention Trial (PCPT), men receiving finasteride had a 24.8% lower risk of prostate cancer than men receiving placebo but a higher risk of high-grade cancer. We examined the impact of finasteride on the sensitivity and area under the receiver operating characteristic curve (AUC) of prostate-specific antigen (PSA) for detecting prostate cancer. We studied men in the placebo and finasteride groups of the PCPT who had a prostate biopsy and concurrent PSA tests during the 7-year study. We compared the placebo and finasteride groups for sensitivity and AUC of PSA for the detection of all prostate cancer, of Gleason grade 7 or higher prostate cancer, and of Gleason grade 8 or higher prostate cancer. All statistical tests were two-sided. Of 5112 men in the placebo group, prostate cancer was detected in 1111. Gleason tumor grade was available for 1100 men, of whom 240 had grade 7 or higher and 55 had grade 8 or higher. Of 4579 men in the finasteride group, 695 had prostate cancer. Gleason grade was available for 686 men, of whom 264 had grade 7 or higher and 81 had grade 8 or higher. The AUC of PSA for all outcomes was greater for the finasteride group than the placebo group. For detecting prostate cancer versus no cancer, the AUCs were 0.757 and 0.681, respectively (P < .001); for detecting Gleason grade > or = 7 versus < or = 6 or no cancer, the AUCs were 0.838 and 0.781, respectively (P = .003); and for detecting Gleason grade > or = 8 versus < or = 7 or no cancer, the AUCs were 0.886 and 0.824, respectively (P = .071). The sensitivity of PSA was higher for men in the finasteride group than in the placebo group at all PSA cutoffs matched by specificity. PSA had statistically significantly better sensitivity and AUC for detecting prostate cancer in the finasteride arm of the PCPT than in the placebo arm. This bias would be expected to contribute to greater detection of all grades of prostate cancer with finasteride.

Finasteride effects on hypoxia and angiogenetic markers in benign prostatic hyperplasia

Objectives To assess the effects of finasteride on angiogenetic and hypoxia markers in benign prostatic hyperplasia. Methods A total of 178 patients aged 51 to 85 years (mean 68.7) with benign prostatic hyperplasia and awaiting transurethral prostate resection were prospectively randomized into a group of patients receiving finasteride (group 1; 88 patients) and a group of patients who received no medication until transurethral prostate resection (group 2; 90 patients). Tissue specimens were immunohistochemically stained with monoclonal antibodies against CD34 for microvessel density (MVD), vascular endothelial growth factor (VEGF), and hypoxia inducible factor-1alpha (HIF-1α). Results Blood loss during transurethral prostate resection was significantly higher in group 2 compared with group 1 ( P <0.001). The distribution of CD34 immunostaining was mainly at the suburethral prostate. MVD, VEGF, and HIF-1α values were significantly lower statistically ( P <0.001) in group 1 compared with group 2. In the finasteride group (group 1), the positive correlation of the immunoreactivity of CD34 and HIF-1α, VEGF and HIF-1α, and VEGF and CD34 was statistically significant ( P <0.001). In the same group, MVD and VEGF and HIF-1α expression correlated statistically with the treatment duration. Conclusions Finasteride administration in benign prostatic hyperplasia results in statistically significant suppression of MVD, VEGF, and HIF-1α in a time-dependent manner.