72 CHAPTER 3 Bladder outlet obstruction

Why do men seek treatment for their symptoms?

Men seek treatment for their LUTS for several reasons:

•The symptoms may be bothersome.

•They may fear that the symptoms are a warning sign that acute urinary retention will develop.

•They may be concerned that their symptoms indicate that they have prostate cancer.

Establish what the patient wants from his consultation with you. Once reassured that the likelihood of urinary retention and prostate cancer is low, he may not want treatment for symptoms that on the surface may appear quite bad and he may be happy to adopt a policy of watchful waiting.

Bothersome symptoms

Bothersome symptoms do not necessarily equate with symptom severity as assessed by symptom scores. Thus, a man with a low symptom score may find his symptoms very bothersome and may want treatment, whereas another man with a high symptom score may not be bothered and may want no treatment.

If one symptom is particularly bad, but the other 6 symptoms in the 7-symptom score are minimal, overall symptom score will obviously be relatively low, but the patient may find that one symptom very bothersome (e.g., urgency and nocturia tend to be more bothersome than hesitancy or poor flow).

“Are my symptoms due to prostate cancer?”

No particular LUTS are specific for prostate cancer. Even if it turns out that the patient does have prostate cancer, a patient’s symptoms might be due to coexistent BPH or some other LUT pathology. If he is concerned about the possibility of prostate cancer, counsel him with regard to PSA testing and prostate biopsy.

“Am I likely to develop retention of urine?”

Many patients are understandably concerned that their urinary symptoms may be a harbinger for the development of acute urinary retention. This may influence their decision to seek help for symptoms that they may perceive as indicating a risk of subsequent retention, and it may affect the type of treatment they choose.

Table 3.1 can help give the patient some idea of his risk of developing urinary retention.

WHY DO MEN SEEK TREATMENT FOR THEIR SYMPTOMS? 73

Table 3.1 Yearly risk of retention according to age and symptom score (number of men experiencing an episode of retention every year)*

Adjusting for age and flow rate, those with an AUA symptom score of 8 or more had a 2.3-fold increased risk of going into urinary retention compared with those with an AUA score of 7

or less. Those men with a peak flow rate of <12 mL/s had a 4-fold increased risk of urinary retention compared with those with a flow rate of >12 mL/s. Prostate volume over 30 mL was associated with a 3-fold increased risk of urinary retention compared with those with prostate volumes <30 mL

This table is from Jacobsen et al.’s (1997) report,1 a 4-year prospective study of a cohort of >2000 men. The presence of LUTS, a low flow rate, an enlarged prostate, and old age were associated with an increased risk of urinary retention.

1 Jacobsen SJ, Jacobson DJ, Girman CJ, et al. (1997) Natural history of prostatism: risk factors for acute urinary retention. J Urol 158:481–487.

Further reading

McConnell JD, Bruskewitz R, Walsh P, et al. (1998). The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med 338(9):557–563.

74 CHAPTER 3 Bladder outlet obstruction

Watchful waiting for uncomplicated BPH

A number of studies have shown that in a substantial proportion of men, symptoms do not progress, even for those with severe symptoms.

Ball et al. study1

A total of 107 men were followed with watchful waiting over 5 years, and none developed an absolute indication for surgery. Half of the patients were obstructed on urodynamic testing. A third of the patients got better, just under a half stayed the same, a quarter got worse (of whom 8 underwent TURP), and 2% went into retention.

PLESS study2

In the Proscar long-term efficacy and safety study (PLESS), 1500 men with moderate to severe symptoms were randomized to placebo (and a similar number to active drug). Those on placebo had an average fall in symptom score of 1 point at 4 years.

Wasson study of watchful waiting vs. TURP3

For men with moderate symptoms, the risk of progression to retention, worsening symptoms, or need for TURP was relatively low in those who chose watchful waiting. Forty percent noticed an improvement in their symptoms, 30% got worse, and TURP was required in about a quarter.

Five centers’ study4

In this study, 500 men referred by their family doctors for consideration for TURP were managed nonoperatively after viewing an educational program. Over the following 4-year period, a proportion of the men chose drug treatment or surgery. For men with mild, moderate, or severe symptoms, 10%, 24%, and 39%, respectively, had undergone surgery at the end of 4 years. For the same symptom categories, 63%, 45%, and 33% were still not receiving any treatment at the end of 4 years. Almost a quarter of men who initially presented with severe symptoms noted an improvement in their symptoms, to mild or moderate.

On the basis of all of these studies we can say that symptoms, even if severe, do not necessarily get worse even over fairly long periods of time. This forms the foundation of watchful waiting as an option for many patients, even if the symptoms at baseline are severe.

The International Prostate Symptom Score (IPSS) measures not only symptom severity but also, more importantly, the bother that the symptoms cause the patient. Thus, if a patient has a high symptom score (severe symptoms) but is not bothered by these symptoms, there is no indication for treatment.

By contrast, some patients have a low symptom score but may find even this degree of symptoms very bothersome. Treatment is indicated in such cases (usually starting with medical therapy such as an A-blocker or 5A-reductase inhibitor).

76 CHAPTER 3 Bladder outlet obstruction

Medical management of BPH: A-blockers

The rationale for A-blocker therapy in BPH

As described earlier, BPO is caused partly by A1-adrenoceptor-mediated prostatic smooth muscle contraction, and this is the rationale for A-adrenoceptor blocker treatment for symptomatic BPO.

There are two broad subtypes of A-adrenoceptor (AR)—A1 and A2. Molecular cloning studies have identified three A1-AR subtypes—A1a (predominant in human stroma and therefore mediates prostate smooth muscle contraction), A1b (predominant in human prostate epithelium), and A1L (believed to be a conformational state of the A1a-AR). The AR subtypes mediating efficacy and side effects of A-adrenoceptor blocking drugs are unknown.

A-Blocker classification

A-Blockers are categorized by their selectivity for the AR and by their elimination half-life.

•Nonselective: phenoxybenzamine or prazosin—effective symptom control, but high side-effect profile

•Long-acting A1: terazosin, doxazosin

•Subtype selective: tamsulosin, alfuzosin, and silodosin—relatively selective for A1a-AR subtype compared to the A1b subtype

No study has directly compared one A-blocker with another in terms of efficacy or side effects.

Indications for treatment

These include bothersome lower urinary tract symptoms where watchful waiting has failed or the patient wishes to have treatment.

Efficacy

Percentage of patients who respond to A-blockers

If response is defined as >25% improvement in symptoms relative to placebo, most studies describe response rates of 30–40%.1 The mean probability for improvement in symptom score after TURP is on the order of 80% (i.e., 8 out of 10 men will notice an improvement in their symptoms after TURP).

Improvements in symptom score in men who respond to A-blockers

The average improvement in symptom score after TURP is about 85%.2 While some of this may represent a placebo response, this improvement is considerably better than that seen with the A-blockers, which result in a 10–30% improvement in symptom score relative to placebo.3 This equates to a 4–5 point improvement in symptom score over placebo.

Side effects

A substantial proportion of men stop taking their medication because of either side effects (15–30% report some constellation of side effects) or a perceived lack of effectiveness.

Side effects include asthenia (weakness, in 5%), dizziness (6%), headache (2%) and postural hypotension (1%), and retrograde ejaculation (8%).

78 CHAPTER 3 Bladder outlet obstruction

Medical management of BPH: 5A-reductase inhibitors

5A-reductase inhibitors inhibit the conversion of testosterone to dihydrotestosterone (DHT), the more potent androgen in the prostate. This causes shrinkage of the prostatic epithelium and thus a reduction in prostate volume, thereby reducing the static component of benign prostatic enlargement. This takes some months to occur, so urinary symptoms will not improve initially.

Finasteride is a competitive inhibitor of the enzyme 5A-reductase (type II isoenzyme), which converts testosterone to DHT. Finasteride therefore lowers serum and intraprostatic DHT levels.

Dutasteride is a dual inhibitor (type I and II isoenzyme) of 5A-reductase. Whether it has any clinically significant advantages over finasteride in the treatment of BPH remains to be established.

Efficacy

A number of large studies have shown symptom improvement over placebo on the order of 2–3 points on the IPSS and improvements in flow rate on the order of 1–2 mL/s (SCARP1 [Scandinavian BPH Study Group], PROSPECT2 [Proscar Safety Plus Efficacy Canadian Two-year Study], PROWESS [Proscar Worldwide Efficacy and Safety Study] Group,3 and, more recently, PLESS4 [Proscar Long-term Efficacy and Safety Study]). The PLESS data also show a small reduction in the risk of urinary retention.

Side effects

Generally speaking, these are fairly mild. Principally they center on sexual problems (e.g., loss of libido, 5%; impotence, 5%; reduced volume of ejaculate in a few percent of patients).

5D-reductase inhibitors and risk of urinary retention

The PLESS data4 have been widely publicized as showing a substantial reduction in the risk of urinary retention. In this 4-year follow-up study, 42 of 1471 men on finasteride went into urinary retention (3%), while 99 of 1404 on placebo experienced an episode of retention (7%). This represents an impressive 43% relative reduction in risk in those taking finasteride.

However, the absolute risk reduction over a 4-year period is a less impressive 4%. So, finasteride does reduce the risk of retention, but it is reducing the risk of an event that is actually quite rare, as suggested by the fact that 93% of men on placebo in this study did not experience retention over a 4-year period. Put another way, to prevent 1 episode of retention, 25 men would have to continue treatment with finasteride for 4 years.

5D-reductase inhibitors for hematuria due to BPH

Shrinking large vascular prostates probably helps reduce the frequency of hematuria in men with BPH.5

MEDICAL MANAGEMENT OF BPH: 5A-REDUCTASE INHIBITORS 79

Further reading

Debruyne FM, Jardin A, Colloi D, et al. (1998). Sustained-release alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia. Eur Urol 34:169–175.

Kirby RS, Roerborn C, Boyle P, et al. (2003). Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology 61:119–126.

Lepor H, Williford WO, Barry MJ, et al. (1996). The efficacy of terazosin, finasteride, or both in benign prostatic hypertrophy. N Engl J Med 335:533–539.

McConnell JD, Roehrborn CG, Bautista OM, et al. (2003). The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. New Engl J Med 349:2387–2398.

1 Andersen JT, Ekman P, Wolf H, et al. (1995). Can finasteride reverse the progress of benign prostatic hyperplasia? A two-year placebo-controlled study. The Scandinavian BPH Study Group. Urology 46:631–637.

2 Nickel J, Fradet Y, Boake RC, et al. (1996). Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomised controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two Year Study. Can Med Assoc J 155:1251–1259.

3 Marberger MJ (1998). Long-term effects of finasteride in patients with benign prostatic hyperplasia: a double-blind, placebo-controlled, multicenter study. PROWESS Study Group. Urology 51:677–686.

4 McConnell JD, Bruskewitz R, Walsh PC, et al. (1998). The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study (PLESS) Group. N Engl J Med 338:557–563.

5 Foley SJ, Soloman LZ, Wedderburn AW, et al. (2000). Finasteride for haematuria due to BPH. A prospective study of the natural history of hematuria associated with BPH and the effect of finasteride. J Urol 163:496–498.