The Medical Therapy of Prostatic Symptoms Study: What Will We Learn?

NEW PERSPECTIVES ON BPH The Medical Therapy of Prostatic Symptoms Study: What Will We Learn? Kevin M. Slawin, MD The Baylor Prostate Center, Scott Department of Urology, Baylor College of Medicine, Houston, TX Until recently, benign prostatic hyperplasia (BPH) was thought of as a relatively uncomplicated disease process resulting from age-related enlargement of the prostate gland, which was thought to cause all of the symptoms associated with the disease. Prostatectomy was considered the state-of-the art treatment of BPH. Advances in our understanding of the pathogenesis of BPH and the relationship among clinical signs and symptoms has allowed for the development of pharmacologic therapies for this disorder, namely, selective -blockers and 5--reductase inhibitors. These 2 classes of drugs have been demonstrated to be safe and effective for the treatment of BPH. Evidence supports different mechanisms of action, suggesting that, when used in combination, these therapies may act synergistically. The Medical Therapy of Prostatic Symptoms study was designed, in part, to test this hypothesis. Initial results of the trial are presented in this article. [Rev Urol. 2003;5(suppl 4):S42-S47] © 2003 MedReviews, LLC Key words: Benign prostatic hyperplasia • Bladder outlet obstruction • Benign prostatic enlargement • Lower urinary tract symptoms • 5--Reductase inhibitors • -Blockers he language we use to define benign prostatic hyperplasia (BPH) reflects changes in our understanding of this disease process that have occurred over time. Before the 1980s, the clinical and basic scientific investigation of BPH was a relatively mundane discipline. Clinical BPH was thought of as an uncomplicated, easy-to-understand disease resulting from the enlargement of the prostate gland that occurs in aging men. Bladder outlet obstruction (BOO) was T S42 VOL. 5 SUPPL. 4 2003 REVIEWS IN UROLOGY The MTOPS Study believed to be a direct result of prostate enlargement, being caused by a mechanical “squeezing" of the prostatic urethra. This, in turn, was believed to cause the common symptoms of BPH: frequency, urgency, hesitancy, slow stream, incomplete bladder emptying, and nocturia. Such a simple disease was treated with a simple solution: prostatectomy, which was pioneered by the likes of Theodore Davis, Nathaniel Alcock, Maximilian Stern, Joseph McCarthy, and Reed Nesbit in the 1920s and 1930s. This singular therapy or other surgical variations remained the state-of-the-art treatment of BPH until the 1980s, when the pioneering work of Marco Caine1,2 and Herbert Lepor3,4 in the identification and characterization of adrenergic receptors in the prostate ushered in the era of medical therapy for BPH. This was accompanied by the discovery of the importance of 5--reductase type 2 deficiency and the role of dihydrotestosterone (DHT) in the development of BPH.5 In 1992, finasteride was established as a medical therapy for BPH.6 Accompanying this evolution, the terms we used to define BPH became more complex. Rather than a singular disease entity with a straightforward natural history and a single effective A B C BOO BPE LUTS Figure 1. In 1989, Hald developed this 3-ring diagram to portray benign hyperplastic hyperplasia (BPH) as a syndrome of 3 overlapping, yet distinct, entities: benign prostatic enlargement (BPE), bladder outlet obstruction (BOO), and lower urinary tract symptoms (LUTS). (A) BPH was originally viewed as a complete overlap of these 3 entities. (B) By the late 1980s and early 1990s, some urologic researchers argued that there is little or no relationship among the 3 entities. (C) The truth seems to lie somewhere in the middle of these 2 extreme views. this change in terminology, a contentious debate arose regarding the true relationship among these 3 entities. Defined in this manner, the early concepts of BPH could be viewed as the complete overlap of the 3 entities (Figure 1A). By the late 1980s and early 1990s, some urologic researchers argued that there was little or no relationship among LUTS, BPE, and BOO (Figure 1B).8-11 However, not sur- Current thought leaders view BPH as a syndrome in which BPE, BOO, and LUTS are interrelated but distinct entities with possibly different etiologies and divergent natural histories. surgical therapy, the notion that BPH was a syndrome of 3 overlapping, yet clinically distinct, entities was established. This schema for BPH was best articulated by Hald,7 who portrayed BPH with his now famous diagram of 3 overlapping rings: benign prostatic enlargement (BPE), BOO, and lower urinary tract symptoms (LUTS). With prisingly, the truth seems to lie somewhere between these 2 extreme views (Figure 1C). Current thought leaders view BPH as a syndrome in which BPE, BOO, and LUTS are interrelated but distinct entities with possibly different etiologies and divergent natural histories. More recent studies, such as the Proscar Long-Term Efficacy and Safety Study (PLESS)12 and phase 3 dutasteride studies,13 have strengthened the relationship between BOO and BPE, while reinforcing the notion that LUTS have a wider range of etiologies and a lessestablished association with BOO and BPE (Figure 2). The Veterans Affairs Cooperative Study 359 (VA 359) initiated a cascade of events that led to a better understanding of the association among prostate size, BOO, and response to therapy. Results of this study showed no improvement in symptoms or flow rate, over that experienced with placebo, after 1 year of finasteride therapy in men with an American Urological Association (AUA) symptom score of 8 or higher and a modestly diminished flow rate.14 Men who received terazosin, however, had significant improvements in both flow rate and symptom score; this improvement was identical to that in men who received a combination of terazosin and finasteride. VOL. 5 SUPPL. 4 2003 REVIEWS IN UROLOGY S43 The MTOPS Study continued BOO BPE LUTS Figure 2. Data from recent studies have strengthened the relationship between bladder outlet obstruction (BOO) and benign prostatic enlargement (BPE); lower urinary tract symptoms (LUTS) seem to have a wider range of etiologies and less association with BOO and BPE. A meta-analysis by Boyle and colleagues15 provided a possible explanation for the discrepancy between the results of this study and previous randomized placebo-controlled trials that demonstrated a clinical improvement in symptoms and flow rate with finasteride therapy: the inconsistency in median prostate volume of the men enrolled in these various studies. This explanation was supported by the results of PLESS, a 4-year, randomized, placebo-controlled trial evaluating the safety and efficacy of finasteride in men with urinary symptoms and enlarged prostates. In PLESS, prostate volume was found to be a significant predictor of progression to acute urinary retention (AUR) and/or surgery; men in the highest tertile of prostate volume who received placebo experienced a 22% incidence of AUR/surgery, compared with an approximate 11% incidence in men in the 2 lower tertiles.16 Despite the controversy regarding the relationship among prostate size and growth, BOO, and LUTS, there has never been any doubt that prostate S44 VOL. 5 SUPPL. 4 2003 size increases as men age. Rather than a diffuse enlargement of the prostate gland, BPE occurs primarily in the transition zone of the prostate. As men enter their thirties and forties, mixed stromal and epithelial “nodules" form within the transition zone and, with macroscopic enlargement, these nodules eventually fill the transition zone in men with severe BPH. As the nodules enlarge, the associated increase in transition zone volume can cause the prostate gland to increase in size from the normal 20 cm3 in young men to 200 cm3 in the most severe cases of BPH— a 10-fold increase. The remainder of the prostate is often passively thinned and compressed around the enlarging prostatic transition zone. The Medical Therapy of Prostatic Symptoms Trial The rationale for the Medical Therapy of Prostatic Symptoms (MTOPS) study was based on a knowledge of the pathogenesis of BPH and an understanding of the mechanisms of action of the 2 classes of medical therapy for the disorder—selective -blockers and 5--reductase inhibitors. The MTOPS study, the most ambitious and important trial of medical therapy for BPH to date, tested the hypothesis that these 2 classes of drugs may act synergistically to delay or prevent the progression of BPH. Study Rationale 5--Reductase inhibitors block either 5--reductase type 2 (eg, finasteride) or both the type 1 and type 2 isoforms of the enzyme (eg, dutasteride). This inhibition leads to a greater than 90% reduction in the level of DHT within the prostate. Through a less-defined pathway, which might include secondary reduction in necessary growth factors or loss of the microvasculature and resultant ischemia, rapid involution of the prostate occurs, REVIEWS IN UROLOGY characterized by increased epithelial apoptosis and a clinically observed decrease in prostate volume of approximately 20% over the ensuing 3 to 6 months. More striking and potentially more important, the loss of DHT in the prostate also leads to a complete abrogation of further prostate growth, as dramatically demonstrated by the PLESS results. These effects are almost certainly mediated through regulation of downstream, androgen-responsive gene expression in the prostate, although the identity of these key genes remains unknown. Selective 1-adrenergic receptor blockers bind to the 1A receptors on prostatic smooth muscle cells, leading to physiologic changes that result in increased flow rate. However, the mechanism mediating the rapid and dramatic improvement in LUTS is less defined. Evidence has accumulated that these effects may be mediated through blockade of  receptors outside of the prostate, perhaps in the spinal cord, central nervous system, or bladder. Although some investigators have demonstrated gene expression changes within the prostate resulting from therapy with selective -blockers, and even evidence of apoptosis, no dramatic changes in prostate morphometry, histology, size, or growth are apparent in clinical trials. However, improvement in symptoms has been universally observed. Thus, the effectiveness of selective -blockade and 5--reductase inhibition for the treatment of BPH, both of which have been established to be safe, appears to occur through unrelated mechanisms, leading to the provocative notion that the combination of these 2 classes of medications might work synergistically to treat BPH. In fact, several short-term studies, such as VA 359, were designed to test this concept. The MTOPS Study With the above thoughts in mind, the MTOPS trial was begun in 1993. In an initial pilot phase of the study, funded by the National Institute of Diabetes and Digestive and Kidney Diseases, 6 centers developed a protocol to answer important questions regarding medical therapy for BPH. Although the efficacy and safety of BPH therapy was already well-established, the role of these therapies in preventing or delaying disease progression remained uncertain. Many urologists believed that medical therapy simply “postponed the inevitable" and that observed symptomatic improvement may have been masking the underlying progression of the disease, leading to long-term complications. Moreover, the basic biology of benign prostatic growth was poorly understood, despite decades of research. Study Design The MTOPS study was a randomized, placebo-controlled clinical trial conducted to determine whether singleagent therapy with finasteride or doxazosin, or a combination of the 2 agents, prevents or delays the clinical progression of BPH.17,18 A total of 3047 men (pilot study [n = 116]; fullscale study [n = 2931]) were recruited from 1993 to 1998. Men were eligible if they were aged 50 years or older, had an AUA symptom score of 8 to 30 during the full-scale study, and had a peak urinary flow rate of 4 mL/s to 15 mL/s. Exclusion criteria included a prior medical or surgical intervention for BPH or a serum prostate-specific antigen (PSA) level higher than 10 ng/mL. Participants were randomly assigned, in a double-blind fashion, to one of the following 4 treatment groups: placebo, doxazosin, finasteride, or combination therapy. The dose of doxazosin was titrated, on a weekly schedule, up to 8 mg. Vital signs, AUA symptom score, peak urinary flow rate, medication compliance, and adverse events were evaluated quarterly; digital rectal examination, serum PSA measurement, and urinalysis were conducted annually. Prostate volume was assessed by transrectal ultrasound (TRUS) at baseline and at end-year 5 or end-of-study follow-up, whichever came first. BPH clinical progression was defined as AUR, renal insufficiency due to BPH, recurrent urinary tract infection (2 or more within 1 year) In the full-scale study, the mean follow-up was 4.5 years. The rate of clinical progression in patients who received placebo was 4.5 per 100 person-years (PY). Compared with placebo, doxazosin therapy reduced the risk of clinical progression by 39% to 2.7 per 100 PY (P < .001) and finasteride reduced the risk by 34% to 2.9 per 100 PY (P = .002). Doxazosin and finasteride produced statistically equivalent risk reduction, whereas combination therapy reduced the risk of progression compared with placebo The MTOPS trial was unique in defining a new, clinically important end point based on the worsening of LUTS. or urosepsis, socially or hygienically unacceptable incontinence, or symptom deterioration. Although the first 4 definitions of BPH clinical progression broke no new ground, the MTOPS trial was unique in defining a new, clinically important end point based on the worsening of LUTS. Subjects were determined to have experienced this end point if they had an increase in AUA symptom score of 4 or more points over their score at time of randomization and confirmed this rise by re-administration of the index within 4 weeks. Results Primary results of the MTOPS trial were presented for the first time at the 2002 AUA Annual Meeting.19 Of the 3047 men who were randomized, no significant differences were noted in baseline age, demographic characteristics, symptom severity score, maximum urinary flow rate, or other characteristics. Although the mean prostate volume was 36.3 cm3, 31% of patients had a prostate volume greater than 40 cm3 and 16% had a volume less than 20 cm3. Mean serum PSA level was 2.4 ng/mL. by 67% to 1.5 per 100 PY (P < .001), a significantly greater risk reduction compared with either drug alone. Seventy-eight percent of progression events were due to an increase in AUA symptom score of 4 points or higher, 12% were due to AUR, and 9% were due to incontinence. Only 5 patients developed recurrent urinary tract infection/urosepsis, and none developed BPH-related renal insufficiency. Compared with placebo, both finasteride and combination therapy significantly reduced the risk and cumulative incidence of AUR; although doxazosin reduced the risk of AUR in the first 2.5 years of the study, resulting in a delay in the time to development of AUR, it did not reduce the long-term cumulative incidence compared with placebo. Furthermore, finasteride therapy and combination therapy significantly reduced the risk of BPH-related invasive therapy by 64% and 67%, respectively, compared with placebo. In contrast, doxazosin did not reduce the long-term cumulative incidence of BPH-related invasive therapy. The 4-year mean reduction in symptom score was 4.9 for the patients who VOL. 5 SUPPL. 4 2003 REVIEWS IN UROLOGY S45 The MTOPS Study continued received placebo, 6.6 for those who received doxazosin, 5.6 for those who received finasteride, and 7.4 for those who received combination therapy. Maximum urinary flow rate also improved over time in all active treatment arms compared with placebo. Not surprisingly, changes in baseline serum PSA level, transition zone volume, and total prostate volume were similar in the placebo and doxazosin groups. Results of the MTOPS trial should be published in more detail before the end of the year. Important new data regarding secondary analyses of the MTOPS trial were presented at the 2003 Annual AUA Meeting in Chicago. Kevin Slawin, MD, presented results of a study by McConnell and colleagues evaluating baseline parameters that predicted BPH progression in the placebo group.20 Not surprisingly, baseline PSA level and prostate volume predicted AUR, as has been shown in other studies, such as PLESS and dutasteride phase 3 pivotal trials. However, these parameters, along with age, flow rate, and post-void residual urine, were also significant predictors of overall BPH and symptom progression. In addition, lower symptom scores were associated with a higher rate of BPH progression, reflecting a “regression to the mean" effect in which patients who entered the trial with a lower AUA symptom score had a greater opportunity to experience a 4-point rise than those who entered with a higher score. Claus Roehrborn, MD, presented MTOPS data on transition zone volume and total prostate volume.21 The data demonstrated that both param- evaluating baseline parameters that predicted BPH progression in the 3 treatment arms—doxazosin, finasteride, and combination therapy.22 Overall results demonstrated that the profile of baseline parameters that predicted BPH progression was most similar between the doxazosin and placebo groups, suggesting that doxazosin has the least impact on the natural history of BPH progression. In contrast, finasteride and combination therapy eliminated the predictive parameters evident in the placebo Lower symptom scores were associated with a higher rate of BPH progression, reflecting a “regression to the mean" effect. eters were associated with increased age and PSA level, as has been previously shown. Furthermore, transition zone volume and total prostate volume changes in the placebo group exactly mirrored those in the doxazosin group, further emphasizing the different mechanisms of action of selective -blockers and 5--reductase inhibitors. Steve Kaplan, MD, presented data group, demonstrating the power of these therapies to affect BPH progression across a broad range of patients. The MTOPS trial has emphasized some key points regarding the natural history of BPH and the expectations associated with medical therapy for this disease. In addition to reinforcing previous notions regarding the progressive nature of BPH, the relationship between PSA level and Main Points • Until recently, benign prostatic hyperplasia (BPH) was thought to be an uncomplicated disease process resulting from the enlargement of the prostate that occurs with aging; prostatectomy was considered state-of-the-art treatment of BPH. In the 1980s, advances in our understanding of the pathophysiology of BPH, including the characterization of adrenergic receptors in the prostate, ushered in the era of medical therapy for BPH, namely, 5--reductase inhibitor and -blocker therapy. • 5--Reductase inhibitors and -blockers, both of which have been shown to be safe and effective for the treatment of BPH, appear to work through unrelated mechanisms. With this in mind, the Medical Therapy of Prostatic Symptoms (MTOPS) trial was initiated to determine if these 2 classes of drugs act synergistically to delay or prevent the progression of BPH. • In the MTOPS study, the combination of finasteride and doxazosin was found to be more effective than either therapy alone in preventing the progression of BPH: the risk of clinical progression was reduced by 39%, 34%, and 67%, in the doxazosin, finasteride, and combination therapy groups, respectively, compared with placebo. • Both finasteride and combination therapy significantly reduced the risk of acute urinary retention (AUR) and BPH-related invasive therapy. Although doxazosin reduced the risk of AUR in the initial 2.5 years of the study, it did not reduce the long-term incidence compared with placebo. In addition, doxazosin did not reduce the long-term incidence of BPH-related invasive therapy. • Prostate-specific antigen level, prostate volume, age, flow rate, and post-void residual urine were shown to be significant predictors of overall BPH and symptom progression. S46 VOL. 5 SUPPL. 4 2003 REVIEWS IN UROLOGY The MTOPS Study prostate size and growth, and progression as measured by AUR and BPH surgery rates, the MTOPS trial has added a new understanding regarding the importance of these parameters in predicting symptom progression. Furthermore, the MTOPS trial has increased our appreciation of the long-term natural history of BPH which, until recently, had only been evaluated primarily in shortterm 1- or 2-year studies. The synergy created by the dual mechanisms of action of selective -blockers and 5--reductase inhibitors has now been clearly established and will likely impact the choice of therapy for BPH patients around the world. References 1. 2. 3. 4. 5. Caine M. Medical management of prostatic hyperplasia. Compr Ther. 1986;12:21-25. Caine M. Clinical experience with alphaadrenoceptor antagonists in benign prostatic hypertrophy. Fed Proc. 1986;45:2604-2608. Shapiro E, Lepor H. Alpha 2 adrenergic receptors in hyperplastic human prostate: identification and characterization using [3H] rauwolscine. J Urol. 1986;135:1038-1042. Lepor H, Shapiro E. Characterization of alpha1 adrenergic receptors in human benign prostatic hyperplasia. J Urol. 1984;132:1226-1229. Walsh PC, Madden JD, Harrod MJ, et al. Familial incomplete male pseudohermaphroditism, type 2: decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med. 1974;291:944-949. 6. Gormley GJ, Stoner E, Bruskewitz RC, et al, for the Finasteride Study Group. The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med. 1992;327:1185-1191. 7. Hald T. Urodynamics in benign prostatic hyperplasia: a survey. Prostate Suppl. 1989;2:69-77. 8. Jensen KM, Bruskewitz RC, Iversen P, Madsen PO. Significance of prostate weight in prostatism. Urol Int. 1983;38:173-178. 9. Barry MJ, Cockett AT, Holtgrewe HL, et al. Relationship of symptoms of prostatism to commonly used physiological and anatomical measures of the severity of benign prostatic hyperplasia. J Urol. 1993;150:351-358. 10. Graversen PH, Gasser TC, Wasson JH, et al. Controversies about indications for transurethral resection of the prostate. J Urol. 1989;141:475481. 11. Christensen MM, Bruskewitz RC. Clinical manifestations of benign prostatic hyperplasia and indications for therapeutic intervention. Urol Clin North Am.1990;17:509-516. 12. McConnell JD, Bruskewitz RC, Walsh P, et al, for the Finasteride Long-Term Efficacy and Safety Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med. 1998;338:557-563. 13. Roehrborn CG, Boyle P, Nickel JC, et al. Efficacy and safety of a dual inhibitor of 5alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002;60:434-441. 14. Lepor H, Williford WO, Barry MJ, et al, for the Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. The efficacy of terazosin, finasteride, or both in benign pro- static hyperplasia. N Engl J Med. 1996; 335:533-539. 15. Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: metaanalysis of randomized clinical trials. Urology. 1996;48:398-405. 16. Roehrborn CG, Boyle P, Bergner D, et al, for the PLESS Study Group. Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. Urology. 1999; 54:662-669. 17. Bautista OM, Kusek JW, Nyberg JW, et al. Study design of the Medical Therapy of Prostatic Symptoms (MTOPS) trial. Control Clin Trials. 2003;24:224-243. 18. Kusek JW, Ahrens A, Burrows PK, et al. Recruitment for a clinical trial of drug treatment for benign prostatic hyperplasia. Urology. 2002;59:63-67. 19. McConnell JD, for the MTOPS Steering Committee. The long term effects of medical therapy on the progression of BPH: results from the MTOPS trial. J Urol. 2002;167(4 suppl):265. Abstract 1042. 20. Baseline measures predict the risk of benign prostatic hyperplasia clinical progression in placebo-treated patients. J Urol. 2003;169(4 suppl):332. Abstract 1287. 21. Roehrborn CG, McConnell J, Jacobs S, et al. Baseline prostate volume and serum PSA predict rate of prostate growth: analysis of the MTOPS data [abstract]. J Urol. 2003;169(4 suppl):364. Abstract 1361. 22. Kaplan SA, Roehrborn CG, McConnell JD, et al. Baseline symptoms, uroflow and post-void residual urine as predictors of BPH clinical progression in the medically treated arms of the MTOPS trial. J Urol. 2003;169(4 suppl):332. Abstract 1289. VOL. 5 SUPPL. 4 2003 REVIEWS IN UROLOGY S47