Do 5a-Reductase Inhibitors Alter Prostate Cancer Detection and What Are the Implications?

european urology supplements 5 (2006) 752 757 available at www.sciencedirect.com journal homepage: www.europeanurology.com Do 5a-Reductase Inhibitors Alter Prostate Cancer Detection and What Are the Implications? M. Scott Lucia * Prostate Cancer Research Laboratories, Department of Pathology, University of Colorado at Denver and Health Science Center, Campus Box 8104, Biomedical Research Tower (RC1-North), Room 5128, Denver, CO, United States Article info Keywords: Biopsy Chemoprevention Detection 5a-reductase inhibitor Gleason grade Prostate cancer Abstract The 5a-reductase inhibitors (5-ARIs) have a number of effects on benign, hyperplastic, and malignant prostate epithelium. The extent of these effects appears to differ significantly among patients, and on average, appears less than that observed with luteinising hormone-releasing hormone (LHRH) agonist therapy. Indeed, the characteristic changes observed for hormonal therapy may not be so specific after all, if such changes can also be observed in men not receiving 5-ARIs or hormonal therapy. Although prostate specimens derived from men receiving a 5-ARI need to be interpreted with care, currently little evidence supports the original contention that use of a 5-ARI can result in significant misinterpretation of Gleason grade in those with prostate cancer. Data from the Prostate Cancer Prevention Trial (PCPT) strongly suggest that the reduction in prostate volume combined with changes in the performance of prostate-specific antigen (PSA) observed with 5-ARI treatment results in an excess detection of tumours, especially high-grade lesions, compared with untreated men. The effects of 5-ARIs on PSA appear to improve the predictive value of PSA as a diagnostic test for prostate cancer, possibly by differential suppression of PSA derived from cancerous and noncancerous tissue. New analyses, under development, are seeking to examine how this increased detection affects the reduction in risk of prostate cancer observed with 5-ARI therapy during the 7 yr of the PCPT. # 2006 Published by Elsevier B.V. on behalf of European Association of Urology. * Tel. +1 303 724 3470. E-mail address: scott.lucia@uchsc.edu. 1. Introduction It has been understood for some time that treatment with 5a-reductase inhibitors (5-ARIs) has the ability to influence prostate cancer detection. Through inhibition of dihydrotestosterone (DHT) synthesis, 5-ARIs significantly reduce androgen drive to the prostate, which in its normal, hyperplastic, or cancerous state is androgen sensitive [1,2]. Androgens, particularly DHT, are recognised as the major regulator of prostate growth and differentiation. Interfering with the actions of androgen on the prostate results in glandular atrophy causing shrinkage of the prostate and reduction of prostate-specific antigen (PSA) synthesis [3]. The use of 5-ARIs, therefore, has the potential to alter 1569-9056/$ see front matter # 2006 Published by Elsevier B.V. on behalf of European Association of Urology. doi:10.1016/j.eursup.2006.06.015

european urology supplements 5 (2006) 752 757 753 prostate cancer detection in three ways: through effects on prostate histology that may alter the pathologist s view of a biopsy or radical prostatectomy specimen; through a decrease in the volume of the prostate, leading to alterations in suspicion of cancer on digital rectal examination (DRE) or through altered biopsy sampling; and through a reduction in serum PSA levels, resulting in an altered performance as a marker of suspicion for prostate cancer. Although postulated for years, more recent clinical data have produced a dramatic expansion of our knowledge of these effects and of their clinical implications. The completion of the Prostate Cancer Prevention Trial (PCPT) [4] and subsequent controversies over the incidence of tumours with high Gleason grades detected in the finasteride arm [5] have focussed considerable attention on these issues. The PCPT, sponsored by the National Cancer Institute and coordinated by the Southwest Oncology Group, evaluated the ability of finasteride to reduce the period-prevalence of prostate cancer, defined as the total number of prostate cancers diagnosed over a 7-yr period, in men taking the drug compared with placebo. Over 18,000 men were randomised to receive either finasteride (5 mg/d) or placebo and followed with annual examinations and PSA measurements. Biopsies of theprostatewereobtainedduringthestudydueto abnormal examination or PSA findings (for cause) and also at the end of the study regardless of examination or PSA findings. The study observed a 24.8% reduction in prostate cancer in the finasteride group compared with placebo [4].However,ahigher proportion of tumours with a Gleason score of 7 10 were detected in the finasteride group versus the placebo group (37.0% vs. 22.2% of graded tumours; p < 0.001), with the majority of this difference accounted for in the for-cause biopsies (Fig. 1). This raised the concern that alteration of the androgen balance through inhibition of 5a-reductase may promote the growth of more aggressive prostate tumours [4]. An important observation that pointed to an artifactual cause for this observation, rather than a true potentiation effect, was that the proportions of high-grade tumours in the two treatment arms did not diverge with time, a trend that would be expected if finasteride did promote the development of more aggressive tumours [6]. Furthermore, if finasteride did potentiate growth of high-grade cancer, then pathologic prognostic factors associated with tumour volume and extent would be expected to be greater in the high-grade tumours in the finasteride arm of the study compared with the Fig. 1 Gleason grade 7 10 tumours diagnosed in the Prostate Cancer Prevention Trial by timing of biopsy [4]. placebo arm. In contrast, preliminary results from the PCPT indicate that the tumours with Gleason scores 7 10 were less extensive in the finasteride arm compared with placebo for all of these features [7]. Other potential explanations for these observations therefore need to be examined. 2. Histopathologic effects of 5-ARIs For some time it has been known that treatment of benign prostatic hyperplasia (BPH) with the type-2 selective 5-ARI, finasteride, results in a reduction of prostate epithelial volume and an increase in the stromal-epithelial ratio of similar magnitude in the transitional and peripheral zones of the prostate [8]. Finasteride treatment of normal or hyperplastic prostate tissue results in atrophy and involution [9 14], smaller nuclei and nucleoli [11], increased apoptosis [12,15], decreased microvessel density [16,17], and no increase in cellular proliferation [15]. Although 5-ARIs are known to cause a number of histologic changes in normal and hyperplastic prostatic tissues, their direct effects on the morphology of prostate cancer are less clear. It is well established that luteinising hormone-releasing hormone (LHRH) agonist therapy has a profound impact on the morphology of cancer and the accuracy of Gleason grading, causing tumours of lower grade to artifactually appear high grade [18]. This has led to the consensus that Gleason grading should not be performed on tumours that have been hormonally treated [19]. However, substantive data of the effects of 5-ARIs on Gleason grading have not, until recently, become available.

754 european urology supplements 5 (2006) 752 757 Two early studies examining the histologic effects of finasteride in men with prostate cancer provided differing results. Radical prostatectomy specimens reported alterations similar to, but less prominent than, those of LHRH agonists, with these changes occurring focally and only noticeable in low-grade tumours [9]. However, an examination of a subgroup of needle biopsy specimens from the Proscar Long-term Efficacy and Safety Study (PLESS) failed to demonstrate any effect of finasteride on tumour morphology [20]. More recent studies have again provided conflicting results. One study has examined the effects of the dual 5-ARI dutasteride. Among men with T1 or T2 prostate cancer scheduled to undergo radical prostatectomy who received dutasteride for 5 11 wk, tumour size was smaller, the stroma-gland ratio was increased, and the mean percentage of cancer epithelium with atrophic change was doubled compared with untreated men [21,22]. Yet, in another study of 45 men pretreated with finasteride for a minimum of 6 mo, the authors concluded that assignment of Gleason grade on biopsies or radical prostatectomy specimens was not compromised [23]. Furthermore, a recent study in 56 men receiving finasteride found that, although the characteristic changes of hormonal effects were observed in a higher proportion of men receiving a 5-ARI versus a group of matched controls, this difference was not statistically significant. This suggests that the characteristic changes observed are not specific for 5-ARI therapy [24]. Preliminary results from the PCPT are also in agreement with this last study [25]. Thus, although a consensus on the grading of cancer treated with 5-ARIs has not yet been reached, it can be said that 5-ARI therapy may be associated with changes in prostatic architecture, but such changes differ among subjects and may not always be readily separable from nontreatment-related changes. It was concluded that a grading bias as a result of 5-ARI therapy did not likely account for the Gleason observations in the PCPT, although the possibility remains that this may have confounded the grading in certain cases. Whether the effects differ significantly between dutasteride and finasteride remains to be elucidated. 3. Effects of 5-ARIs on prostate volume The effects of 5-ARIs in reducing prostate volume in men with BPH are well documented, with similar reductions in the transition and peripheral zones [8,26]. Finasteride treatment results in a reduction in total prostate volume of 18% over 4 yr [27], rising to 25% at 7 yr [4]. In a different patient population, treatment with dutasteride resulted in mean reductions of 26.0% at 24 mo and 27.3% at 48 mo [28]. The implication of these reductions for prostate cancer detection rests on the observation that tumours are easier to detect in smaller prostates [29]. Thus, in a prostate cancer prevention study using a 5-ARI, active treatment can enhance prostate cancer detection. This phenomenon likely led to a bias against the finasteride arm of the PCPT, with enhanced prostate cancer detection in men treated with finasteride. To what extent would this contribute to an excess detection of high-grade tumours in the finasteride arm of the PCPT? A recent retrospective review of transurethral ultrasound (TRUS)-guided prostate biopsies in 1475 men with prostate cancer with a PSA 10 ng/ml, of whom 369 underwent radical prostatectomy, has shown that a lower TRUSmeasured prostate volume was a significant predictor of a tumour of high Gleason grade at biopsy but not at radical prostatectomy. This demonstrates that smaller glands are associated with an increased detection of high-grade tumours presumably due to more thorough and comprehensive tumour sampling [30]. In the PCPT, a preliminary review of prostatectomy specimens indicates that the sensitivity of needle biopsy for detecting prostatectomyconfirmed high-grade cancer was almost 20% greater in the finasteride group than the placebo group (69.7% vs. 50.5%) [7]. Thus, the most likely explanation for the excess detection of tumours of high Gleason grade in the finasteride arm of the PCPT is the effect of finasteride on reducing prostate volume. It is also possible that effects on prostate histology and PSA, as discussed elsewhere in this article, could have biased prostate cancer detection in the finasteride arm. The induction of high-grade disease by finasteride also remains a possibility although this is considered significantly less likely by the PCPT investigators. 4. Effects of 5-ARIs on serum PSA Another important effect of 5-ARIs on prostate cancer detection is their known effect in reducing serum PSA levels over time. Early studies with finasteride demonstrated that it reduced serum PSA by a median of 50% over 12 mo [31], an observation that led to the introduction of the doubling rule to preserve the validity of the PSA value. Equivalent reductions in free and total PSA occur with 5-ARI treatment; an observation that has been made with both finasteride [32] and dutasteride [33]. Although it

european urology supplements 5 (2006) 752 757 755 soon became clear that finasteride treatment beyond 1 yr resulted in further suppression of PSA in men with BPH, the sensitivity/specificity relationship for PSA in finasteride-treated men in one study was similar to that of placebo-treated men over 4 yr [34]. Comparable findings were also seen with the dual 5-ARI, dutasteride, which caused a median 59.5% decrease in PSA at 2 yr in men without a prostate cancer diagnosis [35]. One important limitation of these studies is that prostate biopsies were not mandatory either before or during the studies and, therefore, cancer detection by biopsy was conducted on a for-cause basis. It is very likely that a significant number of cases of prostate cancer went undetected and would therefore not have been part of the data set examining the sensitivity and specificity of PSA in men treated with a 5-ARI. It has also been recognised that for treatment periods of <12 mo, use of the generalised doubling rule could result in a higher rate of false-positive results (35% vs. 25%) for men receiving finasteride [36]. A subsequent study, which recruited men with biopsy-proven BPH or concomitant BPH/prostate cancer, demonstrated that, in the first 6 mo of treatment, more men with cancer receiving finasteride than placebo had a rise in PSA to >4 ng/ml and fewer had a decrease to <4 ng/ml, with the doubling rule applied [37]. This occurs because the median PSA in finasteride-treated men decreases steadily over the course of a year to reach a value of around 50% of baseline. Doubling in the first year can therefore significantly overestimate PSA. This phenomenon could potentially lead to an increased biopsy rate in finasteride-treated men in the first year of treatment. This was demonstrated in the PCPT where the biopsy rate was higher in the first year in finasteride- than placebo-treated men, despite being lower in every other year of the study, an observation that may have critical importance for the interpretation of the PCPT results [4]. Until the publication of data from the PCPT, the operating characteristics of PSA for detection of prostate cancer of different Gleason grades was not well understood. Derived from the placebo arm of the study, the area under the receiver operating characteristic curve (AUC) for PSA for any prostate cancer versus no prostate cancer was 0.678, a figure comparable with many other studies of the sensitivity and specificity of PSA (Fig. 2) [38]. However, the AUC for cancer of Gleason grade 7 versus no cancer or one with a Gleason grade of <7 was 0.782 and that for cancer of Gleason grade 8 versus no cancer or one with a Gleason grade of <8 was 0.827. These data demonstrate that PSA performs better for detecting Fig. 2 Receiver operating characteristic (ROC) curve of prostate-specific antigen (0 3.0 ng/ml) for the detection of prostate cancer of any grade and Gleason grades > 7 and > 8 from the Prostate Cancer Prevention Trial [38]. high-grade than low-grade cancer. Furthermore, when the AUC values were examined for the finasteride versus the placebo arm of the PCPT, the AUC values were higher in the finasteride arm for any prostate cancer, tumours with a Gleason score 7, and a Gleason score 8 [39]. Because, gram for gram, hyperplastic prostate tissue produces more PSA than prostate cancer tissue [40], and PSA may be a more accurate marker of hyperplasia than prostate cancer [41], it can be hypothesised that this increase in the AUC is related to suppression of PSA derived from normal or hyperplastic tissue to a greater extent than that from a prostate tumour. 5. Conclusions In conclusion, the 5-ARIs have a number of effects on benign, hyperplastic, and malignant prostate epithelium. The extent of these effects appears to differ significantly among patients, and on average, appears less than that observed with LHRH agonist therapy. Indeed the characteristic changes observed for hormonal therapy may not be so specific after all, if such changes can also be observed in men not receiving 5-ARIs or hormonal therapy. Although prostate specimens derived from men receiving a 5-ARI need to be interpreted with care, currently little evidence supports the original contention that 5-ARI use can result in significant misinterpretation of Gleason grade in those with prostate cancer.

756 european urology supplements 5 (2006) 752 757 Data from the PCPT strongly suggest that the reduction in prostate volume combined with changes in the performance of PSA observed with 5-ARI treatment results in an excess detection of tumours, especially high-grade lesions, compared with untreated men. The effects of 5-ARIs on PSA appear to improve the predictive value of PSA as a diagnostic test for prostate cancer, possibly by differential suppression of PSA derived from cancerous and noncancerous tissue. New analyses, under development, are seeking to examine how this increased detection affects the reduction in risk of prostate cancer observed with 5-ARI therapy during the 7 yr of the PCPT. References [1] Isaacs JT. Antagonistic effect of androgens on prostatic cell death. Prostate 1984;5:545 57. [2] Kyprianou K, English HF, Isaacs JT. Programmed cell death during regression of PC-82 human prostate cancer following androgen ablation. Cancer Res 1990;50:3748 53. [3] Rittmaster RS. 5 alpha-reductase inhibitors. J Androl 1997;18:582 7. [4] Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215 24. [5] Scardino PT. The prevention off prostate cancer the dilemma continues. N Engl J Med 2003;349:293 5. [6] Marberger M, Adolfsson J, Borkowski A, et al. The clinical implications of the prostate cancer prevention trial. BJU Int 2003;92:667 71. [7] Lucia MS, Darke A, Goodman P, et al. Pathological assessment of high grade tumors in the Prostate Cancer Prevention Trial (PCPT). Abstract presented at the American Urological Association Annual Meeting, San Antonio, TX, 21 26 May 2005. [8] Marks LS, Partin AW, Dorey FJ, et al. Long-term effects of finasteride on prostate tissue composition. Urology 1999;53:574 80. [9] Civantos F, Watson RB, Pinto JE, Korman RB, Soloway MS. Finasteride effect on prostatic hyperplasia and prostate cancer: a comparative clinico-pathologic study of radical prostatectomies. J Urol Pathol 1997;6:1 14. [10] Montironi R, Valli M, Fabris G. Treatment of benign prostatic hyperplasia with 5-alpha-reductase inhibitor: morphological changes in patients who fail to respond. J Clin Pathol 1996;49:324 8. [11] Pomante R, Santinelli A, Muzzonigro G, Montironi R. Nodular hyperplasia of the prostate. Quantitative evaluation of secretory cell changes after treatment with finasteride. Anal Quant Cytol Histol 1999;21:63 9. [12] Rittmaster RS, Norman RW, Thomas LN, Rowden G. Evidence for atrophy and apoptosis in the prostates of men given finasteride. J Clin Endocrinol Metab 1996;81: 814 9. [13] Saez C, Gonzalez-Baena AC, Japon MA, et al. Regressive changes in finasteride-treated human hyperplastic prostates correlate with an upregulation of TGF-beta receptor expression. Prostate 1998;37:84 90. [14] Thomas LN, Wright AS, Lazier CB, Cohen P, Rittmaster RS. Prostatic involution in men taking finasteride is associated with elevated levels of insulin-like growth factor-binding proteins (IGFBPs)-2, -4, and -5. Prostate 2000;42:203 10. [15] Glassman DT, Chon JK, Borkowski A, Jacobs SC, Kyprianou N. Combined effect of terazosin and finasteride on apoptosis, cell proliferation and transforming growth factorbeta expression in benign prostatic hyperplasia. Prostate 2001;46:45 51. [16] Hochberg DA, Basillote JB, Armenakas NA, et al. Decreased suburethral prostatic microvessel density in finasteride treated prostates: a possible mechanism for reduced bleeding in benign prostatic hyperplasia. J Urol 2002;167:1731 3. [17] Pareek G, Shevchuk M, Armenakas NA, et al. The effect of finasteride on the expression of vascular endothelial growth factor and microvessel density: a possible mechanism for decreased prostatic bleeding in treated patients. J Urol 2003;169:20 3. [18] Civantos F, Soloway MS, Pinto JE. Histopathological effects of androgen deprivation in prostatic cancer. Semin Urol Oncol 1996;14:22 31. [19] Reuter VE. Pathological changes in benign and malignant prostatic tissue following androgen deprivation therapy. Urology 1997;49:16 22. [20] Yang XJ, Lecksell K, Short K, et al. Does long-term finasteride therapy affect the histologic features of benign prostatic tissue and prostate cancer on needle biopsy? Urology 1999;53:696 700. [21] Iczkowski KA, Qiu J, Qian J, et al. The dual 5-alpha-reductase inhibitor dutasteride induces atrophic changes and decreases relative cancer volume in human prostate. Urology 2005;65:76 82. [22] Andriole GL, Humphrey P, Ray P, et al. Effect of the dual 5alpha-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer. J Urol 2004;172:915 9. [23] Carver BS, Kattan MW, Scardino PT, Eastham JA. Gleason grade remains an important prognostic predictor in men diagnosed with prostate cancer while on finasteride therapy. BJU Int 2005;95:509 12. [24] Rubin MA, Allory Y, Molinie V, et al. Effects of long-term finasteride treatment on prostate cancer morphology and clinical outcome. Urology 2005;66:930 4. [25] Klein E, Tangen C, Goodman P, Lippman S, Thompson I. Assessing benefit and risk in the prevention of prostate cancer: the Prostate Cancer Prevention Trial revisted. Abstract presented at the American Society of Clinical Oncology Prostate Cancer Symposium, Orlando, FL, 17 19 February 2005. [26] Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002;60:434 41. [27] McConnell JD, Bruskewitz R, Walsh PC, et al. The effect of finasteride on the risk of acute urinary retention and the

european urology supplements 5 (2006) 752 757 757 need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338:557 63. [28] Debruyne F, Barkin J, van Erps P, et al. Efficacy and safety of long-term treatment with the dual 5a-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol 2004;46:488 95. [29] Remzi M, Djavan B, Wammack R, et al. Can total and transition zone volume of the prostate determine whether to perform a repeat biopsy? Urology 2003;61:161 6. [30] Kulkarni G, Al-Azab R, Lockwood G, et al. Evidence for a biopsy-derived grade artifact among larger prostate glands: implications for the Prostate Cancer Prevention Trial. Abstract presented at the American Urological Association Annual Meeting, San Antonio, TX, 21 26 May 2005. [31] Guess HA, Heyse JF, Gormley GJ, Stoner E, Oesterling JE. Effect of finasteride on serum PSA concentration in men with benign prostatic hyperplasia. Results from the North American phase III clinical trial. Urol Clin North Am 1993;20:627 36. [32] Espana F, Martinez M, Royo M, et al. Changes in molecular forms of prostate-specific antigen during treatment with finasteride. BJU Int 2002;90:672 7. [33] Andriole GL, Kirby R. Safety and tolerability of the dual 5areductase inhibitor dutasteride in the treatment of benign hyperplasia. Eur Urol 2003;44:82 8. [34] Andriole GL, Guess HA, Epstein JI, et al. Treatment with finasteride preserves usefulness of prostate-specific antigen in the detection of prostate cancer: results of a randomized, double-blind, placebo-controlled clinical trial. Urology 1998;52:195 201. [35] Andriole GL, Marberger M, Roehrborn CG. Clinical usefulness of serum prostate specific antigen for the detection of prostate cancer is preserved in men receiving the dual 5alpha-reductase inhibitor dutasteride. J Urol 2006;175: 1657 62. [36] Guess HA, Gormley GJ, Stoner E, Oesterling JE. The effect of finasteride on prostate specific antigen: review of available data. J Urol 1996;155:3 9. [37] Oesterling JE, Roy J, Agha A, et al. Biologic variability of prostate-specific antigen and its usefulness as a marker for prostate cancer: effects of finasteride. Urology 1998;51:58 63. [38] Thompson IM, Ankerst DP, Chi C, et al. Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower. JAMA 2005; 294:66 70. [39] Thompson IM, Chi C, Goodman P, et al. Comparison of the operating characteristics of PSA for prostate cancer detection for finasteride and placebo in the Prostate Cancer Prevention Trial. Abstract presented at the American Urological Association Annual Meeting, Atlanta, GA, 20 25 May 2006. [40] Magklara A, Scorilas A, Stephan C, et al. Decreased concentrations of prostate-specific antigen and human glandular kallikrein 2 in malignant versus nonmalignant prostatic tissue. Urology 2000;56:527 32. [41] Bartsch G, Fitzpatrick J, Schalken J, et al. Consensus statement: role of prostate-specific antigen in managing the patient with benign prostatic hyperplasia. BJU Int 2004; 93:27 9.