Module 3: Treatment of BPH

Module 3: Treatment of BPH
J. Curtis Nickel, MD, FRCSC Program Chair, Chief Editor Professor of Urology, Department of Urology Queens University Kingston General Hospital Kingston, Ontario Module 3: Treatment of BPH The principle author for this module is Dr. J. Curtis Nickel, Professor of Urology at Queen’s University and Kingston General Hospital in Kingston, Ontario. Understanding Concepts in BPH: From the Science to the Clinical Setting

3.1 Learning Objectives After reviewing this module, the learner will be better able to: Describe the lifestyle modifications that are appropriate for men with BPH Identify the appropriate candidates and best practices for the conservative approach of watchful waiting Describe options for the pharmacological treatment of men with LUTS 3.1 Learning Objectives After reviewing this module, the learner will be better able to: Describe the lifestyle modifications that are appropriate for men with BPH. Identify the appropriate candidates and best practices for the conservative approach of watchful waiting. Describe options for the pharmacological treatment of men with LUTS. BPH = Benign Prostatic Hyperplasia, LUTS = Lower Urinary Tract Symptoms Understanding Concepts in BPH: From the Science to the Clinical Setting

After reviewing this module, the learner will be better able to: Identify the indications for minimally invasive surgical therapies that are appropriate for the treatment of men with moderate to severe LUTS, who request Minimally Invasive Surgical Therapies (MIST) Describe the surgical options for the treatment of men with BPH and bothersome moderate to severe LUTS who request active therapy 3.1 Learning Objectives, cont’d After reviewing this module, the learner will be better able to: Identify the indications for minimally invasive surgical therapies that are appropriate for the treatment of men with moderate to severe LUTS, who request Minimally Invasive Surgical Therapies (MIST). Describe the surgical options for the treatment of men with BPH and bothersome moderate to severe LUTS who request active therapy. BPH = Benign Prostatic Hyperplasia, LUTS = Lower Urinary Tract Symptoms Understanding Concepts in BPH: From the Science to the Clinical Setting

3.2 Introduction Treatment of BPH is based primarily on symptomatology: the severity of symptoms and the bother that they cause to the patient’s QoL The risk of progression of symptoms, complications, and the need for surgery must be assessed when deciding upon treatment. The goal of treatment is 2-fold: to improve symptoms to delay disease progression 3.2 Introduction Treatment of BPH is based primarily on symptomatology: the severity of symptoms and the bother that they cause to the patient’s quality of life. But the risk of progression of symptoms, complications, and the need for surgery must be assessed when deciding upon treatment. In essence, the goal of treatment is 2-fold: to improve symptoms and to delay disease progression. BPH = Benign Prostatic Hyperplasia; QoL = Quality of Life Understanding Concepts in BPH: From the Science to the Clinical Setting

Current guidelines recommend a formal symptom inventory to accurately assess the severity of symptoms and guide treatment choices:1,2 International Prostate Symptom Score (IPSS) / American Urological Association (AUA) Symptom Score Current guidelines recommend a formal symptom inventory, such as the International Prostate Symptom Score (IPSS) [also called the American Urological Association (AUA) Symptom Score] to accurately assess the severity of symptoms and guide treatment choices.1,2 1. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): 2. Nickel JC, Herschorn S, Corcos J, et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: AUA guideline on management of benign prostatic hyperplasia (2003). J Urol. 2003;170(2 Pt 1): Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: Understanding Concepts in BPH: From the Science to the Clinical Setting

Once severity, bother, and risk are assessed, then patient preference becomes one of the most important determinants of treatment The benefits and harm of BPH treatment options should be explained to all patients who are bothered enough to consider therapy, and patients should be invited to participate as much as possible in the choice of treatment 3 Even patients with severe symptoms may decide to choose a less effective therapy against their physician’s advice, if they feel there is less risk Once severity, bother, and risk are assessed, then patient preference becomes one of the most important determinants of treatment. The benefits and harm of BPH treatment options should be explained to all patients who are bothered enough to consider therapy, and patients should be invited to participate as much as possible in the choice of treatment.3 Even patients with severe symptoms may decide to choose a less effective therapy against their physician’s advice, if they feel there is less risk. 3. Nickel JC, Herschorn S, Corcos J, et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 3. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

The decision to Treat BPH: 4,5 Symptom severity and discomfort brings the patient to the physician Bother of symptoms leads to treatment Risk assessment directs the physicians treatment recommendations The patient makes an informed choice regarding treatment The Decision to Treat BPH: 4,5 Symptom severity and discomfort brings the patient to the physician Bother of symptoms leads to treatment Risk assessment directs the physicians treatment recommendations The patient makes an informed choice regarding treatment 4. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): 5. Nickel JC, Herschorn S, Corcos J, et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 4. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol. 2003;170(2 Pt 1): 5. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Canadian BPH Guidelines:6
Module 3: Treatment of BPH Canadian BPH Guidelines:6 “Treatment choices should be governed both by the severity of the symptoms, bother and patient preference. Such a decision depends upon patients being sufficiently informed about treatment options, and the harms and benefits of such treatment.” Canadian BPH Guidelines:6 “Treatment choices should be governed both by the severity of the symptoms, bother and patient preference. Such a decision depends upon patients being sufficiently informed about treatment options, and the harms and benefits of such treatment.” 6. Nickel JC, Herschorn S, Corcos J, et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 6. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Treatment Options Mild or minimally bothersome symptoms may only require lifestyle modification with watchful waiting For moderate or severe BPH (AUA/IPSS score ≥8): 7 lifestyle modifications with watchful waiting medical therapy (e.g. alpha-blockers and/or 5-reductase inhibitors) minimally invasive therapies (e.g., transurethral needle ablation) surgery (e.g., transurethral resection of the prostate) Mild or minimally bothersome symptoms may only require lifestyle modification with watchful waiting. For moderate or severe BPH (AUA/IPSS score ≥8), treatment options consist of lifestyle modifications with watchful waiting, medical therapy (e.g. alpha-blockers and/or 5-reductase inhibitors), minimally invasive therapies (e.g., transurethral needle ablation), or surgery (e.g., transurethral resection of the prostate).7 7. Nickel JC, Herschorn S, Corcos J, et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 7. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: BPH = Benign Prostatic Hyperplasia; AUA = American Urological Association; IPSS = International Prostate Symptom Score Understanding Concepts in BPH: From the Science to the Clinical Setting

Over the last two decades, treatment options for men with BPH have expanded significantly Use of α1-blockers in ameliorating BPH symptoms is now accepted clinical practice Introduction of 5α-reductase inhibitors and emergence of clinical evidence on their use has resulted in a paradigm shift from an emphasis on symptomatic treatment to the prevention of clinical progression in men with BPH Parallel technological developments have introduced minimally invasive surgical procedures with less risk and comparable results to traditional surgery Along with the conservative approach to therapy, this chapter will review these therapeutic options Over the last two decades, treatment options for men with BPH have expanded significantly. The use of alpha-blockers in ameliorating BPH symptoms is now accepted clinical practice. The introduction of 5-reductase inhibitors and emergence of clinical evidence on their use from large-scale, randomized, well-controlled trials has resulted in a paradigm shift from an emphasis on symptomatic treatment to the prevention of clinical progression in men with BPH. Parallel technological developments have introduced minimally invasive surgical procedures with less risk and comparable results to traditional surgery. Along with the conservative approach to therapy, this chapter will review these therapeutic options. BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

3.3 Deciding on a Treatment Approach and Counseling the Patient
Module 3: Treatment of BPH 3.3 Deciding on a Treatment Approach and Counseling the Patient Choosing a treatment strategy for BPH can be a difficult task This should be a joint process involving both physician and patient For the most severely affected patient, the obvious option may be limited to surgery However, for most men, the clinician must balance the relative benefits and risks of each treatment option and discuss them thoroughly with the patient Consulting the evidence regarding the benefits and risks of each treatment will enable wise treatment decisions 3.3 Deciding on a Treatment Approach and Counseling the Patient After diagnosis of BPH, choosing a treatment strategy for BPH can be a difficult task. As noted, this should be a joint process involving both physician and patient. For the most severely affected patient, the obvious option may be limited to surgery, however, for most men, the clinician must balance the relative benefits and risks of each treatment option and discuss them thoroughly with the patient. Consulting the evidence regarding the benefits and risks of each treatment will enable wise treatment decisions. BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Table 3.1 Evidence Table MEDICAL OPTIONS SURGICAL OPTIONS Watchful Waiting α1 Blocker 5α-Reductase Inhibitor Balloon Dilation TUIP Open Surgery TURP Chance for Improvement of Symptoms (90% confidence interval) Degree of Symptom Improvement (% reduction in symptom score) < 32 51 31 73 79 85 Morbidity / Complications Associated with Surgical or Medical Treatment (90 % confidence interval) Assume that about 20% of all complications are significant 1 - 5 Complica-tions from BPH progression Chance of Dying within Days of Treatment (90% confidence interval) .8 Chance of death < 90d for 67 yo man Pat. treated were high risk/elderly Risk of Total Urinary Incontinence (90% confidence interval) ? Incontinence due to aging Need for Operative Treatment for Surgical Complications in the Future (90% confidence interval) Table 3.1 Evidence Table Adapted from Roehrborn CG. BPH: From treatment to prevention: A change in paradigm prevention. AUA 2005. These tables provide the evidence for the various medical and surgical options for the treatment of LUTS associated with BPH. Adapted from Roehrborn CG. BPH: From treatment to prevention: A change in paradigm prevention. AUA TUIP = Transurethral Incision of the Prostate TURP = Transurethral Resection of the Prostate Understanding Concepts in BPH: From the Science to the Clinical Setting

In a study where 74 men with BPH were given questionnaires, over half of patients were significantly concerned about the prospect of acute urinary retention and over two thirds were significantly concerned about the prospect of surgery 8 However, more patients considered that the insertion of a catheter for acute urinary retention would be a problem and more detrimental to their QoL than surgery 3 In a study where 74 men with BPH were given questionnaires, over half of patients were significantly concerned about the prospect of acute urinary retention and over two thirds were significantly concerned about the prospect of surgery.8 However, more patients considered that the insertion of a catheter for acute urinary retention would be a problem and more detrimental to their quality of life than surgery.3 8. J, Nickel JC. Acute urinary retention and surgery for benign prostatic hyperplasia: the patient's perspective. Can J Urol. 1999;6: 8. Nickel JC. Can J Urol. 1999;6: BPH = Benign Prostatic Hyperplasia; QoL = Quality of Life Understanding Concepts in BPH: From the Science to the Clinical Setting

Issues to discuss with the patient: Severity of symptoms Extent to which symptoms adversely affect the patient’s QoL (i.e., “bother”) Risk of BPH progression Risk of prostate cancer Long-term efficacy and retreatment rate of each therapeutic option Realistic expectation of improvement Likelihood of treatment-associated morbidity or complications Patient preference Financial considerations Among the issues that need to be discussed with the patient are: The severity of symptoms The extent to which the symptoms adversely affect the patient’s quality of life (i.e., “bother”) The risk of BPH progression The risk of prostate cancer The long-term efficacy and retreatment rate of each therapeutic option Realistic expectation of improvement The likelihood of treatment-associated morbidity or complications Patient preference Financial considerations QoL = Quality of Life; BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

If the patient achieves a good understanding of why they are being given a particular treatment for BPH and the likely outcomes, they are much more likely to adhere to the treatment If the patient achieves a good understanding of why they are being given a particular treatment for BPH and the likely outcomes, they are much more likely to adhere to the treatment. BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

2005 Canadian Guidelines for the Management of BPH
Module 3: Treatment of BPH 2005 Canadian Guidelines for the Management of BPH Published June 2005, in The Canadian Journal of Urology 9 (See Module 4) These guidelines stress that information on the benefits and harms of BPH treatment options should be explained to all patients who are bothered enough to consider therapy The guidelines urge physicians to invite patients to participate as much as possible in the choice of treatment In June 2005, the Canadian guidelines for the management of BPH were published in The Canadian Journal of Urology.9 (Module 4 in this CD-ROM contains a summary of these treatment recommendations.) These guidelines stress that information on the benefits and harms of BPH treatment options should be explained to all patients who are bothered enough to consider therapy. The guidelines urge physicians to invite patients to participate as much as possible in the choice of treatment. 9. Nickel JC, Herschorn S, Corcos J, et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 9. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Module 3: Treatment of BPH Canadian BPH Guidelines:10 “Information on the benefits and harms of BPH treatment options should be explained to all patients who are bothered enough to consider therapy. Patients should be invited to participate as much as possible in the treatment choice.” Canadian BPH Guidelines:10 “Information on the benefits and harms of BPH treatment options should be explained to all patients who are bothered enough to consider therapy. Patients should be invited to participate as much as possible in the treatment choice.” 10. Nickel JC, Herschorn S, Corcos J, et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 10. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

3.4 Lifestyle Modification with Watchful Waiting
Module 3: Treatment of BPH 3.4 Lifestyle Modification with Watchful Waiting Lifestyle modification with watchful waiting is the first consideration in discussions of treatment strategies for BPH and the preferred management strategy for men with mild symptoms (AUA symptom score <8) or men who have moderate-to-severe symptoms (AUA symptom score ≥8) but are not yet bothered by their symptoms or have not yet developed complications of BPH 11 3.4 Lifestyle Modification with Watchful Waiting Lifestyle modification with watchful waiting is the first consideration in discussions of treatment strategies for BPH and the preferred management strategy for men with mild symptoms (AUA symptom score <8) or men who have moderate-to-severe symptoms (AUA symptom score ≥8) but are not yet bothered by their symptoms or have not yet developed complications of BPH.11 11. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 11. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: AUA = American Urological Association; BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Watchful Waiting In Canada, the treatment strategy of lifestyle modification with watchful waiting is often a shared responsibility between the urologist and family physician 12 Patients on watchful waiting should have periodic physician- monitored visits to watch for progression, and physicians should identify patients at risk They can use baseline age, the severity of LUTS, and serum PSA values to advise patients of: 13 risk of symptom progression acute urinary retention future need for BPH-related surgery monitor risk for development of prostate cancer Watchful Waiting In Canada, the treatment strategy of lifestyle modification with watchful waiting is often a shared responsibility between the urologist and family physician.12 Patients on watchful waiting should have periodic physician-monitored visits to watch for progression, and physicians should identify patients at risk. They can use baseline age, the severity of Lower Urinary Tract Symptoms (LUTS), and serum PSA values to advise patients of their individual risk of symptom progression, acute urinary retention, future need for BPH-related surgery as well as monitor risk for development of prostate cancer.13 12. Nickel JC, Saad F. The American Urological Association 2003 guideline on management of benign prostatic hyperplasia: A Canadian opinion. Can J Urol 2004;11: p2189 13. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 12. Nickel JC, Saad F. Can J Urol 2004;11: p2189 13. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: LUTS= Lower Urinary Tract Symptoms; PSA = Prostate-Specific Antigen; BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Lifestyle Modification
Module 3: Treatment of BPH Lifestyle Modification Physicians should advise all patients that certain lifestyle modifications may help to alleviate bothersome mild-to-moderate symptoms 14 Lifestyle Modification Physicians should advise all patients that certain lifestyle modifications may help to alleviate bothersome mild-to-moderate symptoms.14 14. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 14. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: Understanding Concepts in BPH: From the Science to the Clinical Setting

Module 3: Treatment of BPH Canadian BPH Guidelines:15 A variety of lifestyle changes may be suggested for patients with non- bothersome symptoms, including: Fluid restriction in the evening Avoiding irritating foods or beverages, e.g., alcohol or caffeine Avoiding or monitoring certain drugs, e.g., diuretics, decongestants, antihistamines, antidepressants Timed or organized voiding (bladder retraining) Pelvic floor exercises Avoiding or treating constipation Canadian BPH Guidelines:15 A variety of lifestyle changes may be suggested for patients with non-bothersome symptoms. These can include the following: Fluid restriction in the evening Avoiding irritating foods or beverages, e.g., alcohol or caffeine Avoiding or monitoring certain drugs, e.g., diuretics, decongestants, antihistamines, antidepressants Timed or organized voiding (bladder retraining) Pelvic floor exercises Avoiding or treating constipation 15. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 15. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: Understanding Concepts in BPH: From the Science to the Clinical Setting

3.5 Pharmacological Therapy
Module 3: Treatment of BPH 3.5 Pharmacological Therapy Medical treatment options for BPH have expanded over the past two decades, providing physicians and patients with more choices Several factors influence the choice of medical therapies versus MIST or surgery, including: 16 Nature and extent of symptoms Extent to which symptoms are bothersome and affect the patients’ QoL Whether urine flow is significantly reduced and associated with an appreciable volume of PVR urine Complications of BPH (e.g. obstructive renal failure, bladder stones, chronic urinary tract infections, prostate related bleeding) Patient preference 3.5 Pharmacological Therapy Medical treatment options for BPH have expanded over the past two decades, providing physicians and patients with more choices. Several factors influence the choice of medical therapies versus Minimally Invasive Surgical Therapies (MIST) or surgery, including: 16 Nature and extent of symptoms Extent to which symptoms are bothersome and affect the patients’ quality of life (QOL) Whether urine flow is significantly reduced and associated with an appreciable volume of post-void residual urine (PVR) Complications of BPH (e.g. obstructive renal failure, bladder stones, chronic urinary tract infections, prostate related bleeding) Patient preference 16. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. Fifth edition. Oxford: Health Press, 2005, p38 16. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p38 MIST = Minimally Invasive Surgical Therapies; PVR = Post-Void Residual Urine; QoL=Quality of Life Understanding Concepts in BPH: From the Science to the Clinical Setting

Alpha 1 (α1)-adrenoceptor Blockers
Module 3: Treatment of BPH Alpha 1 (α1)-adrenoceptor Blockers α1-adrenergic receptors mediate tension in smooth muscle tissue surrounding the prostate stroma, urethra, and bladder neck Rationale of α1-adrenoceptor blocking agents: by inhibiting these receptors, muscular tone along these tissues will be reduced, allowing for easier passage of urine and the reduction of LUTS 17 Alpha 1 (α1)-adrenoceptor Blockers α1-adrenergic receptors mediate tension in smooth muscle tissue surrounding the prostate stroma, urethra, and bladder neck. The rationale behind the development of α1-adrenoceptor blocking agents is that, by inhibiting these receptors, muscular tone along these tissues will be reduced, allowing for easier passage of urine and the reduction of LUTS.17 17. Leveillee R. Benign Prostatic Hyperplasia. eMedicine. Accessed June 5, 2005 17. Leveillee R. Benign Prostatic Hyperplasia. eMedicine. Accessed June 5, 2005 LUTS = Lower Urinary Tract Symptoms Understanding Concepts in BPH: From the Science to the Clinical Setting

Figure 3.1 α-Adrenoceptors
Module 3: Treatment of BPH Figure 3.1 α-Adrenoceptors 1 α1D α1A α1B Prostate Peripheral Liver 11.5 6.5 7.5 8.5 9.5 10.5 Alfuzosin Tamsulosin Mean Total Symptom Score Vasoconstriction Spleen Bladder Figure 3.1: α-adrenoceptors Buzelin JM, et al. Br J Urol 1997;80: Tamsulosin is a specific α1A-adrenergic receptor antagonist while Alfuzosin is a less selective but uroselective antagonist. Both medications result in similar symptom amelioration. 2 6 12 Buzelin JM, et al. Br J Urol 1997;80: Understanding Concepts in BPH: From the Science to the Clinical Setting

α1 Receptor Blockers Approved in Canada
Module 3: Treatment of BPH α1 Receptor Blockers Approved in Canada Currently, there are four α1 receptor blockers approved in Canada for the treatment of BPH: Terazosin Doxazosin Tamsulosin Alfuzosin The use of prazosin not approved for BPH in Canada, nor is it recommended 18 Currently, there are four α1 receptor blockers approved in Canada for the treatment of BPH: terazosin, doxazosin, tamsulosin and alfuzosin. The use of prazosin not approved for BPH in Canada, nor is it recommended.18 18. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 18. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: Understanding Concepts in BPH: From the Science to the Clinical Setting

α1 receptor blockers that are selective for the α1A subtype may have a potential therapeutic advantage mainly in terms of tolerability (less effect on blood pressure) Tamsulosin Currently the only α1 receptor blocker that targets selectively the α1A receptor which is predominant in the prostate Alfuzosin Non-specific α1 receptor blocker Shows preferential distribution in the prostate in patients with BPH This preference distribution may play a role in the functional uroselectivity reported with α1 receptor blocker Terazosin and doxazosin are not uroselective α1 receptor blockers that are selective for the α1A subtype may have a potential therapeutic advantage mainly in terms of tolerability (less effect on blood pressure). Tamsulosin is currently the only α1 receptor blocker that targets selectively the α1A receptor which is predominant in the prostate. Alfuzosin is a less-specific α1 receptor blocker. However, it shows a preferential distribution in the prostate in patients with BPH. This preference distribution may play a role in the functional uroselectivity reported with α1 receptor blocker. The other α1 receptor blockers, terazosin and doxazosin are not as receptor selective or uroselective. Understanding Concepts in BPH: From the Science to the Clinical Setting

The four recommended α1-receptor blockers are believed to have equal clinical effectiveness, partially relieving symptoms of LUTS On average, they produce a 4- to 6-point improvement in the IPSS Patients generally regard this improvement as a meaningful change 19 α1-receptor blockers relax the contraction of smooth muscle in the bladder neck and prostatic urethra by blocking the α1- adrenoreceptors The four recommended α1-receptor blockers are believed to have equal clinical effectiveness, partially relieving symptoms of LUTS. On average, they produce a 4- to 6-point improvement in the IPSS. Patients generally regard this improvement as a meaningful change.19 α1-receptor blockers relax the contraction of smooth muscle in the bladder neck and prostatic urethra by blocking the α1-adrenoreceptors. 19. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): 19. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol LUTS = Lower Urinary Tract Symptoms; IPSS = International Prostate Symptom Score Understanding Concepts in BPH: From the Science to the Clinical Setting

The primary side effects of α1-receptor blockers are 20 Orthostatic hypotension Dizziness Tiredness (asthenia) Ejaculatory problems Nasal congestion The primary side effects of α1-receptor blockers are: 20 Orthostatic hypotension Dizziness Tiredness (asthenia) Ejaculatory problems Nasal congestion 20. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): 20. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol Understanding Concepts in BPH: From the Science to the Clinical Setting

Slight differences in the adverse-event profiles of the four recommended agents: Tamsulosin: appears to have a lower probability of orthostatic hypotension but a higher risk of ejaculatory problems than other α1-receptor blockers Doxazosin: In men with hypertension and cardiac risk factors, doxazosin has been associated with a higher incidence of congestive heart failure than other antihypertensive agents and this agent should not be assumed to constitute optimal hypertension management in men with concomitant LUTS 21 There are slight differences in the adverse-event profiles of the four recommended agents. For example, tamsulosin appears to have a lower probability of orthostatic hypotension but a higher risk of ejaculatory problems than other α1-receptor blockers. In men with hypertension and cardiac risk factors, doxazosin has been associated with a higher incidence of congestive heart failure than other antihypertensive agents and this agent should not be assumed to constitute optimal hypertension management in men with concomitant LUTS.21 21. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): 21. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol LUTS = Lower Urinary Tract Symptoms Understanding Concepts in BPH: From the Science to the Clinical Setting

α-Blockers: Overview Similar efficacy Efficacy remains long-term (5-year data is currently available) Difference between α1-adrenoceptor blockers is related to the side effect profile (uroselective agents are better tolerated) Alfuzosin and tamsulosin appear to be better tolerated than doxazosin and terazosin -Blockers: Overview Roehrborn CG. Urol 2001;58(Suppl 6A):55-64 In summary, the α blockers available in Canada have similar efficacy and that efficacy is durable. Five year data is currently available. Differences between the α1-adrenoreceptor blockers is related to the side effect profile where the more uroselective agents are better tolerated. Alfuzosin and tamsulosin appear to be better tolerated than doxazosin and terazosin. Roehrborn CG. Urol 2001;58(Suppl 6A):55-64 Understanding Concepts in BPH: From the Science to the Clinical Setting

Module 3: Treatment of BPH Canadian BPH Guidelines:22 “Although there are differences in the adverse-event profiles of these agents, the Committee believes that all four agents have equal clinical effectiveness. Choice of agent should depend on patient’s comorbidities, side effect profiles, and tolerance.” Canadian BPH Guidelines:22 “Although there are differences in the adverse-event profiles of these agents, the Committee believes that all four agents have equal clinical effectiveness. Choice of agent should depend on patient’s comorbidities, side effect profiles, and tolerance.” 22. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 22. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

5α-Reductase Inhibitors
Module 3: Treatment of BPH 5α-Reductase Inhibitors Unlike α1-receptor blockers, 5α-reductase inhibitors address the underlying pathophysiology of BPH, shrinking the prostate size and reversing the clinical progression 5α-Reductase Inhibitors Unlike α1-receptor blockers, 5α-reductase inhibitors address the underlying pathophysiology of BPH, shrinking the prostate size and reversing the clinical progression. BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

5-Reductase Inhibitors: Overview
Module 3: Treatment of BPH 5-Reductase Inhibitors: Overview Types: Finasteride and Dutasteride Improves LUTS in men with large prostate (DRE, PSA, TRUS) Reduces risk of acute retention and surgery Has long latency period before effect Reduces PSA (50% at 6 months to one year) Alters sexual function in some men 5-Reductase Inhibitors Gurunadha Rao Tunuguntla HS. Clin Geriat 2002;10(5):20-5; Kasraeian A. Gormley GJ, et al. NEJM 1992;327: There are 2 types of 5-Reductase Inhibitors available in Canada: Finasteride and Dutasteride. Both of these agents improve Lower Urinary Tract Symptoms (LUTS) in men with large prostates determined either by Digital Rectal Examination (DRE), Prostate-specific antigen (PSA) or Transrectal Ultrasound (TRUS). Both of these agents reduce the risk of Acute Urinary Retention (AUR) and surgery. It must be remembered that both of these agents reduce PSA by about 50% at 6 months to 1 year. These agents can sometimes alter sexual function in some men. Gurunadha Rao Tunuguntla HS. Clin Geriat 2002;10(5):20-5; Kasraeian A. Gormley GJ, et al. NEJM 1992;327: LUTS = Lower Urinary Tract Symptoms, DRE = Digital Rectal Examination, PSA = Prostate-Specific Antigen TRUS = Transrectal Ultrasound of the Prostate Understanding Concepts in BPH: From the Science to the Clinical Setting

The 5α-reductase inhibitors act by inhibiting the enzyme, 5α- reductase, which occurs as two isoforms, 5α-reductase types 1 and 2 These enzymes convert testosterone to dihydrotestosterone (DHT), which binds to receptors on prostatic cell nuclear membranes and stimulates prostate tissue growth (see Module 1) The 5α-reductase inhibitors act by inhibiting the enzyme, 5α-reductase, which occurs as two isoforms, 5α-reductase types 1 and 2. These enzymes convert testosterone to dihydrotestosterone (DHT), which binds to receptors on prostatic cell nuclear membranes and stimulates prostate tissue growth (see Module 1). Understanding Concepts in BPH: From the Science to the Clinical Setting

In addition to preventing disease progression, 5α-reductase inhibitors increase peak urinary flow rate and reduce BPH symptoms The average patient will experience a 3-point reduction of AUA symptom scores This improvement can be greater in men with larger prostates 5α-reductase inhibitors are not appropriate treatments for men with LUTS who do not have clinical evidence of prostatic enlargement These agents do not appear to be as effective for symptomatic relief as α1-receptor blockers 23,24 In addition to preventing prostate disease progression, 5α-reductase inhibitors increase peak urinary flow rate and reduce BPH symptoms. The average patient will experience a 3-point reduction of AUA symptom scores. This improvement can be greater in men with larger prostates. 5α-reductase inhibitors are not appropriate treatments for men with Lower Urinary Tract Symptoms (LUTS) who do not have clinical evidence of prostatic enlargement. These agents do not appear to be as effective for symptomatic relief as α1-receptor blockers.23,24 23. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. Fifth edition. Oxford: Health Press, 2005, p43 24. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. Fifth edition. Oxford: Health Press, 2005, p44 23. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p43 24. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p44 AUA = American Urological Association ; LUTS = Lower Urinary Tract Symptoms Understanding Concepts in BPH: From the Science to the Clinical Setting

Figure 3.2 Finasteride 5mg Daily, 12-months
Module 3: Treatment of BPH Figure 3.2 Finasteride 5mg Daily, 12-months a) Symptom Score 4 3 Year Finasteride Placebo 2 Figure 3.2: Finasteride 5mg daily, a) Symptom Score Adapted from McConnell JD, et al. NEJM 1998;338(9):557-63 The average patient will experience a 3-point reduction of AUA symptom scores. This improvement can be greater in men with larger prostates. 1 -3.5 -3 -2.5 -2 -1.5 -1 -0.5 Mean Change Adapted from McConnell JD, et al. NEJM 1998;338(9):557-63 Understanding Concepts in BPH: From the Science to the Clinical Setting

Figure 3.2 Finasteride 5mg Daily, 12-months b) Prostate Volume 4 Finasteride Placebo 3 Year 2 Figure 3.2: Finasteride 5mg daily, b) Prostate Volume Adapted from McConnell JD, et al. NEJM 1998;338(9):557-63 Compared to placebo, 5α-reductase inhibitors significantly decrease prostate volume. This prostate volume reduction is durable as long as the patient stays on the 5α-reductase inhibitor. 1 -25 -20 -15 -10 -5 5 10 15 Mean Change (%) Adapted from McConnell JD, et al. NEJM 1998;338(9):557-63 Understanding Concepts in BPH: From the Science to the Clinical Setting

Figure 3.2 Finasteride 5mg Daily, 12-months c) Maximal Urinary Flow Rate 0.5 1 1.5 2 2.5 3 4 Year Finasteride Placebo Figure 3.2: Finasteride 5mg daily, c) Maximum Urinary Flow Rate Adapted from McConnell JD, et al. NEJM 1998;338(9):557-63 The 5α-reductase inhibitor Finasteride results in clinically significant improvement in maximal urinary flow rate compared to placebo. Mean Change (mL/sec) Adapted from McConnell JD, et al. NEJM 1998;338(9):557-63 Understanding Concepts in BPH: From the Science to the Clinical Setting

Long-term clinical trials have shown that, due to the progressive nature of BPH, 5α-reductase inhibitors can prevent BPH-related complications, such as acute urinary retention and the need for surgery25 Long-term clinical trials have shown that, due to the progressive nature of BPH related to progressive prostate growth, 5α-reductase inhibitors can prevent BPH-related complications, such as acute urinary retention and the need for surgery.25 25. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): 25. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Currently, two 5α-reductase inhibitors are available: finasteride and dutasteride Finasteride specifically blocks 5α-reductase type II, whereas dutasteride blocks both isoforms Randomized clinical trials have shown that both agents have similar efficacy in reducing prostatic size and preventing disease progression Both produce similar improvements in AUA symptom scores/IPSS and urinary flow rates. They have a similar safety profile 26 The side effects of each agent will be discussed in the following sections Currently, two 5 α -reductase inhibitors are available: finasteride and dutasteride. Finasteride specifically blocks 5α-reductase type II, whereas dutasteride blocks both isoforms. Randomized clinical trials have shown that both agents have similar efficacy in reducing prostatic size and preventing disease progression. Both produce similar improvements in AUA symptom scores and urinary flow rates. They have a similar safety profile.26 The side effects of each agent will be discussed in the following sections. 26. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): 26. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol AUA = American Urological Association IPSS = International Prostate Symptom Score Understanding Concepts in BPH: From the Science to the Clinical Setting

Table 3.3 Clinical Efficacy of 5-Reductase Inhibitors is Similar* Finasteride** 48-Mo Controlled Trial in 3,040 Men Dutasteride*** 24-Mo Controlled Trial in 4,325 Men Finasteride Placebo Dutasteride Volume changes -18% +14% -26% -2% IPSS reduction -3.3 -1.3 -4.5 -2.3 Qmax improvement (mL/sec) +1.9 +0.2 +2.2 +0.6 AUR risk reduction 57% Surgery risk reduction 55% 48% Table 3.3: Clinical Efficacy of 5α-reductase Inhibitors is Similar McConnell JD et al. NEJM. 1998;338: Roehrborn C et al. Urology. 2002;60: This chart compares the clinical efficacy of the two 5α-reductase inhibitors. Compared to placebo, both agents result in similar volume, symptom and flow rate changes as well as risk reduction in terms of acute urinary retention and future surgery. *Not from a comparative trial. ** McConnell JD et al. NEJM. 1998;338: *** Roehrborn C et al. Urology. 2002;60: AUR = Acute Urinary Retention; IPSS = International Prostate Symptom Score Understanding Concepts in BPH: From the Science to the Clinical Setting

Table 3.4(a) Adverse Events of 5α-Reductase Inhibitors Are Similar* Finasteride** Placebo Year 1 (% of Patients) Years (% of Patients) Erectile dysfunction 8.1 5.1 3.7 Altered libido 6.4 2.6 3.4 Ejaculatory disorder 0.8 0.2 0.1 Gynecomastia and breast tenderness 0.4 0.7 0.3 Table 3.4(a): Adverse Events of 5α-reductase Inhibitors is Similar McConnell JD et al. NEJM. 1998;338: This table describes the adverse events associated with 5α-reductase inhibitor Finasteride. Note that the differences between Finasteride and Placebo are only evident at year 1. Erectile dysfunction, altered libido and ejaculatory disorder did not appear to occur in higher incidence after year 1 in treated patients compared to placebo. *Not from a comparative trial. ** McConnell JD et al. NEJM. 1998;338: Understanding Concepts in BPH: From the Science to the Clinical Setting

Table 3.4(b) Adverse Events of 5-Reductase Inhibitors Are Similar* Dutasteride*** Placebo Month 0-6 (% of Patients) Month (% of Patients) Month (% of Patients) Month (% of Patients) Erectile dysfunction Altered libido Ejaculatory disorder Gynecomastia and breast tenderness Table 3.4(b): Adverse Events of 5α-reductase Inhibitors is Similar Roehrborn C et al. Urology. 2002;60: This table describes the adverse events of the 5α-reductase inhibitor Dutasteride. Note that there is a similar occurance of erectile dysfunction, altered libido and ejaculatory disorder noted with Finasteride and also that the side effects appear to occur at least compared to placebo in the first year of therapy. *Not from a comparative trial. *** Roehrborn C et al. Urology. 2002;60: Understanding Concepts in BPH: From the Science to the Clinical Setting

5α-Reductase Inhibitors (5 ARIs) Are Similarly Effective in Treating BPH Both 5 ARIs (finasteride and dutasteride) have similar efficacy and safety profiles They improve symptoms and flow rate and shrink prostate volume by 15-25%, onset 3-6 months They decrease the risk for acute urinary retention (AUR) and surgery Adverse events are mainly sexually related Effect in general is greater in patients with larger glands or higher PSA values Serum PSA is reduced by ~50% requiring adjustment (multiplication x 2 of PSA) after 6 months of treatment Both 5α-reductase inhibitors are similarly effective in treating BPH in terms of symptoms, flow rate, prostate size reduction and risk reduction. Adverse events are very similar and they both result in a serum PSA reduction of about 50%. PSA = Prostate-Specific Antigen Understanding Concepts in BPH: From the Science to the Clinical Setting

Single Versus Dual Inhibition
Module 3: Treatment of BPH Single Versus Dual Inhibition A comparison of data from two studies done in different populations is difficult at best, incorrect at worst However, in regards to most BPH related measures single and dual 5 AR inhibition achieve similar clinical results Current data suggests that the additional reduction of serum DHT with dual inhibition does not translate into greater clinical efficacy Intraprostatic DHT data for the 0.5 mg dutasteride dosage is not available It is difficult to compare data collected from the Finasteride trials to that collected in the Dutasteride trials. However, it is quite obvious that similar clinical results were achieved with both of these 5α-reductase inhibitors. It appears that additional reduction of serum DHT with the dual inhibition does not translate in a greater clinical efficacy. BPH = Benign Prostatic Hyperplasia DHT = Dihydrotestosterone Understanding Concepts in BPH: From the Science to the Clinical Setting

Module 3: Treatment of BPH Canadian BPH Guidelines:27 “5α-reductase inhibitors are not appropriate for men with LUTS who do not have clinical evidence of prostatic enlargement.” Canadian BPH Guidelines:27 “5α-reductase inhibitors are not appropriate for men with Lower Urinary Tract Symptoms (LUTS) who do not have clinical evidence of prostatic enlargement.” 27. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 27. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: DHT = Dihydrotestosterone LUTS = Lower Urinary Tract Symptoms Understanding Concepts in BPH: From the Science to the Clinical Setting

Finasteride Shown to reduce prostate volume by approximately 20% and improves both symptom scores and peak urine flow rate 28 After 1 year of treatment, symptom scores improve by approximately one-third and peak urine flow increases by 1.3 to 1.6 mL/second In one study, peak urine flow increased by 2.3 mL/second after 4 years of treatment with finasteride 29 The clinical effects of finasteride often become evident after 3 to 6 months of treatment, and patients with large prostates and serum PSA values >1.4ng/mL seem to derive the most benefit 30,31 Finasteride Finasteride has been shown to reduce prostate volume by approximately 20% and improves both symptom scores and peak urinary flow rate.28 After 1 year of treatment, symptom scores improve by approximately one-third and peak urine flow increases by 1.3 to 1.6 mL/second. In one study, peak urine flow increased by 2.3 mL/second after 4 years of treatment with finasteride.29 The clinical effects of finasteride often become evident after 3 to 6 months of treatment, and patients with large prostates and serum PSA values >1.4ng/mL seem to derive the most benefit. 30,31 28. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p44 29. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p44 30. McConnell JD, Bruskewitz R, Walsh P, Andriole G, 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: 31. Roehrborn CG et al for the PLESS Study Group. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. Urology 1999;53(3):473-80 28. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p44 29. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p44 30. McConnell JD et al. N Engl J Med. 1998;338: 31. Roehrborn CG et al for the PLESS Study Group. Urology 1999;53(3):473-80 PSA = Prostate-Specific Antigen Understanding Concepts in BPH: From the Science to the Clinical Setting

Figure 3.3 PLESS Design Moderate to severe symptoms of BPH, Decreased Urinary Flow Rate, Enlarged Prostate on DRE Screening PSA and prostate biopsy for patients with PSA between 4.0 to 9.9 ng/mL, symptom score, urinary flow rate, prostate volume (subset) 1-month placebo run-in period (single blind) Baseline measurements Randomization (n= 3040) Finasteride 5mg/day (n=1524) Placebo (n=1516) Visit every 4 months: BPH symptom score, urinary flow rate Outcomes (BPH-related surgery & urinary retention) and safety assessment Annual visit: Physical examination, laboratory testing Prostate volume (subset, n=157) Visit every 4 months: BPH symptom score, urinary flow rate Outcomes (BPH-related surgery & urinary retention) and safety assessment Annual visit: Physical examination, laboratory testing Prostate volume (subset, n=155) Figure 3.3: PLESS Study Design Adapted from McConnell JD et al. N Engl J Med 1998; 338(9): PLESS, the Proscar Long-Term Efficacy and Safety Study is a randomized, double-blind, placebo-controlled trial conducted over 4 years at 95 centres, which included 3040 men between the ages of 45 and 78, with enlarged prostates detected on digital rectal examination, and moderate-to-severe symptoms of benign prostatic hyperplasia. Prostate volume was assessed yearly by magnetic resonance imaging in a subset of patients. 32 32. Roehrborn CG et al for the PLESS Study Group. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. Urology 1999;53(3):473-80 4-year study Completed trial (n=1000) 4-year study Completed trial (n=883) Adapted from McConnell JD et al. N Engl J Med 1998; 338(9): BPH = Benign Prostatic Hyperplasia; DRE = Digital Rectal Examination; PLESS = Proscar Long-term Efficacy & Safety Study; PSA = Prostate-Specific Antigen Understanding Concepts in BPH: From the Science to the Clinical Setting

Figure 3.4 Effect of Finasteride on Development of AUR Through 4 years in PLESS 15 Probability of AUR (%) 1 2 3 4 6 9 12 Placebo Finasteride 5mg o.d. 57% Risk Reduction* p<0.001 Figure 3.4: Effect on AUR Adapted from McConnell JD et al. N Engl J Med 1998;338(9): In PLESS, finasteride reduced the long-term risk of acute urinary retention (AUR) in men with BPH by 57%. Finasteride decreased significantly the risk of both spontaneous and precipitated acute urinary retention.33 33. McConnell JD, Bruskewitz R, Walsh P, Andriole G, 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: Years *At year 4; 95% confidence interval: 40-69% Adapted from McConnell JD et al. N Engl J Med 1998;338(9): AUR = Acute Urinary Retention; PLESS = Proscar Long-term Efficacy and Safety Study Understanding Concepts in BPH: From the Science to the Clinical Setting

Figure 3.5 Effect of Finasteride on Development of BPH-Related Surgery Through 4 years in PLESS 15 Probability of Surgery (%) 1 2 3 4 6 9 12 Placebo Finasteride 5mg o.d. 55% Risk Reduction* p<0.001 Figure 3.5: Effect on Surgery Adapted from McConnell JD et al. N Engl J Med 1998;338(9): In PLESS, finasteride reduced the long-term risk of the need for surgery over 4 years in men with BPH by 55%. Years *At year 4; 95% confidence interval: 41-65% Adapted from McConnell JD et al. N Engl J Med 1998;338(9): AUR = Acute Urinary Retention; PLESS = Proscar Long-term Efficacy and Safety Study Understanding Concepts in BPH: From the Science to the Clinical Setting

Figure 3.6 MTOPS: Study Design
Module 3: Treatment of BPH Figure 3.6 MTOPS: Study Design Multicenter, double-blind, placebo-controlled, randomized trial Mean follow-up 4.5 years Primary study endpoint: Overall clinical progression* of BPH Men ≥ 50 years of age AUA symptom score 8-30 points** Qmax*** 4-15mL/s Voided volume ≥ 125mL Entry Criteria: Randomized (n=3047) Figure 3.6: MTOPS Study Design Adapted from McConnell JD et al. N Engl J Med 2003;349: The landmark Medical Therapy of Prostatic Symptoms trial or MTOPS is a randomized, double-blind, placebo-controlled study conducted at 17 centres, which included 3047 men at least 50 years of age who had an AUA symptom score of 8 to 35 during the pilot phase and 8 to 30 during the full-scale study and a maximal urinary flow rate between 4 and 15 mL per second, with a voided volume of at least 125 mL. Patients were randomized to receive one of the following: comparing placebo (n=737), doxazosin 4 mg or 8 mg once daily (o.d.) after titration (n=756), finasteride 5 mg o.d. (n=768) or combination therapy, finasteride and doxazosin (n=786) at the same dosage.34 34. PROSCAR Product Monograph. Merck Frosst Canada & Co. 2004 Placebo (n=737) Doxazosin† 4mg or 8mg o.d. (n=756) Finasteride 5mg o.d. (n=768) Combination Therapy Finasteride 5mg o.d. and Doxazosin† 4mg or 8mg o.d. (n=786) *defined as an increase of ≥ 4pts over baseline in AUA symptom score, AUR, urinary incontinence, renal insufficiency, or recurrent urinary tract infection. **8-35 points during pilot phase, *** Qmax=maximal urinary flow rate †Participants were titrated upto 8mg. Those not able to tolerate 8mg received 4mg. Those not able to tolerate either dosage were counted as having discontinued doxazosin. MTOPS=Medical Therapy of Prostatic Symptoms Trial Adapted from McConnell JD et al. N Engl J Med 2003;349: Understanding Concepts in BPH: From the Science to the Clinical Setting

MTOPS The primary outcome defined was overall clinical progression of BPH DRE, measurements of serum PSA and urinalysis were performed annually Prostate volume was assessed by transrectal ultrasonography, once at baseline and at the end of Year 5 or at the end of the study follow- up, whichever came first Mean follow-up was 4.5 years in the full-scale study and 6.0 years in the pilot phase 35 The primary outcome defined was overall clinical progression of BPH. Digital rectal examination, measurements of serum prostate-specific antigen (PSA) and urinalysis were performed annually. Prostate volume was assessed by transrectal ultrasonography, once at baseline and at the end of Year 5 or at the end of the study follow-up, whichever came first. Mean follow-up was 4.5 years in the full-scale study and 6.0 years in the pilot phase.35 35. PROSCAR Product Monograph. Merck Frosst Canada & Co. 2004 35. PROSCAR Product Monograph. Merck Frosst Canada & Co MTOPS = Medical Therapy of Prostatic Symptoms; DRE = Digital Rectal Examination; PSA = Prostate-Specific Antigen Understanding Concepts in BPH: From the Science to the Clinical Setting

Figure 3.7 MTOPS: Reduction in Risk of AUR
Module 3: Treatment of BPH Figure 3.7 MTOPS: Reduction in Risk of AUR Cumulative Incidence of †AUR over a mean follow-up of 4.5 years 3.0 68*% 81**% Combination Therapy (Finasteride 5 mg o.d + Doxozosin 4mg or 8mg o.d) Placebo Doxazosin (doubled each week beginning at 1mg o.d until 4mg or 8mg o.d) 2.5 2.0 Finasteride (5mg o.d) Cumulative Incidence of Acute Urinary Retention (%) 1.5 1.0 *Risk Reduction: Finasteride vs. Placebo (0.2 vs 0.6 events/100 person-years, p=0.009) **Risk Reduction: Combination Therapy vs. Placebo (0.1 vs 0.6 events/100 person-years, p<0.001) Figures 3.7: MTOPS Reduction in Risk of AUR Adapted from McConnell JD et al. N Engl J Med 2003; 349: MTOPS found that finasteride, either alone or in combination with doxazosin, significantly reduced the long-term risk of acute urinary retention (AUR) over a mean follow-up of 4.5 years in 3047 men with BPH.36 36. Roehrborn CG et al for the PLESS Study Group. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. Urology 1999;53(3):473-80 0.5 YEARS 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 Table of values (Number of Men at Risk) Follows †Defined as the inability to void (AUR in men with an obvious precipitating cause, such as anesthesia, was included as a primary outcome only after a voiding trial without a catheter was unsuccessful). Adapted from McConnell JD et al. N Engl J Med 2003; 349: Understanding Concepts in BPH: From the Science to the Clinical Setting

Figure 3.8 MTOPS: Reduction in Need for Invasive Therapy
Module 3: Treatment of BPH Figure 3.8 MTOPS: Reduction in Need for Invasive Therapy Cumulative Incidence of BPH Invasive Therapy† over a mean follow-up of 4.5 years 8 Combination Therapy (Finasteride 5 mg o.d + Doxozosin 4mg or 8mg o.d) Placebo Doxazosin (doubled each week beginning at 1mg o.d until 4mg or 8mg o.d) 6 Finasteride (5mg o.d) 64*% 67**% Cumulative Incidence of Invasive Therapy (%) 4 2 Figures 3.8: MTOPS Reduction in Need for Invasive Therapy Adapted from McConnell JD et al. N Engl J Med 2003; 349: MTOPS found that finasteride, either alone or in combination with doxazosin, significantly reduced the need for surgery over a mean follow-up of 4.5 years in 3047 men with BPH.37 37. Roehrborn CG et al for the PLESS Study Group. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. Urology 1999;53(3):473-80 *Risk Reduction: Finasteride vs. Placebo (0.5 vs 1.3 events/100 person-years, p<0.001) **Risk Reduction: Combination Therapy vs. Placebo (0.3 vs 1.3 events/100 person-years, p<0.001) YEARS 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 Table of values (Number of Men at Risk) Follows †Invasive Therapy: Transurethral prostatectomy, transurethral incision of the prostate, laser therapy, stenting, open prostatectomy, and transurethral microwave therapy. Adapted from McConnell JD et al. N Engl J Med 2003; 349: Understanding Concepts in BPH: From the Science to the Clinical Setting

Figure 3.9 MTOPS: Reduction in AUA Symptom Scores
Module 3: Treatment of BPH Figure 3.9 MTOPS: Reduction in AUA Symptom Scores Mean Reduction in AUA Symptom Score from Baseline at Year 4 p=0.001 p<0.001 p=0.006 -2 -4 -6 -8 -4.9 -5.6 -6.6 -7.4 Mean Change from Baseline Placebo Finasteride 5mg o.d.* Doxazosin 4mg to 8mg o.d.* Figure 3.9: AUA Symptom Scores Adapted from McConnell JD et al. N Engl J Med 2003; 349: Finasteride significantly lowered the risk of clinical progression, defined as a 4-point increase on the AUA symptom score, and significantly improved AUA symptom scores versus placebo over the study period. Combination Therapy** *Once Daily **Finasteride 5mg & Doxazosin 4mg to 8mg o.d. MTOPS=Medical Therapy of Prostatic Symptoms Study; AUA = American Urological Association Adapted from McConnell JD et al. N Engl J Med 2003; 349: Understanding Concepts in BPH: From the Science to the Clinical Setting

There is no evidence of increased adverse experiences with increased duration of treatment with finasteride. The incidence of new drug related sexual adverse experiences decreased with duration of treatment 38 There is no evidence of increased adverse experiences with increased duration of treatment with finasteride. The incidence of new drug related sexual adverse experiences decreased with duration of treatment.38 38. PROSCAR Product Monograph. Merck Frosst Canada & Co. 2004 38. PROSCAR Product Monograph. Merck Frosst Canada & Co. 2004 Understanding Concepts in BPH: From the Science to the Clinical Setting

Dutasteride Due to its dual inhibition of both isoforms of 5α-reductase enzyme, dutasteride exhibits greater suppression of DHT than finasteride. 39 However, the clinical relevance of this is unknown In three 2-year, placebo-controlled studies (n=4325), dutasteride achieved a statistically significant improvement in symptom scores and urine flow, compared to placebo. 40 Men with larger prostate volumes benefited most Dutasteride Due to its dual inhibition of both isoforms of 5α-reductase enzyme, dutasteride exhibits greater suppression of serum DHT than finasteride.39 However, the clinical relevance of this is unknown. In three 2-year, placebo-controlled studies (n=4325), dutasteride achieved a statistically significant improvement in symptom scores and urine flow, compared to placebo.40 Men with larger prostate volumes benefited most. 39. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th Ed. Oxford: Health Press, 2005, p46 40. AVODART® Product Monograph. GlaxoSmithKline 2003 DHT = Dihyrdotestosterone 39. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. Fifth edition. Oxford: Health Press, 2005, p46 40. AVODART® Product Monograph. GlaxoSmithKline 2003 Understanding Concepts in BPH: From the Science to the Clinical Setting

Dutasteride Dutasteride has also been shown to reduce the BPH-related risks of acute urinary retention and need for surgery by 48 and 57%, respectively 41 The incidence of impotence, decreased libido, and ejaculatory disorders with dutasteride is similar to finasteride. In clinical trials, breast enlargement and nipple tenderness occured in 1 to 1.9% of patients each year 42 Dutasteride has also been shown to reduce the BPH-related risks of acute urinary retention and need for surgery by 48 and 57%, respectively.41 The incidence of impotence, decreased libido, and ejaculatory disorders with dutasteride is similar to finasteride. In clinical trials, breast enlargement and nipple tenderness occured in 1 to 1.9% of patients each year.42 41. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th Ed. Oxford: Health Press, 2005, p46 42. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th Ed. Oxford: Health Press, 2005, p46 41. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. Fifth edition. Oxford: Health Press, 2005, p46 42. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. Fifth edition. Oxford: Health Press, 2005, p46 BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Combination Therapy There is a strong rationale for combining drugs with different mechanisms to treat a single disease For example, bronchodilators and inhaled steroids are often used together to treat asthma, and coronary heart disease is commonly treated with drugs that lower cholesterol, inhibit angiotensin II, decrease blood pressure, and increase high-density lipoprotein cholesterol This rationale has also proven to be valid for treating BPH Combination Therapy There is a strong rationale for combining drugs with different mechanisms to treat a single disease. For example, bronchodilators and inhaled steroids are often used together to treat asthma, and coronary heart disease is commonly treated with drugs that lower cholesterol, inhibit angiotensin II, decrease blood pressure, and increase high-density lipoprotein cholesterol. This rationale has also proven to be valid for treating BPH. BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

The 5-year MTOPS study demonstrated that the combination of an α1-receptor blocker (doxazosin) and a 5α-reductase inhibitor (finasteride) was more effective than either drug alone in delaying the clinical progression of BPH and improving LUTS and flow rate 43 The 5-year MTOPS study demonstrated that the combination of an α1-receptor blocker (doxazosin) and a 5α-reductase inhibitor (finasteride) was more effective than either drug alone in delaying the clinical progression of BPH and improving LUTS and flow rate.43 43. McConnell JD, Roehrborn CG, Bautista OM, 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: McConnell JD et al. N Engl J Med. 2003;349: MTOPS = Medical Therapy of Prostatic Symptoms; BPH = Benign Prostatic Hyperplasia; LUTS = Lower Urinary Tract Symptoms Understanding Concepts in BPH: From the Science to the Clinical Setting

Figure 3.8 MTOPS: Reduction in Need for Invasive Therapy
Module 3: Treatment of BPH Figure 3.8 MTOPS: Reduction in Need for Invasive Therapy Cumulative Incidence of BPH Invasive Therapy† over a mean follow-up of 4.5 years 8 Combination Therapy (Finasteride 5 mg o.d + Doxazosin 4mg or 8mg o.d) Placebo Doxazosin (doubled each week beginning at 1mg o.d until 4mg or 8mg o.d) 6 Finasteride (5mg o.d) 64*% 67**% Cumulative Incidence of Invasive Therapy (%) 4 2 Figures 3.8: MTOPS Reduction in Need for Invasive Therapy Adapted from McConnell JD et al. N Engl J Med 2003; 349: Although doxazosin delayed the short-term progression of acute urinary retention and the need for invasive therapy, only finasteride and combination therapy demonstrated significant long-term reduction in these two risk factors. *Risk Reduction: Finasteride vs. Placebo (0.5 vs 1.3 events/100 person-years, p<0.001) **Risk Reduction: Combination Therapy vs. Placebo (0.3 vs 1.3 events/100 person-years, p<0.001) YEARS 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 Table of values (Number of Men at Risk) Follows †Invasive Therapy: Transurethral prostatectomy, transurethral incision of the prostate, laser therapy, stenting, open prostatectomy, and transurethral microwave therapy. Adapted from McConnell JD et al. N Engl J Med 2003; 349: Understanding Concepts in BPH: From the Science to the Clinical Setting

The reduction in the risk of clinical progression with combination therapy was 66% compared to placebo (p<0.001) The MTOPS study clearly shows that combination therapy is more effective than monotherapy in the long-term management of BPH Patients most likely to benefit from combination therapy are those with a significantly higher baseline risk of progression, in other words, those with larger glands and higher PSA values 44 The side effects of combination therapy reflect the combined adverse-event profiles of the α1-receptor blocker and 5α-reductase inhibitor 45 sThe reduction in the risk of clinical progression with combination therapy was 66% compared to placebo (p<0.001). The MTOPS study clearly shows that combination therapy is more effective than monotherapy in the long-term management of BPH. Patients most likely to benefit from combination therapy are those with a significantly higher baseline risk of progression, in other words, those with larger glands and higher PSA values.44 The side effects of combination therapy reflect the combined adverse-event profiles of the α1-receptor blocker and 5α-reductase inhibitor.45 44. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): 45. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): 44. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol 45. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol MTOPS = Medical Therapy of Prostatic Symptoms ; BPH = Benign Prostatic Hyperplasia; LUTS = Lower Urinary Tract Symptoms Understanding Concepts in BPH: From the Science to the Clinical Setting

Module 3: Treatment of BPH Canadian BPH Guidelines:46 “Patients successfully treated with combination therapy may be given the option of discontinuing the α1-blocker after 6-12 months. If symptoms recur, the α1-blocker should be restarted.” Canadian BPH Guidelines:46 “Patients successfully treated with combination therapy may be given the option of discontinuing the alpha-blocker after 6-12 months. If symptoms recur, the alpha-blocker should be restarted.” 46. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 46. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Phytotherapy Phytotherapeutic agents for LUTS/BPH have become increasingly popular since about 1990 First popular in Europe, they have crossed the Atlantic and become more popular in Canada than the medications discussed previously The increase in the use of herbs for treating BPH is closely correlated with the rising interest in alternative or complementary medicine seen across the continent Phytotherapy Phytotherapeutic or herbal agents for LUTS associated with BPH have become increasingly popular since about First popular in Europe, they have crossed the Atlantic and become more popular in Canada than the medications discussed above. The increase in the use of herbs for treating BPH is closely correlated with the rising interest in alternative or complementary medicine seen across the continent. LUTS = Lower Urinary Tract Symptoms; BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Indeed, an increasing number of patients are taking various over the counter preparations to treat or prevent the occurrence of prostatic conditions, on the recommendations of friends, family or even advertisements in the media Usually, they do not even consider that it is important to mention this fact to the physician at a consultation As a significant number of these plants extracts may indeed have a significant impact on the prostate, it is important that practicing physicians are aware of this fact Indeed, an increasing number of patients are taking various over the counter preparations to treat or prevent the occurrence of prostatic conditions, on the recommendations of friends, family or even advertisements in the media. Usually, they do not even consider that it is important to mention this fact to the physician at a consultation. As a significant number of these plants extracts may indeed have a significant impact on the prostate, it is important that practicing physicians are aware of this fact. Understanding Concepts in BPH: From the Science to the Clinical Setting

Table 3.5 Some Plant Extracts Used to Treat BPH
Module 3: Treatment of BPH Table 3.5 Some Plant Extracts Used to Treat BPH Species Common Name Serenoa repens, Sabal serrulata Saw palmetto berry/ American dwarf palm Hypoxis rooperi South African star grass Pygeum africanum African plum tree Urtica dioica Stinging nettle Secale cereale Rye pollen Cucurbita pepo Pumpkin seed Opuntia Cactus flower Pinus Pine flower Picea Spruce Table 3.5: Some Plant Extracts Used to Treat BPH Adapted from Walsh PJ, Campbell’s Urology, 8th ed, p1368. This chart describes some of the plant extracts used to treat BPH. In Canada, the most common used are Serenoa repens or Saw palmetto berry extract and Pygeum africanum. Adapted from Walsh PJ, Campbell’s Urology, 8th ed, p1368. BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Plant extracts are complex compounds containing substances with different mechanisms of action It is poorly understood how these phytochemicals act on BPH, but the three that have received the most attention are: Anti-inflammatory effects 5α-reductase inhibition Interference with growth factor 47 Plant extracts are complex compounds containing substances with different mechanisms of action. It is poorly understood how these phytochemicals act on BPH, but the three that have received the most attention are: Anti-inflammatory effects 5α-reductase inhibition Interference with growth factor47 47. Walsh PC. Campbell’s Urology, 8th Edition (2002), p1368 47. Walsh PC. Campbell’s Urology, 8th Edition (2002), p1368 BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Serenoa repens (Saw Palmetto Berry Extract)
Module 3: Treatment of BPH Serenoa repens (Saw Palmetto Berry Extract) Received the most clinical study and is furthest along in development The anti-BPH mechanism of action of Serenoa repens is most likely 5α-reductase inhibition,48 although studies have shown evidence of other mechanisms, including:49 Inhibition of DHT binding to the androgen receptor in prostate cells Inhibition of nuclear prostatic estrogen receptors Inhibition of fibroblast growth factor-induced prostatic epithelial proliferation Anti-proliferative effects; Anti-inflammatory effects; Anti-edematous effects on prostatic tissues Noncompetitive α-adrenergic antagonism Modulation of prolactin-induced prostatic growth by receptor signal transduction Serenoa repens (Saw Palmetto Berry Extract) Of the many plants used to treat BPH, Serenoa repens, an extract from the Saw Palmetto berry, has received the most clinical study and is furthest along in development. The most likely anti-BPH mechanism of action of Serenoa repens is 5α-reductase inhibition,48 although studies have shown evidence of other mechanisms, including: inhibition of DHT binding to the androgen receptor in prostate cells, antiproliferative effects, inhibition of nuclear prostatic estrogen receptors, noncompetitive α-adrenergic antagonism, anti-inflammatory effects, inhibition of fibroblast growth factor-induced prostatic epithelial proliferation, antiedematous effects on prostatic tissues, and modulation of prolactin-induced prostatic growth by receptor signal transduction.49 48. Fong YK, Milani S, Djavan B. Role of phytotherapy in men with lower urinary tract symptoms. Curr Opin Urol 2005;15:45-48. 49. Fong YK, Milani S, Djavan B. Role of phytotherapy in men with lower urinary tract symptoms. Curr Opin Urol 2005;15:45-48, p45-6 48. Fong YK, Milani S, Djavan B. Curr Opin Urol 2005;15:45-48. 49. Fong YK, Milani S, Djavan B. Curr Opin Urol 2005;15:45-48, p45-6 BPH = Benign Prostatic Hyperplasia; DHT = Dihydrotestosterone Understanding Concepts in BPH: From the Science to the Clinical Setting

In a properly designed randomized placebo controlled trial, Serenoa repens was found to be only slightly better than placebo in ameliorating symptoms, improving flow rate and decreasing prostate volume 50 In a properly designed randomized placebo controlled trial, Serenoa repens was found to be only slightly better than placebo in ameliorating symptoms, improving flow rate and decreasing prostate volume.50 50. Bent S, Kane CJ, Shinohara K, Goldberg H, Newhaus J et al. A randomized controlled trial of saw palmetto for the treatment of benign prostatic hyperplasia. J Urol 173(Suppl 4):443 Abstract # 1637 50. Bent S et al. J Urol 173(Suppl 4):443 Abstract # 1637 Understanding Concepts in BPH: From the Science to the Clinical Setting

Pygeum africanum (African Plum Tree)
Module 3: Treatment of BPH Pygeum africanum (African Plum Tree) Extract used since the mid-1960s to treat men suffering from BPH and currently the most commonly used medicine in France for BPH 51 Mechanism of action is unclear, but has been shown in animal studies to modulate bladder contractility by reducing the sensitivity of the bladder to electrochemical stimulation 52 Pygeum africanum (African Plum Tree) Pygeum africanum, an extract from the inner bark of the African plum tree, has been used since the mid-1960s to treat men suffering from BPH and currently, Pygeum is the most commonly used medicine in France for BPH.51 Although its mechanism of action is unclear, Pygeum africanum has been shown in animal studies to modulate bladder contractility by reducing the sensitivity of the bladder to electrochemical stimulation.52 51. Pygeum africanum (Prunus africanus) (African plum tree). Monograph. Altern Med Rev 2002;7:71-4. 52. Pygeum africanum (Prunus africanus) (African plum tree). Monograph. Altern Med Rev 2002;7:71 51. Pygeum africanum (Prunus africanus) (African plum tree). Monograph. Altern Med Rev 2002;7:71-4. 52. Monograph, p71 BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Also demonstrated to have: 53 Anti-inflammatory activity Inhibit fibroblast production Increase adrenal androgen secretion Restore the activity of the prostate and bulbourethral epithelium Several small clinical studies have been conducted, but they are inconclusive and more research is needed before it can be considered as standard treatment 54 Pygeum has also been demonstrated to have anti-inflammatory activity, to inhibit fibroblast production, to increase adrenal androgen secretion, and to restore the activity of the prostate and bulbourethral epithelium.53 Although several clinical studies have been conducted on Pygeum africanum, they have been small and inconclusive and more research is needed before it can be considered as a standard treatment for BPH.54 53. Pygeum africanum (Prunus africanus) (African plum tree). Monograph. Altern Med Rev 2002;7:71 54. Nickel JC, Herschorn S, Corcos J, et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 53. Monograph, p71 54. Nickel JC, Herschorn S, Corcos J, et al. Can J Urol 2005;12: Understanding Concepts in BPH: From the Science to the Clinical Setting

Module 3: Treatment of BPH Canadian BPH Guidelines:55 “If patients are interested in complementary approaches (phytotherapeutic or other supplements) for LUTS secondary to BPH, they may be counseled that some plant extracts (particularly saw palmetto berry extract and pygeum Africanum) have shown some efficacy in small but unconvincing studies. Further proof is required before phytotherapy can be recommended as standard therapy; however, these agents do appear to be safe.” Canadian BPH Guidelines:55 “If patients are interested in complementary approaches (phytotherapeutic or other supplements) for lower urinary tract symptoms (LUTS) secondary to BPH, they may be counseled that some plant extracts (particularly saw palmetto berry extract and pygeum Africanum) have shown some efficacy in small but unconvincing studies. Further proof is required before phytotherapy can be recommended as standard therapy; however, these agents do appear to be safe.” 55. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 55. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: LUTS = Lower Urinary Tract Symptoms; BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

3.6 Minimally Invasive Surgical Therapies
Module 3: Treatment of BPH 3.6 Minimally Invasive Surgical Therapies The number of MIST for BPH has grown substantially over the last two decades, paralleling technological innovations in other medical spheres This is an area where experimentation is rich with possibility, but clinical evidence is often inadequate to support the inclusion of such procedures in the treatment recommendations of national and international guidelines Over the years, MIST have fallen in and out of favour as further evidence of their safety and efficacy has emerged from clinical data 3.6 Minimally Invasive Surgical Therapies The number of minimally invasive surgical therapies (MIST) for BPH has grown substantially over the last two decades, paralleling technological innovations in other medical spheres. This is an area where experimentation is rich with possibility, but clinical evidence is often inadequate to support the inclusion of such procedures in the treatment recommendations of national and international guidelines. Over the years, MIST have fallen in and out of favour as further evidence of their safety and efficacy has emerged from clinical data. MIST = Minimally Invasive Surgical Therapies; BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

At present, only three MIST are recommended for treatment of BPH in Canada: 56 Transurethral microwave therapy (TUMT) Transurethral needle ablation of the prostate (TUNA) Prostatic stents At present, only three MIST are recommended for treatment of BPH in Canada:56 1. Transurethral microwave therapy (TUMT) 2. Transurethral needle ablation of the prostate (TUNA) 3. Prostatic stents 56. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 56. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: Understanding Concepts in BPH: From the Science to the Clinical Setting

Transurethral Microwave Thermotherapy
Module 3: Treatment of BPH Transurethral Microwave Thermotherapy Transurethral microwave thermotherapy (TUMT) is one of a group of thermal-based therapies designed to produce coagulation necrosis of the prostate through the application of high temperatures Several TUMT devices are currently available, although there is no data to suggest superiority of one device over another 57 Evidence shows that for the average patient, TUMT is more effective than medical therapy but less effective than surgery in relieving symptoms. Transurethral Microwave Thermotherapy Transurethral microwave thermotherapy (TUMT) is one of a group of thermal-based therapies designed to produce coagulation necrosis of the prostate through the application of high temperatures. Several TUMT devices are currently available, although there is no data to suggest superiority of one device over another.57 Evidence shows that for the average patient, TUMT is more effective than medical therapy but less effective than surgery in relieving symptoms. 57. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): p537 57. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol Understanding Concepts in BPH: From the Science to the Clinical Setting

Module 3: Treatment of BPH Canadian BPH Guidelines:58 “TUMT is a reasonable treatment choice for the patient who has moderate symptoms, small to moderate gland size, and a desire to avoid more invasive therapy for potentially less effective results.” Canadian BPH Guidelines: 58 “TUMT is a reasonable treatment choice for the patient who has moderate symptoms, small to moderate gland size, and a desire to avoid more invasive therapy for potentially less effective results.” 58. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 58. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Transurethral Needle Ablation
Module 3: Treatment of BPH Transurethral Needle Ablation Transurethral needle ablation (TUNA) involves the use of radio frequency (RF) waves (490 KHz) to heat and coagulate hyperplastic prostatic tissue The RF waves are transmitted through two 18-gauge needles at the tip of a TUNA catheter, which contains a lens to visually guide placement in the urethra After advancing into the prostate parenchyma through the urethra, tissue in the lateral prostatic lobes is heated to 100ºC Transurethral Needle Ablation Transurethral needle ablation (TUNA) involves the use of radio frequency (RF) waves (490 KHz) to heat and coagulate hyperplastic prostatic tissue. The RF waves are transmitted through two 18-gauge needles at the tip of a TUNA catheter, which contains a lens to visually guide placement in the urethra. After advancing into the prostate parenchyma through the urethra, tissue in the lateral prostatic lobes is heated to 100ºC. Understanding Concepts in BPH: From the Science to the Clinical Setting

According to AUA guidelines, the ideal patient for TUNA is a man who has obstructive BPH, i.e., a prostate of ≤ 60 grams with predominantly lateral lobe enlargement 59 The Canadian guidelines recommend TUNA as a reasonable option for the relief of symptoms in younger, active men in whom sexual function remains an important quality-of-life issue (less risk of retrograde ejaculation). Limited data are available on long-term outcomes 60 According to AUA guidelines, the ideal patient for this procedure is a man who has obstructive BPH, i.e., a prostate of ≤60 grams with predominantly lateral lobe enlargement.59 The Canadian guidelines recommend TUNA as a reasonable option for the relief of symptoms in younger, active men in whom sexual function remains an important quality-of-life issue (less risk of retrograde ejaculation). Limited data are available on long-term outcomes.60 59. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): p537 60. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 59. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol 60. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: AUA = American Urological Association ; TUNA = Transurethral Needle Ablation; BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Canadian BPH Guidelines: 61
Module 3: Treatment of BPH Canadian BPH Guidelines: 61 “TUNA may be a reasonable option for the relief of symptoms in the younger, active individual in whom sexual function remains an important quality of life issue (less risk of retrograde ejaculation). Limited data is available on long-term outcomes.” Canadian BPH Guidelines: 61 “TUNA may be a reasonable option for the relief of symptoms in the younger, active individual in whom sexual function remains an important quality of life issue (less risk of retrograde ejaculation). Limited data is available on long-term outcomes.” 61. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 61. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: TUNA = Transurethral Needle Ablation; BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Prostatic Stents Metal or polyurethane stents may be placed into the prostatic urethra where, when expanded, they mechanically relieve the obstruction from the surrounding hyperplastic prostatic tissue Over a period of weeks to a few months, the permanent stents could become covered with normal transitional epithelial tissue Temporary stents are also available but the problem of migration is a significant issue 62 Prostatic Stents Metal or polyurethane stents may be placed into the prostatic urethra where, when expanded, they mechanically relieve the obstruction from the surrounding hyperplastic prostatic tissue. Over a period of weeks to a few months, the permanent stents could become covered with normal transitional epithelial tissue. Temporary stents are also available but the problem of migration is a significant issue.62 62. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): 62. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol. 2003;170(2 Pt 1): Understanding Concepts in BPH: From the Science to the Clinical Setting

Module 3: Treatment of BPH Canadian BPH Guidelines: 63 “Temporary and permanent stents may be considered for patients with severe urinary obstruction secondary to BPH who are medically unfit for surgery (or waiting to become medically fit for surgery or MIST). Stents are not recommended as standard therapy for LUTS associated with BPH.” Canadian BPH Guidelines: 63 “Temporary and permanent stents may be considered for patients with severe urinary obstruction secondary to BPH who are medically unfit for surgery (or waiting to become medically fit for surgery or MIST). Stents are not recommended as standard therapy for lower urinary tract symptoms (LUTS) associated with BPH.” 63. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 63. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: MIST = Minimally Invasive Surgical Therapies LUTS = Lower Urinary Tract Symptoms BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

3.7 Surgery Surgical intervention is the appropriate treatment for patients with refractory or recurrent AUR or BPH-related complications (hematuria, stones, infection, obstructive renal failure) Surgery is also recommended for patients who have moderate-to- severe LUTS and are either inadequately controlled by medical therapy or who opt for a more definitive treatment 64 3.7 Surgery Surgical intervention is the appropriate treatment for patients with refractory or recurrent acute urinary retention (AUR) or BPH-related complications (hematuria, stones, infection, obstructive renal failure). Surgery is also recommended for patients who have moderate-to-severe lower urinary tract symptoms (LUTS) and are either inadequately controlled by medical therapy or who opt for a more definitive treatment.64 64. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): p538 64. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol. 2003;170(2 Pt 1): p538 AUR = Acute Urinary Retention BPH = Benign Prostatic Hyperplasia LUTS = Lower Urinary Tract Symptoms Understanding Concepts in BPH: From the Science to the Clinical Setting

Although surgery can produce the best improvements in symptoms and flow rates, it does have a higher incidence of complications. The standard options are: Transurethral resection of the prostate (TURP) Transurethral incision of the prostate (TUIP) Open prostatectomy Although surgery can produce the best improvements in symptoms and flow rates, it does have a higher incidence of complications. The standard options are: Transurethral resection of the prostate (TURP) Transurethral incision of the prostate (TUIP) Open prostatectomy Understanding Concepts in BPH: From the Science to the Clinical Setting

Transurethral Resection of the Prostate (TURP)
Module 3: Treatment of BPH Transurethral Resection of the Prostate (TURP) The main goal of prostatic surgery is to remove the hyperplastic tissue obstructing the urethra, while minimizing damage to the surrounding tissues TURP is an endoscopic procedure that accesses this tissue through the urethra, thus avoiding the invasiveness of open surgery For many years, TURP has been considered the gold standard for the surgical treatment of BPH Transurethral Resection of the Prostate The main goal of prostatic surgery is to remove the hyperplastic tissue obstructing the urethra, while minimizing damage to the surrounding tissues. Transurethral resection of the prostate (TURP) is an endoscopic procedure that accesses this tissue through the urethra, thus avoiding the invasiveness of open surgery. For many years, TURP has been considered the gold standard for the surgical treatment of BPH. BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

After preparation, the surgeon distends the bladder with fluid in order to better visualize the prostate, bladder neck, median lobe, and bladder wall A resectoscope sheath is inserted into the urethra, through which an electrified loop is inserted into the region of the prostate Surgery consists of excision and removal of hyperplastic tissue through the urethra After preparation, the surgeon distends the bladder with fluid in order to better visualize the prostate, bladder neck, median lobe, and bladder wall. A resectoscope sheath is inserted into the urethra, through which an electrified loop is inserted into the region of the prostate. Surgery consists of excision and removal of hyperplastic tissue through the urethra. Understanding Concepts in BPH: From the Science to the Clinical Setting

Although TURP can be performed under spinal epidural or light general anesthesia, it usually requires a short hospital stay After TURP, symptoms are improved in about 70 to 90% of patients, and peak urine flows of mL/sec or more can be achieved 65 Reductions in symptom scores have been reported to be 85% with a 16 to 20% likelihood of further surgery within 8 years 66 Although TURP can be performed under spinal epidural or light general anesthesia, it usually requires a short hospital stay. After TURP, symptoms are improved in about 70 to 90% of patients, and peak urine flows of mL/sec or more can be achieved.65 Reductions in symptom scores have been reported to be 85% with a 16 to 20% likelihood of further surgery within 8 years.66 65. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p58. 66. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p58. (table) 65. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p58. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p58. (table) TURP = Transurethral Resection of the Prostate Understanding Concepts in BPH: From the Science to the Clinical Setting

Complications of TURP are not infrequent, with an overall rate of 16.1% being reported 67 Complications include: Incontinence (0.2-1%) Erectile dysfunction (2-5%) Need for further surgery to address complications (3.3%), Small but not insignificant likelihood of death within 90 days of surgery ( %) Complications of TURP are not infrequent, with an overall rate of 16.1% being reported.67They include: Incontinence (0.2-1%) Erectile dysfunction (2-5%) Need for further surgery to address complications (3.3%) A small but not insignificant likelihood of death within 90 days of surgery ( %). 67. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p58. (table) Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p58. (table) TURP = Transurethral Resection of the Prostate Understanding Concepts in BPH: From the Science to the Clinical Setting

Most common complication is retrograde ejaculation, which occurs in 70 to 90% of men. As a result of the loss of the bladder-neck sphincter mechanism, the bladder neck may fail to close during ejaculation, allowing semen to pass into the bladder instead of through the urethra 68 Another complication is the TURP syndrome, a dilutional hyponatremia that occurs when irrigant solution is absorbed into the bloodstream during the procedure 69 The most common complication is retrograde ejaculation, which occurs in 70 to 90% of men. As a result of the loss of the bladder-neck sphincter mechanism, the bladder neck may fail to close during ejaculation, allowing semen to pass into the bladder instead of through the urethra.68 Another complication is the TURP syndrome, a dilutional hyponatremia that occurs when irrigant solution is absorbed into the bloodstream during the procedure.69 68. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p59. 69. Issa MM, Young MR, Bullock AR, Bouet R, Petros JA. Dilutional hyponatremia of TURP syndrome: a historical event in the 21st Century. Urology. 2004;64: 68. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p59. 69. Issa MM et al. Urology. 2004;64: TURP = Transurethral Resection of the Prostate Understanding Concepts in BPH: From the Science to the Clinical Setting

Sexual dysfunction is thought not to be attributable to surgery in all cases but rather to a psychosomatic response or the result of aging 70 Thermal damage to the nerves near the apical tissue of the prostate could be one of the explanations 71 Sexual dysfunction is thought not to be attributable to surgery in all cases but rather to a psychosomatic response or the result of aging.70 Thermal damage to the nerves near the apical tissue of the prostate could be one of the explanations. 71 70. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p58. 71. In a conversation with Dr. Mostafa Elhilali (July 2005). 70. Kirby RS, McConnell JD. Benign Prostatic Hyperplasia. 5th ed. Oxford: Health Press, 2005, p58. 71. In a conversation with Dr. Mostafa Elhilali (July 2005). Understanding Concepts in BPH: From the Science to the Clinical Setting

Module 3: Treatment of BPH Canadian BPH Guidelines: 72 Absolute indications to recommend TURP include: Failure of medical therapy Intractable urinary retention Renal insufficiency (caused by BPO) Relative indications to recommend TURP include: Recurrent cystitis Bladder calculi Persistent prostatic bleeding Canadian BPH Guidelines: 72 Absolute indications to recommend TURP include: Failure of medical therapy Intractable urinary retention Renal insufficiency (caused by benign prostatic obstruction - BPO) Relative indications to recommend TURP include: Recurrent cystitis Bladder calculi Persistent prostatic bleeding 72. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 72. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: TURP = Transurethral Resection of the Prostate BPO = Benign Prostatic Obstruction Understanding Concepts in BPH: From the Science to the Clinical Setting

Transurethral Incision of the Prostate (TUIP)
Module 3: Treatment of BPH Transurethral Incision of the Prostate (TUIP) TUIP is an outpatient endoscopic procedure in which the surgeon makes a deep cut in the prostate from the bladder neck to the veru montanum using a Collings knife, thus relieving pressure on the urethra TUIP is limited to patients with smaller prostates (<30 grams) with an elevated bladder neck TUIP can result in levels of symptomatic improvement similar to TURP, and has the advantage of having a lower incidence of retrograde ejaculation 73 However, TUIP is associated with a slightly higher rate of secondary procedures. Transurethral Incision of the Prostate Transurethral incision of the prostate (TUIP) is an outpatient endoscopic procedure in which the surgeon makes a deep cut in the prostate from the bladder neck to the veru montanum using a Collings knife, thus relieving pressure on the urethra. TUIP is limited to patients with smaller prostates (<30 grams) with an elevated bladder neck. It can result in levels of symptomatic improvement similar to TURP, and has the advantage of having a lower incidence of retrograde ejaculation.73 However, TUIP is associated with a slightly higher rate of secondary procedures. 73. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): p538 73. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol. 2003;170(2 Pt 1): p538 TURP = Transurethral Resection of the Prostate Understanding Concepts in BPH: From the Science to the Clinical Setting

Module 3: Treatment of BPH Canadian BPH Guidelines: 74 “TUIP is appropriate surgical therapy for prostate glands less than 30 cc or grams. These patients should experience results similar to TURP with lower incidence of retrograde ejaculation than TURP.” Canadian BPH Guidelines: 74 “TUIP is appropriate surgical therapy for prostate glands less than 30 cc or grams. These patients should experience results similar to TURP with lower incidence of retrograde ejaculation than TURP.” 74. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 74. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: TUIP = Transurethral Incision of the Prostate TURP = Transurethral Resection the Prostate BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Transurethral Electrovaporization of the Prostate (TUVP)
Module 3: Treatment of BPH Transurethral Electrovaporization of the Prostate (TUVP) TUVP is a procedure which applies electrical energy to electrosurgically vaporize or remove the obstructive hyperplastic prostatic tissue The technique involves the application of a simple, specially designed, grooved rollerball electrode, which allows the surgeon to vaporize the prostatic tissue thus opening the obstructed urethral lumen The rollerball is put into the resectoscope and, using a technique similar to TURP, rolled over the hyperplastic tissue The electrical wattage is higher than that of TURP, so that the rollerball rapidly heats the tissue cells, vaporizing them into steam Transurethral Electrovaporization of the Prostate Transurethral electrovaporization of the prostate (TUVP) is a procedure which applies electrical energy to electrosurgically vaporize or remove the obstructive hyperplastic prostatic tissue. The technique involves the application of a simple, specially designed, grooved rollerball electrode, which allows the surgeon to vaporize the prostatic tissue thus opening the obstructed urethral lumen. The rollerball is put into the resectoscope and, using a technique similar to TURP, rolled over the hyperplastic tissue. The electrical wattage is higher than that of TURP, so that the rollerball rapidly heats the tissue cells, vaporizing them into steam. TURP = Transurethral Resection of the Prostate Understanding Concepts in BPH: From the Science to the Clinical Setting

One advantage of this technique is the reduction of bleeding due to the cauterization of tissues surrounding the ablated region 75 Laser therapy, which operates on a similar principle, is discussed later Compared to TURP, TUVP results in equivalent, short-term improvements in symptom severity scores, urinary flow rate, and quality of life However, there is a higher incidence of postoperative irritative voiding symptoms, dysuria, urinary retention, and the need for unplanned secondary catheterization 76 One advantage of this technique is the reduction of bleeding due to the cauterization of tissues surrounding the ablated region.75 Laser therapy, which operates on a similar principle, is discussed later. Compared to TURP, TUVP results in equivalent, short-term improvements in symptom severity scores, urinary flow rate, and quality of life. However, there is a higher incidence of postoperative irritative voiding symptoms, dysuria, urinary retention, and the need for unplanned secondary catheterization.76 75. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): p538 76. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): p538 75. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol. 2003;170(2 Pt 1): p538 76. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol. 2003;170(2 Pt 1): p538 TURP = Transurethral Resection of the Prostate TUVP = Transurethral Electrovaporization of the Prostate Understanding Concepts in BPH: From the Science to the Clinical Setting

Module 3: Treatment of BPH Canadian BPH Guidelines: 77 “TUVP is an alternative operation to TURP or TUIP and short-term results are comparable to TURP, particularly in men with small prostates. Patients experience higher incidence of irritative symptoms, dysuria, and urinary retention and few long-term studies are available.” Canadian BPH Guidelines: 77 “TUVP is an alternative operation to TURP or TUIP and short-term results are comparable to TURP, particularly in men with small prostates. Patients experience higher incidence of irritative symptoms, dysuria, and urinary retention and few long-term studies are available.” 77. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: 77. Nickel JC et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol 2005;12: TUVP = Transurethral Electrovaporization of the Prostate TURP = Transurethral Resection of the Prostate TUIP = Transurethral Incision of the Prostate BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Laser Prostatectomy Laser energy is used to produce coagulation necrosis, tissue vaporization, or tissue resection A variety of lasers (KTP, Holmium:YAG) and delivery systems (end- firing, side-firing, interstitial) are available for prostatic tissue coagulation or ablation Investigators of laser systems do not agree on the optimal technique or energy delivery. Each offers particular features and potential benefits In Canada, the two most popular lasers used are the KTP and Holmium lasers Laser Prostatectomy Laser energy is used to produce coagulation necrosis, tissue vaporization, or tissue resection. A variety of lasers (KTP, Holmium:YAG) and delivery systems (end-firing, side-firing, interstitial) are available for prostatic tissue coagulation or ablation. Investigators of laser systems do not agree on the optimal technique or energy delivery. Each offers particular features and potential benefits. In Canada, the two most popular lasers used are the KTP and Holmium lasers. Understanding Concepts in BPH: From the Science to the Clinical Setting

The Holmium laser enucleation of the prostate (HoLEP) procedure may require a steep learning curve, however, other techniques like Holmium laser ablation of the prostate (HoLAP) and KTP laser or photoselective vaporization of the prostate (PVP) are very easy to learn Holmium laser enucleation of the prostate is the only laser technology to date that has had its efficacy documented in randomized trials against TURP and open prostatectomy 78 The Holmium laser enucleation of the prostate (HoLEP) procedure may require a steep learning curve, however, other techniques like Holmium laser ablation of the prostate (HoLAP) and KTP laser or photoselective vaporization of the prostate (PVP) are very easy to learn. Holmium laser enucleation of the prostate is the only laser technology to date that has had its efficacy documented in randomized trials against TURP and open prostatectomy. 78 78. In a conversation with Dr. Mostafa Elhilali (July 2005). 78. In a conversation with Dr. Mostafa Elhilali (July 2005). TURP = Transurethral Resection of the Prostate Understanding Concepts in BPH: From the Science to the Clinical Setting

Transurethral Laser Vaporization (TLV)
Module 3: Treatment of BPH Transurethral Laser Vaporization (TLV) TLV uses laser energy to vaporize prostatic tissue The laser fibre is held in contact with hyperplastic tissue to carve a series of furrows, until a wide channel is obtained Like TUVP, TLV leads to short-term improvement in symptom scores, urinary flow rate, and QoL indices comparable to TURP However, the incidence of postoperative urinary retention and the need for unplanned secondary catheterization with TLV are higher than that observed with TURP 79 Transurethral Laser Vaporization Transurethral laser vaporization (TLV) uses laser energy to vaporize prostatic tissue. In TLV, the laser fibre is held in contact with hyperplastic tissue to carve a series of furrows, until a wide channel is obtained. Like TUVP, TLV leads to short-term improvement in symptom scores, urinary flow rate, and quality-of-life indices comparable to TURP. However, the incidence of postoperative urinary retention and the need for unplanned secondary catheterization with TLV are higher than that observed with TURP.79 79. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): p539 79. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol. 2003;170(2 Pt 1): p539 TUVP = Transurethral Electrovaporization of the Prostate TURP = Transurethral Resection of the Prostate QoL = Quality of Life Understanding Concepts in BPH: From the Science to the Clinical Setting

Transurethral Holmium Laser Resection/Enucleation of the Prostate (HoLEP) HoLEP is a relatively new technique in which the prostate hyperplastic tissue is resected using a holium laser fibre and a specially adapted resectoscope 80 Studies by Gilling and colleagues suggest that in the intermediate- term, symptomatic improvement obtained after holmium laser treatment is similar to that of TURP, with a lowered risk of bleeding and need for blood transfusion 81,82 Transurethral Holmium Laser Resection/Enucleation of the Prostate (HoLEP) Transurethral holmium laser resection/enucleation of the prostate (HoLEP) is a relatively new technique in which the prostate hyperplastic tissue is resected using a holium laser fibre and a specially adapted resectoscope.80 Studies by Gilling and colleagues suggest that the intermediate-term, symptomatic improvement obtained after holmium laser treatment is similar to that of TURP, with a lowered risk of bleeding and need for blood transfusion.81,82 80. Gilling PJ, Cass CB, Cresswell MD, Fraundorfer MR. Holmium laser resection of the prostate: preliminary results of a new method for the treatment of benign prostatic hyperplasia. Urology 1996;47:48-51. 81. Gilling PJ, Cass CB, Cresswell MD, Fraundorfer MR. Holmium laser resection of the prostate: preliminary results of a new method for the treatment of benign prostatic hyperplasia. Urology 1996;47:48-51. 82. Gilling PJ, Mackey M, Cresswell M, et al. Holmium laser versus transurethral resection of the prostate: a randomized prospective trial with 1-year followup. J Urol 1999;162: 80. Gilling PJ et al. Urology 1996;47:48-51. 81. Gilling PJ et al. Urology 1996;47:48-51. 82. Gilling PJ et al. J Urol 1999;162: TURP = Transurethral Resection of the Prostate Understanding Concepts in BPH: From the Science to the Clinical Setting

HoLEP has been successfully applied to the treatment of very large prostates with results comparable to open prostatectomy, and long- term data on this technique show that the benefits are durable 83 While the AUA Guidelines Committee recommends that TURP remains the treatment of choice for patients who elect or require surgery for BPH 84, this recommendation may change as more data becomes available in regard to laser resection/enucleation of the prostate. The Canadian guidelines recommend its use as a therapeutic option for BPH Holmium laser enucleation has been successfully applied to the treatment of very large prostates with results comparable to open prostatectomy, and long- term data on this technique show that the benefits are durable.83 While the AUA Practice Guidelines Committee recommends that TURP remains the treatment of choice for patients who elect or require surgery for BPH84, this recommendation may change as more data becomes available in regard to laser resection/enucleation of the prostate. The Canadian guidelines recommend its use as a therapeutic option for BPH. 83. Elzayat E, Habib E, Elhilali M. Holmium Laser Enucleation of the Prostate (HOLEP): A Size Independent New Gold Standard. Urology. In press 84. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): p539 83. Elzayat E, Habib E, Elhilali M. Holmium Laser Enucleation of the Prostate (HOLEP): A Size Independent New Gold Standard. Urology. In press 84. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol. 2003;170(2 Pt 1): p539 TURP = Transurethral Resection of the Prostate AUA = American Urological Association BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Photoselective Vaporization of the Prostate (PVP)
Module 3: Treatment of BPH Photoselective Vaporization of the Prostate (PVP) Recent improvements in laser technology have led to promising new treatment modalities, including the potassium-titanyl-phosphate (KTP) laser This high-power photoselective technique effectively vaporizes the obstructing prostatic tissue in an outpatient surgical procedure Current results show that this procedure is a feasible option for men seeking relief of BOO due to BPH 85 The technique does not require a steep learning curve and most urologists familiar with TURP have little problem picking it up Photoselective Vaporization of the Prostate (PVP) Recent improvements in laser technology have led to promising new treatment modalities, including the potassium-titanyl-phosphate (KTP) laser. This high-power photoselective technique effectively vaporizes the obstructing prostatic tissue in an outpatient surgical procedure. Current results show that this procedure is a feasible option for men seeking relief of bladder outlet obstruction (BOO) due to benign prostatic hyperplasia (BPH).85 The technique does not require a steep learning curve and most urologists familiar with TURP have little problem picking it up. 85. Backmann A, Ruszat R, Wyler S, Reich O, et al. Photoselective vaporization of the prostate: the basal experience after 108 procedures. Eur Urol. 2005;47: 85. Backmann A, Ruszat R, Wyler S, Reich O, et al. Eur Urol. 2005;47: TURP = Transurethral Resection of the Prostate BOO = Bladder Outlet Obstruction BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Short-term results of a study of 108 patients who underwent 80W KTP laser vaporization of the prostate showed that this procedure is safe and effective for surgical treatment of BPH-related LUTS Low complication rate, and efficacy at 12 months is comparable to that of TURP and other laser therapies over the same period Data on the long term durability of the benefits are pending However, since neither comparison trials nor long-term studies are available, this therapy has not been recommended by AUA guidelines The Canadian guidelines recommend its use as a therapeutic option for BPH Short-term results of a study of 108 patients who underwent 80W KTP laser vaporization of the prostate showed that this procedure is safe and effective for surgical treatment of BPH-related lower urinary tract symptoms (LUTS). It has a low complication rate, and its efficacy at 12 months is comparable to that of TURP and other laser therapies over the same period. Data on the long term durability of the benefits are pending. However, since neither comparison trials nor long-term studies are available, this therapy has not been recommended by AUA guidelines. The Canadian guidelines recommend its use as a therapeutic option for BPH. LUTS = Lower Urinary Tract Symptoms TURP = Transurethral Resection of the Prostate AUA = American Urological Association BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Open Prostatectomy Involves the surgical removal of the inner portion of the prostate via a suprapubic or retropubic incision in the lower abdomen This procedure is normally performed on patients with prostate volumes greater than 80 to 100 mL 86 Open Prostatectomy Open prostatectomy involves the surgical removal of the inner portion of the prostate via a suprapubic or retropubic incision in the lower abdomen. This procedure is normally performed on patients with prostate volumes greater than 80 to 100 mL.86 86. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170(2 Pt 1): p539 86. AUA guideline on management of benign prostatic hyperplasia (2003). J Urol. 2003;170(2 Pt 1): p539 Understanding Concepts in BPH: From the Science to the Clinical Setting

3.8 Summary The choice of treatment for BPH is primarily based on symptomatology, severity and bother of LUTS, and patient preference Other considerations include the risk of progression, complications, and the need for surgery Patients should be informed of the risks and benefits of all therapeutic options and actively participate in the choice of therapy 3.8 Summary The choice of treatment for BPH is primarily based on symptomatology, severity and bother of lower urinary tract symptoms (LUTS), and patient preference. Other considerations include the risk of progression, complications, and the need for surgery. Patients should be informed of the risks and benefits of all therapeutic options and actively participate in the choice of therapy. LUTS = Lower Urinary Tract Symptoms BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

For most men with mild BPH and little or no bothersome symptoms, a conservative approach of lifestyle modification with watchful waiting is appropriate Periodic physician-supervised visits are essential Prior to the decision to choose this treatment plan, the physician should assess the patient’s risk of progression For most men with mild BPH and little or no bothersome symptoms, a conservative approach of lifestyle modification with watchful waiting is appropriate. Periodic physician-supervised visits are essential. Prior to the decision to choose this treatment plan, the physician should assess the patient’s risk of progression. BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

The choice of medical agents depends largely on patient symptoms, bother, age, size of prostate gland, baseline PSA, comorbidities, and expected drug tolerance. Medical therapies are appropriate for men with moderate / severe LUTS and significant bother Two drug classes are available: α1-receptor blockers and 5α-reductase inhibitors Both are effective in managing LUTS secondary to BPH; however, combination therapy with an agent from each class is more effective in controlling the symptoms and clinical progression of BPH The choice of medical agents depends largely on patient symptoms, bother, age, size of prostate gland, baseline PSA, comorbidities, and expected drug tolerance. Medical therapies are appropriate for men with moderate / severe lower urinary tract symptoms (LUTS) and significant bother. Two drug classes are available: α1-receptor blockers and 5α-reductase inhibitors. Both are effective in managing LUTS secondary to BPH; however, combination therapy with an agent from each class is more effective in controlling the symptoms and clinical progression of BPH. PSA = Prostate-Specific Antigen LUTS = Lower Urinary Tract Symptoms BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Minimally invasive surgical therapies (MIST) are appropriate for men with moderate to severe LUTS secondary to BPH, who opt for more active therapy The indications for these procedures vary, and clinical evidence of long-term efficacy may be lacking In Canada, the following procedures are recommended as optional therapy: TUMT TUNA Stents Minimally invasive surgical therapies (MIST) are appropriate for men with moderate to severe lower urinary tract symptoms (LUTS) secondary to BPH, who opt for more active therapy. The indications for these procedures vary, and clinical evidence of long-term efficacy may be lacking. In Canada, the following procedures are recommended as optional therapy: TUMT TUNA Stents TUMT = Transurethral Microwave Thermotherapy TUNA = Transurethral Needle Ablation LUTS = Lower Urinary Tract Symptoms BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

TURP is the gold standard for the surgical treatment of men with bothersome moderate to severe LUTS who request active treatment with a moderately enlarged prostate (<60-80 cc) TUIP is appropriate in men with smaller prostate (<30 cc) For glands over cc, open prostatectomy is the gold standard Other surgical options include: TUVP Laser prostatectomy (Holmium/YAG) Laser vaporization of the prostate (PVP, HoLAP) TURP is the gold standard for the surgical treatment of men with bothersome moderate to severe LUTS who request active treatment with a moderately enlarged prostate (<60-80 cc). TUIP is appropriate in men with smaller prostate (<30 cc). For glands over cc, open prostatectomy is the gold standard. Other surgical options include: TUVP Laser prostatectomy (Holmium/YAG) Laser vaporization of the prostate (PVP, HoLAP) TURP = Transurethral Resection of the Prostate LUTS = Lower Urinary Tract Symptoms TUIP = Transurethral Incision of the Prostate TUVP = Transurethral Electrovaporization of the Prostate Understanding Concepts in BPH: From the Science to the Clinical Setting

3.9 Quiz Which treatment option is preferred for men with a moderate size prostate and IPSS (AUA) symptom score of ≤ 7? 5α-reductase inhibitor TUMT α1-receptor blocker Watchful waiting (Correct) 3.9 Quiz 1. Which treatment option is preferred for men with a moderate size prostate and IPSS (AUA) symptom score of ≤7? 5-reductase inhibitor TUMT 1-receptor blocker Watchful waiting (Correct) IPSS = International Prostate Symptom Score AUA = American Urological Association TUMT = Transurethral Microwave Thermotherapy Understanding Concepts in BPH: From the Science to the Clinical Setting

What measure can physicians use to assess a patient’s individual risk of clinical progression? Prostate size Patient age PSA All of the above (Correct) 3.9 Quiz 2. What measure can physicians use to assess a patient’s individual risk of clinical progression? Prostate size Patient age PSA All of the above (Correct) PSA = Prostate-Specific Antigen Understanding Concepts in BPH: From the Science to the Clinical Setting

The MTOPS study reported that finasteride could significantly reduce clinical progression in men with BPH when combined with which of the following drugs? testosterone doxazosin (Correct) saw palmetto dutasteride 3.9 Quiz 3. The MTOPS study reported that finasteride could significantly reduce clinical progression in men with BPH when combined with which of the following drugs? Testosterone Doxazosin (Correct) Saw palmetto Dutasteride Understanding Concepts in BPH: From the Science to the Clinical Setting

Transurethral incision of the prostate (TUIP) is indicated for men with moderate to severe LUTS and which of the following limitations? Smaller prostates (<30 g) (Correct) Larger prostates (>30 g) Obstructive BPH Sexually active men 3.9 Quiz 4. Transurethral incision of the prostate (TUIP) is indicated for men with moderate to severe LUTS and which of the following limitations? Smaller prostates (<30 g) (Correct) Larger prostates (>30 g) Obstructive BPH Sexually active men LUTS = Lower Urinary Tract Symptoms; BPH = Benign Prostatic Hyperplasia Understanding Concepts in BPH: From the Science to the Clinical Setting

Transurethral electrovaporization of the prostate (TUVP) employs which form of technology to vaporize obstructive hyperplastic prostatic tissue? KTP laser Rollerball electrode Holmium:YAG laser All of the above (Correct) 3.9 Quiz 5. Transurethral electrovaporization of the prostate (TUVP) employs which form of technology to vaporize obstructive hyperplastic prostatic tissue? KTP laser Rollerball electrode Holmium:YAG laser All of the above (Correct) Understanding Concepts in BPH: From the Science to the Clinical Setting

Module 3: Treatment of BPH

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