REVIEW The utility of serum prostatic-specific antigen in the management of men with benign prostatic hyperplasia

(2008) 20, S19 S26 & 2008 Nature Publishing Group All rights reserved 0955-9930/08 $30.00 www.nature.com/ijir REVIEW The utility of serum prostatic-specific antigen in the management of men with benign prostatic hyperplasia Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA Several analyses have demonstrated a clinically useful relationship between serum prostate specific antigen (PSA) and prostate volume in men with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). Both prostate volume and serum PSA predict certain aspects of the natural history of LUTS and BPH, and men with higher PSA and larger glands in general have a higher rate of progression measured by various parameters. Serum PSA also predicts the response to certain types of medical therapy in men with LUTS and BPH and is thus useful in the evaluation and management of these patients. Lastly, serum PSA does not loose its usefulness as a cancer marker for prostate cancer even if certain medications reduce serum PSA values predictably by 50%. (2008) 20, S19 S26; doi:10.1038/ijir.2008.53 Introduction Benign prostatic hyperplasia (BPH) is the most common benign tumor in men with prevalence estimates ranging from 50% for men in their 50s to 90% for men in their 90s. 1 Although not all men suffer from this condition, approximately 50% of those developing histological hyperplasia eventually will develop moderate-to-severe and bothersome, storage and voiding symptoms collectively called the lower urinary tract symptoms (LUTSs). Because of its extraordinarily high prevalence of this in general nonlethal disease as well as in the aging of the population, health care providers in primary care and in urology will see themselves confronted with an ever-enlarging number of men seeking consultation, advice and treatment for LUTSs often associated with BPH. This review article will focus on the utility of serum prostate-specific antigen (PSA) in the management of men with LUTSs secondary to BPH. We will review the relationship between prostate size or volume and serum PSA, and subsequently the importance of prostate volume and serum PSA in predicting the natural history of the condition. Furthermore, we will examine the role of PSA in Correspondence: Dr, Department of Urology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., J8.148, Dallas, TX, USA. E-mail: claus.roehrborn@utsouthwestern.edu predicting response to medical therapy for LUTS and BPH, and lastly, we will examine how PSA changes under medical or surgical treatment for BPH and the important role it plays in monitoring men on treatment or after surgery. The relationship between prostate volume and serum PSA As we shall discuss in a subsequent section of this review, prostate volume and a proxy for prostate volume, serum total PSA, are powerful predictors both of the natural history of LUTS and BPH as well as the response to certain medical therapies. Therefore, it is clear that a knowledge of these parameters would be beneficial in the everyday management of patients presenting to health care providers. Intuitively, it may appear easiest to use prostate volume for such purposes. However, this undertaking has some problems, most notably owing to the fact that digital rectal examination is quite inaccurate in estimating the correct prostate size when measured by either transrectal ultrasound (TRUS) or other imaging modalities such as computerized tomography or magnetic resonance imaging. An analysis of the relationship between digital rectal examination estimates and TRUS volumes was conducted using four sources, in which either a single nurse, a single urologist or multiple personnel examined men and estimated the prostate size. 2 Subsequent to it, an ultrasound was performed to

S20 determine the actual prostate size. Digital rectal examination estimates and TRUS volumes were significantly correlated with an r-value between 0.4 and 0.9, but prostate size was underestimated by 25 55% for men with a prostate volume of over 40 ml depending on the study, with greater variability for studies involving multiple examiners. Of course, it might be possible to measure each man s prostate size by either TRUS, CT scanning or magnetic resonance imaging; however, the logistics as well as the cost of such undertakings would be prohibitive, and if it were to be performed only for the purpose of assessing prostate size in an effort to predict the natural history or response to medication for BPH, this policy would likely not be economically sustainable. It is, therefore, logical to search for proxy parameters that could be used instead of prostate volume. One such parameter is the serum prostatespecific antigen. PSA is produced in the glandular epithelial portion of the prostate and is the most widely used prostate cancer screening marker ever since its introduction in the early 1990s. PSA has significant drawbacks as a screening test for prostate cancer, most notably because there is no single cutpoint, which indicates the presence or absence of prostate cancer. Rather, findings from the prostate cancer prevention study suggest that the risk for prostate cancer increases with increasing PSA value and decreases with decreasing PSA, but it never reaches zero risk 3 (Figure 1). In the management of men with prostate diseases, it is of great importance to recognize that, in fact, the notion of a monolithic cut-point for serum PSA of 4.0 ng ml 1 is no longer valid. All providers should view serum PSA as a risk continuum, and referrals or indications for TRUSguided biopsies should be based on the current serum PSA, the PSA history and velocity over time, and on patient-related factors, such as age, comorbidities and so on. Serum PSA is not only widely used as a screening and testing tool for prostate cancer, but it is also of considerable help in the management of men with LUTS and BPH. With increasing age, both prostate volume and serum PSA increase. The former has been recognized for a long time and can be observed in longitudinal as well as cross-sectional studies, 1 and the latter is well documented and has led to the development of so-called age-specific reference ranges for serum PSA. 4 8 Considering that both prostate volume and serum PSA increase with age, it seemed reasonable to assume some relationship between serum PSA and prostate volume as well. Analyses of a database of over 4600 men with LUTS and BPH, but no cancer demonstrated, in fact, that prostate volume and serum PSA have an age-dependent log-linear relationship (that is, their logarithms are linearly related, and the parameters of the relationship depend on age). Older men tend to have a steeper rate of increase in prostate volume with increasing serum PSA 9 (Figure 2). Perhaps a more practical question might be what serum PSA predicts with reasonable clinical certainty the presence of a prostate greater than 30 ml (or cc or g; all are interchangeable, as the specific gravity of prostate tissue is barely greater than 1.0) or greater than 40 ml. To maintain a specificity of approximately 70%, thus accepting a 30% false-positive rate, the following thresholds of serum PSA need to be applied to yield a sensitivity between 60 and 70% as an answer to this question (Table 1). Although the graphical display can be used to estimate prostate volume by serum PSA and age or vice versa, these thresholds indicate the likelihood of the prostate to be greater than 30 or 40 ml, respectively a parameter that is useful in clinical practice. It should be noted that several independent investigators verified the log-linear relationship between serum PSA and prostate volume in different population and ethnic groups with similar results. 10 14 60 75 70 65 Risk 0.40 0.20 Risk of prostate cancer Risk of high-grade disease Prostate volume (ml) 50 40 60 55 50 0.00 0 1 2 3 4 PSA (ng ml -1 ) Figure 1 Estimated risk of prostate cancer and high-grade cancer as a function of serum PSA levels in the PCPT trial. 3 PCPT, prostate cancer prevention; PSA, prostate-specific antigen. 30 1 2 3 4 5 6 7 Serum PSA Figure 2 Log-linear relationship between serum PSA and prostate volume. 9 PSA, prostate-specific antigen.

Table 1 age Prostate volume by serum prostate-specific antigen and Age group 30 ml 40 ml 50 59 years 41.3 41.6 60 69 years 41.5 42.0 70 79 years 41.7 42.4 Rate per 100 PYR 6 4 2 <1.4 1.4 to 3.9 PSA 4.0 S21 Summary There is a strong and clinically useful relationship between serum PSA and prostate volume, which enables the clinicians to estimate prostate size in men with LUTS and BPH, and also to identify men with prostate above certain thresholds. Serum PSA predicts the natural history of LUTS and BPH Longitudinal data from the Olmsted County Community Study of Urinary Symptoms in men suggest that, on average, the prostate grow by 1.6% or approximately 1 ml per year. 15,16 In the 5-year Medical Therapy of Prostatic Symptoms (MTOPS) study, the growth rate in the placebo-treated patients was shown to depend on baseline serum PSA. 17 In those men with a PSA from 0.0 to 0.8 ng ml 1,the average yearly growth rate was in fact 1 ml, but in thosemenwithapsagreaterthan3.0ngml 1,itwas 3 ml per year. A similar analysis of the placebo-treated patients in the 4-year Proscar Long-term Efficacy and Safety Study (PLESS) also suggested a growth rate difference based on the baseline serum PSA in the lowest tertile of PSA, the growth rate was 7.4%; in the middle tertile, it was 16.2% and in the highest tertile of PSA, it was 22 or 5.4% per year, more than three times the amount seen in the community-dwelling men in Olmsted county. The serum PSA predicts not only the future growth of the prostate, but also the changes in the symptoms, bother, interference with daily activities and maximum urinary flow rate in the PLESS. 18 Djavan et al. 19 reported that the serum PSA was a highly significant predictor of symptomatic progression in a cohort of conservatively managed patients, with the mean PSA being 2.2 in those with and 0.83 in those without progression. Similarly, serum PSA as well as prostate volume were found to be the predictors of symptom progression in the placebo group in the MTOPS study (Figure 3). 20 Bruskewitz et al. 21 reported on the placebo-treated patients in the 4-year PLESS, and their analysis suggests that with increasing PSA tertiles, there is a linear deterioration of frequency of sexual activity, sexual satisfaction and the perception of overall general health (Figure 4). Although this may have been a surprising finding at the time, it is now clear that there is a relationship between LUTS severity 0 Progression >4-Pt rise AUR Figure 3 Risk of overall progression, symptomatic worsening and acute urinary retention stratified by serum PSA tertiles over 5 years in the placebo-treated patients in the MTOPS study. 20 PSA, prostate-specific antigen. Mean (s.e) change from baseline 0.30 0.10 0.10 0.30 Sexual activity Sexual frequency General health 1 2 3 1 2 3 1 2 3 Tertiles Figure 4 Mean change from baseline in sexual activity, sexual frequency and general health perception in placebo-treated patients over 4 years in the PLESS stratified by PSA tertiles (1: PSA 0.0 1.3; 2: PSA 1.4 3.2 and 3: PSA 3.3 12 ng ml 1 ). 21 PSA, prostate-specific antigen. and erectile dysfunction and a variety of sexual health measures. It does, therefore, seem logical to assume that men with larger glands and higher serum PSA may have an accelerated deterioration of their sexual health as well. Perhaps best understood and most significant is the relationship between baseline serum PSA and the risk for outcomes from LUTS and BPH, namely acute urinary retention (AUR) and LUTS- and BPHrelated surgery. The placebo cohort in the PLESS trial showed a nearly linear increase in risk for either AUR or surgery with increasing serum PSA levels over 4 years (Figure 5). 22 Similar observations were made in the placebo group in the MTOPS study (Figure 3), 20 in the Phase III trial program with dutasteride 23,24 as well as in the Olmsted County Study, where the risk for AUR and/or treatment for LUTS and BPH in men with baseline 1.4 or greater was significantly higher. 25 It is natural that the risk for initiation of treatment in previously untreated

S22 Cumulative incidence (%) 30 20 10 0 >0.0 >0.5 >1.5 Either Surgery AUR >1.5 >2.0 >2.5 >3.0 >3.5 >4.0 >4.5 >5.0 >5.5 >6.0 >6.5 >7.0 >7.5 >8.0 Figure 5 Linear increase in risk for AUR and/or surgery in men treated for 4 years with placebo in the PLESS trial. 22 AUR, acute urinary retention. men, and specifically the risk for surgery, behaves similarly to the risk of AUR as many AUR episodes result in surgical treatment. symptoms to an equal degree. 30,31 Urinary flow rate parameters and postvoid residual urine amount may be of some additional help; however, they are, in general, not available to the general practitioner at the time of consultation. More successful are the attempts to predict the response to different therapies by baseline prostate volume and baseline serum PSA values. Serum PSA is readily available to all health care providers, while prostate size is not. Since both are are related as discussed before, we shall consider them interchangeably. The general categories of response that we would like to consider are: (1) Changes in prostate volume over time. (2) Changes in LUTS severity over time (also representing the likely changes in bother, interference with activities and quality of life impairment). (3) Likelihood of progression to AUR or surgery. Summary When first counseling a patient with LUTS and presumed BPH, the serum PSA at that time is a powerful predictor of the natural history current prostate size, future prostate growth, symptom and bother deterioration, sexual dysfunction, urinary flow rate worsening, AUR and even surgery. In general, the higher the serum PSA, the greater the risk and the faster the progression, or, the more accelerated the natural history. Serum PSA and response to medical therapy Serum PSA is useful not only in estimating the prostate size, but also in predicting the response to medical management with a-blockers (alfuzosin, doxazosin, tamsulosin and terazosin), and five a- reductase inhibitors (five ARIs; dutasteride and finasteride). Although in the early 1990s, both classes of drugs were used interchangeably for the treatment of men with LUTS and BPH, a more sophisticated approach has resulted from a better understanding of the mechanisms of action and the response to different treatments in men with different baseline parameters. What are these parameters? It has been shown in many publications that the response to a-blockers and 5-ARIs is similarly independent of the patient s age and even symptom severity at the beginning of treatment, 26,27 although the adverse events reported with different a-blockers may vary with age. 28,29 Breaking down the LUTS into irritative/ storage vs obstructive/voiding symptoms may help to some degree in distinguishing responses to 5-ARIs but not necessarily to a-blockers, which reduce all Ad 1 It is quite clear from large datasets that treatment with a-blockers does not change prostate volume over the short-to-intermediate term, 32,33 and neither does it prevent the long-term volume increases commensurate with the natural history of the condition as measured by placebo control groups. In fact, in the MTOPS study, both groups of patients treated with placebo and doxazosin experienced an identical increase in volume, namely 18% over 4 years or approximately 4.5% per year. 34 In contrast, treatment with 5-ARIs induces, over a period of 6 12 months, on average, a 25% reduction in prostate size, which is independent of the baseline prostate size, baseline serum PSA or any other tested parameter. In addition, as long as patients stay on such medications, there seems to be no attenuation of the effect, that is, the prostate gland does not seem to change in size significantly over even longer time periods of follow-up. 23,35 Ad 2 An early meta-analysis of all terazosin trials suggested that it was effective and superior to placebo in reducing symptoms and increasing the peak urinary flow rate. The effect of terazosin on the peak urinary flow rate was apparent in studies as short as 8 weeks. Most importantly, the effect of terazosin on the symptoms and peak urinary flow rate was independent of the baseline prostate size for the range of prostate volumes reported. 36 In fact, the longest controlled trials with a-blockers in the 5-year MTOPS and the 2-year Alfuzosin Long-term Efficacy and Safety Study (ALTESS) studies suggested a sustained improvement in symptoms over

Percent with the event 0.20 0.10 0.00 0 90 180 270 360 450 540 630 720 Time (days) In both the MTOPS and the ALTESS studies, a-blocker therapy was superior to placebo in terms of prevention of symptomatic progressi on defined as an increase of X4 points on the international prostate symptom score or International Prostate Symptom Score (IPSS) (Figure 6). The symptomatic response to 5-ARI treatment, however, is dependent on the baseline serum PSA/ prostate volume as was shown in two meta-analyses summarizing data from all 1-year finasteride studies available at the time. 38,39 In general, the larger the prostate gland and the higher the serum PSA, the greater is the benefit of the 5-ARI over placebo, which is a measure of therapeutic efficacy. Symptomatic improvements once achieved are also sustained over long periods of time. 23,35 MTOPS allows a stratified analysis of the prevention of symptomatic worsening by treatment group and serum PSA. With increasing serum PSA, progression was increasingly more common in the placebo group, the a-blocker reduced the risk equally well in all PSA stratification, 5-ARI treatment was moderately effective in the intermediate group and more effective compared with a-blocker in the higher PSA groups, and the combination therapy achieved the best reduction, particularly in patients with the highest serum PSA (Figure 7). time. 17,37 Log-rank test P=0.0013 Placebo Alfuzosin 30% Figure 6 The a-blocker is superior to placebo in preventing longterm symptomatic worsening or progression of LUTS defined by a worsening in the symptom score by 4 points or greater. 37 LUTS, lower urinary tract symptoms. Ad 3 There is now evidence from several studies to suggest that a-blockers are less effective in preventing episodes of AUR and ineffective in preventing surgical interventions over time, and this effect is most likely because of the ongoing growth of the prostate, which in turn is directly related to the risk of AUR and surgery. The evidence comes from the MTOPS and ALTESS studies, 37,40 and Figure 8 demonstrates that the a-blocker treatment is effective in regard to AUR in men with serum PSA o4.0 ng ml 1, but not in men with higher values, whereas the 5-ARIs are effective across the entire Cumulative incidence (%) 20 10 0 Placebo Dox Fin Comb <1.4 1.4 3.9 Baseline serum PSA (ng ml -1 ) Figure 7 Cumulative incidence of symptomatic worsening by X4 points in MTOPS for all four treatment groups stratified by serum PSA. 17 PSA, prostate-specific antigen. Cumulative incidence (%) 6 4 2 0 Placebo Dox Fin Comb <1.4 1.4 3.9 Baseline serum PSA (ng ml -1 ) Figure 8 Cumulative incidence of progression to AUR in MTOPS for all four treatment groups stratified by serum PSA. 17 AUR, acute urinary retention; PSA, prostate-specific antigen. range of serum PSA values. As the risk for AUR and/ or surgery increases with increasing serum PSA values, the higher the PSA, the greater is the benefit from 5-ARI treatment, as the risk reduction is 50% independent of baseline risk (that is, a patient with a 10% baseline risk would experience a reduction from 10 to 5%, and a patient with a 4% baseline risk, a reduction from 4 to 2%, which would be less cost-effective). 24,41,42 Summary Serum PSA is an excellent tool to determine how to treat a patient with LUTS and BPH. In men with PSA values of o1.5 ng ml 1, treatment with an a-blocker is sufficient for symptomatic relief, and as the risk of progression to AUR/surgery is low, treatment with additional 5-ARIs is not necessary. In men with a serum PSA of 41.5 ng ml 1, however, a-blockers provide only symptomatic relief and prevent symptom progression. In these patients, 4.0 4.0 S23

S24 the risk of AUR or surgery increases, however, and thus treatment with 5-ARI in addition to the a-blocker is recommended. Utility of serum PSA under medical treatment for LUTS and BPH Treatment with a-blockers neither affects the serum PSA nor the PSA velocity or change over time. 43 Thus, the utility of serum PSA is maintained unaltered even during and after the long-term therapy with this class of drugs. 5-ARIs predictably and reliably reduce serum PSA and serum-free PSA on average by 50% after about 3 6 months of therapy a fact that has been confirmed in many randomized studies with both finasteride and dutasteride. 17,33,44 46 However, individual results may vary greatly and the range of the observed PSA changes is tremendous. 47 This leaves the practicing physicians with the following concerns: (1) What to do if the PSA level does not decrease by at least 50% after 3 6 months (assuming that a greater than 50% would indicate effective treatment with no increased risk for cancer). (2) How to interpret the new nadir PSA level. (3) How to interpret the changes from the new PSA nadir level. Ad1 If a patient does not have the expected decrease in serum PSA, this may be because of either noncompliance with the drug or because of factors such as concomitant inflammation in the prostate, manipulation of the prostate, or the presence of prostate cancer. Referral and/or biopsy of the prostate may be indicated. Ad 2 In the past, the uniform recommendation had been to multiply the new baseline nadir PSA value 2andto use the usual cut-points for referral and/or TRUSguided biopsy of the prostate. Sensitivity and specificity analysis have demonstrated that in this setting, the serum PSA may maintain at least equal, if not better, sensitivity/specificity when using such logic. 48 Ad 3 Given the uncertainty over fixed cut-points to recommend referral and/or TRUS biopsy, another approach is to monitor the serum PSA nadir value for changes in a positive direction, that is, an increase. 49 51 An increase from stable nadir by 0.3 or 0.5 should trigger a check regarding the patient s compliance and perhaps a verification. If consistent, however, it should trigger a referral/trus biopsy to rule out cancer. Summary Under treatment with a-blocker, PSA may be used as in a nontreated patient. Under treatment with 5-ARI, a 50% reduction of serum PSA on average is expected. Less than a 50% decrease, a value above thresholds for referral/trus biopsy after multiplying the nadir value 2, or an increase from nadir in a fully treatment-compliant patient should trigger further action, such as referral, for a TRUS biopsy. Disclosure Claus G Roehrborn has received consulting fees and lecture fees from GSK, Eli Lilly, Spectrum Pharmaceuticals, Aeterna Zentaris, Pfizer and AMS. References 1 Roehrborn C, McConnell J. Etiology, pathophysiology, epidemiology and natural history of benign prostatic hyperplasia. In: Walsh P, Retik A, Vaughan E, Wein A (eds). Campbell s Urology, 8th edn. Saunders: Philadelphia, 2002, pp 1297 1336. 2 Roehrborn CG, Girman CJ, Rhodes T, Hanson KA, Collins GN, Sech SM et al. Correlation between prostate size estimated by digital rectal examination and measured by transrectal ultrasound. Urology 1997; 49: 548 557. 3 Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL et al. 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Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology 1996; 48: 398 405. 39 Boyle P, Roehrborn C, Gould L. Baseline serum PSA levels predict degree of symptom improvement following therapy of BPH with finasteride. J Urol 1997; 157: 134A. 40 McConnell JD, Roehrborn CG, Bautista OM, Andriole Jr GL, Dixon CM, Kusek JW et al. 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. 41 Boyle P, Roehrborn C, Harkaway R, Logie J, de la Rosette J, Emberton M. 5-Alpha reductase inhibition provides superior benefits to alpha blockade by preventing AUR and BPH-related surgery. Eur Urol 2004; 45: 620 626; discussion 626 627. 42 Roehrborn C, Bruskewitz R, Nickel GC, Glickman S, Cox C, Anderson R et al. 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S26 47 Brawer MK, Lin DW, Williford WO, Jones K, Lepor H. Effect of finasteride and/or terazosin on serum PSA: results of VA Cooperative Study #359. Prostate 1999; 39: 234 239. 48 Thompson IM, Chi C, Ankerst DP, Goodman PJ, Tangen CM, Lippman SM et al. Effect of finasteride on the sensitivity of PSA for detecting prostate cancer. J Natl Cancer Inst 2006; 98: 1128 1133. 49 Andriole GL, Roehrborn C, Schulman C, Slawin KM, Somerville M, Rittmaster RS. Effect of dutasteride on the detection of prostate cancer in men with benign prostatic hyperplasia. Urology 2004; 64: 537 541; discussion 542 533. 50 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 5 alphareductase inhibitor dutasteride. J Urol 2006; 175: 1657 1662. 51 Marks LS, Andriole GL, Fitzpatrick JM, Schulman CC, Roehrborn CG. The interpretation of serum prostate specific antigen in men receiving 5alpha-reductase inhibitors: a review and clinical recommendations. J Urol 2006; 176: 868 874.