Therapeutic Strategies for Managing BPH Progression

Transcription

1 european urology supplements 5 (2006) available at journal homepage: Therapeutic Strategies for Managing BPH Progression John M. Fitzpatrick a, *, Walter Artibani b a Department of Surgery, Mater Hospital, Dublin, Ireland b Department of Oncological and Surgical Sciences, Urology Clinic, University of Padua, Padua, Italy Article info Keywords: BPH Disease progression LUTS 5a-Reductase inhibitors TURP Abstract The aim of therapy for benign prostatic hyperplasia (BPH) is to improve quality of life by providing symptom relief and an increased maximum flow rate (Q max ), as well as to reduce disease progression and the development of new morbidities. Watchful waiting can be recommended when the International Prostate Symptom Score is 7, that is, mild symptoms that do not interfere with daily life activities. The a 1 -blockers are an established therapy for BPH and onset of action is rapid, generally within 2 wk of commencing treatment. Intermediate-term benefits can be seen in an improvement in Q max of 10 15% and in symptom scores of 15 20%. The other main medical therapies for BPH are the 5a-reductase inhibitors (5ARIs), which not only reduce symptoms and improve Q max, but also importantly reduce prostate volume. Dutasteride, a dual 5ARI, can provide benefits in symptom score and Q max within 1 mo. The improvements in symptom score and Q max continue up to 4 yr, with stabilisation of prostate volume. In the long-term, unlike a 1 -blockers, 5ARIs reduce the risk of BPH progression. The risk of acute urinary retention for men taking dutasteride was reduced by 48% compared with placebo at 2 yr ( p < 0.001) and the risk of BPH-related surgery by 55% ( p < 0.001). The combination of an a 1 -blocker and a 5ARI could be considered to provide added benefits over either therapy alone. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Surgery, Mater Hospital, 47 Eccles Street, Dublin 7, Ireland. Tel ; Fax: address: jfitzpatrick@mater.ie (J.M. Fitzpatrick). 1. Introduction Clinical benign prostatic hyperplasia (BPH) represents the clinical consequences of, or can be attributed to, an increased prostate volume and is characterised by lower urinary tract symptoms (LUTS), bladder outflow obstruction, incomplete bladder empting, acute and chronic urinary retention, urinary tract infection, urosepsis, bladder stones, and haematuria [1]. BPH is the most important pathologic condition that contributes to LUTS [2]. LUTS also result from storage or emptying problems that may be related to intrinsic bladder problems, such as overactive bladder [3] or other downstream pathology, such as urethral stricture disease. Men do not actually complain of BPH per se, unlike LUTS, so the patient-based focus of therapy for BPH must be directed not only at what they are /$ see front matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 998 european urology supplements 5 (2006) experiencing now, but at what they might experience later, that is, the downstream consequences of disease progression. The extent to which LUTS can be attributed to BPH and bladder pathology alone has been estimated to be about 87% [4]. In a study of 5100 men, 13.4% had at least one pre-existing condition that could be considered a differential diagnosis for an underlying cause of LUTS (7.8% for prostate cancer or surgery, 4.8% for back surgery, 1.3% for bladder surgery, and 1.4% for neurologic conditions). The alternate explanations for LUTS identified above increased with age [4]. Despite the difficulties in using clinical criteria as definitive markers for a pathologic entity, a number of studies illustrate the likely prevalence, incidence, and progression of BPH. By use of autopsy studies, Berry et al identified an incidence rate of 51% in men at age 50 yr that rose to 88% in men aged 90 yr [5]. BPH was almost never observed in men under age 30 yr. A review of the utility of clinical symptoms and signs as indicators of prostatic volume has shown consistently that all markers of BPH worsen with age [6]. Prostate volume, clinical symptoms, and peak urinary flow demonstrate the progressive nature of BPH and men with prostatic enlargement >50 ml are 3.5 times as likely to have moderate to severe symptoms. 2. BPH progression Two main sources of information regarding the progression of BPH are the Olmsted County Study, where true longitudinal data are serially updated, and the placebo arms of clinical trials, such as the Proscar Long-term Efficacy and Safety Study (PLESS) and the Medical Therapy of Prostatic Symptoms (MTOPS) study, where the follow-up periods were shorter. The Olmsted County Study showed an average increase in scores on the American Urological Association Symptom Index (AUA-SI) of 0.18 points/yr [7], with a peak average change from baseline of 1.5 points in men aged yr. Other findings included a reduction of 2%/yr in peak flow rates (Q max ) [8] and an increase in prostate volume of 1.9%/yr over baseline [9]. The estimates of natural progression rate of BPH from these two sources have been compared using a selected cohort of the Olmsted County Study. A sub-cohort was identified who complied with the inclusion criteria for the MTOPS study. In these 238 men, the incidence rates per 1000 person-years were calculated for four major outcomes and compared with the equivalent rates in the MTOPS study placebo arm of 737 men (Table 1) [10]. Two relevant conclusions from these data are that placebo and community-dwelling patients may not be representative of each other and that the natural history of BPH derived from clinical trials may be overly optimistic in its description of outcome events [10]. The implication is that prevalence and progression may be on the high side of previous estimates. In deciding treatment options, particularly a watchful waiting strategy, physicians would be advised to share this information with their patients. Progression of BPH can be defined by the occurrence of any of the following events: need for invasive therapy, acute urinary retention (AUR), renal failure, recurrent urinary tract infections, urinary incontinence or documented symptomatic progression (+4 points on the International Prostate Symptom Score [IPSS] with respect to baseline). A greater risk of progression is associated with certain baseline parameters, such as higher IPSS, older age, increased prostate-specific antigen (PSA) and prostate volume, and reduced Q max [11]. One clearly important outcome of progression is the onset of AUR and this and many of the other indicators of progression are more likely with higher baseline prostate volumes [12]. PSA has been shown to be well correlated with prostate volume and, indeed, PSA proves to be a good predictor of the likelihood of AUR. In the 3040 men enrolled in PLESS, dividing PSA into tertiles revealed that the risk of AUR was 7.8% in the lowest and 19.9% in the highest tertile of PSA. In untreated men, the risk of AUR rose with the baseline PSA [13]. Table 1 A comparison of community-dwelling and clinical trial placebo progression and incidence rates for men with benign prostatic hypertrophy [10] Per 1000 person-years Olmsted County sub-cohort incidence rates (n = 238) MTOPS study placebo incidence rates (n = 737) Acute urinary retention 18.3% 6% Symptom progression 86.5% 36% Surgery or minimally invasive treatment 16.8% 13% Any outcome 109.4% 45% MTOPS = Medical Therapy of Prostatic Symptoms.

3 european urology supplements 5 (2006) A recent analysis of the MTOPS study has also revealed an association between baseline serum PSA, prostate volume, and disease progression. In the placebo arm, patients with a baseline prostate volume 31 ml and a baseline PSA level 1.6 ng/ml had a significantly greater risk of overall clinical progression, symptom progression, risk of AUR, and invasive surgery compared with a volume of <31 ml ( p < ) and a PSA level <1.6 ng/ml ( p < 0009) [14]. In addition, a baseline Q max < 10.6 ml/s, postvoid residual 39 ml, or age 62 yr all significantly increased the risk of clinical progression. 3. Goals of therapy The primary goal of therapy for BPH is to improve the quality of life (QOL) for patients by reducing symptoms, improving Q max, and reducing the risk of AUR and BPH-related surgery. From the perspective of the patient, the goal becomes a current reduction in bother and a reduction in the fear of significant consequences of BPH by treating the underlying cause of the disease [15]. The advent of measures of bother and selective health-related QOL scales relevant to BPH has enabled a more accurate picture of the baseline status and the potential benefit with treatment. It has been noted that in a group of patients with an average AUA-SI of 12.2, 57% were significantly concerned about the prospect of AUR and 67% about the possibility of surgery [16]. Therefore, despite the fact that the absolute rates of AUR and surgery may be low (6.5% and 2.7%, respectively, in a 2-yr period), the real impact on patient well-being may be significant if these complications are avoided [17]. A medical treatment for BPH should reduce the risk of major complications (viewed by 88% as very important) [18] and the need for surgery (viewed by 93% as very important). Although medical therapies have the targets of reducing the present symptoms and the likelihood of future major events, the mechanism of these therapies must be seen in the reduction of prostate size and growth rate or a direct sustained effect on the symptoms themselves. 4. Watchful waiting Watchful waiting cannot physiologically reduce the present symptoms or the likelihood of future major events any more than it can have a direct impact on prostate size or growth. However, watchful waiting is a well-established and accepted course of action that is recommended when the symptom score is 7, that is, mild symptoms that do not interfere with daily life activities [19]. In arriving at the decision to monitor a patient, it is suggested that account be taken of the presence of symptoms, their bothersome aspects, and their influence on daily life, as well as cost considerations. Watchful waiting is not equivalent to placebo treatment [20] because no drug is given; neither can phytotherapy, whether self-administered or taken under medical instructions, be considered simple watchful waiting [21]. However, it is clear that supportive care including information about the condition of BPH and its relation to prostate cancer is an important part of watchful waiting. In men in whom the extent of current symptoms or the prospect of future morbidity (AUR and other events of progression) appear to be high enough, consideration of therapeutic intervention may be justified [22]. The information supporting a decision to treat comes in part from an understanding of the natural history of BPH from the Olmstead County and MTOPS studies. In the absence of a symptom score high enough to trigger therapy, the main criterion should be the prostate volume, possibly using PSA as a surrogate. 5. a-blockade a-blockade became established as a therapy for BPH on the basis of its effects on symptoms and flow rates. The benefits of a 1 -blocker therapy appear shortly after starting therapy due to the alteration in dynamic smooth muscle tension within the prostate and bladder neck. The intermediate-term benefits of a 1 -blockers can be seen in terms of an improvement in Q max of 10 15% and in symptom scores of 15 20% [23]. In a 12-mo study of terazosin (the Veterans Affairs [VA] study), symptom problem score (mean of 3.1 points lower) and BPH impact score (mean of 1.1 points lower) were highly statistically and clinically improved compared with placebo [24]. The changes were seen within 2 wk of starting treatment and were maintained for the year of treatment. Global assessments of improvement confirmed the benefits of a 1 -blocker therapy. In the long-term, the effects of doxazosin, as a prototypical a 1 -blocker, can be seen from the MTOPS study. At 4 yr, clinical progression was evident in 10%, a 4-point increase in AUA-SI in 7%, AUR in 1%, and the need for surgical intervention in 3% [25]. The prostate volume in men receiving doxazosin increased by a median of 24% at an average of 4.5 yr. The known side-effects of a 1 -blockers are orthostatic hypotension, dizziness, tiredness, stuffy

4 1000 european urology supplements 5 (2006) Fig. 1 Cumulative treatment discontinuation rates in men with benign prostatic hyperplasia in individual studies [28]. nose, ejaculatory dysfunction, or refractoriness; adverse events (AEs) are the most commonly cited reasons for drug discontinuation. Although there are differences regarding the AEs associated with these agents, particularly sexual function, the results of a meta-analysis of randomised clinical trial data conducted by the 2003 AUA guideline panel suggest that the four main a 1 -blockers (alfuzosin, doxazosin, tamsulosin, and terazosin) have comparable clinical efficacy [26,27]. Discontinuation rates for a 1 -blockers are high compared with 5a-reductase inhibitors (5ARIs), as confirmed in a meta-analysis of clinical studies (Fig. 1) [28]. The meta-analysis involving 6840 patients showed that discontinuation rates were different with different a 1 -blockers [23]. With regard to BPH progression a number of studies have examined the effect of the a 1 -blocker alfuzosin on the risk of AUR; however, none have shown conclusively that there is a risk reduction [29,30]. greater and more consistent with dutasteride 0.5 mg than with finasteride or placebo; the mean decrease in DHT was 94.7% 3.3% for dutasteride compared with a mean decrease of 70.8% 18.3% for finasteride 5.0 mg at 6 mo ( p < 0.001). Dutasteride can be shown to have beneficial effects on prostate volume and Q max within 1 mo [32]. The extent of change in prostate volume was 23.5% and symptom score was reduced by 4.5 points over the course of a 2-yr study [33]. A 2-yr open-label extension of the study indicated continuing reduction in prostate volume by 27.3% and further improvements in urinary symptoms, resulting in a reduction of 6.5 points from baseline [33]. Similarly for Q max, the increase of 0.6 ml/s at 2 yr was further improved to 1.9 ml/s at 4yr[33]. The risk of AUR for men taking dutasteride was reduced by 48% compared with placebo at 2 yr ( p < 0.001) and the risk of BPH-related surgery by 55% ( p < 0.001) [28]. Drug-related AEs are mainly concentrated in the first 6 mo of treatment and focus on sexual side-effects such as decreased libido and erectile difficulties [28]. The European Association of Urology guidelines on BPH recognise that 5ARI treatment is more effective in patients with larger prostate volumes (>30 40 ml) [34]. One possible algorithm for treatment of patients with BPH is shown in Fig. 2. Finasteride, 5 mg/d, decreases total urinary symptom scores, increases Q max by 1.6 ml/s, and decreases prostatic volume by 19%. The AEs included recognised sexual side-effects: decreased libido, erectile dysfunction, and ejaculatory disorders [35]. A 4-yr study by McConnell and coworkers in 3040 men with BPH showed that finasteride reduced the risk of AUR by 57% and the risk of BPHrelated surgery by 55% [36]. In the MTOPS study, finasteride reduced the risk of clinical progression of BPH, defined as a 4-point increase in AUA-SI, 6. 5ARIs Therapy of BPH with a 5ARI is based on the fact that inhibiting dihydrotestosterone (DHT) production will, in the prostate, alter epithelial growth, cause atrophy, and, thereby, reduce prostate volume and increase flow rate. Dutasteride, a 5ARI that inhibits both type I and type II isoforms of 5a-reductase, has a greater effect on DHT levels than does finasteride, a type II inhibitor. In a study by Clark et al [31], suppression of DHT from baseline was significantly Fig. 2 One of the possible algorithms for management of patients with benign prostatic hyperplasia. LUTS = lower urinary tract symptoms; IPSS = International Prostate Symptom Score; PV = prostate volume; 5ARI = 5a-reductase inhibitor.

5 european urology supplements 5 (2006) AUR, urinary incontinence, renal insufficiency, or recurrent urinary tract infection by 34% compared with placebo [25]. A recent analysis has compared the effect of a 1 -blockers and finasteride on AUR in a cohort of 4500 men with BPH from the General Practice Research Database (United Kingdom) [37]. Results showed that patients prescribed an a 1 -blocker were significantly more likely to experience AUR or surgery than those prescribed a 5ARI. 7. Combination therapies Several sources of data suggest that in the longterm, reducing prostate volume or limiting prostate growth may be key in controlling prostate symptoms and risk from prostate-based morbidities. These arguments point to the potential benefit of combining an a 1 -blocker with a 5ARI as a long-term treatment option. Additionally, the rapid action of the a 1 -blockers supports their role at the start of therapy for symptomatic BPH and the presence of another effective agent during ongoing therapy mitigates their relatively high discontinuation rates. Cardiovascular tolerability may partially account for such a discontinuation rate, but long-term treatment failure may also be a factor. The treatment failure rate of a 1 -blockers is related to prostate volume, being 48% when the prostate volume is <40 ml and 72% when the volume is >40 ml [38]. In view of the link between prostate volume and PSA, the further finding that baseline PSA predicts treatment failure of doxazosin is entirely supportive of the concern that long-term therapy of high-volume prostates requires more than an a 1 -blocker [39]. The 5ARIs are effective in patients with prostate volumes >30 ml and even more so when the prostate volume is >40 ml [40]. This has been confirmed for dutasteride; surgical intervention was reduced by 52% and 35% in prostates >40 ml and ml, respectively, and volume-related changes in symptom scores, BPH Impact Index, and Q max were seen [41]. The possibility of combining dutasteride with an a 1 -blocker is supported by pharmacokinetic and pharmacologic data, which indicate no interaction between the agent and tamsulosin or terazosin [42]. In terms of clinical evidence of the effectiveness of combination therapy, the MTOPS study, in which finasteride was combined with doxazosin, indicated that the absolute risk of clinical progression was reduced from 4.5/100 person-years in the placebo group to 1.5/100 person-years in the combination therapy group, with a relative risk reduction as high as 66% compared with placebo ( p < 0.001) [43].Inan effort to minimise the exposure to pharmaceuticals, AEs, and cost, studies have been done to test whether only 5ARIs are needed in long-term medical management of selected men with BPH. The Symptom Management After Reducing Therapy (SMART) study has shown that following an initial period of combination therapy with the a 1 -blocker tamsulosin and dutasteride, tamsulosin could be withdrawn without loss of symptom relief [44]. Where there was a high risk of progression and significant symptoms (IPSS >20) the continued use (from weeks 24 36) of both tamsulosin and dutasteride was superior to the sole use of dutasteride. 8. Conclusions Several medical therapies are available for the treatment of BPH. The a 1 -blockers provide rapid symptom relief but do not reduce prostate volume or the incidence of long-term complications. In contrast, the 5ARIs not only improve symptoms but also reduce prostatic volume and the long-term risk of progression. The 5ARI dutasteride has demonstrated sustained improvement in symptoms and Q max, currently out to 4 yr, with stabilisation of prostate volume. The risk of progression is primarily indicated by the presence of a prostate volume >30 40 ml, although PSA criteria are satisfactory proxies in men with established BPH. Patients at higher risk of progression would benefit from a treatment regimen containing a 5ARI. References [1] Jepsen JV, Bruskewitz RC. Clinical manifestation and indications for treatment. In: Lepor H, editor. Prostatic diseases. Philadelphia: WB Saunders; p [2] Reynard JM, Peters TJ, Lamond E, Abrams P. The significance of abdominal straining in men with lower urinary tract symptoms. Br J Urol 1995;75: [3] Jaffe WI, Te AE. Overactive bladder in the male patient: epidemiology, etiology, evaluation, and treatment. Curr Urol Rep 2005;6: [4] Gades NM, Jacobson DJ, Girman CJ, Roberts RO, Lieber MM, Jacobsen SJ. Prevalence of conditions potentially associated with lower urinary tract symptoms in men. BJU Int 2005;95: [5] Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol 1984;132: [6] Girman CJ, Jacobsen SJ, Guess HA, et al. Natural history of prostatism: relationship among symptoms, prostate volume and peak urinary flow rate. J Urol 1995;153: [7] Jacobsen SJ, Girman CJ, Guess HA, Rhodes T, Oesterling JE, Lieber MM. Natural history of prostatism: longitudinal

6 1002 european urology supplements 5 (2006) changes in voiding symptoms in community dwelling men. J Urol 1996;155: [8] Roberts RO, Jacobsen SJ, Jacobsen DJ, Rhodes T, Girman CJ, Lieber MM. Longitudinal changes in peak urinary flow rates in a community-based cohort. J Urol 2000;163: [9] Rhodes T, Girman CJ, Jacobsen DJ, Roberts RO, Lieber MM, Jacobsen SJ. Longitudinal prostate volume in a community-based sample: 7 year follow up in the Olmsted County Study of urinary symptoms and health status among men. J Urol 2000;163:249 (abstract no. 1105). [10] Roberts RO, Lieber MM, Jacobson DJ, Girman CJ, Jacobsen SJ. Limitations of using outcomes in the placebo arm of a clinical trial of benign prostatic hyperplasia to quantify those in the community. Mayo Clin Proc 2005;80: [11] Emberton M. The hallmarks of BPH progression and risk factors. Eur Urol Suppl 2003;2(8):2 7. [12] Jacobsen SJ, Jacobson DJ, Girman CJ, et al. Natural history of prostatism: risk factors for acute urinary retention. J Urol 1997;158: [13] Roehrborn CG, McConnell JD, Lieber M, et al. Serum prostate-specific antigen concentrations a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. PLESS Study Group. Urology 1999;53: [14] Crawford ED, Wilson SS, McConnell JD, et al. Baseline factors as predictors of clinical progression of benign prostatic hyperplasia in men treated with placebo. J Urol 2006;175: [15] Teillac P. Relief of BPO or improvement in quality of life? Eur Urol 1998;34:3 9. [16] Kawakami J, Nickel JC. Acute urinary retention and surgery for benign prostatic hyperplasia: the patient s perspective. Can J Urol 1999;6: [17] Andersen JT, Nickel JC, Marshall VR, Schulman CC, Boyle P. Finasteride significantly reduces acute urinary retention and need for surgery in patients with symptomatic benign prostatic hyperplasia. Urology 1997;49: [18] Teillac P. Benign prostatic hyperplasia: patients perception of medical treatment and their expectations: results of a French survey involving patients treated with finasteride. Therapie 2002;57: [19] de la Rosette JJMCH, Alivizatos G, Madersbacher S, et al. EAU guidelines on benign prostatic hyperplasia (BPH). Eur Urol 2001;40: [20] Sech SM, Montoya JD, Bernier PA, et al. The so-called placebo effect in benign prostatic hyperplasia treatment trials represents partially a conditional regression to the mean induced by censoring. Urology 1998;51: [21] Moyad MA. The placebo effect and randomized trials: analysis of conventional medicine. Urol Clin North Am 2002;29: [22] Lepor H. Pathophysiology, epidemiology, and natural history of BPH. Rev Urol 2004;6 (Suppl 9). [23] Djavan B, Marberger M. A meta-analysis on the efficacy and tolerability of a1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol 1999;36:1 13. [24] Lepor H, Williford WU, Barry MJ, et al. The impact of medical therapy on bother due to symptoms, quality of life and global outcome and factors predicting response. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. J Urol 1998;160: [25] McConnell JD, Roehrborn CG, Bautista O, et al. The longterm effects of doxazosin, finasteride and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349: [26] AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1. Diagnosis and treatment recommendations. J Urol 2003;170: [27] AUA Guidelines on BPH guidelines/bph.cfm. [28] Roehrborn CG, McNicholas T. The management of prostatic obstruction: how to determine the best options? Eur Urol Suppl 2003;2(8):13 9. [29] Hartung R. Do alpha-blockers prevent the occurrence of acute urinary retention? Eur Urol 2001;39:13 8. [30] Desgrandchamps F, De La Taille A, Doublet JD, Reten- France Study Group. The management of acute urinary retention in France: a cross-sectional survey in 2618 men with benign prostatic hyperplasia. BJU Int 2006;97: [31] Clark RV, Hermann DJ, Cunningham GR, Wilson TH, Morrill BB, Hobbs S. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5a-reductase inhibitor. J Clin Endocrinol Metab 2004;89: [32] O Leary MP, Roehrborn C, Andriole G, Nickel C, Boyle P, Hofner K. Improvements in benign prostatic hyperplasiaspecific quality of life with dutasteride, the novel dual 5a-reductase inhibitor. BJU Int 2003;92: [33] 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: [34] Madersbacher S, Alivizatos G, Nordling J, Sanz CR, Emberton M, de la Rosette JJ. EAU 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (BPH guidelines). Eur Urol 2004;46: [35] Gormley GJ, Stoner E, Bruskewitz RC, et al. The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group. N Engl J Med 1992;327: [36] 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. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med 1998;338: [37] 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: [38] de la Rosette JJ, Kortmann BB, Rossi C, et al. Long-term risk of retreatment of patients using a-blockers for lower urinary tract symptoms. J Urol 2002;167: [39] Jaffe JS, Ginsberg PC, Harkaway RC. Prostate size and PSA predict failure in patients undergoing a blocker monotherapy. J Urol 2001;165:262 (abstract no. 1078).

7 european urology supplements 5 (2006) [40] Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts the outcome of treatment of benign prostatic hyperplasia with finasteride: Meta-analysis of randomized clinical trials. Urology 1996;48: [41] Boyle P, Roehrborn CG, Marks L, Vela-Navarette R, Nickel JC. The novel dual 5a-reductase inhibitor dutasteride is effective for the treatment and prevention of complications in men with a PV cc and 40 cc. Eur Urol Suppl 2003;2(1):160 (abstract no. 632). [42] Dutasteride SPC. Accessed at [43] McConnell JD, Roehrborn CG, Bautista O, et al. The longterm effects of doxazosin, finasteride and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349: [44] Barkin J, Guimaraes M, Jacobi G, Pushkar D, Taylor S, van Vierssen Trip OB, on behalf of the SMART-1 Investigator Group. Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5a-reductase inhibitor dutasteride. Eur Urol 2003;44:461 6.