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New Therapies for Benign Prostatic Hyperplasia
Editorial New Therapies for Benign Prostatic Hyperplasia
and also in other countries.' Threefold to fourfold variations in surgical rates from one locale to another are common. Thus, the mainstay urologic treatment of BPH-transurethral resection of the prostate-has been subjected to close scrutiny, and no ideal therapeutic substitute is available for many patients who historically were treated surgically. Other Therapeutic Options.-A plethora of alternative therapeutic modalities for severely symptomatic BPH in elderly men has emerged (Table 1). In addition to the early experience with thermotherapy clearly described by Blute and associates in this issue of the Mayo Clinic Proceedings (pages 417 to 421), balloons are available for dilation, stainless steel or titanium stents can be used to maintain the lumen of the prostatic urethra, and a variety of alternative energy sources in addition to the electrocautery used in transurethral resection of the prostate can now remove, incise, or vaporize prostatic tissue. Such energy sources include thermotherapy with use of microwave antennas or coiled wires as well as ultrasonically or endoscopically guided laser systems (neodymium:yttrium-aluminum-garnet free beam or contact laser devices) (Table 2). All these approaches seem to be associated with less pain and perhaps less morbidity than is a standard surgical procedure. Prostatic Changes.-The prostate begins undergoing hyperplastic changes when men are in their 30s. Clinical manifestations of BPH often become apparent 10 to 20 years after onset of the process. The actual degree of enlargement is variable, ranging from minimal to substantial. Although many clinicians believe that enlargement of the prostate, such as can be confirmed by digital rectal examination,
For decades, urologists have relied on prostatectomy for treating benign prostatic hyperplasia (BPH). Although transurethral resection of the prostate was pioneered soon after the tum of the century, early prostatectomies were usually performed as open surgical procedures with digital enucleation of the enlarged prostate. With the development of more advanced endoscopic technology, surgical treatment of BPH shifted to transurethral resection of the prostate. The indications for that operation have expanded from correction of the severe manifestations of BPH, including hydronephrosis, profuse hematuria, urinary retention, and complicated infections of the urinary tract, to current-day applications that also include alleviation of bothersome symptoms of BPH or early treatment to prevent progression of disease. Natural History ofBPH.-The general belief that BPH is a relentless disease that ultimately causes azotemia or urinary retention, severe symptoms, and irreversible bladder dysfunction is no longer tenable. Although much remains to be learned about the natural history of BPH, currently available information suggests that, in most patients, the condition does not progress from mild or moderate symptomatic manifestations to a more severe form. We are also beginning to understand that, although complete resolution of symptoms of prostatism is uncommon, progression to more serious sequelae such as urinary retention likewise is infrequent. In fact, severe manifestations of BPH are present at the time of initial assessment in approximately 5% of all older men for whom intervention for BPH is considered. Although more information is needed, observation without active surgical treatment is clearly a more reasonable option than previously believed. Analysis ofSurgical Treatment.-Recently, the surgical treatment of BPH has been scrutinized. Outcome studies have identified a higher mortality and a greater reoperation rate than have heretofore been recognized for patients who have undergone transurethral resection of the prostate.' In addition, the use of surgical treatment of BPH varies considerably from one region to another within the United States
Table I.-Available Therapeutic Options for Benign Prostatic Hyperplasia
Address reprint requests to Dr. Reginald Bruskewitz, Division of Urology, G5/333 Clinical ScienceCenter, University of Wisconsin MedicalSchool, 600 HighlandAvenue,Madison, WI 53792. Mayo Clin Proc 67:493-495,1992
493
Prostatectomy Open surgical procedure Transurethral resection of the prostate Prostatic incision (transurethral incision of the prostate) Pharmacologic therapy Antiandrogens a)-Adrenergic inhibitors Balloon dilation Prostatic stents Thermotherapy
494
EDITORIAL
Mayo Clin Proc, May 1992, Vol 67
treatment session with acceptable patient tolerance and low associated morbidity has emerged. In the current study by Blute and colleagues, transurethral Guidancesystems Energy sources microwave thermotherapy used in a single l-hour session Laser Ultrasonic significantly decreased the symptoms of prostatism, as reFree beam Fluoroscopic flected by symptom scores. These changes are comparable Digital Contact to the changes noted after transurethral resection of the prosCatheter-loaded Electrocautery tate. The reduction in peak urinary flow was less dramatic Hydraulic (for example,balloon,stent) Endoscopic Ultrasonic than that noted after transurethral resection of the prostate, Thermal but the tendency was toward improvement. Readers should Electriccoil note, however, that this is a preliminary study and that the Microwave efficacy of thermotherapy and of transurethral resection of *Mechanisms rangefrom widespread tissueablation, to incision,to the prostate cannot be directly compared at this early stage compression. The optimal extent of tissue destruction and the precise site for maximizing efficacy and minimizing side effects and in the absence of a controlled study of the two ap(includingsexual dysfunction) have not been clearly established. proaches to treatment of BPR. Sexual Function.-Unlike transurethral resection of the prostate, which results in diminished or absent ejaculation in is a prerequisite for the development of symptoms, that two-thirds of the patients and development of impotence in 2 is a misconception. Minimal or no enlargement may ac- to 5%,3 transurethral microwave thermotherapy caused no company clinically significant BPH that would benefit from identifiable adverse effect on sexual function. Theoretically, treatment. tissue ablation might eventuate in a reduced volume of Pharmacologic Treatment.-Prostatic hyperplasia is ejaculate or even occlusion of the ejaculatory ducts. The manifested by nodular changes in the epithelium and stroma. absence of sexual dysfunction after transurethral microwave This process is androgen dependent, and one approach to thermotherapy must be addressed in future studies. treatment of BPH is to decrease the amount of androgen Cost.-Transurethral resection of the prostate necessiavailable to the hyperplastic prostate. One class of drugs tates inpatient hospital care usually for 2 to 5 days, and the currently being evaluated is 5a-reductase inhibitors; these total cost of the procedure exceeds $10,000 per case. More agents interfere with the conversion of testosterone to dihy- than 400,000 transurethral resections of the prostate are perdrotestosterone, the more important hormone in develop- formed annually in the United States; thus, it is the most ment of BPR. Another antiandrogen approach being investi- frequently performed surgical procedure among male patients who qualify for Medicare reimbursement." Because gated is inhibition of aromatase. In most men, prostatic hyperplasia is predominantly a no anesthesia is needed for transurethral microwave therstromal as opposed to an epithelial process. The stroma motherapy, it can be done in an outpatient or office setting. contains substantial amounts of smooth muscle, which re- Therefore, if the cost of the procedure per se is substantially ceives adrenergic innervation. Selective ai-adrenergic in- less than that for transurethral resection of the prostate, it hibitors, developed for the treatment of hypertension, have may have a cost-containment advantage, in that charges for a been successfully used for symptomatic BPR as well. surgical room and inpatient care would be eliminated. The Hyperthermia and Thermotherapy.- The initial appli- duration of effect of transurethral microwave thermotherapy cation of hyperthermia to prostatic disease focused on is unknown. Re-treatment rates for this procedure and for prostatic cancer. Investigators developed transrectal probes other alternatives are as yet unestablished, but they will be a to heat the prostate to less than 45°C, and multiple treat- major factor in the computations oftotal management cost. ments-often as many as 10 sessions-were used. This Prostatic Cancer.-Screening for prostatic carcinoma approach was then applied to BPH. Subsequently, other has become a more frequent and more controversial practice investigators used a transurethral probe to apply hyperther- since the introduction of prostate-specific antigen testing. In mia (less than 45°C) in multiple sessions in patients with the current study by Blute and co-workers, rectal examination and prostate-specific antigen testing were used in part to BPH. In thermotherapy, temperatures exceed 45°C. Appar- screen for baseline adenocarcinoma of the prostate. Despite ently, use of higher temperatures has decreased the need for a paucity of evidence that use of either digital rectal examimultiple treatments. For minimizing the discomfort that nation or prostate-specific antigen testing for screening remight accompany an anesthesia-free application of transure- sults in decreased morbidity and mortality from cancer of the thral thermotherapy, a water-cooled jacket in the thermother- prostate, these tests are widely used for this purpose. More apy catheter allows cooling of the urethral mucosa. A single information on the development of induration, which would Table 2.-Various Strategies for Management of Benign Prostatic Hyperplasia*
Mayo CIiDProc, May 1992, Vol 67
be detected on digital rectal examination, and the short- and long-term effects on prostate-specific antigen is needed to ascertain the influence of transurethral microwave thermotherapy on the detection of cancer. Because not all prostatic tissue is ablated or necrosed during transurethral microwave thermotherapy, a decrease in the incidence or prevalence of prostatic cancer would be unlikely (similar to what has been observed after transurethral resection of the prostate). Conclusion.-Thermotherapy is a new technology. The addition of urethral cooling has resulted in the ability to increase the temperature delivered to the prostatic tissue without an increase in patient discomfort. This advantage and the decrease in the number of treatments needed make thermotherapy widely acceptable if efficacy, re-treatment, and total cost issues are favorable. Further refinements in the delivery of microwave energy and catheter design can be expected. Recently, interest in developing nonsurgical alternatives for the management of BPH has surged. Transurethral resection of the prostate is a safe and effective treatment for BPH but nonetheless is a surgical procedure, and patients understandablyare seeking less invasive approaches to their medical problems. Many of the studies evaluating new alternative therapies have not as yet provided data on long-term efficacy or compared the new therapy in a prospective, randomized fashion with an established treatment such as trans-
EDITORIAL
495
urethral resection of the prostate. Physicians and patients must resist the temptation or the pressure to embrace these new treatments until safety, efficacy, and cost benefits have been clearly demonstrated. Reginald Bruskewitz, M.D. Morten Riehmann, M.D. Division of Urology University of Wisconsin-Madison Medical School Madison, Wisconsin REFERENCES 1. Wennberg IE, Roos N, Sola L, Schon A, Jaffe R: Use of claims data systems to evaluate health care outcomes: mortality and reoperation following prostatectomy. JAMA 257:933-936, 1987 2. Wennberg J, Gittelsohn A: Variations in medical care among small areas. Sci Am 246:120-126; 129; 132; 134, April 1982 3. Mebust WK, Holtgrewe HL, Cockett ATK, Peters PC, Writing Committee: Transurethral prostatectomy: immediate and postoperative complications; a cooperative study of 13 participating institutions evaluating 3,885 patients. J Urol 141:243247, 1989 4. Holtgrewe HL, Mebust WK, Dowd JB, Cockett ATK, Peters PC, Proctor C: Transurethral prostatectomy: practice aspects of the dominant operation in American urology. J Urol 141:248-253,1989
and also in other countries.' Threefold to fourfold variations in surgical rates from one locale to another are common. Thus, the mainstay urologic treatment of BPH-transurethral resection of the prostate-has been subjected to close scrutiny, and no ideal therapeutic substitute is available for many patients who historically were treated surgically. Other Therapeutic Options.-A plethora of alternative therapeutic modalities for severely symptomatic BPH in elderly men has emerged (Table 1). In addition to the early experience with thermotherapy clearly described by Blute and associates in this issue of the Mayo Clinic Proceedings (pages 417 to 421), balloons are available for dilation, stainless steel or titanium stents can be used to maintain the lumen of the prostatic urethra, and a variety of alternative energy sources in addition to the electrocautery used in transurethral resection of the prostate can now remove, incise, or vaporize prostatic tissue. Such energy sources include thermotherapy with use of microwave antennas or coiled wires as well as ultrasonically or endoscopically guided laser systems (neodymium:yttrium-aluminum-garnet free beam or contact laser devices) (Table 2). All these approaches seem to be associated with less pain and perhaps less morbidity than is a standard surgical procedure. Prostatic Changes.-The prostate begins undergoing hyperplastic changes when men are in their 30s. Clinical manifestations of BPH often become apparent 10 to 20 years after onset of the process. The actual degree of enlargement is variable, ranging from minimal to substantial. Although many clinicians believe that enlargement of the prostate, such as can be confirmed by digital rectal examination,
For decades, urologists have relied on prostatectomy for treating benign prostatic hyperplasia (BPH). Although transurethral resection of the prostate was pioneered soon after the tum of the century, early prostatectomies were usually performed as open surgical procedures with digital enucleation of the enlarged prostate. With the development of more advanced endoscopic technology, surgical treatment of BPH shifted to transurethral resection of the prostate. The indications for that operation have expanded from correction of the severe manifestations of BPH, including hydronephrosis, profuse hematuria, urinary retention, and complicated infections of the urinary tract, to current-day applications that also include alleviation of bothersome symptoms of BPH or early treatment to prevent progression of disease. Natural History ofBPH.-The general belief that BPH is a relentless disease that ultimately causes azotemia or urinary retention, severe symptoms, and irreversible bladder dysfunction is no longer tenable. Although much remains to be learned about the natural history of BPH, currently available information suggests that, in most patients, the condition does not progress from mild or moderate symptomatic manifestations to a more severe form. We are also beginning to understand that, although complete resolution of symptoms of prostatism is uncommon, progression to more serious sequelae such as urinary retention likewise is infrequent. In fact, severe manifestations of BPH are present at the time of initial assessment in approximately 5% of all older men for whom intervention for BPH is considered. Although more information is needed, observation without active surgical treatment is clearly a more reasonable option than previously believed. Analysis ofSurgical Treatment.-Recently, the surgical treatment of BPH has been scrutinized. Outcome studies have identified a higher mortality and a greater reoperation rate than have heretofore been recognized for patients who have undergone transurethral resection of the prostate.' In addition, the use of surgical treatment of BPH varies considerably from one region to another within the United States
Table I.-Available Therapeutic Options for Benign Prostatic Hyperplasia
Address reprint requests to Dr. Reginald Bruskewitz, Division of Urology, G5/333 Clinical ScienceCenter, University of Wisconsin MedicalSchool, 600 HighlandAvenue,Madison, WI 53792. Mayo Clin Proc 67:493-495,1992
493
Prostatectomy Open surgical procedure Transurethral resection of the prostate Prostatic incision (transurethral incision of the prostate) Pharmacologic therapy Antiandrogens a)-Adrenergic inhibitors Balloon dilation Prostatic stents Thermotherapy
494
EDITORIAL
Mayo Clin Proc, May 1992, Vol 67
treatment session with acceptable patient tolerance and low associated morbidity has emerged. In the current study by Blute and colleagues, transurethral Guidancesystems Energy sources microwave thermotherapy used in a single l-hour session Laser Ultrasonic significantly decreased the symptoms of prostatism, as reFree beam Fluoroscopic flected by symptom scores. These changes are comparable Digital Contact to the changes noted after transurethral resection of the prosCatheter-loaded Electrocautery tate. The reduction in peak urinary flow was less dramatic Hydraulic (for example,balloon,stent) Endoscopic Ultrasonic than that noted after transurethral resection of the prostate, Thermal but the tendency was toward improvement. Readers should Electriccoil note, however, that this is a preliminary study and that the Microwave efficacy of thermotherapy and of transurethral resection of *Mechanisms rangefrom widespread tissueablation, to incision,to the prostate cannot be directly compared at this early stage compression. The optimal extent of tissue destruction and the precise site for maximizing efficacy and minimizing side effects and in the absence of a controlled study of the two ap(includingsexual dysfunction) have not been clearly established. proaches to treatment of BPR. Sexual Function.-Unlike transurethral resection of the prostate, which results in diminished or absent ejaculation in is a prerequisite for the development of symptoms, that two-thirds of the patients and development of impotence in 2 is a misconception. Minimal or no enlargement may ac- to 5%,3 transurethral microwave thermotherapy caused no company clinically significant BPH that would benefit from identifiable adverse effect on sexual function. Theoretically, treatment. tissue ablation might eventuate in a reduced volume of Pharmacologic Treatment.-Prostatic hyperplasia is ejaculate or even occlusion of the ejaculatory ducts. The manifested by nodular changes in the epithelium and stroma. absence of sexual dysfunction after transurethral microwave This process is androgen dependent, and one approach to thermotherapy must be addressed in future studies. treatment of BPH is to decrease the amount of androgen Cost.-Transurethral resection of the prostate necessiavailable to the hyperplastic prostate. One class of drugs tates inpatient hospital care usually for 2 to 5 days, and the currently being evaluated is 5a-reductase inhibitors; these total cost of the procedure exceeds $10,000 per case. More agents interfere with the conversion of testosterone to dihy- than 400,000 transurethral resections of the prostate are perdrotestosterone, the more important hormone in develop- formed annually in the United States; thus, it is the most ment of BPR. Another antiandrogen approach being investi- frequently performed surgical procedure among male patients who qualify for Medicare reimbursement." Because gated is inhibition of aromatase. In most men, prostatic hyperplasia is predominantly a no anesthesia is needed for transurethral microwave therstromal as opposed to an epithelial process. The stroma motherapy, it can be done in an outpatient or office setting. contains substantial amounts of smooth muscle, which re- Therefore, if the cost of the procedure per se is substantially ceives adrenergic innervation. Selective ai-adrenergic in- less than that for transurethral resection of the prostate, it hibitors, developed for the treatment of hypertension, have may have a cost-containment advantage, in that charges for a been successfully used for symptomatic BPR as well. surgical room and inpatient care would be eliminated. The Hyperthermia and Thermotherapy.- The initial appli- duration of effect of transurethral microwave thermotherapy cation of hyperthermia to prostatic disease focused on is unknown. Re-treatment rates for this procedure and for prostatic cancer. Investigators developed transrectal probes other alternatives are as yet unestablished, but they will be a to heat the prostate to less than 45°C, and multiple treat- major factor in the computations oftotal management cost. ments-often as many as 10 sessions-were used. This Prostatic Cancer.-Screening for prostatic carcinoma approach was then applied to BPH. Subsequently, other has become a more frequent and more controversial practice investigators used a transurethral probe to apply hyperther- since the introduction of prostate-specific antigen testing. In mia (less than 45°C) in multiple sessions in patients with the current study by Blute and co-workers, rectal examination and prostate-specific antigen testing were used in part to BPH. In thermotherapy, temperatures exceed 45°C. Appar- screen for baseline adenocarcinoma of the prostate. Despite ently, use of higher temperatures has decreased the need for a paucity of evidence that use of either digital rectal examimultiple treatments. For minimizing the discomfort that nation or prostate-specific antigen testing for screening remight accompany an anesthesia-free application of transure- sults in decreased morbidity and mortality from cancer of the thral thermotherapy, a water-cooled jacket in the thermother- prostate, these tests are widely used for this purpose. More apy catheter allows cooling of the urethral mucosa. A single information on the development of induration, which would Table 2.-Various Strategies for Management of Benign Prostatic Hyperplasia*
Mayo CIiDProc, May 1992, Vol 67
be detected on digital rectal examination, and the short- and long-term effects on prostate-specific antigen is needed to ascertain the influence of transurethral microwave thermotherapy on the detection of cancer. Because not all prostatic tissue is ablated or necrosed during transurethral microwave thermotherapy, a decrease in the incidence or prevalence of prostatic cancer would be unlikely (similar to what has been observed after transurethral resection of the prostate). Conclusion.-Thermotherapy is a new technology. The addition of urethral cooling has resulted in the ability to increase the temperature delivered to the prostatic tissue without an increase in patient discomfort. This advantage and the decrease in the number of treatments needed make thermotherapy widely acceptable if efficacy, re-treatment, and total cost issues are favorable. Further refinements in the delivery of microwave energy and catheter design can be expected. Recently, interest in developing nonsurgical alternatives for the management of BPH has surged. Transurethral resection of the prostate is a safe and effective treatment for BPH but nonetheless is a surgical procedure, and patients understandablyare seeking less invasive approaches to their medical problems. Many of the studies evaluating new alternative therapies have not as yet provided data on long-term efficacy or compared the new therapy in a prospective, randomized fashion with an established treatment such as trans-
EDITORIAL
495
urethral resection of the prostate. Physicians and patients must resist the temptation or the pressure to embrace these new treatments until safety, efficacy, and cost benefits have been clearly demonstrated. Reginald Bruskewitz, M.D. Morten Riehmann, M.D. Division of Urology University of Wisconsin-Madison Medical School Madison, Wisconsin REFERENCES 1. Wennberg IE, Roos N, Sola L, Schon A, Jaffe R: Use of claims data systems to evaluate health care outcomes: mortality and reoperation following prostatectomy. JAMA 257:933-936, 1987 2. Wennberg J, Gittelsohn A: Variations in medical care among small areas. Sci Am 246:120-126; 129; 132; 134, April 1982 3. Mebust WK, Holtgrewe HL, Cockett ATK, Peters PC, Writing Committee: Transurethral prostatectomy: immediate and postoperative complications; a cooperative study of 13 participating institutions evaluating 3,885 patients. J Urol 141:243247, 1989 4. Holtgrewe HL, Mebust WK, Dowd JB, Cockett ATK, Peters PC, Proctor C: Transurethral prostatectomy: practice aspects of the dominant operation in American urology. J Urol 141:248-253,1989