Introduction

Benign prostatic hyperplasia (BPH) is a common disorder of aging men that is often accompanied by lower urinary tract symptoms (LUTS).¹ Historically, surgery and watchful-waiting were the only widely accepted management options for LUTS suggestive of prostate enlargement. Since its development in the 1920s, transurethral resection of the prostate (TURP) has remained a gold standard for treatment. However, surgery was associated with postoperative complications of bleeding, urinary tract infection, 'TUR syndrome' (dilutional hyponatremia), increased length of hospitalization and hematuria; long-term complications included bladder–neck contracture, erectile dysfunction, incontinence and retrograde ejaculation.² Early removal of catheter in these patients, although associated with reduced length of hospital stay, did not reduce the incidence of postoperative complications.³ Careful management of surgery and modifications to TURP have reduced the significance and number of postoperative complications.⁴ However, with the advent of effective medical therapies and minimally invasive surgical procedures, the popularity of surgery has declined considerably. The last decade has witnessed a change in urological clinical practice reflecting an increased use of these alternative treatments.⁵

Key goals in the management of BPH are controlling symptoms along with preventing complications and improving quality of life (QOL) of affected individuals. Choosing among the various treatment options to achieve these goals is a challenge to urologists and should be based not only on the best available evidence but also on patients' circumstances and personal choices.⁶ In addition, the benefits of treatment should be balanced against the risk of adverse events associated with therapy.⁶

In this review, we discuss the progressive nature of BPH, current treatment trends and the clinical utility of medical and minimally invasive therapies in the management of this condition. We review the relative advantages and disadvantages of both treatment classes, including efficacy and safety data, and we provide guidance on selecting between them.

Discussion

BPH: a progressive disease

In the United States, approximately 20 million men over the age of 50 years suffer from BPH, resulting in an estimated 6.4 million annual office visits and 402 000 annual hospital admissions.⁷ Similar incidences have been reported in Africa, Asia, South America and Europe.⁸ Although the course of BPH is variable among men, it is often a progressive condition and 55% will experience symptom deterioration over time.⁹ Recognized risk factors for BPH progression include enlarged prostate (>30 ml), weak urinary flow and prostate-specific antigen (PSA) levels 1.4 ng/ml.^{10, 11} The prevalence of BPH is age-related; 50% of men aged 51–60 years have histological signs of enlarged prostate and this increases to >70% by ages 61–70 years and >90% by ages 81–90 years.¹² The prevalence of moderate-to-severe symptoms also increases with age from an odds ratio of 1.9 for men aged 50–59 years to 3.4 for men aged 70–79 years, relative to men aged 40–49 years.¹³ The Olmsted County study, a longitudinal epidemiological study, provides the largest body of evidence on the progressive nature of BPH. Both 5- and 7-year data from this study demonstrate a cumulative increase in prostate volume,¹⁴ a worsening of LUTS¹⁵ and a decrease in urinary flow rate.¹⁶

Left untreated, serious complications such as acute urinary retention (AUR) necessitating surgical intervention, bladder decompensation and upper urinary tract compromise can develop in men with enlarged prostate.¹⁷ In the Olmsted County Study, the cumulative incidence of AUR in a random sample of 2119 men aged 41–79 years increased over 5 years, with 57 first episodes of AUR (overall incidence: 6.8 episodes/1000 person-years).¹⁸ Moreover, severity of LUTS, large prostate size and age were associated with an increased risk of AUR.^{18, 19} Men with prostate volumes >30 ml had a threefold increase in the risk of AUR and a fourfold increase in the risk of BPH-related surgery compared with men who had prostate volumes <30 ml.^{18, 19} Similar findings have been reported from the Baltimore Longitudinal Study of Aging, where men with prostate enlargement and obstructive symptoms were five to eight times more likely to require prostatectomy within 10 years than those of the same age without prostate enlargement.²⁰ These epidemiological findings have been confirmed in randomized clinical trials. In the Department of Veterans Affairs Cooperative Study, men (n=276, mean age 66 years) with moderate symptoms randomized to watchful waiting had a higher incidence of AUR, higher symptom scores and greater residual urinary volumes over time compared with patients randomized to surgical intervention. The crossover rate to surgery at 5 years in these men was 36% and was positively associated with degree of symptom bother.²¹ Likewise, the placebo arm of two randomized prospective studies investigating the effect of finasteride and dutasteride, respectively, on short- and long-term clinical end points over 4 years have provided further evidence on the progressive nature of BPH and resultant complications of AUR and surgery.^{22, 23} In both these studies, 5–10% of placebo-treated patients underwent BPH-related surgery and AUR developed in 5–7% of patients.^{22, 23}

Benign prostatic hyperplasia progression leading to deterioration of clinical outcomes (increased severity of symptoms, increased risk of AUR and surgery) can have a negative impact on the patient's QOL. Men with prostate enlargement were twice as likely to experience interference of activity compared with men without prostate enlargement.²⁴ Disease-specific, health-related QOL for men with prostate enlargement is comparable to patients with other common chronic conditions, such as epilepsy, asthma or chronic obstructive lung disease.²⁵ The potential for AUR and/or surgery is indeed a major concern to patients with BPH.²⁵ In one survey, reduction in the risk of major urological complications and the need for surgery was of more importance to patients than improving symptoms and QOL.²⁶

Treatment trends of benign prostatic hyperplasia in America over the decade

Surgery, specifically TURP, has been a standard of care for BPH for more than 80 years and was the second most commonly performed operation in the United States.⁵ However, with the advent of effective medical therapy and minimally invasive surgical therapies (MISTs), hospitalizations for TURP have markedly declined over the last decade.⁵

An American Urological Association (AUA) Gallop Poll conducted in 1997 showed that medical therapy was first-line treatment in a majority of patients with moderate LUTS (AUA-SI, 8–19) and prostate size <40 ml;²⁷ TURP was the most commonly recommended treatment for severely symptomatic patients irrespective of gland size.²⁷ In this survey, terazosin was the primary pharmacological agent prescribed in 14–15% of visits for enlarged prostate between 1994 and 1996. In 2000, however, this agent was replaced by more selective agents such as doxazosin and tamsulosin.⁵ The prescriptions for 5-alpha-reductase inhibitors (5ARIs) during these years remained relatively stable.⁵

The use of MISTs was minimal in 1997, with only 26% of urologists performing laser prostatectomy and 3% performing transuretheral needle ablation (TUNA) or transurethral microwave therapy (TUMT). In recent years however, the use of TUNA and TUMT has increased along with a simultaneous increase in ambulatory setting surgeries from 264/100 000 in 1998 to 357/100 000 in 2000.⁵

At present, use of conventional TURP is in decline⁵ and only reserved for urinary retention.²⁸ There appears to be a shift in the management of prostate enlargement from in-patient to outpatient treatments with increasing use of medical therapy and MISTs. As such, the number of TURP surgeries is likely to stabilize and may already be reaching a plateau.

Medical therapies

Medical therapies for the treatment of BPH include alpha-blockers and 5ARIs. The four widely available alpha-blockers are doxazosin, terazosin, tamsulosin and alfuzosin, and the two widely available 5ARIs are finasteride and dutasteride. Advantages of medical therapy include convenience, avoidance of potential morbidity associated with surgery and the ability to reverse the side effects of treatment (e.g., retrograde ejaculation), if needed.²⁹ A significant disadvantage of medical therapy, however, is the need for indefinite therapy to maintain improvements,³⁰ which can be associated with long-term costs and compliance issues.

5-Alpha-reductase inhibitors

5-Alpha-reductase is an enzyme that converts testosterone to the more potent androgen dihydrotestosterone (DHT). Two distinct isoforms of 5-alpha-reductase enzymes exists in the human body, each encoded by separate genes. Immunohistochemical studies have clearly demonstrated a differential distribution of these two isoforms with type 1 isoenzyme highly expressed in the liver, skin and prostate, and type 2 isoenzyme found predominantly in the prostate and other genital tissues.³¹ Although the precise role of DHT in prostate enlargement is not fully determined, it appears that DHT has a dual function in promoting cell proliferation and differentiation. Dihydrotestosterone has a beneficial role in the developing prostate, but can be detrimental in the adult prostate, causing pathologic prostate growth (Figure 1).³²

Figure 1.

Benign prostatic hyperplasia (BPH) progression is primarily mediated by androgen-fueled prostate growth.⁷⁸

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5-Alpha-reductase inhibitors suppress the production of DHT, reduce prostate volume, arrest the disease process and improve symptoms over time.³² To date, these agents are the sole hormonal therapy available for the management of BPH. The major advantage of 5ARIs compared with alpha-blockers is that 5ARIs prevent disease progression. However, they have a slow onset of action and have to be administered for up to 3–6 months before a symptomatic benefit can be measured.³³ Reducing prostate volume contributes to their disease modification properties of reducing the risks for AUR and surgery.^{10, 22, 34} Data from studies of both finasteride and dutasteride in men with moderate-to-severe symptoms of LUTS and enlarged prostate (measured by digital rectal examination (DRE): prostate volume >30 ml, or as identified by PSA levels >1.5 ng/ml) demonstrate the efficacy of these agents in improving symptoms and flow rate, and preventing disease progression (Table 1).^{22, 23, 34} In a randomized, 4-year, double-blind study, finasteride reduced symptom score by 3.3 points, decreased prostate volume by 18% and improved peak urinary flow (Q_max) to 1.9 ml/s.²² In a randomized, 2-year, double-blind study with 2-year, open-label follow-up phase, dutasteride reduced symptom score by 6.5 points, decreased prostate volume by 27% and improved Q_max to 2.7 ml/s over 4 years.²³ Finasteride and dutasteride reduced the risk of AUR and the need for surgery by 50% compared with placebo at 4 and 2 years, respectively,^{10, 22, 34} regardless of the baseline symptom severity.³⁵ The risk-reducing effect of 5ARIs was further confirmed by the Medical Therapy of Prostatic Symptoms study (MTOPS), which enrolled 3047 men of at least 50 years of age with moderate-to-severe symptoms (AUA symptom score of 8–35) and a maximum urinary flow rate between 4 and 15 ml/s who were followed for 5 years. In this study, the rate of overall clinical progression (defined as the first occurrence of an increase over baseline of at least 4 points in the AUA-SI score, AUR, renal insufficiency, recurrent urinary tract infection or urinary incontinence) at 4 years was 17% in the placebo group, 10% each in the doxazosin group (P<0.001 vs placebo) and finasteride group (P=0.002 vs placebo), and 5% in the combination group (P<0.001 vs placebo). However, when the events of AUR and risk of invasive surgery were analyzed, significant treatment differences were observed with alpha-blocker vs 5ARI and combination therapy. Compared with the placebo group (18 events in 737 patients), the rate of AUR in both the finasteride group (six events in 768 patients; risk reduction, 68%; P=0.009) and the combination group (four events in 786 patients; risk reduction, 81%; P<0.001) was significantly lower, unlike the rate of AUR in the doxazosin group (nine events in 756 patients; risk reduction, 45%; P=NS). Likewise, compared with the placebo group, treatment with finasteride and combination therapy significantly reduced the risk of invasive therapy by 64 and 67%, respectively, compared with 3% in the doxazosin group.

Table 1 - Efficacy of medical therapies in the management of BPH.

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The two 5ARIs currently available differ in their activity against the 5-alpha-reductase isoenzymes. Finasteride competitively inhibits type 2 5-alpha-reductase, but is weakly active against type 1.³⁶ Finasteride suppresses DHT by about 70–80%.³⁶ Dutasteride inhibits both 5-alpha-reductase isoenzymes and causes >90% suppression of DHT.³⁶ Inhibition of both 5-alpha-reductase isoenzymes results in greater and more consistent suppression of DHT,³⁶ and theoretically, dutasteride may exhibit a more potent action. In a prospective observational study of 240 men prescribed dutasteride (n=120) or finasteride (n=120), the onset of symptom relief was observed at 3 months with dutasteride and a significantly greater proportion of patients experienced improvement in AUA-SI score vs finasteride (44 vs 23%).³⁷

The adverse-event profiles of finasteride and dutasteride are similar, with erectile dysfunction, decreased libido and decreased volume of ejaculate occurring twice as often as placebo, particularly during the first year of treatment.^{22, 34} Overall, up to 10% of patients treated with 5ARIs report sexually related adverse events within the first year of study participation (Table 2). Not unexpectedly, the rate of adverse events with combination therapy is approximately equivalent to the sum of the individual adverse events of each drug, alpha-blocker and 5ARI. However, sexual side effects, dyspnea and peripheral edema occurred more frequently with combination therapy.¹⁰

Table 2 - Estimated incidence (%) of adverse events with medical therapies.

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Based on this evidence, 5ARIs are generally recommended for patients with LUTS associated with demonstrable prostate enlargement to prevent progression of the disease.^{1, 39} In patients with bothersome LUTS associated with demonstrable prostate enlargement, the combination of an alpha-blocker and 5ARI is an appropriate therapy to control symptoms and prevent the progression of the disease.^{1, 39} Evidence from the MTOPS study on the 45% overall risk reduction of symptomatic progression for doxazosin, 30% for finasteride and 64% for combination therapy clearly supports this recommendation.¹⁰ Additional data indicate that alpha-blocker treatment can potentially be withdrawn after an initial period of combination therapy without subsequent deterioration in symptoms.^{37, 40}

Alpha-blockers

Alpha-blockers are the most commonly prescribed medical therapy in clinical management of BPH.^{5, 41} Among the currently available alpha-blockers, tamsulosin is selective to the alpha_1A-adrenergic receptor subtype that is predominant in the human prostate, whereas other alpha-blockers do not discriminate among alpha-adrenergic receptor subtypes.³⁸ Although tamsulosin is superselective, its efficacy is similar to terazosin and doxazosin, which are non-subtype-selective agents. Likewise, the cardiovascular side effects of tamsulosin are similar to alfuzosin.⁴² Thus, the clinical significance of the superselectivity of tamsulosin is currently not fully investigated. Alpha-blockers rapidly relieve LUTS by relaxing smooth muscle tone in the prostate and bladder neck. They are initially effective regardless of prostate size³⁸ and are generally well tolerated. Their efficacy appears to be well maintained over time with no evidence of intolerance or tachyphylaxis after 6–12 months of treatment.⁴³ In terms of efficacy, all four alpha-blockers have been shown to provide statistically significant improvements in symptom scores (on average a 4–6 point improvement in AUA-SI) within 3–9 months (Table 1).^{1, 38} In all trials, the range of improvement in symptoms was about 30–50%.^{38, 44} Regardless of their selectivity, alpha-blockers improve Q_max by approximately 15–30%,⁴⁴ with a mean increase in maximal flow rate of 1.85–3.11 ml/s.¹

The main adverse events reported with alpha-blockers include orthostatic hypotension, dizziness, tiredness, ejaculatory problems and nasal congestion.¹ The alpha-blockers differ in their tolerability profile. In general, patients tolerate alfuzosin (extended-release formulation) and tamsulosin better than terazosin and doxazosin (including extended-release gastrointestinal therapeutic system (GITS) formulation)). Alfuzosin appears to be associated with a greater incidence of vasodilatory adverse events, including dizziness, compared with tamsulosin.⁴⁴ Dizziness leading to falls and fractures is of particular concern for the elderly and/or those with concomitant cardiovascular comorbidity/comedication.⁴⁴ In these patients, tamsulosin may be an agent of choice owing to its low drug-interaction potential with antihypertensive agents and limited vasodilatory adverse events.⁴⁴ Tamsulosin, however, is associated with a high incidence of abnormal ejaculation (3–14%) (Table 2),^{38, 44} and in a recent, specific, ejaculatory function study, Hellstrom et al.⁴⁵ reported even higher (8–14%) rates than these previous studies. Furthermore, this study found tamsulosin caused ejaculatory dysfunction in most subjects and resulted in no ejaculate in one-third of patients. This higher, more pronounced observation of ejaculatory dysfunction may reflect the difference in study design, as the study by Hellstrom and co-workers looked specifically at this issue, whereas other studies included only spontaneous patient reports. Ultimately, less than 1% of all treated patients discontinue treatment because of this adverse event.⁴⁴

Although alpha-blockers offer rapid symptom relief, they do not reduce the overall size of the prostate or alter BPH progression. Consequently, the benefits of alpha-blockers are limited to symptom relief and patients eventually may need surgery. The landmark MTOPS study investigated whether therapy with an alpha-blocker (doxazosin) or a 5ARI (finasteride), alone or in combination, would delay or prevent clinical progression of BPH.¹⁰ Significant treatment differences were observed with alpha-blocker vs 5ARI and combination therapy in the events of AUR and risk of invasive therapy at the end of 4 years. Although doxazosin delayed the time to AUR, it did not significantly reduce the cumulative incidence compared with placebo (P=0.23). Likewise, the cumulative incidence of invasive therapy was not reduced in doxazosin-treated patients compared with placebo.¹⁰ These findings have also been reported in real-life clinical practice. Retrospective analyses of data from the General Practice Research Database from the United Kingdom⁴⁶ and from the Netherlands PHARMO Record Linkage System⁴⁷ reported that patients prescribed an alpha-blocker were significantly more likely to experience AUR (hazard ratio 2.35) or had a higher risk of prostate surgery (hazard ratio 1.52–1.78) than patients prescribed a 5ARI.^{46, 47} Another recent study from Netherlands demonstrated that patients with enlarged prostate (prostate volume 30 ml) treated with alpha-blockers experience a 5-year cumulative risk of 35% in the incidence of invasive surgery compared with a 21% cumulative risk in patients with smaller prostates (<30 ml).⁴⁸

Based on their efficacy, it is apparent that alpha-blockers are appropriate treatment options for patients with bothersome symptoms of LUTS secondary to BPH regardless of whether prostate enlargement is present.^{1, 38}

Minimally invasive surgical therapies

MISTs began to emerge in the last decade as a result of research and development strategies aimed at finding simpler and less morbid alternatives to TURP. Today there are many types of MISTs available, including TUMT, TUNA, interstitial laser coagulation, visual laser ablation of the prostate, transurethral electrovaporization of the prostate, water-induced thermotherapy, transurethral ethanol ablation of the prostate, high-intensity focused ultrasound and others. The technology continues to evolve and improve, but because of constant changes in technology, long-term data on any one therapy is difficult to amass. Most MISTs use heat energy to cause necrosis/thermoablation. The necrotic tissue is then either absorbed or turned into scar. Energy sources include microwave thermotherapy, water-induced thermotherapy, radiofrequency, ultrasound and laser. The application of heat ranges from minutes to an hour, depending on the procedure.⁴⁹ All MISTs are less invasive than surgery, and they require minimal anesthesia.⁴ Most of these procedures are performed in office and patients can resume their regular daily activities within a few days.⁴ The main advantages of MISTs are the avoidance of risks and complications of surgery, such as spinal, epidural, or general anesthesia, hospital stay, potential morbidity (bleeding, infection, prolonged catheterization, TURP syndrome and urethral stricture) and potential mortality for those at high surgical risk (Table 3). Most MISTs result in long-lasting improvements in symptoms, flow rates and QOL scores (Table 4), although not to the extent of TURP, with low morbidity, minimal erectile dysfunction and less risk for retrograde ejaculation compared with surgery. Minimally invasive surgical therapies also avoid the side effects and compliance issues that can be associated with medical therapies as they afford a one-time intervention with lasting effects.⁵⁴ The main concern with MISTs is the scarcity of long-term safety and efficacy data. It has been reported that the need for subsequent therapy varies from 15 to 49% and that transient retention rates vary from 14 to 40%.⁵⁵ Patient satisfaction with treatment is also variable, with a long-term study of 841 patients showing 67% were satisfied after low-energy TUMT and 87% after higher-energy TUMT.⁵⁶ Table 3 lists the adverse events associated with the various procedures as reported in literature.

Table 3 - Adverse events of minimally invasive therapies vs TURP as reported in literature.

Full table

Table 4 - Efficacy of minimally invasive therapies vs TURP as reported in literature.

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Microwave therapy

Transurethral microwave therapy is the most extensively studied MIST and is considered by some to be the gold standard for MISTs.⁵⁰ Transurethral microwave therapy can be performed in a single 1-h session without anesthesia. Higher-energy TUMT is the form of this treatment most often used today. Higher-energy TUMT can be performed in a single 30-min session. There are many types of microwave thermal therapy machines and instruments available that differ in amount of energy, duration and technique. In general, higher energy is associated with better results but has a greater risk of complications. The degree of improvement is variable and depends on the size of the prostate, degree of obstruction, type of machine and treatment protocol used.⁴ The total amount of energy appears to have the most impact in predicting a good or poor response. Thus, mediocre improvements take place after low-energy treatments.⁴ The best candidates for higher-energy TUMT are generally men with larger prostates (>35 ml) and severe symptoms (AUA-SI 12).^{49, 50} Likewise, with the use of low-energy protocols, the best responders are generally those with mild disease and smaller prostates.⁴

Improvements of 43–70% in symptom score and of 19–59% in Q_max have been reported with TUMT.²⁹ Likewise, an improvement of 50% in QOL is reported in 79% of patients.²⁹ Maximum effects of TUMT are evident by 3–6 months after the procedure and endure for at least up to 36 months.²⁹

Major complications associated with TUMT are substantially less frequent than those with TURP.²⁹ Adverse events include pain and discomfort from the procedure, which often necessitates analgesia use, and transient urinary retention requiring temporary urinary catheterization.^{29, 50} The incidence of erectile dysfunction is reported to be between 0.8 and 5% (Table 3).⁵⁷ Thus, complications with TUMT appear comparatively mild and readily managed, although there have been reports of serious adverse events including penile necrosis and urethral fistula.^{58, 59} A recent analysis comparing TUMT to TURP concluded that TUMT was more cost-effective as there was no hospital admission, and the need for retreatment after TUMT compared with that of TURP was limited (18 vs 11%). However, TUMT is available only in few urologic clinics.⁵⁰

Microwave therapy and medical management

A randomized study of 103 patients (International Prostate Symptom Score (IPSS) 9, Q_max <12 ml/s and voided volume 150 ml) comparing the efficacy, safety and durability of TUMT with the alpha-blocker terazosin reported significant differences between treatment modalities in the magnitude and timing of clinical effects.⁶⁰ At 2 weeks, treatment with alpha-blocker exhibited greater improvements in symptoms, Q_max and QOL scores. In contrast, by 12 weeks and thereafter, TUMT was markedly more efficacious than alpha-blockers in all three outcome measures. At 6 months, a 50% or greater improvement in symptoms, Q_max and QOL were achieved in a higher percentage of patients treated with TUMT (78, 65, and 84%, respectively) than alpha-blocker (33, 10 and 40%, respectively), and these outcomes on TUMT were maintained up to at least 18 months.⁶⁰ Adverse events resulting in discontinuation of therapy were reported in 11.5% of patients treated with an alpha-blocker. A limitation of this study is that only one alpha-blocker was evaluated; there was no inclusion of placebo group or sham arm and no placebo lead-in period. Thus, contribution of nonspecific effects on treatment outcomes could not be evaluated. Nevertheless, this study demonstrated that TUMT provides superior longer-term outcomes and is an option for patients when long-term improvement is a priority. In patients requiring rapid relief, however, therapy with an alpha-blocker is appropriate.³⁰ The combination of neoadjuvant and adjuvant alpha-blocker with TUMT has demonstrated early relief with long-term improvement.⁶¹

Transurethral needle ablation

Transuretheral needle ablation uses radio frequency energy to heat the prostate adenoma, which causes necrotic lesions and thermal damage to intraprostatic nerve fibers and results in smooth muscle relaxation and clinical improvement.⁶² The procedure can be performed in the office with local anesthesia and anxiolytics and takes an average of 30–45 min.⁴ About half of patients undergoing this procedure will need a Foley catheter for 1–2 days.⁴ Although there is no published report comparing TUNA and medical therapy, more than 30 studies have analyzed its efficacy. The efficacy of TUNA appears to be similar to that achieved by the TUMT devices (Table 4). However, in general, TUNA has a higher requirement for analgesia, sedation and anesthesia than does TUMT.¹ On average, TUNA reduces subjective symptoms by 60%.⁶³ Improvement in Q_max averages about 70%.⁴ These effects were durable and at 5 years post-treatment, Q_max was still >50% higher than at baseline.⁶⁴ Rates of erectile dysfunction and retrograde ejaculation are <2 and <4%, respectively (Table 3).¹ Another long-term study of patients who were followed for 5 years after they underwent TUNA reported that 24% required additional treatment (medical treatment, 7.4%; second TUNA, 4.3%; surgery, 11.1%).⁶⁵

The best candidates for TUNA are patients with a prostate volume <60 ml, patients with predominant lateral lobe enlargement, chronic urinary retention and high-risk patients who can only be treated under local anesthesia.^{1, 63} The cost of a TUNA system generator has become less expensive than the microwave systems, making it more likely to be available to most urologic centers.⁴ Thus, TUNA appears to be a valuable alternative for treating patients with severe symptoms and an attractive option for men who do not wish to have long-term medical therapy and who are poor candidates for surgery.⁶⁶

Interstitial laser thermal therapy

Interstitial Laser Thermal Therapy (ILTT) is also known as interstitial thermal therapy, interstitial laser therapy, interstitial laser coagulation, laser-induced thermal therapy and laser-delivered interstitial therapy. This is a technique that is still evolving⁶⁷ and long-term data are limited.⁴ A number of systems are in use worldwide, and each uses a laser generator and a flexible optical fiber to deliver laser energy into the prostate using standard cystoscopic equipment.⁴ Most of the data available on ILTT are from uncontrolled non-randomized studies. In one review including 785 patients, AUA-SI scores improved on average 70% (range, 32–92%) and Q_max improved an average of 98% (range, 35.2–203%). The variation in results is due in part to the evolving technology influencing ongoing procedural modifications.⁴ Retreatment rates at 1 year range from 0 to 15%. Although operative morbidity is virtually non-existent, immediate postoperative complications such as urinary tract infection (27–35%) and irritative voiding symptoms (11–12%) are highly prevalent.^{4, 67} Furthermore, catheterization is longer than 10 days in one-third of treated patients.⁶⁷ Nearly 72% of patients describe perineal pain and discomfort at 2 weeks.⁶⁷ Postoperative erectile dysfunction has not been reported; however, retrograde ejaculation is reported in 11% of patients. The risk for urinary incontinence is rare.⁴ With improvements in this technology, as well as increasing experience, the morbidity profile of ILTT is likely to continue to improve. Indeed, improved laser fiber insertion techniques have been demonstrated to provide more consistent urethral preservation and significantly lower postoperative complications,⁶⁸ whereas randomized, controlled, multicenter studies are beginning to be reported.⁶⁹

Photoselective vaporization

Photoselective vaporization of the prostate (PVP) is a relatively new procedure for treating BPH. Photoselective vaporization of the prostate uses a high-powered laser, also known as 'green light laser', to quickly vaporize and remove the obstructing prostate tissue without harming other tissue. Theoretical advantages include less bleeding, less risk of TUR syndrome and limited hospital stay. Depending on the size of the prostate gland, the surgery can last 20–50 min, and can be performed under local anesthetic on an outpatient basis. Photoselective vaporization of the prostate leads to immediate postoperative symptom relief and considerable improvements in symptoms, urinary flow rates and bladder emptying. Significant improvements have been noted within 1 month of the procedure. In addition to minimal amount of blood loss, the procedure is associated with minimal need for catheter use (many patients require no catheterization while others need it for only 24 h). The postoperative side effects reported have been minimal and transient. Significant improvements in AUA-SI score, QOL score, and Q_max and reduction in prostate volume were noted as early as 1 month after PVP treatment.⁵¹ In a study of 139 men, decreases in AUA-SI score from 23.9 to 4.3, QOL score from 4.3 to 1.1, prostate volume from 54.6 to 34.4 ml and increases in Q_max from 7.8 to 22.6 ml/s were reported at 12 months.⁵¹ This procedure is associated with lower incidence of retrograde ejaculation compared to TURP in sexually active men.⁵¹

Water-induced thermotherapy

Water-induced thermotherapy is a newer MIST with limited data. This procedure uses water as a source to produce heat-induced coagulative necrosis and secondary ablation of the prostate tissue.⁶⁷ The treatment is performed as a 45-min outpatient procedure using only topical anesthesia. Unlike most other MISTs, this form of therapy is operator independent and has a relatively short learning curve. Short-term results appear inferior to TURP. In a trial of 125 patients, IPSS score improved by a median of 12.5 points from baseline, Q_max increased by 6.4 ml/s and QOL score increased by 2.5 points. At the end of 1 year, a total of 61.5% patients achieved >50% improvement in IPSS score, 71.3% patients achieved >50% improvement in Q_max and 71.6% patients had >50% improvement in QOL score.⁵² Disadvantages of the technique include catheterization lasting more than 1 week in many patients.⁵² More long-term follow-up studies are needed to support this procedure.⁶⁷

Conclusions: choosing between medical and minimally invasive surgical therapies

Traditionally, the urologist's approach was to start with medical therapy and the patient was advised to undergo surgery when this failed.⁴ In his review on rationale and assessment of MISTs, Larson provides guidance on selecting among various treatment options (medical therapy, MISTs, surgery) and recommends considering a patient's symptom severity and the risk of complications (Figure 2).⁴⁹ Based on this guidance, medical therapies and surgery lie at the two extreme ends of both variables, with medical therapy as the first-line choice in the lower end of presentation of symptoms and risk of complications and surgery typically reserved for patients with extreme severity of symptoms and very high risk of complications. Minimally invasive surgical therapies are placed in between these two extremes. Minimally invasive surgical therapies are identified as a cost-effective alternative to surgery to attain a substantial improvement without the long-term complications associated with surgery. Patients who are appropriate candidates for MISTs, as outlined by Larson, include those who are poor candidates for surgery, have had limited success with medications and those who want to avoid long-term intake of medications. However, in this and previous reviews, medical therapies are compared with MISTs only in relation to symptom improvement.^{49, 70} Thus from a patient perspective, medical therapies can be viewed as agents to control symptoms alone without any added benefit long term, which can influence their decision against considering medical treatment for long-term management.

Figure 2.

Choosing among treatment options based on symptom presentation and risk of complications.⁴⁹

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The MTOPS study found that combination medical therapy (alpha-blocker+5ARI) not only improves symptoms but also slows clinical progression.¹⁰ Of notable interest were the individual progression events of AUR and invasive therapy; both were significantly reduced by 5ARIs at a rate comparable to combination therapy and the investigators attributed this to a reduction in prostate size.¹⁰ Treatment with doxazosin alone slightly delayed the time to AUR and invasive therapy, but failed to reduce the risk of these events over the duration of the study. This suggests that reduction in prostatic urethral obstruction achieved with alpha-blocker monotherapy is eventually overcome by continued prostate growth,¹⁰ which results in treatment failure. These findings have shifted the paradigm of treatment in the management of BPH. It appears that medical therapy, particularly the use of 5ARIs, provides superior longer-term outcomes and is appropriate to consider for patients to whom the major priority is improvement in terms of lowering the risks of complications. Recently published guidelines on the treatment of BPH^{1, 39} recommend using 5ARIs to reduce the progression of disease and risk of complications in men with evidence of an enlarged prostate; they also recommend using combination medical therapy in patients presenting with bothersome symptoms and an enlarged prostate.^{1, 39} Based on clinical evidence, it appears that both medical therapy and MISTs have similar long-lasting clinical benefits. Thus, guidance to the selection of treatment options as provided by Larson⁴⁹ can be modified as shown in Figure 3.

Figure 3.

Modified guidance for choosing from long-term treatment options based on current clinical evidence. ^*Although short-term efficacy is good, the failure rate is high over the long term.

Full figure and legend (13K)

Current guidelines do not provide clearcut recommendations regarding the choice between medical therapies and MISTs, but do consider incorporation of the patient's view point in treatment selection.^{1, 39} Owing to a lack of studies directly comparing these two approaches, the treating physician has to consider other factors based on clinical evidence such as efficacy, risk factors influencing treatment, presence of comorbid disease such as cardiovascular disease, active sexual life influencing treatment decisions, tolerance to pain and any other factor, including cost, deemed important in the treatment decision. In general, retreatment rates after MISTs are universally higher than after TURP, and the efficacy, cost and long-term durability of these therapies are still uncertain.² In contrast, efficacy of medical therapies has been well established based on evidence from long-term clinical trials.¹⁰ A recent study comparing medication with TUNA reported a high initial cost of TUNA in year 1 when the procedure is performed, at $4067 vs $1844 for combination therapy.⁷¹ At 2 years and 7 months after therapy, the cost of TUNA was similar to combination therapy and at 5 years TUNA was less expensive than combination therapy. At 5 years, alpha-blocker monotherapy was less costly compared with TUNA and the costs associated with 5ARI therapy were comparable to TUNA. This model, however, does not consider that patients undergoing TUNA frequently take medications for the long-term treatment of residual LUTS and thus hidden costs are not addressed.⁷² This level of treatment occurs frequently and adds to the total cost of treatment with MIST. In effect, clearcut cost comparisons between medical therapies and MIST are not yet available and other factors will play a role in the selection of appropriate therapy.

In a patient with an active sexual life, making the appropriate choice between medical therapy and MIST is difficult. Minimally invasive surgical therapies are associated with both ejaculation and erection disorders. Medical treatments also have repercussions on sexuality, although there are significant differences between the various classes of these drugs.⁷³ Numerous epidemiologic studies have clearly demonstrated a linear relationship between the prevalence of BPH and the loss of erectile function, and both these disorders increase with advancing age.^{74, 75, 76} Men with LUTS have sexual dysfunction, including ejaculatory loss, painful ejaculation and erectile dysfunction. Even though the pathogenic relationship between enlarged prostate and erectile dysfunction is not completely understood, a direct association between these two symptom complexes in aging men is now becoming evident.⁷² Sexual function is an important element of QOL and the impact of therapies on long-term sexual dysfunction should be considered. For example, young patients (age >50 to <70 years) with active sexual lives may prefer MIST over long-term combined medical therapy as 5ARIs are associated with more sexual side effects.⁷³ Similarly, in a patient with comorbid medical conditions, particularly cardiovascular conditions, use of MIST may be a preferable option, although certain procedures such as TUNA or TUMT are contraindicated in patients with a cardiac pacemaker. On the other hand, for a patient who cannot tolerate pain, has concern about development of urinary tract infections associated with MISTs or who has an active urinary tract infection (Table 3), long-term medical therapy might be a preferable option. In short, optimal treatment decisions depend critically on how patients value their current state and possible outcomes as a result of treatment.

Summary

BPH is regarded by most urologists as a progressive condition, which underscores the importance of a proactive approach in which at-risk patients are identified and treated.⁴⁴ Risk factors for BPH progression include age,¹⁸ an enlarged prostate >30 ml,^{10, 11} moderate-to-severe urinary symptoms (AUA-SI score >7),¹⁰ a weak urinary flow¹⁰ and a PSA concentration of 1.4 ng/ml.^{10, 11} Indeed, AUR and the future need for related surgery are considered by many men as the most deleterious outcomes of BPH.⁴⁴ The long-term nature of BPH necessitates a therapy that reduces and maintains reductions in prostate volume, has lasting effects on symptoms and minimizes the risk for adverse outcomes. Both medical therapy (with 5ARIs or combined therapy with alpha-blockers) and MISTs are appropriate treatment options in this regard. Lack of studies directly comparing these two approaches has made it difficult to make an appropriate treatment choice. This shortcoming was to have been addressed by the MIST Trial, a US National Institutes of Health study, which was designed to compare the long-term benefits and risks of MISTs with combination medical therapy.⁷⁷ However, this trial was discontinued owing to insufficient recruitment, and urologists will have to continue weighing the benefits associated with medical and minimally invasive treatment options against their risks, patient circumstances and personal choices to make an informed decision.

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Acknowledgements

We acknowledge Kanaka Sridharan, MS, RPh, for editorial assistance with this manuscript.