Benign Prostatic Hyperplasia: Does Prostate Size Matter?

NEW PERSPECTIVES ON BPH Benign Prostatic Hyperplasia: Does Prostate Size Matter? J. Curtis Nickel, MD, FRCSC Department of Urology, Queen’s University, and Kingston General Hospital, Kingston, Ontario, Canada Recent studies and analyses have confirmed that baseline prostate volume is related to progression of benign prostatic hyperplasia (BPH) as well as to negative outcomes related to BPH, such as acute urinary retention (AUR) and need for surgery, and can also predict response to therapy. Other investigations have determined that prostate-specific antigen (PSA) level has good predictive value for assessing prostate volume. Strong evidence exists that baseline serum PSA level, like baseline prostate volume, predicts future prostate growth. Randomized placebo-controlled finasteride trials have shown that men with larger prostate volumes and higher PSA levels experience a clinically significant response to therapy compared with those with smaller prostate volumes and lower PSA levels. It has also been demonstrated that men with larger prostate glands and higher PSA levels are at increased risk for AUR and BPH-related surgery but that finasteride reduces these risks. Moreover, doxazosin and finasteride, alone and in combination, have been shown to significantly reduce BPH clinical progression. [Rev Urol. 2003;5(suppl 4):S12-S17] © 2003 MedReviews, LLC Key words: Benign prostatic hyperplasia • Acute urinary retention • Prostate volume • Prostate-specific antigen • Bladder outlet obstruction enign prostatic hyperplasia (BPH) is the correct term to describe the histopathologic, hyperplastic changes noted in the aging prostate and mediated by circulating and intraprostatic androgens. Clinicians commonly use the term BPH to describe a clinical syndrome consisting of 3 components: lower urinary tract symptoms (LUTS), benign prostatic enlargement (BPE), and bladder outlet obstruction (BOO). Numerous studies, including the population-based Olmsted B S12 VOL. 5 SUPPL. 4 2003 REVIEWS IN UROLOGY Does Prostate Size Matter? Figure 1. Change from baseline in peak flow rate versus baseline prostate volume in placebo- and finasteride-treated patients in 6 clinical studies. Data from Boyle P et al. Urology. 1996;48: 398-405.6 Placebo 2.0 1.5 1.0 0.5 0.0 <20 20-29 30-39 40-49 50-59 ≥60 Baseline Prostate Volume (mL) studies provide concordant evidence that size does matter. Clinical Treatment Trials Suggest Prostate Size Is Important Analyses of multiple finasteride treatment trials have shown prostate volume to be an important factor in BPH. The results of the pivotal phase 2 North American finasteride trial demonstrated a 50% decrease in serum PSA level, a 70% to 80% decrease in dihydrotestosterone (DHT) concentration, and a 20% decrease in prostate volume with finasteride Patients who received finasteride demonstrated significantly greater improvement with increasing prostate volume. has traditionally stated that prostate gland size is not related to symptoms and/or flow rate. However, recent studies and analyses have confirmed that baseline prostate volume is related to BPH progression and negative outcomes related to BPH progression, such as acute urinary retention (AUR) and the need for surgery, and can predict response to therapy. These Finasteride 2.5 Change in Peak Flow Rate (mL/s) County study with long-term longitudinal natural history follow-up, provide convincing evidence for an increase in LUTS and BOO (measured by peak urinary flow rate) over time.1,2 On average, unselected men in the community have an increase in American Urological Association (AUA) symptom score of 0.18 points per year and a 2% decrease in peak urinary flow rate per year. Progressive prostate growth has been confirmed in population-based studies. Median prostate growth has been noted to be approximately 1.9% per year.3 As men age, symptoms worsen and obstruction and prostate volume increase. Are these 3 factors related? Is prostate volume important? Does size matter? Prostate growth appears to be related to prostate volume. In the Olmsted County population-based study, men who had baseline prostate volumes of 30 mL or less had median prostate growth of 1.7% per year, compared with 2.2% per year for men with prostate volumes greater than 30 mL.3 However, there have been no convincing reports correlating presenting symptoms and flow rate with the size of the prostate gland in cross-sectional samples of men with BPH or in populationbased studies. In fact, urologic dogma therapy.4 This corresponded with a significant reduction in AUA symptom score and improvement in peak flow rate compared with placebo. However, the subsequent Veterans Administration study evaluating finasteride, terazosin, and a combination of the 2 agents found that changes in peak flow rate and symptoms after treatment with finasteride were not statistically significantly different from placebo.5 In an attempt to explain these conflicting results, Boyle and colleagues6 analyzed 6 randomized, placebocontrolled trials of finasteride to determine if baseline characteristics, including prostate volume, were predictive of response to finasteride therapy. In this pooled analysis, mean improvements in symptoms and urinary flow rate with finasteride therapy were found to increase with increasing prostate size. In addition, peak flow rate improved in placebo-treated patients in all prostate volume categories, but patients who received finasteride demonstrated significantly greater improvement with increasing prostate volume (ie, >40 mL) (Figure 1). Patients who received finasteride also demonstrated improvements in symptom scores in all prostate volume categories, which were statistically superior to placebo in patients with prostate volumes greater than 40 mL. The results of this meta-analysis demonstrated that baseline prostate volume is a powerful predictor of treatment outcome with finasteride. VOL. 5 SUPPL. 4 2003 REVIEWS IN UROLOGY S13 Percent of Patients With AUR Does Prostate Size Matter? continued 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 <40 mL ≥ 40mL <1.4 ng/mL Prostate Volume ≥1.4 ng/mL Serum PSA Figure 2. Two-year incidence of acute urinary retention (AUR) stratified according to baseline prostate volume and baseline serum prostate-specific antigen (PSA) level. Data from Marberger MJ et al. Eur Urol. 2000;38:563-568.11 Prostate Size Predicts BPH Progression It is generally accepted that significant evidence exists in the literature proving that BPH is a progressive disease.7 Progression of BPH can be defined as worsening of clinical parameters, including deterioration of symptoms and disease-specific quality of life, deterioration in urinary flow rate, outcomes such as AUR and the need for BPH-related surgery, other BPH complications (eg, infection, stones, hematuria, obstructive uropathy), and increase in prostate volume. Because BPH is a progressive disease, its management should focus not only on symptom amelioration but also on risk factors for progression (ie, identifying patients at increased risk of progression). Numerous studies have confirmed that prostate volume is an important predictor of BPH progression. The Olmsted County populationbased study confirmed that the risk of AUR increased with increased prostate size as measured by transrectal ultrasound (a 3-fold increased risk for prostates >30 mL).8 An enlarged prostate gland was also shown to be an independent predictor of treatment intervention.9 Data from the Baltimore Longitudinal Study S14 VOL. 5 SUPPL. 4 2003 of Aging also showed that an enlarged prostate gland is a positive predictor for prostatectomy.10 The combined data from three 2year randomized placebo-controlled trials comparing finasteride with placebo—the Scandinavian Reduction of the Prostate Study (SCARP), the Proscar Safety Plus Efficacy Canadian Trial (PROSPECT), and the Proscar Worldwide Efficacy and Safety Study (PROWESS)—showed that men with larger prostate glands with placebo over 4 years in 3040 men with moderate to severe LUTS, decreased urinary flow rate, and an enlarged prostate gland.12 Overall, the rate of AUR in the placebo arm was 7% (4% spontaneous and 3% precipitous) and the rate of surgery was 10% over 4 years. Prostate volume was a predictor of AUR in the 10% of patients whose prostate volumes were measured.13,14 The risk for both spontaneous and precipitated AUR increased with increasing prostate volume (as well as with PSA level) stratified by tertiles (Figure 3). Similar to the rates of AUR, the rates of surgery increased by 6.7% to 14.0% from the lowest to the highest prostate volume tertile.13,14 Elevated prostate volume also predicted progression in LUTS and urinary flow.15 PSA Is a Surrogate for Prostate Size Serum PSA increases with age. The relationship between age-related increases in prostate volume and serum PSA has been studied, mostly in efforts to increase the usefulness of PSA level in screening for prostate Baseline prostate volume is a powerful predictor of treatment outcome with finasteride. have an increased risk of developing AUR.11 In the placebo arms of these trials, 1.6% of men with baseline prostate volumes less than 40 mL developed AUR at 2 years, compared with 4.2% of men with volumes of 40 mL or greater (Figure 2). These studies provided reasonably longterm, reliable data characterizing prostate volume as a risk factor for AUR over 2 years. The Proscar Long-Term Efficacy and Safety Study (PLESS) was a double-blind, randomized, placebo-controlled trial comparing finasteride REVIEWS IN UROLOGY cancer. As shown, evidence clearly demonstrates that prostate volume strongly predicts BPH-related outcomes, such as symptom progression, AUR, and the need for BPHrelated surgery. Digital rectal examination is an inaccurate determination of prostate size and, in fact, appears to significantly underestimate prostate volume.16 Roehrborn and colleagues17 analyzed placebo-controlled multicenter trials of patients with BPH and a safety study in normal young men to determine the relationship between Does Prostate Size Matter? Incidence of AUR (%) 14 12 10 8 6 4 2 Spontaneous Precipitated Combined PSA Level (ng/mL) 0-1.3 1.4 1.5 2.9 1.4-3.2 2.5 3.3 5.8 ≥3.3 7.6 4.0 11.6 Prostate Volume (mL) 0 14-41 0.0 4.4 4.4 42-57 1.7 3.3 5.0 >57 6.0 8.0 14.0 Figure 3. Incidence rates of spontaneous and precipitated acute urinary retention in the Proscar Long-Term Efficacy and Safety Study over 4 years in placebo-treated patients stratified by prostate-specific antigen (PSA) and prostate volume tertiles. Reprinted from Roehrborn CG. Rev Urol. 2002;4(suppl 5):S29-S38,27 with permission from the author. baseline measurements of serum PSA and prostate volume. The analysis, which included 4627 patients (4448 from the BPH trials and 179 from the safety study), determined that serum PSA and prostate volume have an agedependent log-linear relationship. The investigators determined that PSA had a good predictive value for assessing prostate volume and were able to develop a prostate volume prediction model given a patient’s serum PSA level and age. Clinical trial data further confirm the utility of PSA level in determining risk of BPH progression. Strong evidence exists showing that baseline serum PSA level, like baseline prostate volume, predicts future prostate growth.18 The combined data from the three 2-year finasteride BPH studies 11 showed that men with higher PSA levels had an increased (8-fold) risk of developing AUR. At 2 years, AUR was reported as 0.5% and 3.9% in men with baseline PSA levels of less than 1.4 mL and 1.4 mL or greater, respectively (see Figure 2). The 4-year PLESS study convincingly confirmed that serum PSA level is a powerful predictor of the risk of AUR and the need for surgery.19 The data confirmed a near-linear increase in risk of AUR with increasing baseline serum PSA level (both for spontaneous and precipitated AUR). Figure 3 shows the risk of both types of AUR stratified by serum PSA tertile and prostate volume tertile. Ten percent of patients in the placebo arm of the 4-year PLESS study underwent BPH-related surgery. Similar to the incidence of AUR, the rates of surgery increased by 6.2% to baseline PSA level of 1.4 ng/mL or greater had gradual persistent worsening (after an initial placebo response in the first year) of quality of life, increase in bother associated with urinary symptoms, increase in interference of urinary problems with daily living activities, increase in degree of worry about urinary function, and decrease in sexual activity and interest, over 4 years.20 Subanalyses of the recent 2-year combined dutasteride trials further confirm the PLESS findings in terms of increased risk of AUR and surgery with increasing prostate volume21 and PSA level.22 Prostate Volume (and PSA Level): Implications for Therapy The finasteride meta-analysis showing prostate volume to be a key predictor of outcomes with finasteride therapy was the first to suggest that finasteride is most effective in men with large prostate glands.6 In this analysis, the most clinically significant response (the relative difference between the finasteride- and placebo-treated groups) was seen in men with larger prostate glands and high baseline PSA levels. The combined analyses of the 2-year international Strong evidence exists showing that baseline serum PSA level, like baseline prostate volume, predicts future prostate growth. 14.6% for the patients in the lowest to the highest PSA tertile. Elevated PSA also predicted progression of LUTS and deterioration of urinary flow.15 Stratifying the placebo group of PLESS by PSA tertiles showed a distinct pattern of symptom increase and flow rate deterioration (following the initial placebo response) in the higher-PSA groups. Subanalyses of the PLESS data further showed that men with a randomized placebo-controlled finasteride trials showed that men with larger prostate volumes and higher PSA levels experienced a clinically significant response to therapy compared with those with smaller prostates and lower PSA levels.11 The 4-year PLESS study clearly showed that not only did men with larger prostate glands and higher PSA levels have an increased risk of AUR and surgery (8.9% to 22.0% when VOL. 5 SUPPL. 4 2003 REVIEWS IN UROLOGY S15 Does Prostate Size Matter? continued stratified by increasing prostate volume and 7.8% to 19.9% when stratified by increasing serum PSA level) but also that finasteride treatment reduced the relative risk of needing surgery or developing AUR by 50% to 74% and by 43% to 60% when stratified by increasing prostate volume and increasing serum PSA level, respectively.19 Men with BPH and elevated PSA levels had a significant clinical response in terms of symptom and flow rate improvement15 as well as bother and quality-of-life improvement.20 Therefore, the most clinically eters associated with the risk of treatment failure with -blockade. Preliminary Confirmation of the Importance of Baseline Prostate Size and PSA Level The recently reported Medical Therapy of Prostatic Symptoms (MTOPS) study is the largest and longest BPH study ever undertaken.24 The results of this landmark study demonstrated that doxazosin and finasteride, alone and in combination, significantly reduce the risk of BPH clinical progression; finasteride alone and combination Finasteride treatment reduced the relative risk of needing surgery or developing AUR by 50% to 74% and by 43% to 60% when stratified by increasing prostate volume and increasing serum PSA level, respectively. significant response to finasteride in terms of symptom amelioration, improvement in flow rates, quality of life, and reduction in AUR and surgical rates occurred in the patients at highest risk, that is, those with large prostate glands and higher baseline serum PSA values. Unfortunately, evidence does not exist to determine a differential treatment effect of -blocker therapy for BPH based on prostate size and baseline serum PSA level. It appears that initial symptom amelioration and flow rate improvement seen within the first months (and perhaps year) of -blocker therapy is independent of baseline prostate volume (and likely baseline PSA value),5 whereas the long-term implications in terms of symptom amelioration and risk reduction in relationship to prostate volume (and PSA level) remain largely unknown. De la Rosette and colleagues23 demonstrated that patients given -blockers for LUTS have a high risk of re-treatment. An enlarged prostate gland was one of the param- S16 VOL. 5 SUPPL. 4 2003 therapy appear to be more effective than -blocker therapy in reducing the long-term risk of AUR and incidence of BPH-related surgery. Roehrborn and colleagues25 analyzed prostate volume changes over time in the placebo group of this large long-term study and determined that both baseline prostate volume and PSA level were excellent predictors of future prostate growth. This prediction of prostate growth suggests that baseline prostate volume and PSA level may also have utility in predicting clinical parameters of progression. The MTOPS placebo group was further analyzed to determine if the relative risk of BPH progression, AUR, or the need for BPH-related surgery in untreated patients could be predicted by either prostate volume or PSA level.26 In this study, 737 patients were assigned to placebo and followed for an average of 4.5 years. Clinical progression of BPH was predefined as an increase in AUA symptom score of 4 or more points, AUR, incontinence, renal insufficiency, or recur- REVIEWS IN UROLOGY rent urinary tract infection. The need for BPH-related invasive therapy was a secondary outcome. In these placebo-treated patients, baseline PSA level and prostate volume correlated significantly with the risk of BPH clinical progression and the need for BPH-related invasive therapy (P = .03–<.001). Baseline PSA level and prostate volume also correlated with the risk of AUR (P = .03–.003). The risk of BPH progression increased with increasing baseline serum PSA level. The risk of AUR and BPH-related invasive therapy decreased as baseline serum PSA decreased. This large long-term study further confirmed that a patient’s risk of BPH progression, AUR, and BPH-related invasive therapy can be predicted by baseline serum PSA level (and prostate volume). Further subanalyses of the MTOPS data will likely shed light on the relationship among 5-reductase inhibitor/-blocker therapy, baseline prostate volume/PSA level, and the risk of BPH progression. Conclusion: Size Does Matter Baseline prostate size (and its surrogate baseline PSA level) can be considered a strong indictor of BPH progression, particularly for AUR and BPH-related surgery but also for long-term changes in symptoms, bother, quality of life, and flow rate. Prostate volume and baseline PSA level appear to be the best predictors of clinically significant response to 5--reductase inhibition in terms of both symptom amelioration and BPH progression. Size does matter! References 1. 2. Jacobsen SJ, Girman CJ, Guess HA, Rhodes T, et al. Natural history of prostatism: longitudinal changes in voiding symptoms in community dwelling men. J Urol. 1996;155:595-600. Roberts RO, Jacobsen SJ, Jacobson DJ, et al. Longitudinal changes in peak urinary flow rates in a community-based cohort. J Urol. 2000;163:107-113. Does Prostate Size Matter? 3. 4. 5. 6. 7. 8. 9. 10. 11. Rhodes T, Girman CJ, Jacobsen DJ, et al. Longitudinal prostate volume in a communitybased sample: 7 year followup in the Olmsted County Study of Urinary Symptoms and Health Status among Men. J Urol. 2000;163(suppl):249. Abstract 1105. Gormley GJ, Stoner E, Bruskewitz RC, et al, for the Finasteride Study Group. The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med. 1992;327:1185-1191. Lepor H, Williford WO, Barry MJ, et al. A randomized placebo controlled clinical trial of the safety and efficacy of therapies in men with clinical benign prostatic hyperplasia. N Engl J Med. 1996;335:533-539. Boyle P, Grould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology. 1996;48:398-405. Emberton M, Andriole GL, de la Rosett J, et al. Benign prostatic hyperplasia: a progressive disease of aging men. Urology. 2003;61:267-273. Jacobsen SJ, Jacobson DJ, Girman CJ, et al. Natural history of prostatism: risk factors for acute urinary retention. J Urol. 1997; 158:481-487. Jacobsen SJ, Jacobson DJ, Girman CJ, et al. Treatment for benign prostatic hyperplasia among community dwelling men: the Olmsted County study of urinary symptoms and health status. J Urol. 1999;162:1301-1306. Arrighi HM, Guess HA, Metter EJ, Fozard JL. Symptoms and signs of prostatism as risk factors for prostatectomy. Prostate. 1990;16:253-261. Marberger MJ, Andersen JT, Nickel JC, et al. Prostate volume and serum prostate-specific antigen as predictors of acute urinary retention: combined experience from three large multina- 12. 13. 14. 15. 16. 17. 18. tional placebo-controlled trials. Eur Urol. 2000;38:563-568. McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med. 1998;338:557-563. Roehrborn CG, McConnell JD, Lieber M, et al, for the PLESS Study Group. Serum prostatespecific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. Urology. 1999;53:473-480. Roehrborn CG, Bruskewitz R, Nickel JC, et al, for the PLESS Study Group. Urinary retention in patients with BPH treated with finasteride or placebo over 4 years: characterization of patients and ultimate outcomes. Eur Urol. 2000;37:528-536. Roehrborn CG, Boyle P, Bergner D, et al, for the PLESS Study Group. Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a 4-year randomized trial comparing finasteride versus placebo. Urology. 1999;54:662-669. Roehrborn CG, Girman CJ, Rhodes T, et al. Correlation between prostate size estimated by digital rectal examination and measured by transrectal ultrasound. Urology. 1997;49:548-557. Roehrborn CG, Boyle P, Gould AL, et al. Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology. 1999;53:581-589. Roehrborn CG, McConnell J, Bonilla J, et al. Serum prostate-specific antigen is a strong predictor of future prostate growth in men with benign prostatic hyperplasia: Proscar LongTerm Efficacy and Safety Study. J Urol. 2000;163:13-20. 19. 20. 21. 22. 23. 24. 25. 26. 27. Roehrborn CG, McConnell JD, Lieber M, et al. Serum prostate-specific antigen is a powerful predictor of acute urinary retention and the need for surgery in men with clinical benign prostatic hyperplasia. Urology. 1999;53:473-480. Bruskewitz R, Girman CJ, Fowler J, et al. Effect of finasteride on bother and other health-related quality of life aspects associated with benign prostatic hyperplasia. Urology. 1999;54:670-678. Boyle P, Robertson C, Wilson TH, Benichou J. Predictive model for acute urinary retention in men with benign prostatic hyperplasia. J Urol. 2003;169(4 suppl):333. Abstract 1293. Roehrborn CG, Boyle P, Nickel JC. PSA is a significant predictor of objective parameters in men at risk for BPH progression. J Urol. 2003;169(4 suppl):364. Abstract 1362. de la Rosette JJ, Kortman BB, Rossi C, et al. Long-term risk of re-treatment of patients using alpha-blockers for lower urinary tract symptoms. J Urol. 2002;167:1734-1739. McConnell JD, for the MTOPS Steering Committee. The long term effects of medical therapy on the progression of BPH: results from the MTOPS trial. J Urol. 2002;167(4 suppl):265. Abstract 1042. Roehrborn CG, McConnell J, Jacobs S, et al. Baseline prostate volume and serum PSA predict rate of prostate growth: analysis of the MTOPS data. J Urol. 2003;(4 suppl):364. Abstract 1361. McConnell JD, Roehrborn CG, Slawin KM, et al. Baseline measures predict the risk of benign prostatic hyperplasia clinical progression in placebo-treated patients. J Urol. 2003;169(4 suppl): 332. Abstract 1287. Roehrborn CG. Reducing the risk of benign prostatic hyperplasia progression. Rev Urol. 2002;4(suppl 5):S29-S38. Main Points • Recent studies and analyses have confirmed that baseline prostate volume is related to benign prostatic hyperplasia (BPH) progression and negative outcomes related to BPH progression, such as acute urinary retention (AUR) and the need for surgery, and can predict response to therapy. • In a meta-analysis by Boyle and colleagues, mean improvement in symptoms and urinary flow rate with finasteride were found to increase with increasing prostate size. In addition, peak flow rate improved in placebo-treated patients in all prostate volume categories, but patients who received finasteride demonstrated significantly greater improvement with increasing prostate volume (ie, >40 mL). • The Scandinavian Reduction of the Prostate Study, the Proscar Safety Plus Efficacy Canadian Trial, and the Proscar Worldwide Efficacy and Safety Study provided reasonably long-term, reliable data characterizing prostate volume as a risk factor for AUR over 2 years. • Clinical trial data show evidence that baseline prostate-specific antigen (PSA) level, like baseline prostate volume, predicts future prostate growth and that men with higher serum PSA levels have an increased risk of developing AUR and the need for surgery. • The most clinically significant response to finasteride in terms of symptom amelioration, improvement in flow rates, quality of life, and reduction in AUR and surgical rates occurred in the patients at highest risk, that is, those with large prostate glands and higher baseline serum PSA values. • Roehrborn and colleagues analyzed prostate volume changes over time in the placebo group of the Medical Therapy of Prostatic Symptoms study and determined that both baseline prostate volume and PSA level were excellent predictors of future prostate growth. 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