- Open Access
5-α reductase inhibitors and prostate cancer prevention: where do we turn now?
BMC Medicine volume 9, Article number: 105 (2011)
With the lifetime risk of being diagnosed with prostate cancer so great, an effective chemopreventive agent could have a profound impact on the lives of men. Despite decades of searching for such an agent, physicians still do not have an approved drug to offer their patients. In this article, we outline current strategies for preventing prostate cancer in general, with a focus on the 5-α-reductase inhibitors (5-ARIs) finasteride and dutasteride. We discuss the two landmark randomized, controlled trials of finasteride and dutasteride, highlighting the controversies stemming from the results, and address the issue of 5-ARI use, including reasons why providers may be hesitant to use these agents for chemoprevention. We further discuss the recent US Food and Drug Administration ruling against the proposed new indication for dutasteride and the change to the labeling of finasteride, both of which were intended to permit physicians to use the drugs for chemoprevention. Finally, we discuss future directions for 5-ARI research.
Prostate cancer is the most commonly diagnosed cancer among men and the second leading cause of cancer death . With one in six men destined to be diagnosed with prostate cancer in their lifetimes and the costs associated with prostate cancer care being very high , the potential benefits of an effective chemoprevention agent are obvious . Yet, despite decades of research in the field, there are still no approved pharmaceuticals for the prevention of prostate cancer. The 5-α reductase inhibitors (5-ARIs) finasteride and dutasteride are the most promising to date, but also the most controversial. Recently, the US Food and Drug Administration (FDA) ruled against proposals to add an indication to dutasteride and alter the labeling of finasteride that would allow prescribers to use these drugs for chemoprevention. The impact of this decision on the future of prostate chemoprevention remains to be seen. Is it the nail in the coffin or the needed wake-up call to turn the field in another direction?
In this article, we outline strategies for preventing prostate cancer in general, but focus specifically on the 5-ARIs. We discuss the two landmark randomized, controlled trials (RCTs) of finasteride and dutasteride and highlight the controversies stemming from the results. We address the issue of 5-ARI use and why providers may be hesitant to use these agents for chemoprevention, as well as the recent FDA ruling.
Preventing prostate cancer
Over the years, several nutrients, lifestyle modifications and pharmaceutical agents have been studied as potential chemoprevention candidates . Selenium and vitamin E showed promise [4, 5]. However, these were definitively evaluated in the Selenium and Vitamin E Cancer Prevention Trial, and neither agent reduced prostate cancer risk . Vitamin D analogs, nonsteroidal anti-inflammatory drugs (NSAIDs) and toremifene (a selective estrogen receptor modulator) have all been evaluated in laboratory and/or observational studies [7–9]. However, vitamin D has not been formally tested in primary prevention trials. An attempt was made to study the NSAID rofecoxib, but the trial was closed when the drug was taken off the market for safety reasons . Toremifene showed a modest risk reduction in a phase II trial , but no significant risk reduction in a phase III trial .
Statin medications hold promise for prostate cancer prevention. They appear to reduce prostate-specific antigen (PSA) [13, 14], and while they do not apparently reduce prostate cancer risk overall, they appear to preferentially reduce the risk of advanced or aggressive prostate cancer . They are also associated with improved outcomes after radiation therapy  and radical prostatectomy , though data for the latter are conflicting . The advantage of statins is their proven safety record and their welcome side effects of decreased cholesterol levels and cardiac disease risk reduction. Though no trial of the use of statins in primary prostate cancer prevention is currently underway, two studies of statins as secondary preventive agents are. One trial is randomizing patients to simvastatin or placebo prior to radical prostatectomy and is examining changes in benign and malignant tissue in the prostate specimen . The second trial is a phase II study of atorvastatin and celecoxib in patients with rising PSA levels after definitive local therapy and is examining changes in biomarkers, including PSA .
Taken together, the medical community is unlikely to have a compound with proven ability to prevent prostate cancer emanate from these studies in the forseeable future.
The 5-α reductase inhibitors
Rationale and benefits
By far the most promising and well-studied chemopreventive agents are the 5-ARIs finasteride and dutasteride. The 5-α reductase (5-AR) enzyme is responsible for converting testosterone into dihydrotestosterone. Dihydrotestosterone is a prevalent and potent androgen in prostate tissue and is responsible for embryologic development of the prostate , growth of the prostate and promotion of prostate cancer . Finasteride inhibits 5-AR type 2, and dutasteride inhibits 5-AR types 1 and 2. Both finasteride and dutasteride were designed and approved for the treatment of benign prostatic hyperplasia (BPH) and have proven efficacy in this regard [23–26].
Finasteride was studied in the Prostate Cancer Prevention Trial (PCPT) . In this RCT of 18,000 men ≥ 55 years of age with a normal digital rectal examination (DRE) and PSA level ≤ 3 ng/mL, after seven years, those in the finasteride arm had a 25% reduction in prostate cancer incidence (18.4% vs. 24.4%; P < 0.001). Dutasteride was studied in the REduction by DUtasteride of Prostate Cancer Events (REDUCE) trial . In this RCT of 6,729 men ages 50 to 75 years with a prior negative prostate biopsy who had at least one on-study biopsy, those in the dutasteride arm had a 23% reduction in prostate cancer incidence after four years (19.9% vs. 25.1%; P < 0.001). The two trials are compared in Table 1. These risk reductions translate into a number needed to treat to prevent one case of prostate cancer of 17 for finasteride and 20 for dutasteride. If the story ended there, many men would undoubtedly be taking a 5-ARI drug today.
Unfortunately, the results of the two primary prevention trials are more complicated. First, these trials have been criticized for lack of generalizability because the results were driven largely by end-of-study biopsies as opposed to biopsies clinically triggered by elevated PSA or DRE abnormalities. In fact, subgroup analyses of only biopsies triggered by clinical events suggested 5-ARIs achieved less impressive relative risk reductions (RRRs) (PCPT: 9% RRR; REDUCE: 1% RRR) [27, 28]. It is argued that these risk reduction estimates more closely mirror what would be seen in general practice.
Second, it appears that 5-ARIs preferentially prevent low-grade cancers. In both trials, the overall cancer risk reduction was driven entirely by the reduction in Gleason ≤ 6 tumors. Such low-grade cancers are unlikely to lead to prostate cancer mortality and thus arguably do not warrant preventive efforts [29, 30]. Indeed, a pathological review of cancers in the PCPT demonstrated that 40% of the Gleason ≤ 6 tumors met established pathologic criteria for clinically insignificant disease [31, 32]. A similar analysis of the REDUCE trial cancers has yet been published; however, a pathologic review by an expert genitourinary pathologist commissioned by the FDA concluded that 80% of the Gleason ≤ 6 tumors met the criteria for clinically insignificant disease . Two counterarguments are apparent: (1) In general, as many as 30% of cancers initially deemed insignificant on the basis of the first biopsy are reclassified as significant on the basis of a subsequent biopsy ; and (2) currently in the United States, > 90% of men diagnosed with Gleason 6 tumors undergo surgery or radiotherapy . If these trends continue, reducing the incidence of these often-treated cancers with 5-ARIs may be meaningful.
By far the issue receiving the greatest concern from these two prevention trials is the increased risk of high-grade disease. In the PCPT, the proportion of high-grade tumors (Gleason ≥ 7) was 27% higher in the finasteride arm (280 (6.4%) vs. 237 (5.1%); P = 0.005), and in the REDUCE trial, though no significant difference in Gleason ≥ 7 tumors was reported (220 (6.7%) vs. 233 (6.8%); P = 0.81), there was clearly a trend toward increased risk in Gleason ≥ 8 tumors (29 (0.9%) vs. 19 (0.6%); P = 0.15), particularly in years 3 and 4 (12 (0.5%) vs. 1 (< 0.1%); P = 0.003).
Two theories have been suggested as to why higher-grade disease is noted in the 5-ARI arms: (1) 5-ARIs shrink prostate volume, thus making it more likely to find high-grade disease when it is present ; and (2) 5-ARIs, by reducing confounding from BPH, heighten the sensitivity of the PSA and DRE in the detection of high-grade disease [37, 38]. In a post hoc analysis using imputation based on these two theories, the PCPT group concluded that there was actually a 27% reduction in the risk of Gleason ≥ 7 tumors, though there remained, albeit reduced, a 25% increase in risk of Gleason ≥ 8 tumors . In the REDUCE study, the authors explained that the increased risk of Gleason ≥ 8 tumors was a product of more cancers being detected in the placebo group in years 1 and 2. That is, if these tumors were not detected and therefore not removed from analysis in years 3 and 4, a portion of them would have progressed to high-grade disease and would have balanced the higher-grade tumors seen in the dutasteride arm in years 3 and 4. However, the natural history of low-grade tumors dedifferentiating to high-grade tumors is not known and unlikely to be sufficiently rapid to explain the difference in years 3 and 4.
The fact remains that both trials observed at least concerning trends toward increased high-grade disease, though it should be noted that the absolute risk increase is small. The true extent to which these trends can be explained by the theories proposed is unknown, but for now concern lingers that 5-ARIs may induce or selectively promote growth of high-grade disease.
Use of 5-α reductase inhibitors in practice
The only study exploring the use of 5-ARIs in clinical practice observed that while use slowly increased from 2000 to 2005 in the Veterans Health Administration, there was a subtle trend toward decreased use after publication of the PCPT (Figure 1) . This change did not reach statistical significance, and prescriptions could not be classified by intended use (prostate cancer prevention vs. treatment of BPH).
In the accompanying survey, urologists cited concerns over the risk of high-grade disease as the most common reason not to prescribe 5-ARIs for chemoprevention . This article was written prior to the publication of the REDUCE trial. As such, the extent to which 5-ARIs are currently being used for prostate cancer prevention remains unclear.
Most recently, the FDA Oncology Drugs Advisory Committee (ODAC) reviewed applications by GlaxoSmithKline to add an indication for dutasteride for the prevention of prostate cancer in men at increased risk for prostate cancer and by Merck to alter the labeling for finasteride to reflect a more favorable safety profile with regard to preventing prostate cancer. The FDA conducted its own reanalysis of the PCPT and REDUCE trial results and concluded that (1) the risks of high-grade cancer were likely real and could not be explained entirely by volume grade bias, increased sensitivity of PSA and DRE or removal of low-grade cancers in the REDUCE trial placebo arm, (2) the majority of cancers prevented were low risk and the trials provided no evidence of 5-ARI treatment and prostate cancer mortality reduction and (3) the results were not generalizable to the US population because end-of-study biopsies do not mirror clinical practice. The FDA ODAC voted against the new indication for dutasteride (yes = 2, no = 14, abstain = 2) and against the new labeling for finasteride (yes = 0, no = 17, abstain = 1). GlaxoSmithKline has subsequently announced that it is withdrawing applications for similar approval in other countries .
Though we do not have an up-to-date assessment of whether 5-ARIs are being prescribed for chemoprevention, it is likely, given trepidation before, that the FDA ruling will lead to more hesitation in prescribing 5-ARIs for this indication. Apparent from the FDA ODAC meeting was that even among people who study the issue of 5-ARI chemoprevention extensively, eight years after publication of the PCPT there is still vast disagreement regarding the benefits and harms. With such disagreement among experts, it is not surprising that practicing physicians do not have a clear answer when their patients ask about 5-ARIs.
Since the PCPT, 11 publications have explored various aspects of the trade-offs among the benefits, harms and costs of 5-ARI chemoprevention for prostate cancer. An extensive analysis of these studies is beyond the scope of this review and is complicated by the fact that each is based on a set of assumptions about the PCPT data. For example, some model the risk of high-grade disease at face value from the trial; others impute less risk of high-grade disease based on the volume grade and PSA sensitivity biases; some model the baseline cancer risk from all biopsies in the control arm, which include end-of-study biopsies; and others use Surveillance Epidemiology End Results rates to better approximate real-world incidence. Overall, most conclude that a strategy whereby all men over 55 years of age are recommended to take finasteride is not cost-effective [42, 43]. However, studies analyzing a strategy targeting only men at higher risk of prostate cancer suggest that finasteride chemoprevention is cost-effective [44–47].
The goal of the REDUCE study was to examine 5-ARIs in men at higher risk in hopes of answering that question. As it turned out, that cohort of men with a prior negative biopsy actually had a risk of prostate cancer equal to that of the PCPT cohort (placebo cancer rate 24.4% in PCPT vs. 25.1% in REDUCE). Only one study has examined the cost-effectiveness of dutasteride based on the REDUCE data and similarly concluded that it is unlikely to be cost-effective unless targeted at a high-risk population .
Given the tremendous potential benefits of chemoprevention, there is logic in searching for a different role for 5-ARIs. Indeed, more derivative questions are still being addressed in trials. For example, investigators are studying whether short courses of finasteride improve the discriminating ability of PSA in prostate cancer screening  or the cancer yield at repeat biopsy after a prior negative biopsy , as well as whether dutasteride prevents cancer in men with high-grade prostate intraepithelial neoplasia, a precursor lesion to prostate cancer . Aside from these trials, more work is needed to identify a subgroup of patients, using either clinical or genetic features, who are at increased risk of prostate cancer and/or are most likely to respond to 5-ARI therapy. Perhaps we can identify a genetic signature that predicts those prone to developing high-grade disease in the dihydrotestosterone-depleted prostate environment, and physicians could avoid using 5-ARIs in these men. Selective treatment in men without this signature would be "safer" in that it only reduces prostate cancer risk without increasing high-grade disease.
It may be that 5-ARIs are more appropriate for secondary prevention, that is, in preventing adverse outcomes in men who already have been diagnosed with cancer. The Reduction by Dutasteride of Clinical Progression Events in Expectant Management (ReDEEM) trial has now concluded. Presented only in abstract form to date, this study illustrated that in men with very low-risk prostate cancer treated with active surveillance, dutasteride reduced the time to pathologic or therapeutic progression by 38.9% (95% confidence interval 12.4 to 57.4; P = 0.007) .
With the risk of prostate cancer so high, there is great need for a strategy to reduce the incidence and thus the burden of prostate cancer. Chemoprevention holds such potential in this regard. Yet, the future of 5-ARIs, the most promising chemopreventive agents to date, is uncertain. In the role of wide-scale use to prevent prostate cancer in men of average risk, this is likely the end for 5-ARIs with no further primary prevention trials on the horizon. The widespread acceptance of statins and aspirin for cardiovascular disease prevention proves that patients are willing to take a drug to prevent a disease they may never get. In the case of 5-ARIs, it is likely not the small risk of reversible sexual side effects or the preferential prevention of low-grade disease that are preventing FDA approval and wider adoption. It is the lingering uncertainty surrounding the risk of high-grade disease. No physician or regulatory body is comfortable treating healthy men with a drug that has even the slightest risk of inducing a potentially lethal cancer.
Until more is learned, physicians are unfortunately left in the difficult position of explaining the complicated risks and benefits of 5-ARIs, and while they were never approved for chemopreventive use before, there was always the hope that they would be. Now the hope of their approval is gone, and the scientific community, while still endeavoring to identify a specific subgroup of men who will benefit from 5-ARIs, should begin turning the page toward the next chemoprevention strategy.
5-α reductase enzyme
benign prostatic hyperplasia
digital rectal examination
US Food and Drug Administration
nonsteroidal anti-inflammatory drug
Oncology Drugs Advisory Committee
Prostate Cancer Prevention Trial
randomized; controlled trial
REduction by DUtasteride of Prostate Cancer Events
relative risk reduction.
American Cancer Society. Cancer Facts and Figures 2010. [http://www.cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf]
Stokes ME, Black L, Benedict A, Roehrborn CG, Albertsen P: Long-term medical-care costs related to prostate cancer: estimates from linked SEER-Medicare data. Prostate Cancer Prostatic Dis. 2010, 13: 278-284. 10.1038/pcan.2010.5.
Silberstein JL, Parsons JK: Prostate cancer prevention: concepts and clinical recommendations. Prostate Cancer Prostatic Dis. 2010, 13: 300-306. 10.1038/pcan.2010.18.
Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK, Hartman AM, Haapakoski J, Malila N, Rautalahti M, Ripatti S, Mäenpää H, Teerenhovi L, Koss L, Virolainen M, Edwards BK: Prostate cancer and supplementation with α-tocopherol and β-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst. 1998, 90: 440-446. 10.1093/jnci/90.6.440.
Duffield-Lillico AJ, Dalkin BL, Reid ME, Turnbull BW, Slate EH, Jacobs ET, Marshall JR, Clark LC: Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial. BJU Int. 2003, 91: 608-612. 10.1046/j.1464-410X.2003.04167.x.
Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, Parnes HL, Minasian LM, Gaziano JM, Hartline JA, Parsons JK, Bearden JD, Crawford ED, Goodman GE, Claudio J, Winquist E, Cook ED, Karp DD, Walther P, Lieber MM, Kristal AR, Darke AK, Arnold KB, Ganz PA, Santella RM, Albanes D, Taylor PR, Probstfield JL, Jagpal TJ, Crowley JJ, et al: Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009, 301: 39-51. 10.1001/jama.2008.864.
Ma J, Stampfer MJ, Gann PH, Hough HL, Giovannucci E, Kelsey KT, Hennekens CH, Hunter DJ: Vitamin D receptor polymorphisms, circulating vitamin D metabolites, and risk of prostate cancer in United States physicians. Cancer Epidemiol Biomarkers Prev. 1998, 7: 385-390.
Raghow S, Hooshdaran MZ, Katiyar S, Steiner MS: Toremifene prevents prostate cancer in the transgenic adenocarcinoma of mouse prostate model. Cancer Res. 2002, 62: 1370-1376.
Mahmud SM, Franco EL, Turner D, Platt RW, Beck P, Skarsgard D, Tonita J, Sharpe C, Aprikian AG: Use of non-steroidal anti-inflammatory drugs and prostate cancer risk: a population-based nested case-control study. PLoS One. 2011, 6: e16412-10.1371/journal.pone.0016412.
van Adelsberg J, Gann P, Ko AT, Damber JE, Logothetis C, Marberger M, Schmitz-Drager BJ, Tubaro A, Harms CJ, Roehrborn C: The VIOXX in Prostate Cancer Prevention study: cardiovascular events observed in the rofecoxib 25 mg and placebo treatment groups. Curr Med Res Opin. 2007, 23: 2063-2070. 10.1185/030079907X219526.
Price D, Stein B, Sieber P, Tutrone R, Bailen J, Goluboff E, Burzon D, Bostwick D, Steiner M: Toremifene for the prevention of prostate cancer in men with high grade prostatic intraepithelial neoplasia: results of a double-blind, placebo controlled, phase IIB clinical trial. J Urol. 2006, 176: 965-971. 10.1016/j.juro.2006.04.011.
Taneja SS, Morton RA, Barnette G, Hancock M, Brawer M, Steiner M: Men with isolated high grade prostatic intraepithelial neoplasia (HGPIN) have a high risk of prostate cancer in long-term follow-up: results from a prospective multicenter, randomized, placebo-controlled prostate cancer prevention trial. J Urol. 2011, 185: e484.
Hamilton RJ, Goldberg KC, Platz EA, Freedland SJ: The influence of statin medications on prostate-specific antigen levels. J Natl Cancer Inst. 2008, 100: 1511-1518. 10.1093/jnci/djn362.
Chang SL, Harshman LC, Presti JC: Impact of common medications on serum total prostate-specific antigen levels: analysis of the National Health and Nutrition Examination Survey. J Clin Oncol. 2010, 28: 3951-3957. 10.1200/JCO.2009.27.9406.
Bonovas S, Filioussi K, Sitaras NM: Statin use and the risk of prostate cancer: a metaanalysis of 6 randomized clinical trials and 13 observational studies. Int J Cancer. 2008, 123: 899-904. 10.1002/ijc.23550.
Gutt R, Tonlaar N, Kunnavakkam R, Karrison T, Weichselbaum RR, Liauw SL: Statin use and risk of prostate cancer recurrence in men treated with radiation therapy. J Clin Oncol. 2010, 28: 2653-2659. 10.1200/JCO.2009.27.3003.
Hamilton RJ, Banez LL, Aronson WJ, Terris MK, Platz EA, Kane CJ, Presti JC, Amling CL, Freedland SJ: Statin medication use and the risk of biochemical recurrence after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) Database. Cancer. 2010, 116: 3389-3398. 10.1002/cncr.25308.
Ku JH, Jeong CW, Park YH, Cho MC, Kwak C, Kim HH: Relationship of statins to clinical presentation and biochemical outcomes after radical prostatectomy in Korean patients. Prostate Cancer Prostatic Dis. 2011, 14: 63-68. 10.1038/pcan.2010.39.
National Cancer Institute Clinical Trials (PDQ): Statin Therapy Versus Placebo Prior to Prostatectomy. [http://www.cancer.gov/clinicaltrials/search/view?cdrid=582847&version=HealthProfessional&protocolsearchid=9130632]
National Cancer Institute Clinical Trials (PDQ): Phase II Study of Atorvastatin Calcium and Celecoxib in Patients With Hormone-Dependent Prostate-Specific Antigen Progression After Local Therapy for Prostate Cancer. [http://www.cancer.gov/clinicaltrials/search/view?cdrid=636488&version=HealthProfessional&protocolsearchid=9130632]
Walsh PC, Madden JD, Harrod MJ, Goldstein JL, MacDonald PC, Wilson JD: Familial incomplete male pseudohermaphroditism, type 2: decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med. 1974, 291: 944-949. 10.1056/NEJM197410312911806.
Petrow V, Padilla GM, Mukherji S, Marts SA: Endocrine dependence of prostatic cancer upon dihydrotestosterone and not upon testosterone. J Pharm Pharmacol. 1984, 36: 352-353.
McConnell JD, Roehrborn CG, Bautista OM, Andriole GL, Dixon CM, Kusek JW, Lepor H, McVary KT, Nyberg LM, Clarke HS, Crawford ED, Diokno A, Foley JP, Foster HE, Jacobs SC, Kaplan SA, Kreder KJ, Lieber MM, Lucia MS, Miller GJ, Menon M, Milam DF, Ramsdell JW, Schenkman NS, Slawin KM, Smith JA, Medical Therapy of Prostatic Symptoms (MTOPS) Research Group: The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003, 349: 2387-2398. 10.1056/NEJMoa030656.
Roehrborn CG, Barkin J, Siami P, Tubaro A, Wilson TH, Morrill BB, Gagnier RP: Clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (BPH) by baseline characteristics: 4-year results from the randomized, double-blind Combination of Avodart and Tamsulosin (CombAT) trial. BJU Int. 2011, 107: 946-954. 10.1111/j.1464-410X.2011.10124.x.
Dorsam J, Altwein J: 5α-reductase inhibitor treatment of prostatic diseases: background and practical implications. Prostate Cancer Prostatic Dis. 2009, 12: 130-136. 10.1038/pcan.2008.56.
Becher E, Roehrborn CG, Siami P, Gagnier RP, Wilson TH, Montorsi F: The effects of dutasteride, tamsulosin, and the combination on storage and voiding in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the Combination of Avodart and Tamsulosin study. Prostate Cancer Prostatic Dis. 2009, 12: 369-374. 10.1038/pcan.2009.37.
Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA: The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003, 349: 215-224. 10.1056/NEJMoa030660.
Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, Pettaway CA, Tammela TL, Teloken C, Tindall DJ, Somerville MC, Wilson TH, Fowler IL, Rittmaster RS, REDUCE Study Group: Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010, 362: 1192-1202. 10.1056/NEJMoa0908127.
Albertsen P, Hanley JA, Fine BA: 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA. 2005, 293: 2095-2101. 10.1001/jama.293.17.2095.
Eggener SE, Scardino PT, Walsh PC, Han M, Partin AW, Trock BJ, Feng Z, Wood DP, Eastham JA, Yossepowitch O, Rabah DM, Kattan MW, Yu C, Klein EA, Stephenson AJ: Predicting 15-year prostate cancer specific mortality after radical prostatectomy. J Urol. 2011, 185: 869-875. 10.1016/j.juro.2010.10.057.
Epstein JI, Walsh PC, Carmichael M, Brendler CB: Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA. 1994, 271: 368-374. 10.1001/jama.271.5.368.
Lucia MS, Darke AK, Goodman PJ, La Rosa FG, Parnes HL, Ford LG, Coltman CA, Thompson IM: Pathologic characteristics of cancers detected in the Prostate Cancer Prevention Trial: implications for prostate cancer detection and chemoprevention. Cancer Prev Res. 2008, 1: 167-173. 10.1158/1940-6207.CAPR-08-0078.
US Food and Drug Administration: December 1, 2010 Meeting of the Oncologic Drugs Advisory Committee. FDA core presentation: NDA 020180/s034: Proscar (finasteride 5 mg tablet). [http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM236786.pdf]
Berglund RK, Masterson TA, Vora KC, Eggener SE, Eastham JA, Guillonneau BD: Pathological upgrading and up staging with immediate repeat biopsy in patients eligible for active surveillance. J Urol. 2008, 180: 1964-1968. 10.1016/j.juro.2008.07.051.
Cooperberg MR, Broering JM, Carroll PR: Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol. 2010, 28: 1117-1123. 10.1200/JCO.2009.26.0133.
Kulkarni GS, Al-Azab R, Lockwood G, Toi A, Evans A, Trachtenberg J, Jewett MA, Finelli A, Fleshner NE: Evidence for a biopsy derived grade artifact among larger prostate glands. J Urol. 2006, 175: 505-509. 10.1016/S0022-5347(05)00236-3.
Thompson IM, Chi C, Ankerst DP, Goodman PJ, Tangen CM, Lippman SM, Lucia MS, Parnes HL, Coltman CA: Effect of finasteride on the sensitivity of PSA for detecting prostate cancer. J Natl Cancer Inst. 2006, 98: 1128-1133. 10.1093/jnci/djj307.
Thompson IM, Tangen CM, Goodman PJ, Lucia MS, Parnes HL, Lippman SM, Coltman CA: Finasteride improves the sensitivity of digital rectal examination for prostate cancer detection. J Urol. 2007, 177: 1749-1752. 10.1016/j.juro.2007.01.071.
Redman MW, Tangen CM, Goodman PJ, Lucia MS, Coltman CA, Thompson IM: Finasteride does not increase the risk of high-grade prostate cancer: a bias-adjusted modeling approach. Cancer Prev Res. 2008, 1: 174-181. 10.1158/1940-6207.CAPR-08-0092.
Hamilton RJ, Kahwati LC, Kinsinger LS: Knowledge and use of finasteride for the prevention of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2010, 19: 2164-2171. 10.1158/1055-9965.EPI-10-0082.
GSK Statement on Avodart (dutasteride) for prostate cancer risk reduction. [http://www.gsk.com/media/pressreleases/2011/2011_pressrelease_10043.htm]
Zeliadt SB, Etzioni RD, Penson DF, Thompson IM, Ramsey SD: Lifetime implications and cost-effectiveness of using finasteride to prevent prostate cancer. Am J Med. 2005, 118: 850-857. 10.1016/j.amjmed.2005.03.001.
Grover S, Lowensteyn I, Hajek D, Trachtenberg J, Coupal L, Marchand S: Do the benefits of finasteride outweigh the risks in the prostate cancer prevention trial?. J Urol. 2006, 175: 934-938. 10.1016/S0022-5347(05)00424-6.
Earnshaw SR, McDade CL, Black LK, Bell CF, Kattan MW: Cost effectiveness of 5-α reductase inhibitors for the prevention of prostate cancer in multiple patient populations. Pharmacoeconomics. 2010, 28: 489-505. 10.2165/11531780-000000000-00000.
Reed SD, Scales CD, Stewart SB, Sun J, Moul JW, Schulman KA, Xu J: Effects of family history and genetic polymorphism on the cost-effectiveness of chemoprevention with finasteride for prostate cancer. J Urol. 2011, 185: 841-847. 10.1016/j.juro.2010.10.078.
Vickers AJ, Savage CJ, Lilja H: Finasteride to prevent prostate cancer: should all men or only a high-risk subgroup be treated?. J Clin Oncol. 2010, 28: 1112-1116. 10.1200/JCO.2009.23.5572.
Svatek RS, Lee JJ, Roehrborn CG, Lippman SM, Lotan Y: Cost-effectiveness of prostate cancer chemoprevention: a quality of life-years analysis. Cancer. 2008, 112: 1058-1065. 10.1002/cncr.23276.
Svatek RS, Lotan Y: Cost utility of prostate cancer chemoprevention with dutasteride in men with an elevated prostate specific antigen. Cancer Prev Res (Phila). 2011, 4: 277-283. 10.1158/1940-6207.CAPR-10-0200.
National Cancer Institute Clinical Trials (PDQ): Finasteride Challenge. [http://www.cancer.gov/clinicaltrials/search/view?cdrid=695783&version=HealthProfessional&protocolsearchid=9180532]
National Cancer Institute Clinical Trials (PDQ): A Trial of PROSCAR (Finasteride) Versus Placebo in Men With an Initial Negative Prostate Biopsy. [http://www.cancer.gov/clinicaltrials/search/view?cdrid=656830&version=HealthProfessional&protocolsearchid=9180532]
National Cancer Institute Clinical Trials PDQ: Prevention of Prostate Cancer With Dutasteride in Case of High Grade PIN Neoplasia. [http://www.cancer.gov/clinicaltrials/search/view?cdrid=624271&version=HealthProfessional&protocolsearchid=9180527]
Fleshner NE, Lucia MS, Melich K, Nandy IM, Black L, Rittmaster RS: Effect of dutasteride on prostate cancer progression and cancer diagnosis on rebiopsy in the REDEEM active surveillance study [abstract 2]. J Clin Oncol. 2011, 29 (Suppl 7).
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RJH has no disclosures. SJF is a paid consultant for GlaxoSmithKline.
Both RJH and SJF contributed equally to the manuscript. Both authors read and approved the final manuscript.
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Hamilton, R.J., Freedland, S.J. 5-α reductase inhibitors and prostate cancer prevention: where do we turn now?. BMC Med 9, 105 (2011). https://doi.org/10.1186/1741-7015-9-105
- Prostate Cancer
- Benign Prostatic Hyperplasia
- Digital Rectal Examination