Benign Prostatic Hyperplasia: Current Treatment Strategies

ABSTRACT: Benign prostatic hyperplasia (BPH), one of the most common diseases of men, can lead to bladder outlet obstruction. Progressive BPH manifests as bothersome lower urinary tract symptoms. Current therapeutic options for BPH include active surveillance; medical therapy; and minimally invasive therapies, such as transurethral microwave therapy, transurethral needle ablation, laser therapies, and botulinum toxin injection.

Benign prostatic hyperplasia (BPH)— histologically defined as stromal and epithelial hyperplasia beginning in the periurethral transitional zone of the prostate—affects up to 80% of 80-year-old men.^1,2 With progressive prostatic enlargement, bladder outlet obstruction can result. Although the exact mechanism is unknown, lower urinary tract symptoms (LUTS) can signal progressive BPH.

Here we review current therapeutic options for BPH, including active surveillance; medical therapy (α-blockers, 5α-reductase inhibitors, anticholinergics, phosphodiesterase 5 [PDE-5] inhibitors, and phytotherapy); minimally invasive therapies (MITs), such as transurethral microwave therapy (TUMT) and transurethral needle ablation (TUNA); laser therapies; and botulinum toxin injection.

ACTIVE SURVEILLANCE

This approach is appropriate for patients with minimal LUTS (American Urological Association Symptom Score [AUA SS] of 7 or lower) or those with only mild to moderate symptoms (AUA SS of 8). Active surveillance is distinguished from watchful waiting in that patients are monitored annually for disease progression with a history, physical examination, AUA SS, and a bother score.² If symptoms or bother scores worsen, or if clinical sequelae such as retention or infection develop, treatment is warranted.

MEDICAL THERAPY

Before the late 1970s, the only treatment for patients with BPH was surgical resection, such as open prostatectomy or transurethral resection of the prostate (TURP). In 1978, Caine and colleagues³ reported that phenoxybenzamine, a nonselective α-blocker, was an effective treatment for patients with BPH. This seminal observation formed the basis for substantial research, with the result that α-blockers are currently the initial treatment for most men with symptomatic BPH.

α-Blockers. α-Blockers work by antagonizing the α-adrenergic receptors on the smooth muscle in the prostate.⁴ The α_1a is the predominant receptor in the human prostate.⁵

Currently available α-blockers include doxazosin, terazosin, alfuzosin, and tamsulosin. They are long acting (once-daily dosing) and α_1a- selective. A meta-analysis by Djavan and Marberger⁶ demonstrated a comparable magnitude of improvement in both AUA SS and urinary flow. Tamsulosin and alfuzosin had adverseeffect profiles comparable to those of placebo. Patients treated with terazosin and doxazosin, however, had a 4% to 10% greater dropout rate because of adverse effects than did patients receiving placebo. The adverse effects were typically dizziness, asthenia, somnolence, and headache.^7,8

Ejaculatory dysfunction occurs more frequently with tamsulosin, but the increased frequency is not large enough to be consistently detected in comparative studies.⁹ Both doxazosin and terazosin require dose titration when treatment is initiated because of the potential for hypotension. Tamsulosin and alfuzosin do not.

The Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) randomized patients with hypertension and other cardiac risk factors to receive either doxazosin or chlorthalidone, a diuretic. The doxazosin arm was terminated early because of a statistically significant (25%) higher incidence of major cardiovascular disease events, particularly congestive heart failure.¹⁰ Based on that study, the AUA 2003 Consensus Panel recommended that α-blockade should not be used as monotherapy for patients who have both BPH and hypertension and that a second agent should be used to manage the hypertension.²

The Medical Therapy of Prostatic Symptoms (MTOPS) study and the Alfuzosin Long-Term Efficacy and Safety Study (ALTESS) showed that α-blockers improve BPH symptoms and increase time to disease progression but do not prevent overall progression (defined as acute urinary retention and the need for invasive therapy).^11,12 These studies also showed that α-blockers are less effective in men with large prostates and that dropout rates are relatively high after 3 to 4 years of therapy.

5α-Reductase inhibitors. 5α- Reductase inhibitors manage BPH by decreasing prostate volume. Dihydrotestosterone (DHT) is the primary androgen involved in prostatic growth. 5α-Reductase inhibitors (finasteride and dutasteride) prevent the conversion of testosterone to DHT by competitively inhibiting the enzyme 5α-reductase. There are 2 isoforms of 5α-reductase enzyme, types 1 and 2. Finasteride is a selective inhibitor of only the type 2 enzyme, whereas dutasteride inhibits types 1 and 2.

The 4-year Proscar Long-term Efficacy and Safety Study (PLESS) showed that finasteride increased flow rate, decreased AUA SS, reduced prostate volume by 32%, lowered the risk of acute urinary retention by 57%, and reduced the need for BPH-related surgery by 55%.¹³ The MTOPS study demonstrated that finasteride significantly reduced the risk of clinical progression of BPH by 34% compared with placebo and reduced the risk of acute urinary retention and the need for invasive therapy.¹¹ The latter events (acute urinary retention and the need for invasive therapy) were not reduced in men receiving doxazosin monotherapy. The Prostate Cancer Prevention Trial (PCPT) showed that after 7 years, finasteride has an added benefit of decreasing the risk of prostate cancer by 24.8%.¹⁴

Dutasteride therapy had effects similar to those of finasteride. Roehrborn¹⁵ compared dutasteride with placebo and noted a decreased risk of acute urinary retention and BPHrelated surgery, a continuing improvement in flow rate and urinary symptoms, and a reduction in prostate volume. There was also a 50% reduction in the incidence of prostate cancer.¹⁶ The ongoing Reduction by Dutasteride in Prostate Cancer Events (REDUCE) trial is studying the effects of that drug on the incidence and progression of prostate cancer.¹⁶

Finasteride and dutasteride are well tolerated. Adverse effects (occurring in fewer than 1% of patients) include impotence, decreased libido, ejaculatory disorders, and gynecomastia. In most trials, men who experience adverse effects do so during the first year, with few additional subsequent adverse effects. 5α- Reductase inhibitors tend to have a greater effect in improving total symptom severity, frequency scores, and peak flow rates on prostates of larger volume.¹⁷

Combination therapy (an α- blocker plus a 5α-reductase inhibitor). The MTOPS study showed that management with a combination of finasteride and doxazosin reduced the clinical progression of BPH by 66% compared with treatment with finasteride or doxazosin alone (34% and 39%, respectively).¹¹ While patients in all 3 active treatment arms (finasteride alone, doxazosin alone, and combination) showed a significant improvement in symptom scores compared with placebo, the combination arm was superior.

The Combination Therapy of Dutasteride and Tamsulosin Trial (CombAT) is a 4-year, multicenter, randomized, double-blind, parallel group study comparing the benefits of tamsulosin monotherapy, dutasteride monotherapy, and combination therapy in men older than 50 with an International Prostate Symptom Score (IPSS) greater than 12 and a prostate volume greater than 30 cc.¹⁸ Preliminary 2-year data show a statistically significant reduction in IPSS with combination therapy (6.2 point decrease) versus either dutasteride or tamsulosin monotherapy (4.9 and 4.3 point decrease, respectively). A statistically significant improvement in maximum urinary flow rate (Q_max) from baseline was also noted in the combination therapy arm (2.4 mL/s) compared with the dutasteride and tamsulosin monotherapy arms (1.9 and 0.90 mL/s improvement, respectively).

The MTOPS trial suggests that α-blockers manage symptoms with a relatively rapid onset of action but do not prevent disease progression. This observation gave rise to a strategy of initially combining an α-blocker and a 5α-reductase inhibitor for a short duration (3 to 6 months) followed by withdrawal of the α-blocker and continuation of 5α-reductase inhibitor monotherapy

The Symptom Management After Reducing Therapy (SMART-1) study examined such an approach using dutasteride and tamsulosin. Men were randomized to tamsulosin and dutasteride for 24 weeks, after which 50% discontinued tamsulosin.¹⁹ Most patients (84%), with an initial IPSS of less than 20, who were switched to monotherapy had sustained improvement in BPH symptoms. Therefore, most patients with mild to moderate BPH symptoms may benefit from an initial short duration of combination therapy followed by 5α-reductase monotherapy.

Combined α-blocker therapy and anticholinergic therapy. Patients with BPH often have concomitant irritative voiding symptoms because of an overactive bladder (OAB). Kaplan and colleagues20 performed a randomized, double-blind, placebo-controlled trial comparing tolterodine extended-release (ER), tamsulosin, tolterodine ER plus tamsulosin, and placebo in patients who had mild to moderate BPH and OAB. They found a statistically significant reduction in incontinence, frequency, and nocturia in the tolterodine ER plus tamsulosin group. These patients also had a statistically significant improvement in IPSS and quality of life.

The incidence of acute urinary retention requiring catheterization was low in all arms (less than 0.5%); patients treated with tolterodine ER and those treated with tolterodine ER plus tamsulosin had only a statistically insignificant increase in postvoid residual volume (PVR) from baseline (5- to 6-mL). Blake-James and associates, 21 in a meta-analysis, observed similar results. Anticholinergic use did not significantly alter flow rates, and PVR was increased by only 11.6 mL (statistically insignificant). The rate of acute urinary retention was low (0.3%) and similar in all arms. Based on these data, anticholinergics appear to be safe to use in patients with both BPH and OAB.

PDE-5 inhibitors. Recent studies have shown that PDE-5 is present in human prostate and bladder tissue. This coupled with the observation that erectile function declines in men with increasing severity of LUTS prompted an initial evaluation of PDE-5 inhibitors as a treatment for LUTS. McVary and colleagues²² showed that both the IPSS and the BPH Impact Index were improved in men receiving tadalafil(Drug information on tadalafil). Larger trials are needed to confirm these initial observations.

Phytotherapy. In 2002, more than 2.5 million adults reported using Serenoa repens (saw palmetto).²³ In 1999, an estimated $1 billion was spent on phytotherapy for BPH, and spending has probably increased since that time.²⁴ Despite the widespread use of plant extracts, recent studies do not support their effectiveness in the management of BPH. Bent and coworkers²⁵ conducted a randomized, controlled, double-blind trial in 225 men comparing saw palmetto with placebo. They found no difference in change in AUA SS, Q_max, prostate size, quality of life, and adverse effects between the 2 groups. Until more data are produced, phytotherapy use remains controversial and cannot be currently recommended as a management option for BPH.

MINIMALLY INVASIVE THERAPY

MITs include TUNA and TUMT. They gained widespread use because of their safety profile and because they can be performed as office procedures. Although these management options were initially judged as equivalent to TURP, recent studies do not confirm their long-term effectiveness. Both therapies have significantly higher re-treatment rates compared with those of TURP.

TUNA. Bouza and associates²⁶ performed a meta-analysis on TUNA therapy, including 35 studies (mostly comparing TUNA and TURP). TUNA improved symptom index and quality- of-life scores by 50% to 60% from baseline and provided a 30% to 35% improvement in objective parameters (PVR and Q_max). Only 20% of patients experienced sexual adverse effects. The TUNA procedure had a 19% retreatment rate.

When comparing TUNA with TURP, short-term effectiveness appeared to be equivalent; however, within 1 year, there was a statistically significant difference in favor of TURP over TUNA. The re-treatment rate of men undergoing TUNA was 7.⁴⁴ times higher than the rate of those undergoing TURP. However, TUNA has a significantly lower complication rate than TURP.

TUMT. Hoffman and colleagues²⁷ performed a meta-analysis comparing TUMT with TURP. The pooled mean urinary symptom score decreased by 65% after TUMT and by 77% after TURP. Peak flows increased 70% after TUMT and 119% after TURP. Retrograde ejaculation (57% vs 22%), transfusion rate (5.7% vs 0%), and treatment of strictures (relative hazard, 9.76) were all significantly higher with TURP. However, re-treatment was significantly more common after TUMT (relative hazard, 10).

MITs, including TUNA and TUMT, appear to be safe procedures that provide short-term symptomatic relief. They are not as effective as TURP and have a higher re-treatment rate. Although MITs are not as durable as TURP, they are viable options in patients with significant operative risk. MITs may be an alternative to medical therapy in patients with mild to moderate voiding symptoms who do not want to take a pill every day.

LASER THERAPY

TURP remains the gold standard of treatment for men with BPH. Absolute indications for TURP include refractory urinary retention, persistent prostatic bleeding (after other causes of hematuria have been excluded), bladder calculi, recurrent urinary tract infections, deterioration in renal function, and failure of medical therapy.² Newer therapies, such as photoselective laser vaporization of the prostate (PVP), Holmium laser enucleation of the prostate (HoLEP), and Holmium laser ablation of the prostate (HoLAP), are currently being used widely and may replace TURP as the new gold standards of care.

PVP. This therapy uses the 80- watt potassium-titanyl-phosphate, or “green light laser,” that emits a 532- nm wavelength selectively absorbed by hemoglobin. The wavelength penetrates 2 to 4 mm and causes photoselective vaporization of the prostatic tissue. Because of vaporization and the shallow penetration, large-volume sloughing of the prostate does not occur. The effect of PVP is immediate.

Several articles have examined the safety and effectiveness of PVP among patients with large prostates (more than 60 g, with mean volume of 100 g),²⁸ those receiving anticoagulation medication,29 and those with significant comorbidities.^30,31 PVP can be used with normal saline and is not associated with transurethral resection (TUR) syndrome development even when large prostates are resected.³²

In a nonrandomized trial, Bachmann and coworkers³³ compared 37 patients undergoing TURP with 64 patients undergoing PVP, with 6- month follow-up. PVP patients had a shorter catheterization time (1.8 vs 3.0 days) but had a slightly higher recatheterization rate (7.8% vs 2.7%). The investigators noted similar 6- month improvements in symptom score and flow rate in both arms of the study.

Sarica and associates³⁴ presented the largest series (240 patients) with a 1-year follow-up. Catheterization time averaged 12 hours, and hospitalization stays were all less than 24 hours. At 1 year, mean IPSS decreased from 22.6 to 3.7 (84%), and peak flow rate increased from 7.9 ± 2.7 mL/s to 27.9 ± 10.3 mL/s. Malek and colleagues³⁵ reported durable improvements in symptom score, quality-of-life score, peak flow rates, and PVR up to 5 years. These studies reported minimal adverse effects, the most common of which was transient dysuria that lasted up to 14 days.

One drawback of PVP is the lack of tissue specimen; however, this seems to be less of an issue in the prostate-specific antigen era. Some urologists are bothered by the special glasses required to perform PVP (everything appears orange). Despite these disadvantages, PVP appears to be a safe and efficient alternative to traditional TURP, although long-term (more than 5 years) data are not yet available.

Holmium laser (HoLEP and HoLAP). The Holmium laser has a wavelength of 2140 nm that is strongly absorbed by water. The laser only penetrates 0.4 mm, resulting in precise tissue vaporization without deep coagulation or surrounding char effect. HoLEP involves transurethrally enucleating the individual lobes of the prostate with an end-firing Holmium laser and floating the enucleated lobes into the bladder. The prostate tissue is then removed with a transurethral mechanical morcellator.

Kuntz³⁶ reviewed the use of HoLEP in more than 5000 patients. He reported that HoLEP can be used in prostates of all sizes (even more than 300 g) and in patients receiving anticoagulation medication. Operative times were longer with HoLEP than with TURP, but intraoperative blood loss was less, hospitalization time was shorter, catheterization times were less, and TUR syndrome did not occur.

In the reviewed studies, patients who underwent HoLEP had results— urinary improvement and relief of bladder outlet obstruction based on urodynamics—that were better than or equivalent to those for TURP. Westenberg and associates³⁷ and Kuntz and coworkers³⁸ reported durable results with HoLEP compared with TURP with 4-year and 3- year follow-up. HoLEP provides tissue for diagnosis; the other vaporization procedures do not. Despite these advantages of HoLEP, it is not performed widely, possibly because of its steep learning curve.

HoLAP was initially described in 1994 and has recently gained widespread use with its new 100- watt laser and side-firing arm. Although no long-term data are yet available, it seems to be an attractive treatment for patients with BPH. It has a short learning curve, and it results in minimal or no hospital stay, early catheter removal, and the ability to treat patients with significant medical comorbidities and those receiving anticoagulation medication. HoLAP results in less sloughing and decreased irritative voiding compared with PVP because of its shallower depth of penetration (0.4 mm vs 2 to 4 mm).

The 100-watt Holmium laser is a versatile tool for urologists; it can be used in the management of other conditions, including stones, strictures, and tumors.

BOTULINUM TOXIN

Botulinum toxin type-A (BONTA), produced by the bacterium Clostridium botulinum, has recently gained interest for the management of symptomatic BPH. Botulinum toxin is injected into the prostate either transurethrally, transrectally, or transperineally with transrectal ultrasonographic guidance. Between 100 and 200 units of BONT-A are injected into both lobes of the prostate.

Oeconomou and associates³⁹ recently published a review of the effects of BONT-A on BPH in animal models and the results of 10 clinical trials including 294 patients. Although the mechanism of action is unknown, BONT-A seems to produce apoptosis and atrophy of prostatic tissue in animal models. BONT-A may also have an effect on the dynamic component of BPH; it is effective in patients with small prostates (less than 30 g).

Although the reported studies have small patient numbers (the largest study included 52 patients), preliminary data appear promising, with improvements in symptom score, peak flows, quality of life, and reduction in prostatic volume. Durable results as long as 19 months have been reported. Caution is advised in using BONT-A to manage BPH until the mechanism of action is further defined and large randomized clinical trials are performed to further validate the safety and effectiveness of this treatment. This use of botulinum toxin in this setting is not FDA-approved.