British Journal of Urology (1992), 70, Suppl 1.27-32 01992 British Journal of Urology
Future Directions in the Management of Benign Prostatic Hyperplasia S. KHOURY Clinique Urologique, L ‘HGpital de la PitiQ Paris, France
Summary-A meeting of the International Consultation o n Benign Prostatic Hyperplasia (BPH) in J u n e 1991 provided an update on the management of BPH. It is recognised that the development of complications in what may be regarded as a relatively well tolerated disease may necessitate surgical intervention. Current treatment is directed towards circumventing or ameliorating the complications of BPH and perhaps to find minimally invasive or non-invasive alternatives to surgery that could eliminate this modality altogether. Anticipated changes in the management of BPH include establishment of an improved scoring system and response criteria; implementation of stenting techniques, physical modalities s u c h as hyperthermia and laser therapy to replace transurethral resection of the prostate; development of more specific alpha blockers with fewer adverse effects; and administration of hormonal therapy, possibly as an eventual preventative of BPH. The 1991 International Consultation on Benign Prostatic Hyperplasia (BPH), which took place in Paris, France, under the joint sponsorship of t h e World Health Organization and the major international and national societies of urology, provided an excellent opportunity to review current knowledge o n the subject of BPH and to explore future trends in its management. Most of the information included in this report is drawn from the conclusions of the consultation participants.
These two factors play a variable role in obstruction, but the mechanical component largely predominates. The three major aetiological factors of BPH are (1) the presence of functioning testes, (2) age and (3) race. From the fourth decade of life onward, both Asian and Caucasian men develop micronodules of BPH in their prostate. In native Asians, these microscopic nodules have a lesser tendency to enlarge and cause clinical symptoms and signs than they do in Caucasians. In Asians living in the United States, clinical BPH develops almost as frequently as it does in Caucasians. This epidemiological finding supposes the presence of not only genetic factors but also environmental and dietary factors, which would obviously be important to define. The deterioration of the clinical symptoms and signs of BPH is signified by the development of complications. In fact, the complications of BPH may transform the disease from a relatively well
Aetiology and Pathophysiologyof BPH
Benign prostatic hyperplasia is essentially responsible for bladder neck obstruction, which accounts for the majority of the clinical symptoms of BPH. Classification of these symptoms places them into one of two categories : (1) Obstructive symptoms directly related to the
enlarged prostate impeding urinary flow. (2) Irritative symptoms frequently triggered by the obstruction. The type of bladder neck obstruction that is caused by BPH has two main mechanisms (Caine, 1986) : Mechanical or static mechanism, which depends on the volume, consistency and shape of the prostate. Functional or dynamic mechanism, which is related to the tension exerted by the smooth muscle fibres present in the urethra, prostate and capsule. 27
28
BRITISH JOURNAL OF UROLOGY
tolerated state to one that is incompatible with a normal life for the patient, often necessitating surgery
enced with this application of the drug. (Alpha blocker treatment is discussed in detail in the other chapters of this supplement.)
Treatment
Plant extracts (Phytotherapy) Some authors suggest that there may be a slight advantage to the use of plant extracts over placebo in the medical treatment of BPH (Fitzpatrick et al., 1992). Their long-term benefit remains to be more accurately defined on a more scientific basis. These substances are widely used in some countries, particularly in Europe and Latin America.
Although surgery remains the standard treatment for BPH, a number of less invasive techniques are currently being developed and are starting to occupy a place in the expanding range of treatments available. These techniques are summarised in Table 1. The conclusions concerning the treatment alternatives for BPH as drawn at the International Consultation on BPH were presented by Smith et al. (1992) in an extensively documented report. New high-technology modalities were among the alternatives considered. Conclusions and future prospects regarding BPH treatment are succinctly presented and follow. Table. BPH : Treatment Modalities Functional 0 Medical Alpha blockers Plant extracts
0 Physical Stents Hyperthermia (~45°C) Balloon dilatation
Mass reducing 0 Surgery
0 Physical Thermotherapy (>45"C) Cryosurgery Laser Focused external heat, ultrasound, and high-energy shock waves
0 Medical Hormone therapy
Alpha blockers Alpha hlockers are a therapeutic option for the symptomatic short-term ( 6 months) effectiveness of these agents in BPH management (International Consensus Committee, 1992). The administration of alpha blockers in the treatment of BPH has tended to increase as clinicians have become more experi-
Temporary stents and catheters The intraurethral catheter and the ProstacathTM (Engineers and Doctors, Copenhagen, Denmark) and UrospiralTM (Porges, France) stents offer simple and relatively inexpensive methods of providing relief from retention of urine in patients who are too old or too ill to undergo a prostatectomy. They are simple to insert while the patient is under local anaesthesia and, if necessary, sedated. Apart from causing some irritation for the first few days, stents provide effective relief from retention of urine in two-thirds of the patients. In patients who require prolonged use, the stent should probably be changed at intervals to prevent encrustation (Nielsen et al., 1990; Guazzoni et al., 1991). Permanent stents Both the UroLume Wallstent (American Medical Systems, Minnetonka, USA) and the AS1 stent (Advanced Surgical Interventions, Inc., San Clemente, USA) are suitable for patients in whom prostatectomy is a high-risk procedure. Either stent can be inserted with the patient under local anaesthesia and, if necessary, sedated. The complication rate is low if the stent is carefully placed, and the effect is permanent since the stent gradually becomes epithelialised with prostatic tissue. The diameter of the stent is such that subsequent cystoscopy is practicable without disturbing the stent. These stents are more expensive than temporary ones but are much less expensive than prostatectomy and more convenient for the patient than a permanent urethral catheter (Williams et al., 1989; Williams, 1991). Localised hyperthermia In this technique the prostate is heated to a temperature between 42" and 45°C by the use of probes within the rectum or urethra. It is possible to relieve symptoms and often improve the flow
FUTURE DIRECTIONS IN THE MANAGEMENT OF BENIGN PROSTATIC HYPERPLASIA
rate by 2-4 ml/s. Necrosis within the prostate does not occur, prostate size does not change, and TURP is likely to be required within 2 years for approximately a third of the patients (Baert et al., 1990; Dreikorn et al., 1990; Strohmaier, et al., 1990).
29
Cryotherapy This form of treatment (Gonder et al., 1964; Rigondet, 1976) has been evaluated for > 20 years. While cryotherapy is effective in many patients, especially those in whom the prostate is not very large, the need for prolonged catheterisation in a significant number of patients makes it less attractive than many of the currently available alternatives, which are more convenient for the surgeon and the patient.
Thermotherapy With this form of treatment the prostate is heated to 45"-S0°C with a urethral probe generating microwaves at 915 MHz. The urethra is protected by being kept cool while the prostatic tissue is damaged by the heat therapy; subsequent necrosis Laser therapy is seen. The probe works without the need to sedate The use of a side-firing laser or an open-fibre laser the patient, it produces transient retention in 5- diffusing its energy within a balloon is still in an 40%of patients, and it provides prolonged relief of early stage of development. Both forms of treatment symptoms with sustained increases in peak flow produce tissue destruction and thus far have and reduced bladder pressure in 40% of patients. demonstrated symptom relief in a canine model Therniotherapy is not suitable for the patient (Roth et al., 1991). Laser therapy is likely to develop with bladder neck stenosis, median lobe enlarge- rapidly over the next 5 years and will probably ment or a large prostate gland. However, for the challenge thermotherapy. A clinical trial in which 8 centres are collaboratpatient whose prostate gland is 30-70 g in volume the technique is one that holds promise and is likely ing to compare transurethral laser incision of the to be further refined (Devonec et al., 1990a; 1990b; prostate (TULIP) against conventional TURP is currently under way. The use of a laser at 20-40 1991). watts at a pulse rate of 0.5-1.0 mm/s, with 6-9 Balloon dilatation passes for delivery of 5000-8000 joules, has been This technique (Klein, 1991 ; Long et al., 1991) has proposed. If the median lobe requires treatment, been extensively evaluated and almost certainly additional therapy is given at the same time. The first patient series, which included 20 men, depends on the anterior commissure of the prostate being split by the dilating balloon for its success; has been treated. Operating time averaged less than when this happens, the increase in flow rate is 30min and included a laser application lasting dramatic and the effect may be prolonged. Balloon 4 min. A catheter was left in overnight except in dilatation is carried out with local anaesthesia and those patients who had retention of urine, in which sedation, or with regional anaesthesia. Unfortu- case an indwelling suprapubic catheter was left in nately, this technique is not suitable for patients for 7days. The average time in the hospital was with either a prominent middle lobe enlargement 2.1 days. Of these 20 patients, 19 had 250% of the prostate or a large prostate gland. The improvement in their symptomatic score, or ;> 50% balloons are expensive and in at least 50% of the increase in the maximum flow rate. The improvepatients the effect is short-lived, with symptoms ment occurred gradually, over approximately 6 and signs of obstruction returning within 1 year weeks, and has been maintained. As yet, no side effects have been seen. It seems that laser therapy after dilatation. is applicable to any prostate and is also simple to Surgical treatment learn. However, since the temperatures (7O0-10O0C) Surgery is currently the standard treatment for produced by laser are higher than those produced BPH. It relieves symptoms and obstruction in about by thermotherapy, regional or general anaesthesia 85% of patients. During the past 2 decades, an is essential. Laser therapy for the prostate is also being important shift from open surgery to transurethral investigated by Newman et al. (unpublished data, resection of the prostate (TURP) has been noted. In BPH cases involving small-volume prostates, 1991) at the M.D. Anderson Hospital and Tumor transurethral incision of the prostate (TUIP) gives Institute in Houston, USA. This group hopes that excellent results with less morbidity than TURP. the laser will prove practical for the destruction of This technique is currently underused but will all the glandular tissue within the prostate, which certainly gain preference among urologists in the will render the technique potentially valuable as a treatment for localised prostatic cancer. future.
30 The possible uses of laser therapy are attracting much interest. Other investigators, including Watson of the Institute of Urology in England and Daikuzono of Japan, are experimenting with this modality by using a laser fibre within a balloon that dilates the prostate until a gauge of 60 French is reached and then diffuses the laser beam to achieve an “oven” effect. This technique has now been used by Watson in 10 patients and has produced a cavity in the prostatic urethra akin to that following TURP (unpublished data, 1991). High-energy shock waves, focused external heat and focused ultrasound These three alternative forms of BPH treatment are currently being developed. The first 2 methods require a lithotriptor or similar device for their administration; the last-the focused ultrasoundis delivered transrectally. Each technique has been used in animal models and in a few patients (Foster et al., 1991 ; Lobe1 et al., 1991). Hormonal treatment It has been stated that a large number of men > 50 years of age exhibit some degree of prostatic enlargement due to BPH. The current belief is that a 40-year-old man has a 30% chance in his lifetime of undergoing a prostatectomy, generally TURP, to treat urinary flow obstruction. Given these odds, effective medical treatment of BPH would clearly appear to offer both economic and social benefits. Androgen withdrawal induces the shrinkage of an enlarged prostate, so potential forms of BPH medical therapy have been directed toward blocking the action of androgens or suppressing their production within the prostatic tissue. These methods usually induce impotence and other secondary effects, so that their use in BPH is unacceptable. 5-a Reductase inhibitors. The inhibition of 5-a
reductase and thereby the formation of dihydrotestosterone (DHT) from testosterone was considered a novel approach to BPH treatment and stimulated the search for 5-a reductase inhibitors (Gormley and Stoner, 1991). With the recent production of A-ring heterocyclic steroids and 4-azasteroids, which inhibit 5-a reductase, finasteride (MK-906) was developed and has recently been extensively tested in clinical trials. Finasteride decreases the DHT concentration in prostatic tissue and its administration results in a reduction in the plasma DHT level while the testosterone level is maintained. The effect of testosterone on libido is therefore not affected and
BRITISH JOURNAL OF UROLOGY
its anabolic action on muscle tissue is retained. Finasteride will also maintain the normal androgenic features promoted by testosterone in a manner similar tomale children with inherited 5-a reductase deficiency, who develop a normal libido at puberty as characterised by a deep voice, male sexual features and musculature but have a small prostate and scanty beard growth. In early clinical studies, 50 mg finasteride administered daily for 7 days decreased intraprostatic DHT by 92% but increased the concentration of testosterone from 0.23 +_ 0.18 ng/g to 1.9 ng/g. When administered at a dose of 5 mg daily for 6 months, finasteride decreased the plasma DHT concentration by 80% to “castrate” levels, shrank prostatic volume by 28%, and increased the urine flow rate up to 3 ml/s without adverse clinical effects. Aromatase inhibitors and antioestrogens. The aromatase enzyme system is responsible for the conversion of androgens to oestrogens. It is particularly active in the ovary and placenta but is also present in the testes and such extragonadal sources as adipose tissue and muscle. The possibility that oestrogens may be implicated in the pathogenesis of BPH has consistently provoked interest in the potential value of aromatase inhibitors as well as antioestrogens in the clinical management of the disease. Experimental studies in dogs and monkeys have indicated that prostatic stromal proliferation, which is induced by the administration of androstenedione, can be antagonised by simultaneous administration of aromatase inhibitors such as 4hydroxyandrostenedione and l-methylandrosta1,4-diene-3,17-dione (M-AD). In preliminary studies of patients with BPH, M-AD significantly decreased the plasma concentrations of oestrone and oestradiol (Habenicht and El Etreby, 1987). Nonetheless, it also would seem logical to consider an effective means of blocking the biological effects of oestrogen at the target cells by use of antioestrogen therapy. An earlier study using the antioestrogen tamoxifen administered for 4 weeks before prostatectomy at a dosage of 80mg/d promoted stromal proliferation and was reported to be unsuccessful. It is not surprising that stromal hyperplasia was a consequence of this treatment, because a daily dose of tamoxifen amounting to only 20 mg has been found to be efficacious in the treatment of premenopausal women with breast cancer and because tamoxifen is known to act like a weak oestrogen. Therefore, it would seem more
FUTURE DIRECTIONS IN THE MANAGEMENT OF BENIGN PROSTATIC HYPERPLASIA
31
logical to use lower doses of tamoxifen, possibly in association with a 5-cl reductase inhibitor or a lowdose antiandrogen, for the treatment of BPH. It will soon be possible to consider the new ICI 183,720, which is a complete oestrogen antagonist with no oestrogenic properties, for the management of BPH.
toward replacement of surgical treatment by new, less aggressive methods that will ensure the same reduction in prostatic mass. In turn, these methods will be subsequently replaced by drug treatment only. In the meantime, symptomatic medical treatment will remain important as sole therapy for early-stage disease and as adjuvant therapy for more advanced cases.
Future Prospects in the Treatment of BPH
Over the next 5 years The therapeutic approach to BPH over the next 5 years will be marked by several new elements :
The field of medicine is marked by a number of archetypal constants : (1) Medical progress in surgical diseases involves the use of less invasive surgical methods until surgical treatment is finally replaced by medical treatment. (2) Whenever a drug competes with a surgical procedure, the drug eventually gains preference. Patients have a natural aversion to surgery, however minor, and often prefer even a drug with unpleasant side effects to an operation with no or minimal sequelae. The Figure illustrates the comparative value of the various treatment modalities for BPH over the next 5 years and by the end of the century. There are no quantitative data, which would be impossible to present-simply impressions principally based on current knowledge of the potential uses of new BPH treatment modalities and on analogies of what has evolved in the management of other diseases, such as renal calculi and duodenal ulcers. Future treatment of BPH will inevitably lean p 9 v (
Medical Treatment
I
1995
I
Medical Treatment and Minimally lnvasive Physical Techniques
1 Surgery
I
2000
I
Medical Treatment ind Minimall) lnvasive Physical Techniques
Surgery Surgery
Fig. Comparative value of the various treatment modalities for BPH over the next 5 years and by the end of the century.
(1) A better symptom scoring system and better response criteria will be developed. (2) Physical treatment modalities will be further developed. In view of their minimally invasive nature, which does not necessitate the induction of anaesthesia, they will inevitably replace TURP in a number of years, especially for uncomplicated cases in which surgery is indicated to lessen discomfort and for patients with a relatively short life expectancy or at high risk. The extensive development of these techniques will be the outstanding event in the field of BPH management over the next 5 years. (3) Alpha blockers will confirm their role as the most effective symptomatic medical treatment. (4) Hormone therapy will enter the field. Because several weeks are needed to achieve an effect that will only be partial in a number of cases, these agents will probably be combined with alpha blockers, at least during the initial months of treatment. (5) In the field of surgery, TURP will continue to gain ground on open surgery as a result of constant improvement in surgical devices, the growing experience acquired by urologists and better training methods. The indications for bladder neck incision will increase, given that a large number of BPH cases currently treated by surgery involve prostates weighing approximately 25 g. By the end of the century New, more specific alpha blockers with fewer adverse effects will be developed. Hormonal treatment will become more complex, probably combining 5-cl reductase inhibitors with the new, pure antioestrogens currently under investigation. The possible discovery of a specific growth factor in the prostate could completely change BPH treatment Perspectives. A Preventive approach Will also develop.
32
BRITISH JOURNAL OF UROLOGY
The greatest technical progress will concern the performance of the various physical methods. Lasers will certainly have a place in reducing the prostatic mass. By the end of the century, these techniques will have almost completely replaced surgery as it is known today in the great majority of cases. References Baert, L., Ameye, F., Willemen, P. et d (1990). Transurethral microwave hyperthermia for benign prostatic hyperplasia: preliminary clinical and pathological results. J . Urol., 144, 1383-1 387. Caine, M. (1986). The present role of alpha-adrenergic blockers in the treatment of benign prostatic hypertrophy. J . Urol., 136,l-4. Devonec, M., Berger, N. and Perrin, P. (1991). Transurethral microwave heating of the prostate-r from hyperthermia to thermotherapy. J . Endourol., 5 , 129-1 36. Devonec, M., Cathaud, H., Carter, S. ef d (1990a). Histological and clinical effects of transurethral microwave therapy in patients with benign prostatic hypertrophy. Presented at the XMII Krongres des Deutschen Gesellschaft fur Urologie; September 26-29; Hamburg, Germany. Devonec, M., Cathaud, M., Carter, J. e t d (1990b).Transurethral microwave therapy (TUMT) in patients with benign prostatic hypertrophy. Presented at the 8th World Congress on Endourology and ERSWL; August 29-September 2; Washington, D.C. Abstract. Dreikorn, K., Richter, R. and Schonhofer,P. S. (1990). Konservative nicht-hormonelle Behandlung der benignen Prostata Hyperplasie. Urologe, 29 (Suppl A), 8. Fitzpatrick, J. M., Dreikorn, K., Khoury, S. ef al. (1992). The medicalmanagement of BPH with agents other than hormones and u blockers. In :Proceedingsof the International Consultation on Benign Prostatic Hyperplasia (BPH) ; June 26-27, 1991; Paris; ed. Cockett A. T. K., Aso, Y., Chatelain, C. et al. Pp. 193-199. Paris: SCI. Foster, R. S., Bihrle, R., Sanghvi,N. T. et d (1991). Noninvasive ultrasound produced volume lesion in prostate. J . Urol., 145, 396A. Abstract No. 735. Gonder, M. J., Soanes, W. A. and Smith, V. (1964). Experimental prostate cryosurgery. Invest. Urol., 1,610-619. Gormley, G . J. and Stoner, E. (1991). The role of 5 u-reductase inhibitors in the treatment of benign prostatic hyperplasia. In: Problems in Urology; ed. Lepor, H. and Paulson, D. F. Vol. 5, No. 3 Pp 436-440. Lippincott : Philadelphia. Guazzoni, G., Montorsi, F., Colombo, R. ef d (1991). Long term experience with the prostatic spiral for urinary retention due
,
to benign prostatic hyperplasia. S c a d . J . Urol. Nephrol., 25, 2 1-24. Habenicht,U.-F. and El Etreby,M. F. (1987). Synergic inhibitory effects of the aromatase inhibitor I-methyl-androsta-l,4diene-3,17-dione and the antiandrogen cyproterone acetate on androstenedione-induced hyperplastic effects in the prostates of castrated dogs. Prostate, 11, 133-143. International Consensus Committee. (1992). 4 BPH treatment recommendations. In ; Proceedings ofthe International Consultation on Benign Prostatic Hyperplasia (BPH) ; June 2627, 1991; Paris; ed. Cockett, A. T. K., Aso, Y., Chatelain, C. et a / . Pp. 287-288. Paris: SCI. Klein, L. A. (1991). 2 year follow-up of balloon dilatation of the prostate and an algorithm for future patient selection. J . Endourol.,5, 109-1 12. Lobel, B., Gille, F., Cipolla, B. ef d (1991). High energy shock waves (HESW) for the treatment of benign prostatic hypertrophy (BPH). J . Urol., 145,396A. Abstract No. 735. Long, S. R., Clayman, R. V., Dierks, S. M. e t d (1991). Balloon incision of the prostate: preliminary evaluation of a minimal invasive technique. J . Endourol., 5, 117-122. Nielsen, K. K., Klarskov, P., Nordling, J. et d (1990). The intraprostatic spiral : new treatment for urinary retention. Br. J . Urol., 65,500-503. Rigondet, G. (1976). Etude comparee de 325 cas de cryochirurgie utilisant comme refrigerant le protoxyde d’azote et I’azote liquide. Ann. Urol., 10, 159-162. Roth, R. A., Babayan, R. and Aretz, H. T. (1991). TULIPtransurethral ultrasound-guided laser-induced prostatectomy. J . Urol., 145,390A. Abstract No. 712. Smith, Ph., Chaussy, C., Conort, P. et al. (1992). Report of the committee on other non medical treatment. In: Proceedings of the International Consultation on Benign Prostatic Hyperplasia ( B P H ) ; June 26-27,1991; Paris; ed. Cockett, A. T. K., Aso, Y., Chatelain, C. et al. Pp. 223-257. Paris: SCI. Strohmaier, W. L., Bichler, K. H., Fliichter, S. H. ef d (1990). Local microwave hyperthermia of benign prostatic hyperplasia. J . Urol.,144, 913-917. Williams, G. (1991). Early experience of the use of permanently implanted prostatic stents for the treatment of bladder outflow obstruction. World J . Urol., 9, 26-28. Williams, G., Jager, R., McLoughlii, J. et d (1989). Use of stents for treating obstruction of urinary outflow in patients unfit for surgery. Br. Med. J . , 298, 1429.
The Author S. Khoury, MD, Professor of Urology, Clinique Urologique, L’HBpital de la PitiB, Paris, France. Requests for reprints to: S. Khoury, Clinique Urologique, L’HBpital de la Piti6, Cedex 13,75634 Paris, France.
Future Directions in the Management of Benign Prostatic Hyperplasia S. KHOURY Clinique Urologique, L ‘HGpital de la PitiQ Paris, France
Summary-A meeting of the International Consultation o n Benign Prostatic Hyperplasia (BPH) in J u n e 1991 provided an update on the management of BPH. It is recognised that the development of complications in what may be regarded as a relatively well tolerated disease may necessitate surgical intervention. Current treatment is directed towards circumventing or ameliorating the complications of BPH and perhaps to find minimally invasive or non-invasive alternatives to surgery that could eliminate this modality altogether. Anticipated changes in the management of BPH include establishment of an improved scoring system and response criteria; implementation of stenting techniques, physical modalities s u c h as hyperthermia and laser therapy to replace transurethral resection of the prostate; development of more specific alpha blockers with fewer adverse effects; and administration of hormonal therapy, possibly as an eventual preventative of BPH. The 1991 International Consultation on Benign Prostatic Hyperplasia (BPH), which took place in Paris, France, under the joint sponsorship of t h e World Health Organization and the major international and national societies of urology, provided an excellent opportunity to review current knowledge o n the subject of BPH and to explore future trends in its management. Most of the information included in this report is drawn from the conclusions of the consultation participants.
These two factors play a variable role in obstruction, but the mechanical component largely predominates. The three major aetiological factors of BPH are (1) the presence of functioning testes, (2) age and (3) race. From the fourth decade of life onward, both Asian and Caucasian men develop micronodules of BPH in their prostate. In native Asians, these microscopic nodules have a lesser tendency to enlarge and cause clinical symptoms and signs than they do in Caucasians. In Asians living in the United States, clinical BPH develops almost as frequently as it does in Caucasians. This epidemiological finding supposes the presence of not only genetic factors but also environmental and dietary factors, which would obviously be important to define. The deterioration of the clinical symptoms and signs of BPH is signified by the development of complications. In fact, the complications of BPH may transform the disease from a relatively well
Aetiology and Pathophysiologyof BPH
Benign prostatic hyperplasia is essentially responsible for bladder neck obstruction, which accounts for the majority of the clinical symptoms of BPH. Classification of these symptoms places them into one of two categories : (1) Obstructive symptoms directly related to the
enlarged prostate impeding urinary flow. (2) Irritative symptoms frequently triggered by the obstruction. The type of bladder neck obstruction that is caused by BPH has two main mechanisms (Caine, 1986) : Mechanical or static mechanism, which depends on the volume, consistency and shape of the prostate. Functional or dynamic mechanism, which is related to the tension exerted by the smooth muscle fibres present in the urethra, prostate and capsule. 27
28
BRITISH JOURNAL OF UROLOGY
tolerated state to one that is incompatible with a normal life for the patient, often necessitating surgery
enced with this application of the drug. (Alpha blocker treatment is discussed in detail in the other chapters of this supplement.)
Treatment
Plant extracts (Phytotherapy) Some authors suggest that there may be a slight advantage to the use of plant extracts over placebo in the medical treatment of BPH (Fitzpatrick et al., 1992). Their long-term benefit remains to be more accurately defined on a more scientific basis. These substances are widely used in some countries, particularly in Europe and Latin America.
Although surgery remains the standard treatment for BPH, a number of less invasive techniques are currently being developed and are starting to occupy a place in the expanding range of treatments available. These techniques are summarised in Table 1. The conclusions concerning the treatment alternatives for BPH as drawn at the International Consultation on BPH were presented by Smith et al. (1992) in an extensively documented report. New high-technology modalities were among the alternatives considered. Conclusions and future prospects regarding BPH treatment are succinctly presented and follow. Table. BPH : Treatment Modalities Functional 0 Medical Alpha blockers Plant extracts
0 Physical Stents Hyperthermia (~45°C) Balloon dilatation
Mass reducing 0 Surgery
0 Physical Thermotherapy (>45"C) Cryosurgery Laser Focused external heat, ultrasound, and high-energy shock waves
0 Medical Hormone therapy
Alpha blockers Alpha hlockers are a therapeutic option for the symptomatic short-term ( 6 months) effectiveness of these agents in BPH management (International Consensus Committee, 1992). The administration of alpha blockers in the treatment of BPH has tended to increase as clinicians have become more experi-
Temporary stents and catheters The intraurethral catheter and the ProstacathTM (Engineers and Doctors, Copenhagen, Denmark) and UrospiralTM (Porges, France) stents offer simple and relatively inexpensive methods of providing relief from retention of urine in patients who are too old or too ill to undergo a prostatectomy. They are simple to insert while the patient is under local anaesthesia and, if necessary, sedated. Apart from causing some irritation for the first few days, stents provide effective relief from retention of urine in two-thirds of the patients. In patients who require prolonged use, the stent should probably be changed at intervals to prevent encrustation (Nielsen et al., 1990; Guazzoni et al., 1991). Permanent stents Both the UroLume Wallstent (American Medical Systems, Minnetonka, USA) and the AS1 stent (Advanced Surgical Interventions, Inc., San Clemente, USA) are suitable for patients in whom prostatectomy is a high-risk procedure. Either stent can be inserted with the patient under local anaesthesia and, if necessary, sedated. The complication rate is low if the stent is carefully placed, and the effect is permanent since the stent gradually becomes epithelialised with prostatic tissue. The diameter of the stent is such that subsequent cystoscopy is practicable without disturbing the stent. These stents are more expensive than temporary ones but are much less expensive than prostatectomy and more convenient for the patient than a permanent urethral catheter (Williams et al., 1989; Williams, 1991). Localised hyperthermia In this technique the prostate is heated to a temperature between 42" and 45°C by the use of probes within the rectum or urethra. It is possible to relieve symptoms and often improve the flow
FUTURE DIRECTIONS IN THE MANAGEMENT OF BENIGN PROSTATIC HYPERPLASIA
rate by 2-4 ml/s. Necrosis within the prostate does not occur, prostate size does not change, and TURP is likely to be required within 2 years for approximately a third of the patients (Baert et al., 1990; Dreikorn et al., 1990; Strohmaier, et al., 1990).
29
Cryotherapy This form of treatment (Gonder et al., 1964; Rigondet, 1976) has been evaluated for > 20 years. While cryotherapy is effective in many patients, especially those in whom the prostate is not very large, the need for prolonged catheterisation in a significant number of patients makes it less attractive than many of the currently available alternatives, which are more convenient for the surgeon and the patient.
Thermotherapy With this form of treatment the prostate is heated to 45"-S0°C with a urethral probe generating microwaves at 915 MHz. The urethra is protected by being kept cool while the prostatic tissue is damaged by the heat therapy; subsequent necrosis Laser therapy is seen. The probe works without the need to sedate The use of a side-firing laser or an open-fibre laser the patient, it produces transient retention in 5- diffusing its energy within a balloon is still in an 40%of patients, and it provides prolonged relief of early stage of development. Both forms of treatment symptoms with sustained increases in peak flow produce tissue destruction and thus far have and reduced bladder pressure in 40% of patients. demonstrated symptom relief in a canine model Therniotherapy is not suitable for the patient (Roth et al., 1991). Laser therapy is likely to develop with bladder neck stenosis, median lobe enlarge- rapidly over the next 5 years and will probably ment or a large prostate gland. However, for the challenge thermotherapy. A clinical trial in which 8 centres are collaboratpatient whose prostate gland is 30-70 g in volume the technique is one that holds promise and is likely ing to compare transurethral laser incision of the to be further refined (Devonec et al., 1990a; 1990b; prostate (TULIP) against conventional TURP is currently under way. The use of a laser at 20-40 1991). watts at a pulse rate of 0.5-1.0 mm/s, with 6-9 Balloon dilatation passes for delivery of 5000-8000 joules, has been This technique (Klein, 1991 ; Long et al., 1991) has proposed. If the median lobe requires treatment, been extensively evaluated and almost certainly additional therapy is given at the same time. The first patient series, which included 20 men, depends on the anterior commissure of the prostate being split by the dilating balloon for its success; has been treated. Operating time averaged less than when this happens, the increase in flow rate is 30min and included a laser application lasting dramatic and the effect may be prolonged. Balloon 4 min. A catheter was left in overnight except in dilatation is carried out with local anaesthesia and those patients who had retention of urine, in which sedation, or with regional anaesthesia. Unfortu- case an indwelling suprapubic catheter was left in nately, this technique is not suitable for patients for 7days. The average time in the hospital was with either a prominent middle lobe enlargement 2.1 days. Of these 20 patients, 19 had 250% of the prostate or a large prostate gland. The improvement in their symptomatic score, or ;> 50% balloons are expensive and in at least 50% of the increase in the maximum flow rate. The improvepatients the effect is short-lived, with symptoms ment occurred gradually, over approximately 6 and signs of obstruction returning within 1 year weeks, and has been maintained. As yet, no side effects have been seen. It seems that laser therapy after dilatation. is applicable to any prostate and is also simple to Surgical treatment learn. However, since the temperatures (7O0-10O0C) Surgery is currently the standard treatment for produced by laser are higher than those produced BPH. It relieves symptoms and obstruction in about by thermotherapy, regional or general anaesthesia 85% of patients. During the past 2 decades, an is essential. Laser therapy for the prostate is also being important shift from open surgery to transurethral investigated by Newman et al. (unpublished data, resection of the prostate (TURP) has been noted. In BPH cases involving small-volume prostates, 1991) at the M.D. Anderson Hospital and Tumor transurethral incision of the prostate (TUIP) gives Institute in Houston, USA. This group hopes that excellent results with less morbidity than TURP. the laser will prove practical for the destruction of This technique is currently underused but will all the glandular tissue within the prostate, which certainly gain preference among urologists in the will render the technique potentially valuable as a treatment for localised prostatic cancer. future.
30 The possible uses of laser therapy are attracting much interest. Other investigators, including Watson of the Institute of Urology in England and Daikuzono of Japan, are experimenting with this modality by using a laser fibre within a balloon that dilates the prostate until a gauge of 60 French is reached and then diffuses the laser beam to achieve an “oven” effect. This technique has now been used by Watson in 10 patients and has produced a cavity in the prostatic urethra akin to that following TURP (unpublished data, 1991). High-energy shock waves, focused external heat and focused ultrasound These three alternative forms of BPH treatment are currently being developed. The first 2 methods require a lithotriptor or similar device for their administration; the last-the focused ultrasoundis delivered transrectally. Each technique has been used in animal models and in a few patients (Foster et al., 1991 ; Lobe1 et al., 1991). Hormonal treatment It has been stated that a large number of men > 50 years of age exhibit some degree of prostatic enlargement due to BPH. The current belief is that a 40-year-old man has a 30% chance in his lifetime of undergoing a prostatectomy, generally TURP, to treat urinary flow obstruction. Given these odds, effective medical treatment of BPH would clearly appear to offer both economic and social benefits. Androgen withdrawal induces the shrinkage of an enlarged prostate, so potential forms of BPH medical therapy have been directed toward blocking the action of androgens or suppressing their production within the prostatic tissue. These methods usually induce impotence and other secondary effects, so that their use in BPH is unacceptable. 5-a Reductase inhibitors. The inhibition of 5-a
reductase and thereby the formation of dihydrotestosterone (DHT) from testosterone was considered a novel approach to BPH treatment and stimulated the search for 5-a reductase inhibitors (Gormley and Stoner, 1991). With the recent production of A-ring heterocyclic steroids and 4-azasteroids, which inhibit 5-a reductase, finasteride (MK-906) was developed and has recently been extensively tested in clinical trials. Finasteride decreases the DHT concentration in prostatic tissue and its administration results in a reduction in the plasma DHT level while the testosterone level is maintained. The effect of testosterone on libido is therefore not affected and
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its anabolic action on muscle tissue is retained. Finasteride will also maintain the normal androgenic features promoted by testosterone in a manner similar tomale children with inherited 5-a reductase deficiency, who develop a normal libido at puberty as characterised by a deep voice, male sexual features and musculature but have a small prostate and scanty beard growth. In early clinical studies, 50 mg finasteride administered daily for 7 days decreased intraprostatic DHT by 92% but increased the concentration of testosterone from 0.23 +_ 0.18 ng/g to 1.9 ng/g. When administered at a dose of 5 mg daily for 6 months, finasteride decreased the plasma DHT concentration by 80% to “castrate” levels, shrank prostatic volume by 28%, and increased the urine flow rate up to 3 ml/s without adverse clinical effects. Aromatase inhibitors and antioestrogens. The aromatase enzyme system is responsible for the conversion of androgens to oestrogens. It is particularly active in the ovary and placenta but is also present in the testes and such extragonadal sources as adipose tissue and muscle. The possibility that oestrogens may be implicated in the pathogenesis of BPH has consistently provoked interest in the potential value of aromatase inhibitors as well as antioestrogens in the clinical management of the disease. Experimental studies in dogs and monkeys have indicated that prostatic stromal proliferation, which is induced by the administration of androstenedione, can be antagonised by simultaneous administration of aromatase inhibitors such as 4hydroxyandrostenedione and l-methylandrosta1,4-diene-3,17-dione (M-AD). In preliminary studies of patients with BPH, M-AD significantly decreased the plasma concentrations of oestrone and oestradiol (Habenicht and El Etreby, 1987). Nonetheless, it also would seem logical to consider an effective means of blocking the biological effects of oestrogen at the target cells by use of antioestrogen therapy. An earlier study using the antioestrogen tamoxifen administered for 4 weeks before prostatectomy at a dosage of 80mg/d promoted stromal proliferation and was reported to be unsuccessful. It is not surprising that stromal hyperplasia was a consequence of this treatment, because a daily dose of tamoxifen amounting to only 20 mg has been found to be efficacious in the treatment of premenopausal women with breast cancer and because tamoxifen is known to act like a weak oestrogen. Therefore, it would seem more
FUTURE DIRECTIONS IN THE MANAGEMENT OF BENIGN PROSTATIC HYPERPLASIA
31
logical to use lower doses of tamoxifen, possibly in association with a 5-cl reductase inhibitor or a lowdose antiandrogen, for the treatment of BPH. It will soon be possible to consider the new ICI 183,720, which is a complete oestrogen antagonist with no oestrogenic properties, for the management of BPH.
toward replacement of surgical treatment by new, less aggressive methods that will ensure the same reduction in prostatic mass. In turn, these methods will be subsequently replaced by drug treatment only. In the meantime, symptomatic medical treatment will remain important as sole therapy for early-stage disease and as adjuvant therapy for more advanced cases.
Future Prospects in the Treatment of BPH
Over the next 5 years The therapeutic approach to BPH over the next 5 years will be marked by several new elements :
The field of medicine is marked by a number of archetypal constants : (1) Medical progress in surgical diseases involves the use of less invasive surgical methods until surgical treatment is finally replaced by medical treatment. (2) Whenever a drug competes with a surgical procedure, the drug eventually gains preference. Patients have a natural aversion to surgery, however minor, and often prefer even a drug with unpleasant side effects to an operation with no or minimal sequelae. The Figure illustrates the comparative value of the various treatment modalities for BPH over the next 5 years and by the end of the century. There are no quantitative data, which would be impossible to present-simply impressions principally based on current knowledge of the potential uses of new BPH treatment modalities and on analogies of what has evolved in the management of other diseases, such as renal calculi and duodenal ulcers. Future treatment of BPH will inevitably lean p 9 v (
Medical Treatment
I
1995
I
Medical Treatment and Minimally lnvasive Physical Techniques
1 Surgery
I
2000
I
Medical Treatment ind Minimall) lnvasive Physical Techniques
Surgery Surgery
Fig. Comparative value of the various treatment modalities for BPH over the next 5 years and by the end of the century.
(1) A better symptom scoring system and better response criteria will be developed. (2) Physical treatment modalities will be further developed. In view of their minimally invasive nature, which does not necessitate the induction of anaesthesia, they will inevitably replace TURP in a number of years, especially for uncomplicated cases in which surgery is indicated to lessen discomfort and for patients with a relatively short life expectancy or at high risk. The extensive development of these techniques will be the outstanding event in the field of BPH management over the next 5 years. (3) Alpha blockers will confirm their role as the most effective symptomatic medical treatment. (4) Hormone therapy will enter the field. Because several weeks are needed to achieve an effect that will only be partial in a number of cases, these agents will probably be combined with alpha blockers, at least during the initial months of treatment. (5) In the field of surgery, TURP will continue to gain ground on open surgery as a result of constant improvement in surgical devices, the growing experience acquired by urologists and better training methods. The indications for bladder neck incision will increase, given that a large number of BPH cases currently treated by surgery involve prostates weighing approximately 25 g. By the end of the century New, more specific alpha blockers with fewer adverse effects will be developed. Hormonal treatment will become more complex, probably combining 5-cl reductase inhibitors with the new, pure antioestrogens currently under investigation. The possible discovery of a specific growth factor in the prostate could completely change BPH treatment Perspectives. A Preventive approach Will also develop.
32
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The greatest technical progress will concern the performance of the various physical methods. Lasers will certainly have a place in reducing the prostatic mass. By the end of the century, these techniques will have almost completely replaced surgery as it is known today in the great majority of cases. References Baert, L., Ameye, F., Willemen, P. et d (1990). Transurethral microwave hyperthermia for benign prostatic hyperplasia: preliminary clinical and pathological results. J . Urol., 144, 1383-1 387. Caine, M. (1986). The present role of alpha-adrenergic blockers in the treatment of benign prostatic hypertrophy. J . Urol., 136,l-4. Devonec, M., Berger, N. and Perrin, P. (1991). Transurethral microwave heating of the prostate-r from hyperthermia to thermotherapy. J . Endourol., 5 , 129-1 36. Devonec, M., Cathaud, H., Carter, S. ef d (1990a). Histological and clinical effects of transurethral microwave therapy in patients with benign prostatic hypertrophy. Presented at the XMII Krongres des Deutschen Gesellschaft fur Urologie; September 26-29; Hamburg, Germany. Devonec, M., Cathaud, M., Carter, J. e t d (1990b).Transurethral microwave therapy (TUMT) in patients with benign prostatic hypertrophy. Presented at the 8th World Congress on Endourology and ERSWL; August 29-September 2; Washington, D.C. Abstract. Dreikorn, K., Richter, R. and Schonhofer,P. S. (1990). Konservative nicht-hormonelle Behandlung der benignen Prostata Hyperplasie. Urologe, 29 (Suppl A), 8. Fitzpatrick, J. M., Dreikorn, K., Khoury, S. ef al. (1992). The medicalmanagement of BPH with agents other than hormones and u blockers. In :Proceedingsof the International Consultation on Benign Prostatic Hyperplasia (BPH) ; June 26-27, 1991; Paris; ed. Cockett A. T. K., Aso, Y., Chatelain, C. et al. Pp. 193-199. Paris: SCI. Foster, R. S., Bihrle, R., Sanghvi,N. T. et d (1991). Noninvasive ultrasound produced volume lesion in prostate. J . Urol., 145, 396A. Abstract No. 735. Gonder, M. J., Soanes, W. A. and Smith, V. (1964). Experimental prostate cryosurgery. Invest. Urol., 1,610-619. Gormley, G . J. and Stoner, E. (1991). The role of 5 u-reductase inhibitors in the treatment of benign prostatic hyperplasia. In: Problems in Urology; ed. Lepor, H. and Paulson, D. F. Vol. 5, No. 3 Pp 436-440. Lippincott : Philadelphia. Guazzoni, G., Montorsi, F., Colombo, R. ef d (1991). Long term experience with the prostatic spiral for urinary retention due
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to benign prostatic hyperplasia. S c a d . J . Urol. Nephrol., 25, 2 1-24. Habenicht,U.-F. and El Etreby,M. F. (1987). Synergic inhibitory effects of the aromatase inhibitor I-methyl-androsta-l,4diene-3,17-dione and the antiandrogen cyproterone acetate on androstenedione-induced hyperplastic effects in the prostates of castrated dogs. Prostate, 11, 133-143. International Consensus Committee. (1992). 4 BPH treatment recommendations. In ; Proceedings ofthe International Consultation on Benign Prostatic Hyperplasia (BPH) ; June 2627, 1991; Paris; ed. Cockett, A. T. K., Aso, Y., Chatelain, C. et a / . Pp. 287-288. Paris: SCI. Klein, L. A. (1991). 2 year follow-up of balloon dilatation of the prostate and an algorithm for future patient selection. J . Endourol.,5, 109-1 12. Lobel, B., Gille, F., Cipolla, B. ef d (1991). High energy shock waves (HESW) for the treatment of benign prostatic hypertrophy (BPH). J . Urol., 145,396A. Abstract No. 735. Long, S. R., Clayman, R. V., Dierks, S. M. e t d (1991). Balloon incision of the prostate: preliminary evaluation of a minimal invasive technique. J . Endourol., 5, 117-122. Nielsen, K. K., Klarskov, P., Nordling, J. et d (1990). The intraprostatic spiral : new treatment for urinary retention. Br. J . Urol., 65,500-503. Rigondet, G. (1976). Etude comparee de 325 cas de cryochirurgie utilisant comme refrigerant le protoxyde d’azote et I’azote liquide. Ann. Urol., 10, 159-162. Roth, R. A., Babayan, R. and Aretz, H. T. (1991). TULIPtransurethral ultrasound-guided laser-induced prostatectomy. J . Urol., 145,390A. Abstract No. 712. Smith, Ph., Chaussy, C., Conort, P. et al. (1992). Report of the committee on other non medical treatment. In: Proceedings of the International Consultation on Benign Prostatic Hyperplasia ( B P H ) ; June 26-27,1991; Paris; ed. Cockett, A. T. K., Aso, Y., Chatelain, C. et al. Pp. 223-257. Paris: SCI. Strohmaier, W. L., Bichler, K. H., Fliichter, S. H. ef d (1990). Local microwave hyperthermia of benign prostatic hyperplasia. J . Urol.,144, 913-917. Williams, G. (1991). Early experience of the use of permanently implanted prostatic stents for the treatment of bladder outflow obstruction. World J . Urol., 9, 26-28. Williams, G., Jager, R., McLoughlii, J. et d (1989). Use of stents for treating obstruction of urinary outflow in patients unfit for surgery. Br. Med. J . , 298, 1429.
The Author S. Khoury, MD, Professor of Urology, Clinique Urologique, L’HBpital de la PitiB, Paris, France. Requests for reprints to: S. Khoury, Clinique Urologique, L’HBpital de la Piti6, Cedex 13,75634 Paris, France.
