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Vol. 332 No. 2 DRUG THERAPY 99

DRUG THERAPY

ALASTAIR J. J. WOOD , M.D.,Editor

BENIGN PROSTATIC HYPERPLASIA

Medical and Minimally Invasive TreatmentOptions

JOSEPH E. OESTERLING

, M.D.

From the Michigan Prostate Center, University of Michigan, 1500 E. MedicalCenter Dr., Ann Arbor, MI 48109, where reprint requests should be addressed toDr. Oesterling.

B

ENIGN prostatic hyperplasia is a nonmalignantenlargement of the prostate that is due to exces-

sive cellular growth of both the glandular and the stro-mal elements of the gland. The condition is very com-mon in men over 40 years of age of all races andcultures.

1-8

For the past 50 years, transurethral resec-

tion of the prostate has been the mainstay of treatment.Approximately 400,000 such resections are performedannually in the United States, making this operationthe second most common after cataract extraction inmen older than 65.

9

The associated expense is consid-erable; the total cost is approximately $5 billion per

year.

10

Although transurethral resection of the prostate isan effective treatment for most men with symptomaticbenign prostatic hyperplasia, it is by no means perfect.

Approximately 20 to 25 percent of patients who under-go the operation do not have satisfactory long-termoutcomes.

11

The complications include retrograde ejac-

ulation in 70 to 75 percent of men, impotence in 5 to10 percent, postoperative urinary tract infection in5 to 10 percent, and some degree of urinary inconti-nence in 2 to 4 percent. Approximately 5 to 10 percentreceive a blood transfusion, with its risk of infection.

12-14

Another concern is that the rate of reoperation is ap-proximately 15 to 20 percent in men followed for 10

years or longer (2.2 percent per year).

15

Also, in severalpreliminary retrospective studies, the life expectancy ofmen undergoing transurethral resection of the prostate

was shorter than that of men undergoing open prosta-tectomy as treatment for benign prostatic hyper-plasia

16,17

; additional studies will be necessary to verify

these initial observations. Because of these problems,as well as the desire of many men to avoid surgerywhenever possible, there has been much interest in al-ternative treatments (Table 1).

Currently, the management of benign prostatic hy-perplasia is in transition. Although surgical treat-ment will continue to be widely used, medical therapy

will assume increasing importance. As a result, in-ternists and primary care physicians will have moreinvolvement in the care of men with this conditionthan previously. In this discussion, the most impor-tant medical and minimally invasive treatments for

men with symptomatic benign prostatic hyperplasiaare reviewed.

E

VALUATING

T

REATMENT

O

PTIONS

The efficacy of any medical, minimally invasive, orsurgical treatment for symptomatic benign prostatic

hyperplasia is determined primarily on the basis of twofactors: decrease in the patients symptoms and im-provement in the rate of urinary flow. Other variables,less commonly used, include the residual volume ofurine after voiding and the results of pressureflowurodynamic studies. To assess the symptoms caused byan enlarging prostate gland and the improvement re-sulting from treatment, several different systems havebeen developed, including the MadsenIversen pointsystem, the Boyarsky guidelines, and the Maine Medi-cal Assessment Program score.

33-35

None of these, how-ever, have been formally evaluated with regard to thereliability and reproducibility of results, and all rely on

clinical judgment and interviews with patients. The re-cently formulated and validated American UrologicalAssociation Symptom Index is becoming the standardtest with which to assess symptoms of prostatism.

36,37 Itcontains seven questions and yields a score correspond-ing to ratings from mild to severe; the patient ad-ministers the test to himself to eliminate any bias frominterview technique (Table 2). Unlike prostatic size,

which has no correlation with the degree of prostatism,the score obtained from the symptom index is a reli-able indicator of symptoms.

The other factor that provides objective informationabout a patients ability to urinate is the urinary-flow

rate (Table 3).

39,40

This is determined by electronicallyrecording the velocity of urine expelled from the blad-der during micturition; it is the single best test for as-sessing obstruction of the bladder outlet.

41

The peakflow rate is a more specific indicator of benign prostatichyperplasia than the mean rate. The rate decreases inall men with advancing age and decreasing urine vol-ume.

38,42

For a man in the seventh or eighth decade oflife who voids 150 ml or more, a peak urinary-flow rateof 15 ml per second is normal, whereas the same rate

would be considered abnormal in younger men or menvoiding with very high intravesical pressure. When thisinformation is considered together with the symptom

score, the physician can determine whether the pa-tients prostatism is mild, moderate, or severe and towhat extent it improves during or after any treatment.For men in whom the symptom score and peak uri-nary-flow rate are not in agreement, additional urody-namic evaluation consisting of the measurement of re-sidual urine volume after voiding and pressureflowstudies may be helpful. For each treatment discussedhere, the efficacy is presented in terms of the change insymptom score, peak urinary-flow rate, and other uro-dynamic factors as appropriate.

M

EDICAL

T

REATMENTS

Androgen-Deprivation Therapy

Aging and androgens are required for the develop-ment of benign prostatic hyperplasia. Because the pros-

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100 THE NEW ENGLAND JOURNAL OF MEDICINE Jan. 12, 1995

tate gland is an androgen-sensitive organ, androgendeprivation decreases the size of the prostate and theresistance to outflow through the prostatic urethra, andthe ability of many patients to urinate improves.

43,44

Producing a state of androgen deprivation means inter-rupting the hypothalamicpituitarygonadal axis (Fig.

1).

45-48

Of the agents that diminish androgen secretionor action gonadotropin-releasing hormone (GnRH)analogues,

49-53

antiandrogens,

54-58

and 5

a

-reductase in-hibitors

59-65

the 5

a

-reductase inhibitors have re-ceived the most attention.

Drugs That Inhibit 5a

-Reductase Activity

Type 2 5

a

-reductase catalyzes the conversion of tes-tosterone to dihydrotestosterone in most androgen-sensitive tissues, and blocking the conversion causesandrogen deficiency in those tissues. Finasteride [

N

-(2-methyl-2-propyl)3-oxo-4-aza-5

a

-androst-1-ene-17

b

-carboxamide] is a potent inhibitor of 5

a

-reductase and

can be given orally, once a day. It is the only such com-pound to be approved by the Food and Drug Adminis-tration (FDA) for the treatment of benign prostatic hy-perplasia, although other 5

a

-reductase inhibitors arebeing developed.

The initial studies of finasteride, previously sum-marized in the Journal

by Rittmaster,

64

indicated thatprostate volume decreased by 18 percent, the symptomscore decreased by 26 percent, and the peak urinary-flow rate increased by approximately 23 percent when5 mg of the drug was administered orally on a daily ba-sis. A recent report described the long-term (three

year) safety and efficacy of finasteride.

65

Of 543 men

with benign prostatic hyperplasia who were originallyassigned to receive finasteride (5 mg orally daily) in theNorth American and international trials, 297 (55 per-cent) could be evaluated, 178 (33 percent) withdrewfrom the study for various reasons, and 68 (13 percent)could not be evaluated because of insufficient data. Af-ter three years, prostatic volume was reduced frombase line by approximately 27 percent, the peak uri-nary-flow rate had improved by 2.3 ml per second, and

the symptom score had improved by 3.6 points. Forty-two percent of the men had decreases of 30 percent ormore in prostatic volume, 40 percent had increases of3 ml per second or more in the peak urinary-flow rate,and 48 percent had decreases of 50 percent or more inthe symptom score. Thus, the improvement achieved

after 12 months with 5 mg of finasteride as comparedwith placebo was maintained with extended treatment.Finasteride has few side effects. Approximately

5 percent of men treated with it in the two large trialssubsequently had decreased libido, ejaculatory dysfunc-tion, or impotence, as compared with 1.5 percent of themen receiving placebo (P

0.05).

20,63

Finasteride alsocaused a 50 percent decrease in serum concentrationsof prostate-specific antigen, so the highest value thatshould be considered normal in men treated with finas-teride is lower by half than that in other men.

65-68

Although finasteride is a potent 5

a

-reductase inhib-itor and causes a marked decrease in serum and tissue

concentrations of dihydrotestosterone, it is only moder-ately effective in treating symptomatic benign prostatichyperplasia. For many men, the clinical improvement isminimal. Perhaps the most attractive feature of finas-teride is its excellent toxicity profile. As more men aretreated with the drug, it should be possible to deter-mine its effect on the subsequent development of pros-tate cancer and whether it alters the value of serummeasurements of prostate-specific antigen as an indica-tor of prostate cancer.

a

-AdrenergicAntagonist Drugs

The clinical manifestations of bladder-outlet ob-

struction in men with benign prostatic hyperplasia arecaused by increased resistance to the flow of urinethrough the bladder neck and the prostatic urethra.Historically, this obstruction has been relieved by re-

Table 1. Medical and Minimally InvasiveTreatments for Benign Prostatic Hyper-

plasia.

MedicalAndrogen-deprivation therapyGonadotropin-releasing hormone agonists

18

Antiandrogens

19

5

a

-Reductase inhibitors

20

a

-Adrenergic antagonists

21

Minimally invasiveTransurethral incision of the prostate

22

Balloon dilation of the prostate

23

Prostatic stents

24

Microwave therapyTransrectal hyperthermia

25

Transurethral hyperthermia

26

Transurethral thermotherapy

27

Laser prostatectomyTransurethral ultrasound-guided, laser-induced

prostatectomy

28

Visual laser ablation of the prostate

29

Contact laser ablation of the prostate

30

Transrectal high-intensity focused ultrasoundtherapy

31

Transurethral needle ablation of the prostate

32

Table 2. Questionnaire Used by the American Urological Associ-ation to Determine Symptom Scores for Patients with Benign

Prostatic Hyperplasia.

Question

1. Over the past month or so, how often haveyou had a sensation of not emptying yourbladder completely after you finished uri-

nating?2. Over the past month or so, how often have

you had to urinate again less than twohours after you finished urinating?

3. Over the past month or so, how often haveyou found you stopped and started againseveral times when you urinated?

4. Over the past month or so, how often haveyou found it difficult to postpone urina-tion?

5. Over the past month or so, how often haveyou had a weak urinary stream?

6. Over the past month or so, how often haveyou had to push or strain to begin urina-tion?

7. Over the last month, how many times didyou most typically get up to urinate fromthe time you went to bed at night until the

time you got up in the morning?

Possible answers:0

Not at all1

Less than 1 time in 52

Less than half the time3

About half the time4

More than half the time5

Almost always

0, 1, 2, 3, 4, or

5 times

Symptom score (sum of the answers)

0 7

mild prostatism818

moderate prostatism1935

severe prostatism




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moving the prostatic tissue that obstructs the prostaticurethra. Medical therapies with an endocrine basishave also been devised to decrease the size of the pros-tate. In an attempt to relieve infravesical obstruction,

a

-adrenergicantagonist drugs are given to block theadrenergic receptors in hyperplastic prostatic tissue,the prostatic capsule, and the bladder neck, so that the

smooth-muscle tone of these structures is decreased. Asa result, resistance to urinary flow through the bladderneck and the prostatic urethra decreases, and urinaryflow increases.

Benign prostatic hyperplasia has two components: astatic component that is related to the enlargement ofthe prostate and a dynamic component that reflects thetone or degree of contraction of smooth muscle withinthe prostate.

69

This static as compared with dynamicmodel followed from early studies showing a contrac-tion of prostatic tissue in response to the administra-tion of norepinephrine. Caine and associates

70

demon-strated the presence ofa

-adrenergic receptors in both

the prostatic capsule and hyperplastic prostatic tissue;in the same tissues, the concentration ofb

-adrenergicreceptors was low and cholinergic receptors were bare-ly detectable. These tissues have two types of a

-adre-nergic receptors, denoted a

1

and a

2

.

71

Three subtypesof the a

1

receptor a

1a

, a

1b

, and a

1c

have beenidentified and are present in prostatic tissue

72-74

; thecontraction of prostatic smooth muscle appears to bemediated by the a

1c

subtype.

75

On the basis of thisphysiologic makeup and the fact that tissue affected bybenign prostatic hyperplasia is rich in smooth muscle,

a

1

-adrenergicantagonist drugs should decrease blad-der resistance to urinary outflow and therefore be ef-

fective in treating the condition. Because of the relativesparsity ofa

-adrenergic receptors in the bladder prop-er, this effect should be achieved without interfering

with bladder contraction.A variety of a

-adrenergic antagonists with distinctproperties have been investigated as possible treat-ments for benign prostatic hyperplasia (Table 4). Theone most studied, particularly in North America, is ter-azosin. In a multicenter study of 285 men with symp-tomatic benign prostatic hyperplasia who were as-signed to receive either placebo or 2, 5, or 10 mg ofterazosin once daily, 237 (83 percent) completed the4-week, single-blind, lead-in placebo period and the

12-week, double-blind treatment period.

82

The menwho received terazosin had a greater decrease in thesymptom score than those who received placebo; thedifferences were significant only among the men who

received 5 or 10 mg daily (P

0.04 and P

0.001, re-spectively). With regard to the peak urinary-flow rate,all the men treated with terazosin had greater increasesthan the men receiving placebo, but the mean differ-ence (1.5 ml per second) was significant only amongthe men treated with 10 mg daily (P

0.009). For a giv-

en dosage, the maximal therapeutic effect, as measuredby the symptom score or the urinary-flow rate, wasreached four to six weeks after the start of therapy. Theimprovement in these measures did not, however, reacha plateau within the dose ranges evaluated in the study,suggesting that further benefit may be achieved withhigher doses of terazosin.

In an open-label study of the long-term efficacy andsafety of terazosin in 494 men with benign prostatic hy-perplasia, 351, 206, and 64 men could be evaluated at12, 24, and 30 months, respectively.

83

Improvement inthe symptom score and the peak urinary-flow rate after12 weeks of therapy was maintained throughout the 30-

month follow-up period; treatment was considered to

*The correct interpretation can depend on the volume voidedand on the patients age.

38

Table 3. General Guidelines for the Interpre-tation of Peak Urinary-Flow Rates.

*

R

ATE

OF

F

LOW

D

EGREE

OF

P

ROSTATISM

ml/sec

15 to 20 Mild

10 to

15 Moderate

10 Severe

Figure 1. Regulation of Testicular Androgen Secretion and Mech-

Pituitarygland

GnRHHypothalamus

Prostategland

GnRHagonists

TesticularLeydig cells

T

T

T

LH

A

B

R

R

T

T-R

DHT DHT-R

Antiandrogens

Nucleus

5a-Reductase

5a-Reductaseinhibitors

anism of Androgen Action.

Panel A shows the hypothalamicpituitarygonadal axis, with thesite of action (X) of gonadotropin-releasing hormone (GnRH)agonists and the sites of the inhibitory (

) and stimulatory (

)actions of testosterone (T). LH denotes luteinizing hormone.(Adapted from Oesterling

45

with the permission of the publisher.)

Panel B shows the mechanism by which testosterone stimulatesprostatic-cell activity, with the sites of action (X) of antiandrogensand 5

a

-reductase inhibitors. DHT denotes dihydrotestosterone,

DHT-R dihydrotestosteronereceptor complex, R cytoplasmic re-ceptor for androgens, and T-R testosteronereceptor complex.(Reprinted from Monda and Oesterling

46

with the permission ofthe publisher.)




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have failed in only 10 percent of the men. An importantfinding concerned the selective antihypertensive effectof terazosin. The mean decreases in systolic blood pres-sure in normotensive and hypertensive men duringtreatment were 4 and 18 mm Hg, respectively, an indi-

cation that terazosin can be an effective concomitanttreatment for hypertension.The adverse effects of terazosin in men receiving 5 or

10 mg daily include asthenia in 6 to 10 percent, postur-al hypotension in 6 to 8 percent, and dizziness in 5 to10 percent. Beginning therapy with a titration schedule(for example, 1 mg for 3 days, 2 mg for 11 days, 5 mgfor 7 days, and 10 mg thereafter, given at bedtime) mayminimize these adverse effects as well as any decreasein systolic or diastolic blood pressure. Terazosin has noeffect on sexual function, and neither it nor any of theother selective a

1

-adrenergic antagonists alters the se-rum concentration of prostate-specific antigen.

Doxazosin is another long-acting, selective a

1

-adre-nergic antagonist that is being investigated in the treat-ment of benign prostatic hyperplasia. In a 16-weekdouble-blind, placebo-controlled, dose-titration studyinvolving 100 normotensive men, the mean peak uri-nary-flow rate increased by 2.9 ml per second in thedoxazosin group and by 0.7 ml per second in the place-bo group (P

0.05).

80

The mean symptom score im-proved by 5.7 points in the men treated with doxazosinand by 2.5 points in those given placebo (P

0.05).Adverse effects consisting of dizziness, fatigue, andheadache were more pronounced, though minimal, inthe doxazosin-treated men; the mean decrease in sys-

tolic and diastolic blood pressures was approximately5 mm Hg in these men.Tamsulosin is another long-acting, selective a1-adre-

nergic antagonist that has been used to treat men withbenign prostatic hyperplasia. In a clinical trial evaluat-ing its safety and efficacy,81 270 men with obstructive

voiding symptoms were randomly assigned to receiveplacebo or 0.1, 0.2, or 0.4 mg of tamsulosin once dailyfor four weeks after a two-week lead-in placebo period;12, 15, 40 and 36 percent, respectively, had improve-ment in the mean peak urinary-flow rate (P not signif-icant); 10, 28, 38, and 39 percent had moderate-to-marked improvement in symptom scores; and 0, 1, 3,

and 3 percent had adverse effects.Alfuzosin is a short-acting, selective a1-adrenergicantagonist that has been investigated extensively in

Europe.77 Among 518 men given either placebo or 7.5or 10 mg of alfuzosin once daily for six months, themean symptom score (calculated by the Boyarskymethod) decreased from 9.5 to 5.5 (a 42 percent de-crease) in the alfuzosin group and from 9.4 to 6.4 (a32 percent decrease) in the placebo group (P0.001).

The peak urinary-flow rate increased by 11 percent inthe alfuzosin-treated men and by 12 percent in themen given placebo (P0.21). Fifty percent of the mentreated with alfuzosin rated their degree of improve-ment as good to very good, as compared with 40 per-cent of those given placebo. The frequency of adverseeffects, including dizziness, headache, postural hy-potension, asthenia, and impotence, was similar in thetwo groups.

Although the various a1-adrenergicantagonistdrugs have not been directly compared, their pharma-cologic properties, clinical efficacy, and frequency ofadverse effects are similar.46,76-85 Their therapeutic

effect, as measured by improvement in the symptomscore and the peak urinary-flow rate, is moderate.Their onset of action is rapid, and they may be effectivein patients with mild-to-moderate hypertension. Be-cause these drugs can cause postural hypotension, diz-ziness, headache, and lightheadedness, patients receiv-ing them need to be monitored regularly.

Summary of Medical Therapies

In 1995, medical therapy for benign prostatic hyper-plasia is a reality. Androgen-deprivation therapy (withGnRH agonists, antiandrogens, or 5a-reductase inhib-itors) is effective because it reduces the static compo-

nent of benign prostatic hyperplasia. Of these agents,the 5a-reductase inhibitors have the most promise be-cause of their low toxicity. The others, though effective,cause impotence and loss of libido in most men. Selec-tive a1-adrenergicantagonist drugs, which inhibit thedynamic component of benign prostatic hyperplasia,are also effective. As compared with androgen-depriva-tion therapy, treatment with these drugs offers severaladvantages. Their onset of action is more rapid, theyhave no effect on serum concentrations of prostate-spe-cific antigen, and they can improve hypertension at thesame time. As compared with a1-adrenergic antago-nists, finasteride has minimal side effects, does not re-

quire titration at the start of therapy, and decreasesprostatic size. Because it reduces androgenic stimula-tion to the prostate gland, finasteride may alter the nat-ural history and progression of the disease process inaddition to improving urinary symptoms.

In the future, it may be possible to be selective in de-ciding which men should receive a 5a-reductase inhib-itor and which an a1-adrenergic antagonist. Theformer may be more effective in men with a predomi-nantly glandular component to their benign prostatichyperplasia, whereas the latter may be more effectivein those in whom stromal and smooth-muscle tissue isprimarily affected. The only method currently avail-

able to determine the morphologic features of affectedtissue is biopsy, but less invasive methods may be de-veloped. Also, given the different mechanisms by

Table 4. a-AdrenergicAntagonistDrugs for the Treatment of Benign

Prostatic Hyperplasia.

Nonselective drugsPhenoxybenzamine 76

Thymoxamine46

Selective drugs

Short-actingAlfuzosin77

Indoramin78

Prazosin79

Long-actingDoxazosin80

Tamsulosin81

Terazosin82




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which these two types of medications act, the nextprincipal advance may come from using them in com-bination.

MINIMALLY INVASIVE TREATMENTS

Transurethral Incision of the Prostate

Transurethral incision of the prostate is an ideal pro-cedure for any patient with bladder-outlet obstructionand an enlarged prostate gland weighing 30 g or less orin whom the primary obstruction is located at the blad-der neck.86,87 Most commonly, the procedure is per-formed under regional or general anesthesia. Either asingle incision is made at the six-oclock position (Fig.2A) or two incisions are made at the five- and seven-oclock positions (Fig. 2B).88 The incisions are begundistal to the interureteric ridge and extended across thebladder neck and prostatic urethra to the verumon-tanum. As the incisions are deepened, the bladder neckand prostatic urethra spring open and the bladder-out-

let obstruction is relieved.Four prospective, randomized trials comparingtransurethral incision of the prostate with transure-thral resection have been conducted.89-92 The symptomscore in the men who underwent transurethral incisiondecreased from 16.0 to 3.0 (an 81 percent decrease),

whereas in the men who underwent transurethral re-section the score decreased from 16.7 to 2.3 (an 86percent decrease) (P0.001). The mean peak urinary-flow rate increased from 8.5 to 15.0 ml per second (a76 percent increase) in the men who underwent trans-urethral incision, and from 8.8 to 18.7 ml per second(a 112 percent increase) in the men who underwent

transurethral resection (P

0.001). The complicationrates associated with incision were much lower thanthose associated with resection (impotence, 2 percent

vs. 5 percent; retrograde ejaculation, 15 percent vs. 66percent; incontinence, 1 percent vs. 6 percent; needfor transfusion, 1 percent vs. 6 percent).89-92 In addi-

tion, surgery, hospitalization, and convalescence all re-quired a shorter time.

Transurethral incision of the prostate is ideal notonly for men with a small prostate gland, but also forthose in whom the preservation of potency and capacityfor normal ejaculation are important considerations, as

well as for debilitated men in whom the risks presentedby surgery and anesthesia are substantial. The proce-dure is markedly underused to treat men with sympto-matic benign prostatic hyperplasia.

Prostatic Stents

Several permanently indwelling endoprostheses arebeing tested for the treatment of benign prostatic hy-perplasia.93-97 The two that have been evaluated mostextensively in both Europe and the United States arethe UroLume endoprosthesis (American Medical Sys-tems, Minnetonka, Minn.) and the Intra-Prostatic Stent(Boston Scientific, Watertown, Mass.).98-100

The UroLume endoprosthesis is a biocompatible, in-ert prosthesis made from a nonmagnetic superalloy wo-ven into a tubular mesh. It is flexible and self-expand-ing, with no elastic recoil. When fully expanded, it hasa wide (1.4 cm) internal diameter.101,102 The stent ismade in six lengths: 1.5, 2.0, 2.5, 3.0, 3.5, and 4.0 cm.It can be placed in the prostatic urethra with a special-ly designed deployment tool under direct vision.

The longest experience with the UroLume endopros-thesis has been in Europe, where the device has beenused since 1989, primarily in patients who are consid-ered to present poor surgical risks. In a multicenterstudy, it was used to treat 140 men with infravesical ob-

struction caused by enlarged prostate glands; 94 (67percent) presented with symptoms of benign prostatichyperplasia, and 46 (33 percent) had acute urinary re-tention.93 Before the placement of the stent, the meanpeak urinary-flow rate in the nonretention group was9.4 ml per second. After the insertion of the endopros-

Figure 2. Transurethral Incision of the Prostate.

A B

Panel A shows the incision at six oclock with the prostatic urethra and bladder neck springing open, and Panel B shows the incisionsat five oclock and seven oclock. The solid arrows indicate the trigone of the bladder, and the open arrows the bladder neck. (Reprinted

from Monda and Oesterling46 with the permission of the publisher.)




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thesis, the rate increased to 17.3 ml per second (an 84percent improvement). The mean symptom score (onthe MadsenIversen scale) declined from 15.7 to 7.6 (a52 percent decrease). All the men who had acute uri-nary retention were able to void satisfactorily afterplacement of the stent; the mean peak urinary-flow

rate was 13.5 ml per second and the mean symptomscore was 3.0. A total of 14 stents were removed, 11 (79percent) because of poor placement and 3 (21 percent)because of late untoward effects, such as persistent ir-ritation on voiding (two men) and the formation of en-crustations on the exposed ends at the bladder neck(one man). All 14 endoprostheses were removed intacttransurethrally without sequelae.

The North American UroLume Study Group usedthis endoprosthesis to treat 95 healthy men withobstructive benign prostatic hyperplasia.103 After 12months, the mean symptom score had decreased from15.0 before stent insertion to 6.3 (P0.001), and the

mean (SD) peak urinary-flow rate had increasedfrom 8.63.5 ml per second before insertion to15.66.2 ml per second (P0.001). The mean residualurine volume after voiding decreased from 129 to 24 ml(P0.001). None of the men had any difficulty postop-eratively with infection, erosion, stent migration, incon-tinence, or impaired potency. However, 67 percent hadsome irritative symptoms (urgency, frequency, or dys-uria) for at least one month. The stents were removedin eight men without injury to either the external uri-nary sphincter or the urethra.104 The preliminary re-sults of these two studies suggest that this endoprosthe-sis may be a useful treatment option for men with

obstructive benign prostatic hyperplasia.The Intra-Prostatic Stent is an inert device made oftitanium, with excellent biocompatibility. When fullyexpanded, the stent has an internal diameter of 33French (1.1 cm).105 The Intra-Prostatic Stent is avail-able in lengths ranging from 1.9 to 5.8 cm, in 4-mmincrements; thus, it can be matched precisely to thelength of the patients prostate. Unlike the UroLumeendoprosthesis, it is neither flexible nor self-expanding,

yet it provides enough outward radial force to maintainpatency of the prostatic urethra.

The Intra-Prostatic Stent has been studied primarilyin older men and men in whom the risks of surgery

were high. In a report from England of 50 such menwho had urinary retention, the mean peak urinary-flowrate was 11.3 ml per second six months after the place-ment of the Intra-Prostatic Stent and 12.8 ml per sec-ond at one year among the 43 men available for evalu-ation.106 Most reported some urgency immediately afterthe placement of the device. In three men stent remov-al was necessary; this was accomplished without diffi-culty with a specially designed retrieval tool. In anotherstudy of 30 men with urinary retention caused by be-nign prostatic hyperplasia who were treated with theIntra-Prostatic Stent, 25 (83 percent) could void satis-factorily after insertion of the stent; at one year the

mean peak urinary-flow rate was 10.8 ml per second,and the mean residual urine volume after voiding was

56 ml.107 Ten men (33 percent) had subsequent urinarytract infections that resolved with appropriate antibiot-ic therapy. There were no other untoward effects.

Experience with the Intra-Prostatic Stent in theUnited States has also been encouraging.94 Sixty-eightmen, 38 of whom (56 percent) had acute urinary reten-

tion, were treated with the device and followed forup to 18 months in a multicenter study. The symptomscore decreased from 16.8 before stent insertion to3.2 at 18 months (P0.001), and the peak urinary-flow rate increased from 3.9 to 14.4 ml per second(P0.001). Seventeen endoprostheses (25 percent)

were removed because of technical failure (59 percent)or treatment failure (41 percent); all were removedtransurethrally without sequelae.

On the basis of these preliminary data, stenting theprostatic urethra to relieve bladder-outlet obstructioncaused by an enlarged prostate gland seems reason-able. The prostatic endoprosthesis has several advan-

tages. It can be placed quickly (in 15 minutes or less),with the patient under regional anesthesia or with onlya prostatic block and intravenous sedation. The place-ment causes minimal intraoperative and postoperativehemorrhage. The patient does not need an indwellingurethral catheter after the operation and can be dis-charged from the hospital the same day or the nextmorning, with a minimal period of convalescence. Thestent does not alter the serum concentration of pros-tate-specific antigen. There are also several potentialdisadvantages. The stent is a foreign body, and itslong-term effects are unknown. Some men have irrita-tive voiding symptoms after the procedure. Precise

positioning of the stent in the prostatic urethra suchthat the proximal end does not protrude into the blad-der and the distal end does not extend into the exter-nal urinary sphincter may be difficult. No cathetershould be passed urethrally for six to eight weeks afterplacement to avoid dislodging the stent; postoperativeurinary retention must be treated with a suprapubiccatheter.

Microwave Therapy

Microwave energy can be delivered to the prostategland transrectally108-112 and transurethrally.26,113,114

There are three forms of microwave treatment: hyper-

thermia, thermotherapy, and thermoablation. In hyper-thermia, the prostatic tissue is heated to 42C to 44Cin multiple sessions, with the microwave antennaplaced in either the rectum or the urethra. In thermo-therapy, the prostatic tissue is heated to between 45Cand 60C in a single session, with a transurethral mi-crowave antenna located inside a cooling catheter toprotect the urethral lining.25 In thermoablation, the tis-sue is heated to a temperature between 60C and75C.115

Combining heating with surface cooling is particu-larly important for producing high intraprostatic tem-peratures without injury to the urethra or rectum. In

the absence of surface cooling, the heat generated bythe microwave antenna is highest closest to the anten-




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na, decreasing as a function of distance (Fig. 3A). As aresult, the urethra or rectum is the tissue that is heatedto the highest temperature. To protect these tissues,the microwave antenna is placed inside a catheterthrough which a coolant flows to keep the urethral orrectal epithelium at nearly normal temperatures. The

urethra and rectum therefore remain uninjured whiletherapeutic temperatures are administered deep withinthe prostate (Fig. 3B). The following discussion focuseson the role of transurethral microwave thermotherapy,because it probably has the most potential to treat men

with symptomatic benign prostatic hyperplasia.With transurethral thermotherapy using conductive

cooling, prostatic temperatures ranging from 45Cto 60C can be achieved while the urethral tempera-ture remains below 44.5C and the rectal temperaturebelow 42.5C.25 The treatment is generally adminis-tered in a single session without anesthesia. In the ini-tial study of 37 men, both the symptom score and the

residual urine volume after voiding decreased marked-ly, and the mean peak urinary-flow rate increased from8.4 ml per second before treatment to 10.8 ml persecond three months later (a 29 percent increase)(P0.03).25 Seven men (19 percent), however, hadpostoperative urinary retention and required indwell-ing catheters for one week.

In a multicenter North American clinical trial of 150men with benign prostatic hyperplasia treated withtransurethral microwave thermotherapy, 94 (63 per-cent) were followed for 12 months.27 Their mean symp-tom score decreased from 13.7 to 5.4 (a 61 percent de-crease) (P0.001), and the mean peak urinary-flow

rate increased from 8.5 to 11.3 ml per second (a 33 per-cent increase) (P0.001). The residual urine volumeafter voiding, however, did not change significantlyafter therapy. Forty-three men (46 percent) had uri-nary retention after the procedure for which urinarycatheterization was required. Other adverse effects, in-cluding urethral bleeding, bladder spasm, and he-

matospermia, were rare. No men reported retrogradeejaculation or changes in sexual function. Seventy-fourpercent did not require anesthesia or analgesia duringthe procedure; 26 percent received some oral or intra-

venous analgesia.Three prospective clinical trials have been conduct-

ed in which transurethral microwave thermotherapywas compared with a sham procedure.116-118 The pa-tients in both groups had decreases in symptom scoresin all three studies, but the decrease in the thermother-apy group was significantly greater (P0.05). Withregard to the peak urinary-flow rate, the thermothera-py group had a mean increase of 3 ml per second(P0.05), whereas the group undergoing the shamprocedure had no increase.

Transurethral microwave thermotherapy has notbeen compared directly with transrectal or transure-thral microwave hyperthermia in the treatment of men

with symptomatic benign prostatic hyperplasia, but the

former is probably superior. It is a single-session treat-ment that can be performed on an outpatient basis.Most men require no anesthesia or analgesia, and thecomplications are few. The improvement in symptomscores and peak urinary-flow rates is substantial andsimilar to the improvement with a1-adrenergicantag-onist therapy. One disadvantage of transurethral mi-crowave thermotherapy is postoperative urinary reten-tion in approximately 35 percent of men, which maypersist for up to 10 days.

Laser Prostatectomy

Another minimally invasive procedure that is receiv-

ing much attention is laser prostatectomy, several dif-ferent methods of which are being evaluated. Theselaser-delivery systems include transurethral ultra-sound-guided, laser-induced prostatectomy28,119; visuallaser ablation of the prostate with 90-degree-firing free-beam fibers30; and contact laser ablation of the pros-tate with contact fibers. No meaningful data relating to

Figure 3. Microwave Treatment of the Prostate.

Panel A shows the temperature distribution around the microwave antenna (white central area) without surface conductive cooling,

and Panel B shows the temperature with cooling. When the cooling catheter is used, the temperature where the antenna and the tissue

Temperature TemperatureNecrosisTissue alterationMinimal changeNo reaction

Distancefromurethra

Distancefromurethra

A B

touch is not increased, and the highest temperature is achieved deep within the prostatic tissue.




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the last of these are available. The results obtainedwith the ultrasound-guided procedure are similar tothose with visual laser ablation, which is discussed indetail here.

Visual laser ablation of the prostate uses a neodym-ium:yttriumaluminumgarnet laser as the energy

source. The laser fiber is positioned in the prostaticurethra through the working channel of a standard cys-toscope under direct vision. In 17 men treated with thistype of laser, the mean symptom score decreased from15 before treatment to 4 in six weeks (a 73 percent de-crease), and the mean peak urinary-flow rate increasedfrom 5 to 9 ml per second (an 80 percent increase).29

Two men (12 percent) subsequently required transure-thral resection of the prostate, and one (6 percent)underwent an incision of the bladder neck to relievepersistent bladder-outlet obstructive symptoms. In arandomized, double-blind clinical trial comparing vis-ual laser ablation with transurethral resection in 43

men, 42 of whom completed three months of follow-up,the symptom score decreased by 10.3 points in the menwho underwent ablation and by 11.5 points in the menwho underwent resection (P0.26).120 There was anincrease in the mean peak urinary-flow rate from 9.4 to12.2 ml per second (a 30 percent increase) in the abla-tion group, as compared with an increase from 7.5 to17.4 ml per second (a 132 percent increase) in the re-section group (P0.04). Irritative voiding symptoms

were both more severe and more frequent in the mentreated with ablation. A study that had similar results

with regard to efficacy six months after treatment wasreported recently.121

These preliminary data suggest that visual laser ab-lation of the prostate is an effective and safe treatmentfor benign prostatic hyperplasia. Its advantages are ashort operating time (20 minutes or less), ease of learn-ing, the opportunity to observe the laser tip directly,and the absence of perioperative hemorrhage. The pro-cedure can be performed on outpatients, but most menrequire catheter drainage afterward. Because the treat-ed tissue is gradually sloughed, the maximal therapeu-tic effect may not be appreciated by the patient for sixto eight weeks.

Laser prostatectomy may be a viable alternative totransurethral resection of the prostate for men with

symptomatic benign prostatic hyperplasia. However,the follow-up of the men treated so far has been short.Laser prostatectomy, like prostatic stents and micro-

wave therapy, does not yet have the approval of theFDA for this use.

Summary of Minimally Invasive Treatments

As we have seen regarding the medical therapy ofbenign prostatic hyperplasia, much progress has beenmade in recent years to develop a minimally invasiveprocedure that is effective, easy to perform, safe, andassociated with a minimal hospitalization and a shortconvalescence. Transurethral incision of the prostate is

such a treatment. No new equipment need be pur-

chased, and no additional training is required. Indeed,transurethral incision has been proved with time to beapplicable to 80 percent of the men now undergoingtransurethral resection. Prostatic stents, microwavetherapy, and laser prostatectomy are all being studiedat present, both in this country and abroad.

DECIDINGONTHE RIGHT TREATMENTFOR EACHPATIENT

In the foregoing review, the results obtained with awide variety of medical and minimally invasive treat-ments for benign prostatic hyperplasia have been pre-sented as they were reported by the primary investi-gators. Unfortunately, there have been no studiescomparing these various treatments with each other,

with surgery (either transurethral resection or openprostatectomy), or with watchful waiting. In fact, thereport by Wasson et al. in this issue of the Journal122 isthe first study in which watchful waiting has been com-

pared with transurethral resection in men with moder-ate prostatism. As a result, there are no definitiveguidelines indicating that a particular treatment or thelack thereof (that is, watchful waiting) is preferred inthe care of a specific patient. Until more comparativetrials are conducted, practicing physicians must rely onclinical judgment and intuition, as well as on the rec-ommendations of the Agency for Health Care Policyand Research.123

Although intervention may be appropriate for manymen with prostatism, doing nothing may be the bettermanagement. On the basis of five studies of the naturalhistory of prostatism among men with moderate pros-

tatism who were followed for five years, approximately40 percent will improve, 45 percent will have nochange in symptoms, and only 15 percent will have de-terioration.4-8 The effect of placebo on symptoms ofprostatism is also well recognized. Among 1260 men

with benign prostatic hyperplasia in several studieswho received placebo for 2 to 24 weeks, 42 percent im-proved, 46 percent had no change, and 12 percent had

worsening of symptoms.124 Therefore, all clinical trialsevaluating forms of medical therapy must have a pla-cebo group, and all trials assessing minimally invasiveprocedures must have a no-treatment group. Watchful

waiting must be considered a management option for

men with prostatism.Transurethral resection of the prostate and openprostatectomy must also continue to be considered val-id treatment options in 1995. Of all the treatmentsavailable, they result in the most improvement in symp-toms and in the urinary-flow rate.11 On long-term fol-low-up, more than 75 percent of men undergoing theseprocedures are satisfied and have good ability to uri-nate.125 How then does a practicing clinician decide

which treatment is best for each patient?There is no simple answer. Because the indications

for treating men with symptomatic benign prostatic hy-perplasia are relative rather than absolute, it is very im-

portant to consult the patient. Symptoms considered




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bothersome or even disabling by one man may be nei-ther to another. Thus, a man who considers his symp-toms annoying may want some treatment, whereasanother will elect watchful waiting. Men seeking treat-ment must be informed of the potential benefits andharms associated with each treatment. One man mayprefer medical therapy to avoid an operation; anothermay choose a minimally invasive procedure to avoidhaving to take medication for the rest of his life. As forthe range of therapies available medical, minimallyinvasive, and surgical most are suitable for any man

with moderate prostatism. Watchful waiting, however,is the only one recommended for men with mild pros-

tatism. Surgery and permanent prostatic stenting aresuggested for men with acute urinary retention. Recom-mendations for the use of the various treatments areshown in Table 5. However, the final decision about thebest treatment for a particular man must take into ac-count the patients preference after he has been appro-priately informed.

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Involving placement of permanent endoprostheses.

Table 5. Recommended Treatment Options for Patients with Be-nign Prostatic Hyperplasia, According to Severity of Prostatism.

TREATMENT SEVERITYOF PROSTATISM (SYMPTOM SCORE*)

MILD

(07)

MODERATE

(818)

SEVERE

(1935)

WITH URINARY

RETENTION

Watchful waiting Yes Yes No No

5a-Reductase inhibitors No Yes Yes Noa1-Adrenergic antagonists No Yes Yes No

Microwave therapy No Yes Yes No

Laser prostatectomy No Yes Yes No

Prostatic stents No Yes Yes Yes

Transurethral incision of theprostate

No Yes Yes Yes

Transurethral resection of theprostate

No Yes Yes Yes

Open prostatectomy No No Yes Yes




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