GENDER HEALTH. Benign Prostatic Hyperplasia. Medical and Surgical Treatment Options

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1 GENDER HEALTH Benign Prostatic Hyperplasia Medical and Surgical Treatment Options ABSTRACT Benign prostatic hyperplasia (BPH) affects the aging male. Treatment options vary widely. Some men will elect to conservatively monitor their symptoms and make alterations to their lifestyle choices. Pharmacotherapy options exist as well, and include alpha-blockers, 5-alpha reductase inhibitors and phosphodiesterase-5 inhibitors. Lastly, surgical options are also a viable treatment option, with many types at the disposal of the caregiver. Technological advancements have changed, and will continue to change the field in the near future. This review outlines the important aspects of this common affliction. KEYWORDS: Benign prostatic hyperplasia, management, treatment, referral CME Pre-test Quiz Background Benign prostatic hyperplasia (BPH) is a common condition believed to exist in 50% of men age 60 or older, and 80% of men above the age of As a male ages, the prostate enlarges and may eventually cause bladder outlet obstruction (BOO), resulting in lower urinary tract symptoms (LUTS). 2 LUTS have traditionally been divided into storage and voiding symptoms (with storage LUTS including frequency, urgency and nocturia; and voiding LUTS including weak stream, hesitancy, intermittent stream, straining and incomplete emptying). While initially dormant, the progression of BPH can lead to a significant reduction in quality of life and may produce social isolation and mental health issues. 3 Moreover, there is possibility of the development of urinary retention development, recurrent urinary tract infections (UTIs), and renal injury, if left untreated. Dr. Dean S. Elterman, MD, MSc, FRCSC, Attending Urologic Surgeon, Toronto Western Hospital, University Health Network, Assistant Professor, Division of Urology, Department of Surgery, University of Toronto, Toronto, ON. Udi Blankstein, MD, Department of Urology, McMaster University, Hamilton, Ontario, Canada

2 Diagnosis and workup The spectrum of BPH and associated symptoms is quite broad; some patients experience severe symptoms that significantly impinge on their quality of life and ability to be independent, The digital rectal exam also aids in the assessment of prostate cancer risk as any questionable nodule or prostate asymmetry may indicate a potential malignancy. while others are barely bothered by their condition. As such, the clinical history is the foundation for the diagnosis of BPH-LUTS, and it is important to ascertain other potential factors that may be causing the symptoms. Past medical history (diabetes, metabolic syndrome, ongoing hematuria, neurological disease such as multiple sclerosis or Parkinson s disease), previous surgical history or urethral instrumentation, medication use, social habits (such as caffeine and alcohol intake) and family history of BPH are all essential features that must be assessed. The International Prostate Symptom Score (IPSS) is a questionnaire comprised of 8 items that assists in quantification of symptoms, with a total score between 0 and The 35 Journal of Current Clinical Care Volume 6, Issue 1, 2016 IPSS should also be used in the assessment as it allows for objective assessment, along with the ability to systematically followup for symptom progression. In addition to an abdominal exam and bladder percussion, the digital rectal examination (DRE) is the hallmark maneuver, and is used to estimate the size of the prostate. Prostate volume (cc) is essential in the guidance of treatment as different treatment modalities may work better for varying prostate sizes. DRE also aids in the assessment of prostate cancer risk as any questionable nodule or prostate asymmetry may indicate a potential malignancy. The Canadian Urological Association recommends testing all men with a life expectancy beyond 10 years for Prostate Specific Antigen (PSA) when considering a diagnosis of BPH-LUTS and further medical/interventional treatment. 5 PSA can also serve as a surrogate for prostate volume when prostate cancer is absent, with a PSA of 1.5 ng/ml associated with a prostate volume of 30cc or more, and can be further used to assess risk of prostate cancer. 6 Additionally, a urinalysis (Routine and Microscopy and Culture and Sensitivity) is an important component of the workup and allows the clinician to rule out UTIs and other less common causes of LUTS. 5

3 Benign Prostatic Benign Hyperplasia Prostatic Hyperplasia (BPH) Male Urogenital Anatomy Normal Anatomy Bladder Prostate Urethra Urine being voided from bladder Normal prostate Anatomy with Enlarged Prostate Difficulty voiding urine from bladder due to obstruction Bladder outlet obstruction (BOO) Enlarged prostate 36 Journal of Current Clinical Care Volume 6, Issue 1, 2016

4 TREATMENT Conservative Management Patients with mild symptoms, or those who deny medical treatment, should be advised to keep a voiding diary in order to identify important patterns regarding their urinary habits. Some patients symptoms may spontaneously resolve over a period of time. 7 Nonetheless, patients should modify their fluid intake and limit their total amount to approximately L per day. This is especially important prior to sleep and prior to events that the patient may have a difficult time accessing the bathroom. Reducing the consumption of diuretic beverages such as coffee and alcohol has also been shown to be a helpful method in reducing bothersome symptoms. Timed voiding, double voiding, pelvic floor exercises and urethral milking to avoid postmicturition dribble may also preclude additional complications. Avoidance of constipation and maintaining a regular bowel movement schedule is also a factor in alleviating LUTS. 8,9 Pharmacotherapy Alpha-Blockers Alpha-antagonists work by blocking alpha-1a receptors, and thus relax smooth muscle within the bladder neck and prostate. This allows for opening and relaxation of the tightened urinary channel thereby reducing the impediment to urinary flow. 10,11 Alpha-blockers 37 Journal of Current Clinical Care Volume 6, Issue 1, 2016 have been found to reduce bother symptoms by 30-40%, especially in patients within the smaller spectrum of prostate size (< 30 cc). 12,13 Alpha-blockers begin to work within a matter of hours to days; however, they reach their maximal efficacy within a few weeks. 14 While alpha-blockers are considered to be relatively safe, there are side effects that patients and caregivers should be aware of. Light-headedness, dizziness, headache, nasal congestion, and retrograde ejaculation are the most common side effects. 15 Such side effects used to be more common in the first generation versions of these medications; however, the second and third generations have become significantly more uroselective, and are associated with a lower occurrence of side effects. 5-Alpha Reductase Inhibitors 5-alpha reductase inhibitors (5-ARI) inhibit the conversion of testosterone to DHT, and by doing so are able to halt prostatic tissue growth and reduce prostate size. 16,17 The reduction in prostate size is believed to be 18 28%. Finasteride (Proscar) and dutasteride (Avodart) are currently the two most utilized medications, with subtle differences between them. 18 Adherence to medication is necessary, as symptom reduction may take a minimum of 6 months. Side effects primarily involve symptoms related to testosterone deficiency, such as erectile dysfunction, ejacu-

5 latory dysfunction and decreased libido, and gynaecomastia, which have been shown to occur in approximately 1 2% of patients. 19 As stated above, due to the fact that this medication is known to Newer [surgical] methods, such as PVP [Greenlight laser], are associated with little to no blood loss and shorter lengths of stay within hospital, thus demonstrating to be potentially preferred for anticoagulated patients reduce the PSA level, the clinician must examine PSA level at baseline as well as throughout treatment in order to identify potential spikes, as this may be an early sign for underlying prostate malignancy. 15 Combination Therapy Combination treatment with an alpha-blocker and a 5-alpha-reductase inhibitor may benefit patients with severe symptoms, those with exceptionally large prostates and/ or those who failed monotherapy. The synergistic mechanism of the 5-alpha reductase inhibitor (which shrinks the prostate) along with the alpha-blocker (which relaxes the smooth muscle of the prostate) has been demonstrated to benefit patients. 38 Journal of Current Clinical Care Volume 6, Issue 1, 2016 Two seminal trials, the Medical Therapy Of Prostate Symptoms (MTOPS) trial 19 and The Combination of Avodart and Tamsulosin (CombAT) trial 15, have both shown superior effects with combination therapy versus monotherapy and placebo. The MTOPS study compared 3047 men who were randomized into four main groups of either placebo alone, finaesteride alone, doxazosin alone or combination therapy with finasteride and doxazosin. 19 The study followed the patients over a number of years, and the results demonstrated that combination therapy showed the best profile for symptom improvement and reduction of disease progression. The CombAT trial enrolled over 4000 men and randomized them into receiving tamsulosin alone, dutasteride alone or combination therapy. 15 Similarly, combination therapy was demonstrated to be superior in comparison with either modality alone. PDE5 inhibitors Recent studies have shown that PDE5 inhibitors (PDE5i) that have been traditionally used for erectile dysfunction are another option for the treatment of BPH- LUTS. PDE5i s manipulate the level of intracellular cyclic guanosine monophosphate, forming a nitric oxide mediated reduction in smooth muscle tone of prostate and surrounding structures such as the urethra and blad-

6 SUMMARY OF KEY POINTS There is a spectrum of bother ranging from mild nuisance to significant decrease in quality of life this is largely associated with how the patient perceives the problem. Physical exam and medical history are imperative in the initial assessment of BPH. Conservative measures and lifestyle changes should be the first line treatment choice. Surgical intervention should be attempted after failure of medical therapy to alleviate symptoms and prevent kidney injury or infection. der neck. Currently, Tadalafil is the only medication approved by urological organizations in North America and Europe. Indeed, it has been found to be as effective as an alpha-blocker, and also conferred the added benefit of decreasing ED, thus increasing the attractiveness of taking the medication for men suffering from both BPH and ED. 20 Evidence also supports that combined treatment of tadalafil and finasteride is associated with improvement of BPH-LUTS, regardless of pre-existing ED symptoms. 21 Hypotension is the most severe, albeit unlikely, side effect that PDE5i s are associated with. Interventional Therapy 39 Journal of Current Clinical Care Volume 6, Issue 1, 2016 Refractory urinary retention and evidence of renal insufficiency warrant intervention. Numerous studies have shown that patients who had undergone a surgical intervention procedure had decreased IPSS bother scores, episodes of urinary retention and risk of kidney damage. 22 Additionally, patients may elect to undergo surgery if they are unwilling to tolerate bothersome urinary symptoms despite medical therapy, incur bladder stones or continuously show blood in their urine. Transurethral Resection of Prostate (TURP) and Laser Therapies Prior to the advancement of endoscopic technologies, a simple prostatectomy was the intervention of choice for BPH. While quite effective in the relief of LUTS, the morbidity was high. Today, it is only reserved for cases in which the prostate size is deemed to be too large for endoscopic treatment (>80cc). 23 Fortunately, the urological community continues to improve the modalities employed in treatment. Currently, The TURP is the gold standard for treating BPH. Conducted under direct vision, the surgeon resects parts of the prostate tissue until an opening within the prostatic fossa is achieved. Post-

7 CME Post-test Quiz Members of the College of Family Physicians of Canada may claim MAINPRO-M2 Credits for this unaccredited educational program. operative length of stay is usually 24 hours. Varying types of energy are used for the procedure, ranging from the traditional Monopolar TURP, to the more popular Bipolar electro-cautery. Newer laser therapies such as Greenlight photovaporization (PVP) and holmium laser enucleation (HoLEP) have improved upon traditional TURP in several ways, feature same day surgery, and no requirement to halt anti-coagulation. 24 The more traditional TURP modalities (mono and bi polar) have higher risks of bleeding (with the potential need for blood transfusion), permanent sexual side effects (such as retrograde ejaculation and ED), UTIs and urinary incontinence. TUR syndrome, a constellation of symptoms and signs involving the nervous and cardiorespiratory system, can be caused by absorption of the irrigation fluid into the highly concentrated venous system of the prostate. This complication does still occur, especially when intraoperative time increases. 22 The newer methods, such as PVP, are associated with little to no blood loss and shorter lengths of stay within hospital, thus demonstrating to be potentially preferred for anti-coagulated patients. 25 Bhojani et al. evaluated the safety of the three different surgical interventions and found that all methods were considered to be quite safe. 26 Within that study however, advanced aged and non-caucasian backgrounds were correlated with higher morbidity. Still, the newer technologies are not necessarily recommended for patients with very enlarged prostates, and the general need for redo procedures is thought to be higher. Other Modalities In the past few decades, several new and exciting treatments have been developed, although still under utilized. For example, the prostatic urethral lift system (UroLift) is a minimally invasive approach that works by pulling the lateral lobes of the prostate apart using anchored sutures. 27 Low risk of erectile function and perioperative complications implicate a promising future for this method, with some studies reporting excellent results overall, touting the + CLINICAL PEARLS Ensure that there are no other causes that may cause LUTS such as various medications, and other comorbidities. When considering more invasive intervention, ensure that the surgical team knows the patient s anticoagulation status. 40 Journal of Current Clinical Care Volume 6, Issue 1, 2016

8 method as an excellent choice for those men who cannot withstand general anesthesia. 28 Another example is the transurethral needle ablation (TUNA), a device that delivers radiofrequency energy to the prostate via needles directly into prostatic tissue with the aim of ablating the bothersome tissue and decreasing obstruction. 29 Additionally, there has been shown to be some promise with transurethral microwave thermotherapy (TUMT), which works with microwave radiation that causes tissue destruction to achieve similar channel opening results. 30 TUMT and TUNA achieve comparable results when compared with TURP, however they have been found to be associated with lower flow improvements and higher re-treatment rates. 31 Conclusion While BPH-LUTS is extremely common, the treatment options vary widely and should be tailored to the individual patient. The advancements over the past few decades, both medically and surgically, have considerably changed management of this condition. Promising new medications and tools are likely to emerge in the future. References 1. Roehrborn, C. G. Benign prostatic hyperplasia: An overview. Rev Urol 2005;7:S3. 2. Patel, N. D., Parsons, J. K. Epidemiology and etiology of benign prostatic hyperplasia and bladder outlet obstruction. Indian J Urol 2014;30: Journal of Current Clinical Care Volume 6, Issue 1, Welch, G., Weinger, K., Barry, M. J. Quality-of-life impact of lower urinary tract symptom severity: results from the Health Professionals Follow-up Study. Urology 2002;59: Barry, M. J., Fowler, F. J., Jr., O Leary, M. P. et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992;148: Nickel, J. C., Mendez-Probst, C. E., Whelan, T. F. et al Update: Guidelines for the management of benign prostatic hyperplasia. Can Urol Assoc J 2010;4: Roehrborn, C. G., Boyle, P., Gould, A. L. et al. Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology 1999;53: Chapple, C. R. Pharmacological therapy of benign prostatic hyperplasia/lower urinary tract symptoms: an overview for the practising clinician. BJU Int 2004;94: Burgio, K. L., Newman, D. K., Rosenberg, M. T. et al. Impact of behavior and lifestyle on bladder health. Int J Clin Pract 2013;67: Netto, N. R., Jr., de Lima, M. L., Netto, M. R. et al. Evaluation of patients with bladder outlet obstruction and mild international prostate symptom score followed up by watchful waiting. Urology 1999;53: McVary, K. T., Roehrborn, C. G., Avins, A. L. et al. Update on AUA guideline on the management of benign prostatic hyperplasia. J Urol 2011;185: Boyle, P., Robertson, C., Manski, R. et al. Meta-analysis of randomized trials of terazosin in the treatment of benign prostatic hyperplasia. Urology 2001;58: Djavan, B., Waldert, M., Ghawidel, C. et al. Benign prostatic hyperplasia progression and its impact on treatment. Curr Opin Urol 2004;14: Roehrborn, C. G., Siami, P., Barkin, J. et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol 2010;57: Michel, M. C., Vrydag, W. Alpha1-, alpha2- and betaadrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 2006;147 Suppl 2:S Roehrborn, C. G., Siami, P., Barkin, J. et al. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol 2008;179: Andriole, G., Bruchovsky, N., Chung, L. W. et al. Dihydrotestosterone and the prostate: the scientific rational for 5-alpha reductase inhibitors in the treatment of benign prostatic hyperplasia. J Urol 2004;172: Rittmaster, R. S., Norman, R. W., Thomas, L. N. et al. Evidence for atrophy and apoptosis in the prostates of men given finasteride. J Clin Endocrinol Metab 1996;81: Naslund, M. J., Miner, M. A review of the clinical efficacy and safety of 5a-reductase inhibitors for the enlarged prostate. Clin Ther 2007;29:17.

9 19. McConnell, J. D., Roehrborn, C. G., Bautista, O. M. 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: Oelke, M., Giuliano, F., Mirone, V. et al. Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomized, parallel, placebo-controlled clinical trial. Eur Urol 2012;61: Glina, S., Roehrborn, C. G., Esen, A. et al. Sexual function in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia: results of a 6-month, randomized, double-blind, placebo-controlled study of tadalafil coadministered with finasteride. J Sex Med 2015;12: Ahyai, S. A., Gilling, P., Kaplan, S. A. et al. Meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement. Eur Urol 2010;58: Varkarakis, I., Kyriakakis, Z., Delis, A. et al. Long-term results of open transvesical prostatectomy from a contemporary series of patients. Urology 2004;64: Tholomier, C., Valdivieso, R., Hueber, P. A. et al. Photoselective laser ablation of the prostate: a review of the current 2015 tissue ablation options. Can J Urol 2015;22: Eltabey, M. A., Sherif, H., Hussein, A. A. Holmium laser enucleation versus transurethral resection of the prostate. Can J Urol 2010;17: Naeem, B., Giorgio, G., Akshay, S. et al. Morbidity and Mortality After Benign Prostatic Hyperplasia Surgery: Data from the American College of Surgeons National Surgical Quality Improvement Program. Journal of Endourology 2014;28: Woo, H. H., Bolton, D. M., Laborde, E. et al. Preservation of sexual function with the prostatic urethral lift: A novel treatment for lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Sex Med 2012;9: Roehrborn, C. G., Gange, S. N., Shore, N. D. et al. The prostatic urethral lift for the treatment of lower urinary tract symptoms associated with prostate enlargement due to benign prostatic hyperplasia: the L.I.F.T. Study. J Urol 2013;190: Bouza, C., Lopez, T., Magro, A. et al. Systematic review and meta-analysis of Transurethral Needle Ablation in symptomatic Benign Prostatic Hyperplasia. BMC Urol 2006;6: Hoffman, R. M., Monga, M., Elliott, S. P. et al. Microwave thermotherapy for benign prostatic hyperplasia. Cochrane Database Syst Rev 2012;9:CD Chapple, C. R., Issa, M. M., Woo, H. Transurethral needle ablation (TUNA). A critical review of radiofrequency thermal therapy in the management of benign prostatic hyperplasia. Eur Urol 1999;35: Journal of Current Clinical Care Volume 6, Issue 1, 2016