Highlights of the 2002 Annual Meeting of the American Urological Association

Best of the 2002 AUA Annual Meeting

MEETING REVIEW Best of the 2002 AUA Annual Meeting Highlights of the 2002 Annual Meeting of the American Urological Association May 25–30, 2002, Orlando, FL [Rev Urol. 2002;4(3):122–140] © 2002 MedReviews, LLC Key words: Benign prostatic hyperplasia • Botulinum toxin A • Chronic pelvic pain syndrome • Complexed prostatespecific antigen • Cryosurgery • Digital rectal examination • Dutasteride • Erectile dysfunction • Extracorporeal shock wave therapy • Finasteride • Gleason score • Injection therapy • MTOPS trial • Nephrolithiasis • Nephron-sparing surgery • Overactive bladder • Peyronie’s disease • Prostate biopsy • Prostate cancer • Prostate-specific antigen • Prostatitis • Radical nephrectomy • Radio frequency ablation • Renal cell carcinoma • Serum marker • Shock wave lithotripsy • Sildenafil • Tadalafil • Vardenafil • Vesicoureteral reflux • Voiding dysfunction he Contributing and Medical Editors of Reviews in Urology were among the more than 15,000 attendees of the 2002 American Urological Association (AUA) Annual Meeting in Orlando. Here, they report on the latest developments in their respective areas of expertise. T University of Pittsburgh Researchers Use Botulinum Toxin A to Treat Overactive Bladder Botulinum toxin A (BTX) injections show promise as a treatment for a variety of lower urinary tract dysfunctions, according to a study presented by University of Pittsburgh researchers at the 2002 American Urological Association Centennial Celebration Annual Meeting. Results 122 VOL. 4 NO. 3 2002 were published in abstract 98 in the AUA proceedings. Over 17 million Americans suffer from overactive bladder, a condition that significantly affects the patient’s quality of life. An estimated 80% of these patients do not seek help or treatment for this condition. Overactive bladder is characterized by the following conditions: frequency, urinating more than eight times in a 24-hour period; urgency, the immediate and strong urge to urinate; and urge incontinence, the inability to suppress urgency, resulting in the leaking or loss of urine. “Bladder dysfunction affects a staggering number of people worldwide. The use of Botox injections can offer many of these patients a safe, REVIEWS IN UROLOGY but temporary, solution to this embarrassing problem," said Michael Chancellor, MD, Professor of Urology and Gynecology at the University of Pittsburgh School of Medicine. In the study, 50 patients suffering from a variety of voiding dysfunctions, including multiple sclerosis, spinal cord injury, stroke, interstitial cystitis, and overactive bladder, were injected with BTX into the bladder or urethra. Each patient experienced involuntary contractions of the bladder muscle that caused incontinence, typified by either uncontrolled voiding of urine or the inability to completely empty the bladder. Of these 50 patients,1 41 (82%) reported a decrease or absence of incontinence after the BTX injec- AUA Annual Meeting tions. The decrease was seen within 7 days of the injection, and symptoms were alleviated for up to 6 months, or longer, in some cases. None of the patients experienced long-term complications from the treatment, such as stress incontinence or urinary retention. BTX acts by binding to the nerve endings of muscles, blocking the release of the chemical that causes the muscle to contract. When BTX is injected into specific muscles, the muscle becomes paralyzed or weakened, but leaves surrounding muscles unaffected, allowing for normal muscle function. Common urologic conditions, such as neurogenic detrusor hyperreflexia and overactive bladder, are caused by involuntary contractions of the detrusor muscle, which controls the bladder. This new therapy helps alleviate the contractions, restoring normal bladder function. [Christopher P. Smith, MD, Michael B. Chancellor, MD] Reducing Shock Wave–Induced Renal Injury A medley of papers presented during the nephrolithiasis sessions at the 2002 AUA meeting focused on methods of limiting shock wave–induced renal injury and improving results with shock wave lithotripsy (SWL). It has been previously demonstrated that shock wave energy delivered to the kidney results in renal microvascular injury and interstitial inflammation. Cavitation has been thought to be one of the causes of this small blood vessel disruption. Auge and colleagues from Durham, NC created an in vitro model, which demonstrated that cavitation has the potential to generate such injury.2 They used high-speed imaging to study cavitation bubble dynamics in small cellulose tubes filled with a circulating saline solution. Using an experimental electro- hydraulic lithotripter, they delivered shock wave energy to these vessels. This resulted in large intraluminal cavitation bubble expansion and subsequent bubble collapse. The latter event was associated with disruption of these vessel phantoms. This group also reported on the development of a lithotripter that circumvents cavitation damage.3 They made a modification to a Dornier HM3 lithotripter (Dornier Medical Systems, Marietta, GA): insertion of a thin ellipsoidal reflector into the standard reflector. This modification results in an initial compressive shock wave followed 4 microseconds later by another compressive shock wave. The superposition of these two energy waves results in the attenuation of the trailing tensile wave, which is responsible for generating cavitation. Using the aforementioned phantom vessel model, they demonstrated that this device limited cavitation damage while not significantly impeding the ability to fragment artificial stones. These investigators also assessed this device using a porcine model.3 They treated the kidneys of mature swine using this device with 2000 shocks (24 kV) and another group with 2000 shocks (20 kV) using the standard HM3 lithotripter. They found that the volume of microvascular damage was significantly less in the group treated with the modified lithotripter (1% vs 13%). Previous animal experimentation has demonstrated that both the glomerular filtration rate (GFR) and renal plasma flow (RPF) decrease in the shocked kidney, whereas RPF alone is reduced in the untreated renal unit. These responses have also been demonstrated in humans undergoing SWL. Willis and associates from Indianapolis, IN have used this phenomenon in an effort to reduce SWL-induced renal injury.4 They found that treating one porcine renal unit with a small number of shock waves (100 at 12 kV) before treating the other kidney with a therapeutic dose (2000 shocks at 24 kV) results in minimal histologic evidence of renal injury in the latter organ. The previously mentioned responses in GFR and RPF occurred in the kidney receiving the therapeutic dose. These findings could be due to protective vasospasm. This innovative research has provided a better understanding of the mechanisms of SWL renal injury and potential methods for limiting such damage. Carefully performed clinical trials are needed to confirm the efficacy of this technology and renal protective strategies. [Dean G. Assimos, MD] [Note: Dr. Assimos serves as consultant, speaker, and study participant for Boston Scientific Corporation.] Update on Prostatitis The 2002 Annual Meeting of the American Urological Association (AUA) in Orlando, Florida continued the trend that began approximately 5 years ago, a trend that has completely changed urologic dogma in regard to the epidemiology, etiology, diagnosis, and treatment of chronic prostatitis. Epidemiology A recent prevalence survey of chronic prostatitis in Malaysia confirmed that the diagnosis of chronic prostatitis is a significant worldwide problem.5 Of 3147 subjects surveyed, 8.7% complained of prostatitis-like symptoms. An important finding in this Malaysian study was that clinical evaluation in a subset of cases identified in the survey demonstrated that 75% of the subjects met the necessary clinical criteria for the diagnosis of chronic prostatitis. The National Institutes of Health Chronic Prostatitis Symptom Index VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY 123 AUA Annual Meeting continued (NIH-CPSI), a validated outcome measure for prostatitis research, continues to be popular among researchers internationally and among clinicians in North America as a means of evaluating and following prostatitis patients. The NIH-CPSI is being translated into a number of languages, and the validated German version of the NIH-CPSI was presented at the 2002 AUA meeting.6 The NIH Chronic Prostatitis Collaborative Research Network (CPCRN) compared 463 men enrolled in a chronic prostatitis cohort study and 121 asymptomatic, age–matched controls.7 The investigators showed that socioeconomic or sexual factors were no different among men with and without chronic pelvic pain syndrome (CPPS). Because there were many significant differences among other medical problems present in the two groups, the investigators felt that their findings supported the hypothesis that some medical conditions may predispose men to CPPS. An assessment of symptoms and quality of life in men who received prostatitis diagnoses in primary care and primary urology clinics showed that the average symptom severity of these patients was considerably lower than that of tertiary care patients with very chronic prostatitis.8 It appears that prostatitis patients in primary and secondary care populations may have a less severe condition than those reported in the literature from the tertiary care prostatitis centers. Etiology Abstracts presented at the 2002 AUA suggested a number of etiologic factors that may be responsible for pathogenesis of chronic prostatitis (CP)/CPPS. These included genetic factors,9,10 immunological factors,11 neurogenic factors,12,13 and muscle dysfunction.14 It was suggested again 124 VOL. 4 NO. 3 2002 this year that a substantial portion of CP/CPPS patients may have viable but unculturable bacteria,15 however no relationship could be found between a viral etiology (herpes simplex virus, human papilloma virus, or cytomegalovirus) and CPPS.16 Evaluation Another study by the NIH-CPCRN group compared leukocyte counts and bacterial localization rates in prostate-specific specimens in 463 men enrolled in the NIH chronic prostatitis cohort study and 121 age-matched men without urinary symptoms.17 Men with CPPS have idated outcome parameters. Alpha-blockers have been prescribed for years to patients with chronic prostatitis syndromes, with very little clinical data to confirm efficacy. The findings of a 6-week, double-blind pilot study in which 58 patients were randomized to tamsulosin or placebo suggested that tamsulosin may provide clinical benefit in patients with nonbacterial prostatitis, particularly those with moderate to severe symptoms.18 Similarly, finasteride has also been used, based on anecdotal experience and small, reported studies. A randomized, placebo-controlled, multi- This randomized, controlled trial demonstrated significant improvement in quality of life and significant global improvements in symptoms of CPPS in men following treatment with pentosan polysulfate. statistically higher leukocyte counts in all the segmented urine samples and expressed prostatic secretions compared to controls, except in semen. However, the clinical significance of these elevated leukocyte counts requires further investigation, particularly because of the high prevalence of elevation among the controls. There was no difference in rate of localization cultures for men with CPPS compared to men in the control group. This study suggests that the “gold standard" MearesStamey test should be reassessed for its utility in clinical practice. Treatment This year at the AUA, a number of randomized controlled trials comparing various treatment modalities to placebo or sham therapy were presented. Evidence-based treatment of CP/CPPS will only be possible because of these types of prospective, randomized, controlled trials, using accepted clinical definitions and val- REVIEWS IN UROLOGY center pilot study enrolled 76 patients to evaluate the safety and efficacy of finasteride in the treatment of CP/CPPS, and this pilot study suggested that 6 months of finasteride benefits some men in category IIIA CPPS.19 Many researchers and clinicians feel that chronic prostatitis and interstitial cystitis may be the same disease, or at least diseases along the same spectrum of medical conditions. A double-blind, placebo-controlled, multicenter study evaluated the effects of pentosan polysulfate (PPS) in men with CPPS. In this study, 100 patients were randomized to PPS or placebo for 16 weeks. This randomized, controlled trial demonstrated significant improvement in quality of life and significant global improvements in symptoms of CPPS in men following treatment with PPS.20 A small pilot study to determine whether acupuncture improved the pain, voiding symptoms, and quality of life of men with CPPS assessed AUA Annual Meeting 6 weeks of treatment in 12 men and demonstrated significant improvement in 80%.21 These findings need to be assessed in a sham-controlled trial. A sham-controlled trial evaluating transurethral needle ablation (TUNA) in 33 patients with moderate to severe symptoms of CPPS showed the efficacy of TUNA compared to sham treatment, and the authors did not recommend TUNA as a routine treatment in CPPS.22 Conclusion Significant funding by national research organizations (such as the NIH) and industry, based on recent Radiation Oncology (ASTRO) criteria for interpretation of failure following definitive local therapy. The ASTRO definition of failure (three consecutive rises in prostate-specific antigen [PSA]) was compared with a PSA greater than 0.2 ng/mL as an indication for failure. Using the 0.2 ng/mL cutoff, local failure at 5, 10, and 15 years was observed in 85%, 77%, and 68% of patients, respectively. In contrast, when the ASTRO criteria were applied with backdating to define failure as the midpoint between the nadir and first PSA rise, the percent freedom from biochemical failure rose to 90 at all time points. These Observations clearly indicate that the ASTRO definition is inadvisable for men treated with radical prostatectomy. epidemiological data that has substantiated the extent of this problem among men, has stimulated a renewed worldwide interest in the clinical condition of chronic prostatitis. The results of these concerted efforts by researchers were evident at the 2002 AUA. Great advances are being made in the field of prostatitis, and all researchers and clinicians interested in this condition look forward to these exciting ongoing projects in a very difficult and frustrating field. [J. Curtis Nickel, MD, FRCSC] [Note: Dr. Nickel has served as a study investigator for Merck & Company and Ortho-McNeil Pharmaceutical.] Serum Markers Serum markers were a major focus of discussion at this year’s AUA meeting, and a number of the papers presented were sufficiently important to be highlighted here. In an evaluation of 2497 men undergoing radical prostatectomy, Gretzer and associates23 demonstrated pitfalls in using the American Society for Therapeutic observations clearly indicate that the ASTRO definition is inadvisable for men treated with radical prostatectomy. Because the presence of viable benign prostatic elements following radiation may allow a low level of PSA still to be detectable, evidence of cure will require long-term followup with objective (non-PSA) criteria for failure. Only then can a definitive PSA endpoint be determined. Link and associates24 provided greater understanding of the problems that occur when different PSA assays are compared. They studied 2304 men undergoing prostate cancer screening and compared the Access Hybritech (Beckman Coulter, Fullerton, CA) and Bayer Centaur (Bayer, Berkshire, UK) systems. The assays correlated quite well with each other (R2 = 0.99). However, there was a significant bias with the Hybritech assay, resulting in significantly higher results. A third assay, the Immulite (Diagnostic Products, Los Angeles), was used as a comparator. The results were consistent with those achieved with the Bayer instrument, confirming the high bias with the Hybritech method. This study highlights the clinical dilemma afforded by the variability of PSA results obtained with commonly used assays. Van der Cruijsen-Koeter and associates25 showed that screening detective cases affords more favorable pathology. They compared data from a European randomized study of screening for prostate cancer that included a group offering screening and a control arm. A shift to a more favorable outcome for the screening arm of the trial in virtually every aspect, including clinical stage, Gleason score, and PSA level was observed. A number of papers presented at the AUA meeting addressed the utility of the complexed form of PSA (cPSA). Cheli and associates26 provided the results of a multicenter prospective evaluation of this analyte. In their study, 737 men had the Bayer cPSA assay performed along with the Hybritech methods for free (fPSA) and total PSA (tPSA) before undergoing at least 10 ultrasound-guided core biopsies. Of this group, 297 were shown to have carcinoma. cPSA was shown by area under the curve to provide significantly better performance than tPSA. At the 95% sensitivity level in the tPSA range of 4–10 ng/mL, cPSA provided 9.2% specificity as compared with 5.4% for percent fPSA and 13.5% for percent cPSA. In the range of 2–6 ng/mL for tPSA at the 95% sensitivity level, cPSA provided 19.6% specificity as compared with 11.7% for tPSA. These data demonstrate, in a prospective biopsy population, that cPSA significantly outperforms tPSA. Moreover, percent fPSA or percent cPSA offers little initial benefit. The use of cPSA in the tPSA range of 2.0–4.0 ng/mL was reported by Bartsch and associates,27 whose data are derived from the multicenter trial VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY 125 AUA Annual Meeting continued noted above. Of the 191 men evaluated, 29% were shown to have carcinoma. At the 86% sensitivity level, tPSA provided specificity of 20.6%. Using the cut point of 2.2 ng/mL for cPSA, 36.4% specificity at this 86% sensitivity was realized. These data demonstrate significant utility of the use of cPSA for all diagnostic testing. Moreover, clinically useful biopsy yields may be obtained with a cut point of 2.2 ng/mL for cPSA. The stability of fPSA was recently called into question by Ulmert and associates,28 who analyzed serum and plasma samples that had been collected between 1974 and 1986. The researchers demonstrated signifi- demonstrated that cPSA is the best predictor of metastatic disease. No significant difference was observed in the percent fPSA between those with and those without metastasis. This study confirms other reports indicating that the benefit of complexed versus other forms of PSA extends beyond diagnosis to staging. [Michael K. Brawer, MD] Pediatric Urology: Injection Therapy for Vesicoureteral Reflux The pediatric urology sessions at the annual meeting of the AUA were held on May 26 and 28, 2002. There were two podium and two poster sessions. There was also a video session A number of authors have shown significantly lower specificity for percent fPSA than for cPSA, which is a much more stable analyte. Because handling issues are not problematic, the stability of cPSA makes it more useful in routine clinical practice. cantly lower PSA levels in the serum samples compared with those in plasma samples. Because tPSA levels were not different, percent fPSA was lower in men with long-term storage. Moreover, the authors demonstrated that 3 hours after thawing, fPSA decreased 20%. These data may, in part, explain why a number of authors have shown significantly lower specificity for percent fPSA than for cPSA, which is a much more stable analyte. Because handling issues are not problematic, the stability of cPSA makes it more useful in routine clinical practice. The benefits of complexed versus other forms of PSA as well as a number of PSA derivatives in the staging of prostate cancer were compared by Nakashima and associates.29 In 220 men with untreated prostate cancer, 8% of whom had N+ and 28% of whom had M+ disease, the authors 126 VOL. 4 NO. 3 2002 on new hypospadias and pediatric laparoscopic techniques. Researchers at The Hospital for Sick Children in Toronto examined outcomes of extravesical ureteral reimplantation (EUR) versus endoscopic repair using an injectable soft tissue synthetic bulking agent, Macroplastique (Uroplasty, Inc., Minneapolis, MN) for primary lowgrade reflux (Grade I–III).30 Of 180 patients, 74 (108 ureters) underwent a single Macroplastique subureteric injection and 106 (166 ureters) underwent EUR. The mean age at Macroplastique injection and EUR was 60 and 77 months, respectively, and the mean follow-up was 9 and 15 months, respectively. At 3 and 12 months, the success rate was significantly different between the two groups. Resolution of reflux following Macroplastique injection was 80.6% and 91.6% at 3 months and ~1 year, REVIEWS IN UROLOGY respectively. The EUR group had a 95.8% success rate at 3 months and 98.8% at 1 year. Of the 12 units with persistent postoperative reflux after EUR, three units had spontaneous resolution. There were no complications in the injection group, whereas there were eight complications in the EUR group. Postoperative urinary tract infection occurred in 11% undergoing EUR. Urinary retention, which resolved within 2 weeks, developed in 2 patients who underwent bilateral EUR. One wound seroma occurred and two suprapubic fluid collections formed in the EUR group. From this study, the Toronto group recommends Macroplastique for the endoscopic treatment of low-grade reflux in those patients requiring intervention, because this is a simple, ambulatory procedure with essentially no complications. Macroplastique is not approved in the United States at this time. Safety, efficacy, and durability similar to that with Macroplastique have been reported regarding Deflux (dextranomer/hyaluronic acid copolymer), the first U.S. Food and Drug Administration–approved injectable for the correction of reflux.31 Investigators in Rochester, NY reported their experience using Coaptite (Genesis Medical, Ltd, London, UK), another bulking agent for subtrigonal injection.32 Fifty patients were studied, and a voiding cystourethrogram at 3 months showed that resolution rates for Grades II, III, and IV were 95%, 55%, and 42%, respectively, and success was durable at 6 months in 90%. Importantly, no adverse effects have been reported. These studies provide further evidence of the safety and efficacy of injection therapy as a therapeutic alternative for the treatment of reflux. Upadhay and colleagues of the Toronto group also examined the nat- AUA Annual Meeting ural history of neonatal reflux associated with antenatal hydronephrosis33 and reported that about 42% of highgrade (IV, V) cases either resolved or improved. Those with Grade IV showed a resolution rate of 28% and a 14% improvement rate; Grade V resolved in 20% and improved in 40%. Therefore, in some of the down-graded cases, a subureteric injection may be an alternative to open surgery in patients who historically would have undergone early ureteral reimplantation for highgrade reflux. [Ellen Shapiro, MD] Benign Prostatic Hyperplasia: Results from the MTOPS Trial As in years past, the topic of benign prostatic hyperplasia (BPH) was featured prominently at this year’s AUA meeting in Orlando. Broken down by topic, 50 abstracts were presented on basic research issues in BPH, 20 on epidemiology and natural history, 32 on medical and hormonal therapy, 32 on surgical therapy and minimally invasive therapies, and an additional 12 in a session on BPH and urodynamics, together with female urology issues. Thus, a total of 134 posters and presentations focused entirely on BPH issues, with an additional 12 focusing on urodynamic aspects and lower urinary tract dysfunction in a broader sense. The MTOPS Trial Several large clinical trials were finished in time for abstract submission and thus were presented at this year’s meeting. Clearly, the most significant of these trials is the Medical Therapy of Prostatic Symptoms (MTOPS) trial. This trial deserves both a brief introduction as well as a discussion. The MTOPS trial is easily the longest and largest BPH trial ever conducted. It was conceived some 8–10 years ago, at a time when efficacy and safety of both -adrenergic receptor blockade and 5--reductase inhibition were being established through trials of shorter duration and smaller participant numbers. However, one of the key questions at the time was whether the medications would prevent or delay the progression of BPH or merely postpone the inevitable (ie, subsequent episodes of acute urinary retention and/or the need for surgery). Moreover, the basic biology of benign prostatic growth and its regulation was very poorly understood, and thus the MTOPS trial also had a great emphasis on basic and translational research questions. Trial design. Most traditional BPH studies up to now have focused on the observations of longitudinal Institutes of Health/National Institute of Diabetes & Digestive & Kidney Diseases, agreed to the fundamental design of a progression trial. As evidence for progression, the following events were accepted: • Acute urinary retention episodes; • Renal insufficiency clearly due to BPH, with a >50% increase in the baseline serum creatinine; • Recurrent urinary tract infections or urosepsis; • Socially or hygienically unacceptable urinary incontinence, • And last but not least, a more than 4-point rise in the baseline AUA Symptom Score, confirmed with a second questionnaire administered within 2–4 weeks. This represented a significant departure from prior trial design, The basic biology of benign prostatic growth and its regulation was very poorly understood, and thus the MTOPS trial had a great emphasis on basic and translational research questions. changes of parameters. The primary outcome usually was a change from baseline in either the AUA or International Prostate Symptom Score (IPSS) or the peak urinary flow rate. The active intervention was then compared either to a second active intervention or to a placebo (or sham arm in the case of a device intervention). The AUA Score (IPSS) has been proven to be a reliable instrument to measure symptomatic changes and, at the time MTOPS was begun, it was known through research by Barry and colleagues that, in general, patients would perceive an improvement from baseline by about 3 points as clinically meaningful.34 When designing the MTOPS trial, representatives from 18 academic institutions (forming the Steering Committee), together with the National inasmuch as the primary outcome was a progression of disease as defined above. Although Barry’s article had demonstrated that patients in general can perceive a 3-point change as a clinical improvement, less was known at the time as to whether an increase in the symptom score by the same margin would be considered a worsening in clinical symptoms. Thus, to allow for this uncertainty, a threshold of 4 points was chosen, which had to be verified within 2–4 weeks. As to other trial design characteristics, this was a double-blind, placebocontrolled, multicenter, randomized clinical trial with four study arms (placebo, doxazosin titrated to 4 or 8 mg, finasteride at 5 mg, or a combination of both doxazosin and finasteride). The minimum follow-up was to be 4 years, with an average VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY 127 AUA Annual Meeting continued follow-up of 5 years. Men had to be older than 50 years, with a symptom score ranging from 8 to 30 and a peak urinary flow rate of 4–15 mL/s with a voided volume of 125 mL. The patient had to have a serum prostate-specific antigen (PSA) level of <10 ng/mL. Additionally, a significant subset of patients underwent a baseline, 1-year, and end-of-study biopsy to establish both a serum and a tissue bank for future translation and basic research. A total of 3047 men were randomized to placebo, finasteride, doxazosin, and combination therapy in roughly equal groups. The baseline age was 62 years (median) and the baseline symptom score was 17 (interquartile [IQ] range, 12–21). The peak urinary flow rate was 10.6 (IQ range, 8.5–12.5) mL/s. Transrectal ultrasound (TRUS)defined prostate volume at baseline was 31 mL (IQ range, 23–43.8) mL, and serum PSA 1.6 (IQ range, 0.8–3.8) ng/mL. Concurrent trials. While the MTOPS trial was being conducted, three other significant studies were completed and published that heightened the expectations regarding the outcomes of MTOPS. The first study was the Veteran’s Affairs (VA) Cooperative trial, in which 1229 men were enrolled in a 12-month study comparing placebo, terazosin (titrated to response up to 10 mg), finasteride 5 mg, and a combination of terazosin and finasteride.35 In this trial, the average prostate volume in the four groups ranged from 36 to 38 mL (by TRUS) and the average PSA ranged from 2.2 to 2.4 ng/mL. The mean reduction in symptom score was 2.6 points for the placebo group, 6.1 for terazosin, 3.2 for finasteride, and 6.2 for the combination group. Similar differences were observed regarding the Symptom Problem Index and the BPH Impact Index. Maximum urinary flow rate was improved by 1.4 mL/s 128 VOL. 4 NO. 3 2002 in the placebo group, 2.7 mL/s in the terazosin group, 1.6 mL/s in the finasteride, and 3.2 mL/s in the combination group. However, although the differences between the terazosin and placebo were significant, the differences between finasteride and placebo were not, and neither was there a significant difference between the terazosin and combination groups. This study suggested, therefore, that combination therapy had no additional benefit over -blocker therapy alone, at least in this group of men followed for 1 year. Simultaneously, a very similar trial was conducted in Europe, titled PREDICT. This was also a multicenter, international trial, in which more men with lower urinary tract symptoms (LUTS) and BPH. Savage and colleagues published a single-center study in which 195 men were randomized to treatment with either terazosin, finasteride, or combination therapy.36 This trial, however, suffered from the absence of a placebo arm. Of note in this trial, only men with a prostate volume of >40 mL were enrolled. As an additional caveat, one must note that terazosin was given at a fixed dose of 5 mg, which probably does not elicit the maximum response. The symptom score dropped by 4.1 mL/s in the terazosin group but by 6.4 mL/s in the combination group. Similarly, the flow rate improvement in the combination To date, only one trial has ever demonstrated a benefit of combination medical therapy in the treatment of men with LUTS and BPH. than 1000 patients were randomized to be treated either with placebo, doxazosin (titrated to response), finasteride, or the combination of both doxazosin and finasteride. In this trial, the average PSA level was similar to the one in the VA Cooperative trial, and the prostate volume was only estimated by digital rectal examination. The results were surprisingly similar to the VA Cooperative trial: mean reduction in symptom scores were 4.4 for the placebo, 8.4 for doxazosin, 6.2 for finasteride, and 8.7 for the combination group. Peak urinary flow rate improved by 1.4, 3.6, 1.9, and 4.1 mL/s in the four groups, respectively. Again, doxazosin was superior to placebo, whereas finasteride was not, and the combination therapy was not superior to doxazosin alone. To date, only one trial has ever demonstrated a benefit of combination medical therapy in the treatment of REVIEWS IN UROLOGY therapy group was superior to either one of the single agents, at 4.9 mL/s. Lastly, the Proscar Long Term Efficacy and Safety (PLESS) trial was finished, analyzed, and many aspects of it have been published. In PLESS, over 3000 men with slightly larger prostate volumes were randomized to either placebo or finasteride 5 mg over a period of 4 years. In this trial, finasteride proved to be superior to placebo both in terms of symptom score as well as peak urinary flow rate. However, the most significant finding was that finasteride induced a greater than 50% reduction in the risk for acute urinary retention and the risk for BPH-related surgery.37 Stratified analyses of the PLESS data revealed that the risk reduction was greatest in men with higher PSA values as well as larger prostate volumes.38 It was also noted that in the placebo-treated patients, the risk for symptom progression, acute urinary AUA Annual Meeting retention, and the subsequent need for surgery was significantly greater in those men with higher PSA values and larger prostate volumes at baseline. MTOPS results. Against the backdrop of these findings, it was no surprise that the results of the MTOPS trial were awaited with great anticipation by practicing physicians, industry, and the media. Dr. John McConnell, the Chairman of the Steering Committee, presented the main results from the MTOPS trial in the main podium session on BPH and Medial and Hormonal Therapy.39 Perhaps the most significant finding of the MTOPS study was the observation that only 17% of patients in the placebo group progressed over an average of 4.5 years of follow-up. In other words, 83% of patients did not experience progression as defined by the Steering Committee (urinary retention, renal insufficiency, incontinence, urinary tract infections, or greater than a 4-point progression). The overall crude rate per 100 patientyears of clinical progression was 4.5 for the placebo, 2.7 for doxazosin, 2.9 for finasteride, and 1.5 for the combination therapy. This translates into a risk reduction compared to placebo of 39% for doxazosin, 34% for finasteride, and an astonishing 67% for combination therapy. It should be noted that 78% of progression events were due to a 4-point rise, whereas only 12% were due to acute urinary retention, 9% due to socially or hygienically unacceptable incontinence, 1% due to urinary tract infections or urosepsis, and not a single patient experienced renal insufficiency due to BPH. This in itself is worthy of some discussion. In the past, the risk for acute urinary retention was differently estimated by physicians. Whereas some believed that it was an inevitable outcome of BPH, others expected it to occur in only very small fractions of patients. Clearly, the PLESS and the MTOPS studies give us a very good estimate of the incidence rates of acute urinary retention in placebotreated patients stratified by baseline risk parameters such as PSA and prostate volume. In addition, data from the Olmsted County study of urinary symptoms in men provide data for the risk of acute urinary retention in men not diagnosed with BPH and not enrolled in a clinical impact on our understanding of the medical therapy for BPH were discussed in five separate presentations.40–44 Whereas in the past only one drug was available in the class of 5--reductase inhibitors, these trials introduced a new compound, dutasteride, a novel inhibitor of both isoenzymes of the 5--reductase type I and type II. Previous studies have demonstrated that dutasteride at a dose of 0.5 mg/day effectively reduces serum dihydrotestosterone Clearly, the PLESS and the MTOPS studies give us a very good estimate of the incidence rates of acute urinary retention in placebo-treated patients stratified by baseline risk parameters such as PSA and prostate volume. study and/or on placebo tablets. It may come as a surprise to many practicing urologists that, in the MTOPS study, only 1% of all progression events were due to recurrent urinary tract infections and/or urosepsis, and that not a single patient experienced renal insufficiency due to BPH. The issue of silent prostatism and uremia induced by BPH has always been in the minds of practicing urologists, but as we learned, it was perhaps a risk that was overestimated by many. Clearly, more detailed analyses of various aspects of the MTOPS trial, stratified analyses by baseline risk parameters, in-depth analyses of adverse events, and—perhaps equally important— future studies done on the stored serum and tissue specimens will shed more light on the natural history of BPH, the triggers of progression, and help us understand the pathophysiology of this so common condition. Dutasteride, a New 5-AlphaReductase Inhibitor Several aspects of another large clinical trial with an equally lasting (DHT) and improved the signs and symptoms of LUTS and BPH. GlaxoSmithKline conducted three parallel, 2-year, multicenter, doubleblind, placebo-controlled studies both in the United States and in Europe involving 4325 patients, of whom half were randomized to placebo and the other half to dutasteride 0.5 mg per day over 2 years. Based on the experience with the PLESS trial, in addition to the usual inclusion and exclusion criteria, patients had to have a total prostate volume of >30 mL (by TRUS) and a serum PSA between 1.5 and 10.0 ng/mL. At 1 month, dutasteride induced an 87.5% reduction in circulating DHT and at 24 months a 90.1% reduction. As a result, testosterone increased by 22.5% and 24.5% at 1 and 24 months, respectively. Thus, the nearly complete inhibition of both isoenzymes of the 5--reductase inhibitor resulted in a remarkably precise and nearly complete reduction in circulating DHT even as early as 1 month. Together with the reduction in DHT, serum PSA was reduced by approximately 50%, while in the VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY 129 AUA Annual Meeting continued versus a decrease of 2.3 points in the placebo-treated patients for a  of 2.2 points at the end of 2 years. Similarly, statistically significant changes were observed for the BPH Impact Index and the peak urinary flow rate (2.0 vs 0.9 mL/s; P < .001). A detailed analysis stratifying patients by baseline total and transition zone volume as well as serum PSA was performed and demonstrated that the net improvement of dutasteride over placebo increased with increasing total as well as total and transition zone volume as well as serum PSA (Figure 1). Over 2 years, 90 patients experienced acute urinary retention in the placebo group, versus only 39 in the dutasteride group, for a relative risk of 0.43 and a risk reduction of 57% (P < .001). Similarly, the risk of experiencing BPH-related surgical interventions was reduced by 48%, with a relative risk of 0.52 (P < .001) (Figures 2 and 3). Dutasteride was well tolerated and, as expected, only in terms of erectile dysfunction, altered libido, ejaculatory disorders, and gynecomastia was there an increase in the incidence of reported 2.5 2.0 1.5 1.0 Changes 0.5 0.0 -0 .5 -1 .0 -1 .5 -2 .0 -2 .5 -3 .0 -3 .5 -4 .0 <10 10<20 20<30 30<40 40<50 50<60 >60 TZV Categories Figure 1. Linear regression of difference between placebo and dutasteride for transition zone volume (TZV) categories, with 95% confidence interval. Yellow, confidence band for International Prostate Symptom Score changes; orange, confidence band for benign prostatic hyperplasia II changes; green, confidence bands for maximum flow rate changes. All are stratified by baseline transition zone volume categories. placebo-treated patients an increase of up to 15% was observed at 24 months. These data are very comparable to those obtained with finasteride, and the utility of the PSA testing in screening for prostate cancer is maintained by multiplying the value times 2. A subset of patients also underwent three PSA measurements, and the ratio of free to total PSA was found to be unchanged after treatment. Clinicians, therefore, can use total PSA as well as free PSA after multiplication by 2 and the free-tototal ratio in an unchanged manner when counseling patients regarding their prostate cancer risks. The effect of dutasteride on prostate volume was a reduction of the total prostate volume by 25.7% and of transition zone volume by 20.4% at the end of the 24-month treatment period. Interestingly enough, the volume changes in the dutasteridetreated patients were not dependent on baseline serum PSA, whereas in 130 VOL. 4 NO. 3 2002 the placebo-treated patients the patients with a higher baseline serum PSA value experienced a greater increase in volume over time. Regarding improvement in symptoms, the dutasteride-treated patients experienced a decrease of 4.5 points Figure 2. Pooled data for first episode of acute urinary retention from trials comparing dutasteride to placebo. Data on file, GlaxoSmithKline. REVIEWS IN UROLOGY Patients (%) 6 5 Placebo 4 Dutasteride 0.5 mg 3 2 1 0 0 6 Placebo group No. of events, cumulative 28 No. at risk 2158 Dutasteride group No. of events, cumulative 19 No. at risk 2167 12 18 24 49 2039 70 1919 90 1793 27 2052 31 1928 39 1827 Time (months) AUA Annual Meeting discovered renal masses. These lesions tend to be smaller in size and may be amenable to either nephron-sparing surgery (NSS) or minimally invasive options. Ablative techniques for the treatment of renal tumors are an extension of NSS, and include cryoablation, radio frequency ablation (RFA), and high-intensity focused ultrasound (HIFU). Cryoablation applies freezing applications to eradicate tissue, whereas RFA and HIFU destroy tissue with high temperatures (temperature > 45ºC). Although all three of these options are considered investigational, they are quickly evolving into effective and reasonable treatment modalities for selected patients. Interest in cryosurgery for the prostate has regained a resurgence,45 but we limit our discussion to minimally invasive approaches, as applied to kidney cancer. Dr. Sam Kim presented the Northwestern University experience of 12 patients who underwent laparoscopic renal cryoablation using a 4-port transperitoneal technique.46 Mean tumor size was 2.21 cm (1.2 cm–3.2 cm) and mean estimated blood loss was 60.4 mL. Of the adverse events. Dutasteride appears to be poised to become the second entry in the class of hormonal agents (or more specifically, 5--reductase inhibitors) used in the treatment of LUTS and BPH. Its efficacy and safety profile appears to be similar to finasteride’s, although further analyses of the data and additional studies may reveal subtle but perhaps important differences between the two compounds. Clearly, the AUA provided an abundance of new and exciting data regarding basic research, epidemiology, and the natural history of BPH, in both medical and device-oriented treatments. Nonetheless, the MTOPS trial and the presentation of the dutasteride data likely presented the highlights of an overall very informative and exciting meeting. [Claus G. Roehrborn, MD] Renal Cell Carcinoma Update on Minimally Invasive Ablative Approaches for Renal Cell Carcinomas The widespread of use of imaging modalities has led to a significant increase in the rate of incidentally Figure 3. Pooled data for first benign prostatic hyperplasia–related surgical intervention from trials comparing dutasteride to placebo. Data on file, GlaxoSmithKline. Patients (%) 5 Placebo 4 Dutasteride 0.5 mg 3 2 1 0 0 6 Placebo group No. of events, cumulative 13 No. at risk 2158 Dutasteride group No. of events, cumulative 12 No. at risk 2167 12 18 24 40 2057 59 1944 89 1823 25 2064 39 1944 47 1846 Time (months) 3 patients who underwent postcryosurgery biopsies, 2 patients had residual malignancy. Although radiographic imaging at a mean follow-up of 305 days revealed stable lesions in all patients, Kim and colleagues concluded that incomplete tumor ablation is possible, especially in larger lesions, and that close follow-up with serial imaging and biopsy is warranted. The Cleveland Clinic presented its 3-year follow-up on 25 patients who have undergone laparoscopic renal cryoablation.47 All patients were treated with two freeze–thaw cycles under laparoscopic and ultrasonographic guidance. Mean tumor size was 2.3 cm (1.5 cm–3.7 cm), and all patients underwent a follow-up biopsy at 6 months after the procedure, in addition to follow-up magnetic resonance imaging (MRI) performed on postoperative day 1, and 3 months, 6 months, 1 year, and semiannually thereafter. One patient with an initially negative biopsy was found to have an enhancing lesion on MRI and was found to have residual carcinoma on subsequent biopsy. This patient eventually underwent laparoscopic nephrectomy and remains free of disease. At a mean follow-up of 42 months (36–48 months), the remaining 24 patients are free of disease, confirmed by both MRI and biopsy. Dr. Li-Ming Su reported on the Johns Hopkins University experience of 17 patients who underwent percutaneous CT-guided RFA for 22 lesions.48 All patients were considered high-risk surgical candidates (ie, medical comorbidities, >75 years of age, von Hippel-Landau syndrome) and underwent RFA under local sedation. The mean size of the lesions was 1.9 cm (1.0 cm–3.2 cm), with 4 patients developing asymptomatic, small, perirenal hematomas. Post-RFA creatinine was stable, with VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY 131 AUA Annual Meeting continued Table 1 Comparison of Clinical Outcomes for NSS vs RN NSS (4–7cm) N = 91 RN (4–7 cm) N = 841 5-year local recurrence-free rates 94% 98% 5-year metastasis-free rates 94% 83% 5-year cancer-specific survival rates 98% 86% NSS, nephron-sparing surgery; RN, radical nephrectomy. Table printed with permission from Bradley C. Leibovich, MD. 132 VOL. 4 NO. 3 2002 direct vision. H- and E-staining of all 20 partial nephrectomy specimens revealed unchanged tumor histology in addition to areas of coagulative necrosis. Furthermore, four of the final five specimens demonstrated positive enzymatic activity and cell viability by NADPH assay. The authors concluded that because all specimens revealed evidence of incomplete tumor eradication, RFA should remain an investigational treatment modality. Finally, Shingleton and Sewell reported on 55 patients who underwent percutaneous cryoablation under Should There Be a Size Limit for Nephron-Sparing Surgery? Recent literature has convincingly demonstrated that nephron-sparing Figure 4. Cause-specific survival for patients with 4–7 cm renal cell carcinoma (RCC) treated by either nephron-sparing surgery (NSS) or radical nephrectomy (RN). Figure courtesy of Bradley C. Leibovich, MD. REVIEWS IN UROLOGY 100 NSS 80 % Survival 2 patients experiencing moderate pain. No transfusions were required. One patient required repeat ablation due to the presence of a small area of contrast enhancement 3 months after the procedure. The remaining 21 lesions remained without evidence of enhancement on follow-up imaging at a mean follow-up of 3.2 months (3–9 months). There was no mention of post-RFA biopsies. The National Cancer Institute also presented data on percutaneous RFA under either CT and/or sonographic guidance.49 Nineteen patients with hereditary renal cancers underwent a total of 22 procedures. The median diameters of the tumors decreased from a pretreatment size of 2.5 cm (1.5 cm–3.0 cm) to 1.8 cm (0.5 cm–4.0 cm), 1 year after treatment. Five (23%) of the tumors demonstrated CT-enhancement after RFA treatment. Paulter and colleagues recommended that long-term follow-up is still necessary to assess the efficacy of cancer control using RFA.49 In a late-breaking abstract, researchers from the Lahey Clinic presented updated data on 15 patients (20 tumors) who underwent open RFA immediately prior to partial nephrectomy.50 All tumors were less than 3.5 cm in size and were heated to 90–110ºC for between 6 and 16 minutes. Tumor ablation was monitored via ultrasound and MRI guidance, with an average followup time of 18 months.51 Cryoprobes were used to freeze the mass to a minimum of 40ºC for a total of three freeze–thaw cycles. In their cohort of patients, 51 patients remain alive without evidence of radiographic disease. One patient required transfusion secondary to perinephric hematoma. In conclusion, minimally invasive approaches for the treatment of renal cell carcinoma are evolving, in an attempt to minimize operative time, morbidity, and time to recovery. The majority of candidates should have small, unifocal, and exophytic lesions located away from the collecting system. Long-term studies are still necessary before any definitive conclusions can be reached about cancer control using any of these minimally invasive methods. At this time, all of these minimally invasive options remain investigational at best. RN 60 40 20 P = .023 0 0 2 4 6 8 Years to RCC death or last follow-up 10 AUA Annual Meeting surgery (NSS) for localized renal tumors less than 4 cm is an acceptable treatment option.52–56 Hafez and colleagues from the Cleveland Clinic Foundation recently reported an 88% 5-year, cancer-specific survival rate for patients who underwent NSS for tumors 4–7 cm.54 In comparison, the 5-year, cancer-specific survival rate for tumors less than 4 cm was 98% in their series. Based on these findings, Hafez and colleagues recommended that NSS be limited to tumors less than 4 cm in size. Leibovich and colleagues from the Mayo Clinic presented new data at the 2002 meeting of the AUA that suggest selected kidney tumors up to 7 cm in size are amenable to partial nephrectomy.57 In their retrospective analysis, they identified 91 patients who underwent NSS for tumors 4–7 cm in size and compared the outcome to a group of 841 patients who underwent radical nephrectomy (RN) for tumors 4–7 cm in size. Table 1 compares outcome characteristics of the respective groups, and Figure 4 depicts the Kaplan-Meier estimated cancer-specific survival rate, comparing NSS versus RN in tumors 4–7 cm in size. Patients in this study who had NSS for tumors 4–7 cm had superior cancer-specific survival and metastasis-free survival compared to patients who had RN for tumors 4–7 cm. However, after adjusting for differences in known prognostic features, such as lymph node involvement, nuclear grade, histologic subtype, and the presence of histologic necrosis, the differences in metastatic spread and survival were no longer significant. However, these factors are not available to the clinician at the time of the initial decision to perform NSS versus RN. Therefore, the investigators reviewed the CT scans for a subset of the cases, blind to which surgery was Table 2 Likelihood of Pathologic Factors as a Function of Presenting PSA Levels Total PSA Range (ng/mL) 0.0–1.0 1.1–2.5 2.6–4.0 4.1–10.0 >10.0 Number with cancer (%) 110 (1) 620 (6) 475 (20) 593 (31) 193 (55) Months to cancer diagnosis 37 41 26 2 1 Clinically localized tumors (%) 100 100 100 100 98 Organ-confined tumors (%) 80 79 77 67 41 Gleason score ≥7 (%) 17 14 12 12 33 57 Data from Antenor et al. PSA, prostate-specific antigen. performed, and rated tumors for factors that might be associated with outcome after surgery. They found that patients who had NSS were more likely to have exophytic tumors that were well circumscribed and did not involve hilar structures than patients who had RN. They concluded that in experienced centers, some renal tumors that appear to be amenable to NSS despite their larger size (based on computed tomography findings) should be treated with NSS. In such well-selected patients, cancer-specific survival and metastasis-free survival are expected to be excellent, regardless of the surgical procedure. In conclusion, tumor biology and appearance on imaging studies, rather than the method of treatment (NSS vs RN), likely predict for recurrence and survival rates in patients with localized renal cell carcinoma. In selected patients treated in centers with extensive renal surgery experience, NSS should be considered for tumors 4–7 cm in size that are well circumscribed, exophytic, and are not near hilar structures, if it is technically feasible. [Ken-ryu Han, MD, Matthew H.T. Bui, MD, PhD, Danielo G. Freitas, MD, PhD, Arie S. Belldegrun, MD] Screening Algorithms for Prostate Cancer Since the discovery of prostate-specific antigen (PSA), its widespread use in clinical practice, and acceptance of the digital rectal examination (DRE) by both physicians and patients for early detection of prostate cancer, many algorithms for screening have been recommended. The American Cancer Society and the AUA were the first to publish guidelines recommending yearly measurement of PSA and DRE in men over age 50 years to provide optimal, rational, and efficient detection of prostate cancer. Likewise, these early detection algorithms recommended a PSA cut-off of 4.0 ng/mL as the level at which men should be advised to undergo prostate biopsy. Thus, a great amount of data was amassed regarding the likelihood of having prostate cancer when PSA is greater than 4.0 ng/mL. Most large screening studies (eg, Prostate Cancer Awareness Week Program, the St. Louis Prostate Cancer Screening Project, and the Seattle Prostate Cancer Screening Program) suggested that the probability of having prostate cancer when PSA is between 4.0 and 10.0 ng/mL is about 25%, and both physicians VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY 133 AUA Annual Meeting continued and patients felt that this warranted recommendation of prostate biopsy. Alternate methods for use of PSA (eg, PSA velocity, PSA density, and age-specific PSA cut-offs) in addition to newer definitions of high-risk groups (African-American race and positive family history) caused many at PSA levels less than 4.0 ng/mL are most likely to be organ confined and to have a Gleason score between 2 and 6. Interestingly, the likelihood of organ-confined disease decreases by 10% (77%–67%) when the interval increases from 2.6–4.0 ng/mL to 4.1–10.0 ng/mL, further suggesting Although all tumors are essentially clinically localized, tumors detected at PSA levels less than 4.0 ng/mL are most likely to be organ confined and to have a Gleason score between 2 and 6. men to undergo prostate biopsy for PSA levels of less than 4.0 ng/mL. These new uses and definitions led Dr. Catalona’s St. Louis group58 to recommend lowering the PSA cut-off range to 2.5 ng/mL when they first demonstrated that between 12% and 18% of men with PSA levels within this range had prostate cancer. At this year’s AUA meeting, the researchers furthered their observations.58 They reported on the long-term results of the St. Louis cross-sectional screening experience, in which 26,118 community volunteers underwent PSA testing and DRE every 6–12 months. Biopsy was recommended when either the PSA test or the DRE were suspicious for prostate cancer. The authors reported the likelihood of finding prostate cancer based on the initial PSA group (0.0–1.0, 1.1–2.5, 2.6–4.0, 4.1–10.0, and >10.0 ng/mL). In addition, the pathological stage (tumor aggressiveness), histological grade (Gleason score), and time to diagnosis were compared. This report demonstrated that the initial PSA level correlated with the risk interval to subsequent prostate cancer detection and the aggressiveness of the tumor among those who were biopsied (Table 1). These data demonstrate that, although all tumors are essentially clinically localized, tumors detected 134 VOL. 4 NO. 3 2002 that PSA cut-offs might be lowered. Also of note, 6% of men with PSA levels between 1.1–2.5 ng/mL who were biopsied had prostate cancer, 79% of which was organ confined and 14% of which had a Gleason score of > 7. This finding brought into question previous recommendations suggesting that men with PSA levels of 2.0 ng/mL or less could extend the screening interval to 2 years.59 Further analysis and interpretation of these data will require insight into the reasons why men with PSA levels less than 4.0 ng/mL were biopsied (eg, positive DRE, family history, PSA velocity), the true incidence of cancer when the men are compared with all men within the PSA group (not just those who were biopsied), and the numbers of increased and/or unnecessary prostate biopsies that follow when PSA cutoffs are lowered. Nevertheless, these data are very interesting and important, and will add greatly to our understanding of the use of PSA for early detection of prostate cancer. The St. Louis group60 and a group representing the PLCO (Prostate, Lung, Colon and Ovary) trial61 both presented data evaluating the screening interval for optimal prostate cancer detection. Crawford and associates from the PLCO trial61 reported on data collected from more than 27,000 men who took part in the study and who underwent PSA screening over a 5-year period. Each man had PSA measured yearly for six intervals. The investigators created a commu- Figure 5. Probability of converting from a prostate-specific antigen (PSA) of <4.0 ng/mL to one >4.0 ng/mL, based on PSA level at interval zero (beginning of screening) and the subsequent years of the trial. Reprinted from Crawford et al.61 REVIEWS IN UROLOGY 90 80 70 60 50 Year 1 Year 2 Year 3 Year 4 Year 5 40 30 20 10 0 PSA 0-1 PSA 1-2 PSA 2-3 PSA 3-4 AUA Annual Meeting tative probability model predicting the likelihood of converting from a PSA of less than 4.0 ng/mL to a PSA greater than 4.0 ng/mL at years 1 through 5 of the trial. Figure 5 demonstrates the probability of a 4.0 conversion (bars, percent) based on the PSA value at the beginning of the interval and the PSA at year zero. The Crawford study demonstrated that 98% of men with a PSA level dicts the findings of the PLCO trial. Their data question the safety of the 2- and 4-year screening intervals for men with these low PSA levels. In their paper, 19,444 men who presented with an initial PSA of less than 2.0 ng/mL were followed with PSA testing at 6–12-month intervals for up to 8 years. Overall, 2.5% of the men were found to have prostate cancer of the long-term interval. The The authors found codon 25 in the TGF-B1 gene to have variations similar to what has been found in other fibrotic conditions, suggesting that a genetic alteration in this gene may play a role in determining who develops Peyronie’s disease. below 1.0 ng/mL at baseline (interval zero) continue to have a PSA < 4.0 ng/mL at 5 years. The data also suggest that if PSA at interval zero is < 2.0 ng/mL, 98.8% of men would continue to have a PSA < 4.0 ng/mL the following year. The authors suggest a screening strategy of PSA every 5 years if PSA < 1.0 ng/mL and every 2 years if PSA is 1.0–2.0 ng/mL. They further suggest that this strategy would decrease the number of PSA tests by 55%, with only a small percentage of missed cancers. They estimate the cost savings at one billion dollars per year. This work presumes that prostate cancer will not or should not be detected until a PSA of 4.0 ng/mL is achieved. Based on the previous work of Dr. Catalona’s group,60 we see that this is not true and many more cancers would have been missed by this strategy than the authors expected. On the other hand, maybe these cancers would still have been curable if detected after a PSA threshold of 4.0 ng/mL, as was suggested by Ross and colleagues.59 In a related abstract, Dr. Catalona’s group60 presented data from the St. Louis Screening Project that contra- cancer detection rates were relatively constant during the extended time interval (mean 26 cancers/6 months, range 18–36). Interestingly, if a 2-year cycle had been used, 75% of the cancers detected would have had their diagnosis delayed by 6–18 months. Likewise, if the 4-year cycle had been used, 89% of the cancers would have experienced a diagnosis delayed by significant times, ranging from 1 to 3 years. The authors also reported that of the cancers detected, 100% were clinically confined (TNM), 79% were pathologically organ confined, and 24% had a Gleason score ≥ 7. The authors concluded that use of arbitrary intervals of 2 and 4 years in screening programs might cause significant delays in diagnosis and may lead to “missing" the window of opportunity for cure. Like other studies, this analysis has limitations and brings up more questions. We only know about the detected cancers, how many cancers remain undetected? Would the pathological stages have been more favorable if these men had undergone biopsy at a PSA level of 2.5 ng/mL? Will these delays in diagnosis translate into worse outcome and cancer-specific survival? How many unnecessary biopsies would these lower cut-offs generate? In spite of these additional questions, many of which will be addressed as this study is completed and reported in its final form, these data bring to question the recommendations for changing our PSA screening intervals. Stay tuned. [Alan W. Partin, MD, PhD] Peyronie’s Disease Peyronie’s disease (PD) still continues to engender confusion and angst amongst urologists, mainly because the etiology and pathophysiology is not completely understood. Although there have been a number of important discoveries and findings regarding this disorder, this has not been translated to anything meaningful at the bedside. At this year’s meeting of the AUA, 12 abstracts were presented at the Podium Session on the disorder. Here are the salient and important facts gleaned from this session. First of all, Mulhall and colleagues62 found that the incidence of PD is probably higher than is currently reported, based on their finding of a 6.7% incidence in men (n = 534) who presented for screening for prostate cancer at three different institutions. Furthermore, these men with PD had a significant reduction in their erectile function when compared to those without PD. There have been preliminary reports in the literature regarding the use of extracorporeal shock wave therapy (ESWT) for the treatment of PD. Awogu and coworkers63 gave an update on their series of patients (n = 31) with PD who were treated with this modality monthly for 3 months with 3000 shock waves at a power setting of 4–5. Some patients (n = 10) were given an additional three sessions (for a total of VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY 135 AUA Annual Meeting continued six sessions) depending on whether improvement occurred. The results demonstrated an improvement in angulation in 74%, improvement in erectile function, and cessation of pain with erection right after the conclusion of the ESWT. Although this study seems to support the use of ESWT as a possible first-line therapy in patients with PD, Neururer authors found codon 25 in the TGF-B1 gene to have variations similar to what has been found in other fibrotic conditions, suggesting that a genetic alteration in this gene may play a role in determining who develops this disease. Finally, Levine and colleagues68 reported favorable results with the Tutoplast® (IOP Inc., Costa Mesa, CA) A clear association between LUTS resulting from BPH and ED, particularly sex drive and self-assessment of function, has been revealed. and colleagues64 used an almost similar protocol but could not identify any efficacy. Additional studies will need to be performed to reach any definite conclusions regarding this treatment regimen. One of the most controversial aspects of the session was the use of transdermal verapamil in the treatment of PD. Fitch and Easterling65 reported that transdermal verapamil gel was effective in improving the curvature in 90% of patients (patient reports), and pain was resolved and plaque was decreased in size in 93% of patients. However, Mulhall and colleagues66 looked at concentrations of verapamil in the tunica of patients given the gel prior to surgery and could not identify any measurable amounts of the calcium channel blocker in their specimens, which calls into question the mechanism of action of this topical medication. Because of the association between PD and other fibrotic conditions, Hauc and coworkers67 looked at the polymorphisms of the TGF-B1 gene in men with PD, comparing it to non-PD patients. This gene was evaluated because TGF-B1 is a known stimulator of fibrosis and has been the cytokine used in the production of the animal model for PD. The 136 VOL. 4 NO. 3 2002 graft in the treatment of men with PD, and Lahme and colleagues69 from Germany described their novel technique of using collagen fleece with a tissue sealant after excision/excision of the plaque with excellent preliminary data. These presentations regarding PD suggest that those investigators who continue to do excellent basic science work and who then team up with the developers of novel surgical approaches will ultimately conquer this perplexing disorder. All that is required are the resources to conduct the necessary studies. [Jacob Rajfer, MD] Erectile Dysfunction Risk factors A U.S. population-based analysis70 has revealed that erectile dysfunction (ED) is a common problem, with 22% of men over 40 years of age reporting “sometimes" or “never" being able to get and keep an erection satisfactory for sexual intercourse, and another 29% reporting “usually" being able to do so. Prevalence increased significantly with increasing age and presence of diabetes. No impact on ED was reported for ischemic heart disease, hypercholesterolemia or hypertension. However, Montorsi and col- REVIEWS IN UROLOGY leagues showed that ED prevalence in patients suffering from ischemic heart disease was very high (54%). A significant number of patients developed ED prior to being diagnosed with ischemic heart disease, at a mean of 53.4 months (range 1–168 months).71 Niederberger and Londsdale conducted a dual-phase, survey-based study in the United States, the United Kingdom, Germany, France, Italy, Spain, Mexico, and Brazil that supported the relatively high prevalence of ED in the population seen in other cross-sectional studies and also confirmed the common comorbidities seen with ED.72 Although many patients have sought treatment, significantly more cases may be recognized if there would be less embarrassment between patient and physician and a recognition that milder, intermittent ED is also important and treatable. Phase I of the study consisted of a 15-minute standard male health survey of 27,839 men (20–75 years of age), 75% selected using randomdigit calling, and 25% from the internet. Phase II focused on the 3389 active and nonactive ED sufferers from this survey and other sources, and evaluated the attitudes to treatment and interactions with doctors. The prevalence of sufferers increased with age: 7% in men 20–29 years of age, 22% in 50–59 years of age, and 36% in 70–75 years of age. The proportions of men with hypertension, hypercholesterolemia, heart condition/angina, and diabetes were higher in men admitting to having ED than in the overall sample. On average, active sufferers had suffered ED for a longer time than those who were non-active (51 vs 36 months). More active sufferers had severe ED than non-active sufferers, with the majority having trouble obtaining rather than maintaining their erections. Active sufferers more often tended to asso- AUA Annual Meeting Main Points • In a University of Pittsburgh study, 50 patients suffering from a variety of voiding dysfunctions were injected with botulinum toxin type A into the bladder or urethra. Of these patients, 82% reported a decrease or absence of incontinence after the injections, and none experienced long-term complications from the treatment. • Working toward reducing shock wave–induced renal injury, researchers compared the use of a modified lithotripter to a standard device in a porcine model and found that the volume of microvascular damage was significantly less with the modified lithotripter. • Great advances are being made in the field of prostatitis, in regard to the epidemiology, etiology, diagnosis, and treatment of the disease, and all researchers and clinicians interested in this condition look forward to further breakthroughs in this very difficult and frustrating field. • Because the presence of viable benign prostatic elements following radiation may allow a low level of prostate-specific antigen (PSA) still to be detectable, the patient will be cured only with longer-term follow-up with objective (non-PSA) criteria for failure following definitive radiation therapy, which is required to assess the best biochemical end point for cure to be delineated. • In a prospective biopsy population, complexed PSA significantly outperforms tPSA. Moreover, percent fPSA or percent cPSA offers little initial benefit. • In a study of men with untreated prostate cancer, 8% of whom had N+ and 28% of whom had M+ disease, it was demonstrated that cPSA is the best predictor of metastatic disease. • Two studies provide further evidence of the safety and efficacy of injection therapy as a therapeutic alternative for the treatment of vesicoureteral reflux. • Perhaps the most significant finding of the MTOPS study—easily the longest and largest benign prostatic hyperplasia (BPH) trial ever conducted—was the observation that only 17% of patients in the placebo group (vs doxazosin, finasteride, or a combination of these) progressed over an average of 4.5 years of follow-up. • Dutasteride, a new 5--reductase inhibitor, appears to be poised to become the second entry in the class of hormonal agents used in the treatment of lower urinary tract symptoms and BPH, with an efficacy and safety profile that appears to be similar to finasteride. • Minimally invasive approaches for the treatment of renal cell carcinoma, including cryoablation, radio frequency ablation, and high-intensity focused ultrasound, are evolving. At this time, all of these options remain investigational at best. • Tumor biology and appearance on imaging studies, rather than the method of treatment (nephron-sparing surgery vs radical nephrectomy), likely predict for recurrence and survival rates in patients with localized renal cell carcinoma. • Early detection algorithms recommended a PSA cut-off of 4.0 ng/mL as the level at which men should be advised to undergo prostate biopsy. Thus, a great amount of data was amassed regarding the likelihood of having prostate cancer when PSA is greater than 4.0 ng/mL. • New uses for and definitions of PSA have led to recommendations of lowering the PSA cut-off range to 2.5 ng/mL when it was first demonstrated that between 12% and 18% of men with PSA levels within this range had prostate cancer. • The likelihood of organ-confined disease decreases by 10% (77%–67%) when the interval increases from 2.6–4.0 ng/mL to 4.1–10.0 ng/mL, further suggesting that PSA cut-offs might be lowered. • The incidence of Peyronie’s disease (PD) is probably higher than is currently reported, based on findings of a 6.7% incidence in men who presented for screening for prostate cancer at three different institutions; conflicting reports on the use of extracorporeal shock wave lithotripsy as a possible first-line therapy in patients with PD were presented. • The proportions of men with hypertension, hypercholesterolemia, heart condition/angina, and diabetes were higher in men admitting to having ED than in the overall sample. • Carson and colleagues confirmed and extended previous research demonstrating the safety of sildenafil treatment for ED. • Brock and colleagues confirmed findings and supported the conclusion that on-demand tadalafil is a well-tolerated treatment that significantly improves erectile function in men with mild-to-severe ED. VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY 137 AUA Annual Meeting continued ciate their ED with other physical problems, in contrast to non-active sufferers who more often blamed psychological and/or temporary circumstances for their ED. Most frequently, ED sufferers did not consult with their physicians due to the intermittent nature of ED, combined with the belief that the ED was temporary, and being embarrassed to discuss the condition with a physician. A clear association between lower urinary tract symptoms resulting from benign prostatic hyperplasia and ED, particularly sex drive and self-assessment of function, has also been revealed.73 Sildenafil Althof and colleagues74 evaluated partner satisfaction using data from three double-blind, randomized, placebo-controlled, multicenter, flexibledose trials of patients treated with sildenafil (50 mg) or placebo for 6–12 weeks. The Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) partner questionnaire was used from 178 partners of patients. The EDITS Index least squares mean was 68.7 (±6.2) among partners of sildenafil-treated patients and 46.1 (±6.2) among partners of placebotreated patients (P = .0001). For partners (n = 91) of sildenafil-treated patients, 54% (95% CI, 44-64) were satisfied with results; for partners (n = 87) of placebo-treated patients, only 21% (95% CI, 14-31) were satisfied with results (P = .0001). The correlation between patient and partner responses on the EDITS was 0.85 (P < .0001). On average, partner EDITS responses were lower (mean=46.8 ± 31.2) than patient EDITS responses (mean=52.3 ± 26.0). Blitz and colleagues75 evaluated the use of sildenafil (50–100 mg) in patients 18–42 years of age with ED and lumbar myelomeningocele. Of 138 VOL. 4 NO. 3 2002 the 25 patients in the trial, 3 (12%) discontinued the medication due to headache. Of the remaining 22 patients, 21 (95%) reported an improvement in sexual function with sildenafil. The average incidence of sexual intercourse increased from 0.68 to 1.5 times per week. Satisfactory intercourse, as defined by the patient, increased from 32.2% the conclusion that on-demand tadalafil is a well-tolerated treatment that significantly improves erectile function in men with mild-to-severe ED. These data suggest that tadalafil may become an important new treatment option for men with ED.78 Results of another trial suggest that, similar to sildenafil, tadalafil should not be used in combination with nitrates.79 Tadalafil treatment has little effect on systemic arterial pressure and has not been associated with an increased incidence of cardiovascular events. to 48.2% with the use of sildenafil. Carson and colleagues 76 combined data from 17 randomized, double-blind, placebo-controlled, flexible-dose trials. Their findings confirmed and extended previous research demonstrating the safety of sildenafil treatment for ED. Although some patients experienced adverse events early in the course of treatment, these events were transient and decreased in frequency to levels indistinguishable from those experienced by placebo-treated patients after 2 months of treatment. New Drugs Kloner and colleagues provided information on the efficacy and safety profiles of vardenafil and tadalafil, two new phosphodiesterase-5 inhibitors. Tadalafil 20 mg in healthy subjects resulted in no significant difference, compared to placebo, in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6 mm Hg), and no change in heart rate. Tadalafil treatment has little effect on systemic arterial pressure and has not been associated with an increased incidence of cardiovascular events.77 Data from Brock and colleagues confirmed findings and supported REVIEWS IN UROLOGY Additionally, Porst and colleagues reported that tadalafil was superior to placebo in enabling men with ED to have successful intercourse up to 36 hours after one 20-mg dose.80 Similar results were reported for vardenafil treatment. Vardenafil treatment resulted in a marked improvement in erectile function in patients with hypertension, hyperlipidemia or diabetes, and therefore appeared to be effective in patients with clinically significant co-morbid conditions.81 Furthermore, Donatucci and colleagues showed that vardenafil significantly improved ED, irrespective of etiology or severity, and especially in those patients with severe ED.82 Moreover, Padma-Nathan and colleagues reported not only an improvement of ED with vardenafil, but at all doses successfully restored erectile function in a significant proportion of men.83 Melanotan II (MT-II) has dramatic erectogenic effects on men with both psychogenic and organic erectile dysfunction. These effects are mediated through melanocortin receptors in the brain. PT-141 (Palatin Technologies, Princeton, NJ), an analog of MT-II, has potent erectogenic activity in rodents and primates and increases sexual receptivity in female AUA Annual Meeting rats. Molinoff and colleagues84 enrolled 56 healthy men in a double blind, placebo-controlled study to evaluate the safety, pharmacokinetic properties, and pharmacodynamic effects (using the Rigiscan® Plus System, Timm Medical Technologies, Eden Prairie, MN) of subcutaneously administered PT-141 doses of 100 µg (a no-effect dose) up to 10 mg (the maximum tolerated dose), or placebo. PT-141 was well tolerated following subcutaneous injection. A dramatic dosedependent increase in the duration and extent of penile rigidity and tumescence was observed. In the case of ED associated with diabetes, a clear role for the rhokinase (a major Ca2+ sensitizing mechanism in smooth muscle) has been established mediating endothelin-induced contraction of the corpus cavernosum.85,86 A role for vascular endothelial growth factor has also been established for radiation-induced and other arteriogenic ED.87,88 These observations open the way for the development of new therapeutic interventions for patients with ED. [Mesut Remzi, MD, Bob Djavan, MD, Michael Marberger, MD] References 1. 2. 3. 4. 5. 6. Chancellor MB, Smith CP. One surgeon’s experience in 50 patients with botulinum toxin injection into the bladder and urethra [abstract]. J Urol. 2002;167(4 suppl):41A. Auge BK, Zhou Y, Zhu S, et al. Dynamics of lithotripter shock-wave induced bubble oscillation in constrained media and mechanisms of vessel rupture during SWL [abstract]. J Urol. 2002;167(4 suppl):261. Auge BK, Delvecchio FC, Lallas CD, et al. Suppression of large intraluminal bubble expansion during SWL [abstract]. J Urol. 2002;167(4 suppl):261. Willis LR, Evan AP, Connors BA, et al. Threshold for prevention of SWL-induced hemorrhagic renal injury by application of low-energy shock waves (12 KV) to one renal pole prior to application of high-energy shock waves (24 KV) to the other pole [abstract]. J Urol. 2002;167(4 suppl):377. Cheah PY, Liong ML, Yuen KH, et al. Chronic prostatitis: symptom survey with follow-up clinical evaluation [abstract]. J Urol. 2002;167(4 suppl):27. Schneider H, Brahler E, Ludwig M, et al. The German version of the NIH-CPSI: evaluation of internal consistency and median scores in 137 patients with CP-NIH IIIA and B [abstract]. J Urol. 2002;167(4 suppl):27. 7. Pontari MA, Litwin MS, O’Leary MP, et al. A case-control study of epidemiological factors in men with chronic pelvic pain syndrome [abstract]. J Urol. 2002;167(4 suppl):24. 8. Turner JA, Hauge S, von Korff M, et al. Primary and secondary care of patients with prostatitis: symptoms and quality of life [abstract]. J Urol. 2002;167(4 suppl):28. 9. Dimitrakov JD, Dikov D. NOD2 – A candidate gene in CPPS? [abstract]. J Urol. 2002;167(4 suppl):25. 10. Shoskes D, Albakri Q, Crook D. Cytokine polymorphisms in men with chronic prostatitis/chronic pelvic pain syndrome: incidence and association with treatment response [abstract]. J Urol. 2002;167(4 suppl):26. 11. Batstone R, Doble A, Gaston H. Men with chronic pelvic pain syndrome (CPPS) show immune memory to seminal plasma antigens [abstract]. J Urol. 2002;167(4 suppl):24. 12. Pontari MA, Maerten SF, Ruggieri MR. Nerve growth factor is elevated in seminal plasma of men with chronic prostatitis/chronic pelvic pain syndrome (CPPS) [abstract]. J Urol. 2002;167(4 suppl):25. 13. Steiner GE, Stix U, Kramer G, Marberger MJ. Are prostate epithelial and/or stromal cells immunocompetent cells? [abstract]. J Urol. 2002;167(4 suppl):26. 14. Hetrick D, Ciol M, Turner J, et al. Musculoskeletal findings in the elevation of men with and without chronic pelvic pain [abstract]. J Urol. 2002;167(4 suppl):28. 15. Riley DE, Miner DC, Ross S, Krieger JN. Bacterial viability in prostate tissue from chronic prostatitis chronic pelvic pain patients [abstract]. J Urol. 2002; 167(4 suppl):28. 16. Leskinen MJ, Vainionpaa R, Syrjanen S, et al. Viral genomes cannot be demonstrated in prostates of patients with symptomatic chronic pelvic pain syndrome (CPPS) and localized prostate cancer [abstract]. J Urol. 2002; 167(4 suppl):28. 17. Nickel JC, Alexander RB, Schaeffer AJ, et al. Leukocyte and bacterial localization comparisons in men with chronic pelvic pain syndrome and asymptomatic men: a case-control study [abstract]. J Urol. 2002; 167(4 suppl):24. 18. Narayan P, McKay J, Doyle C. A 6-week double-blind pilot study of tamsulosin versus placebo in patients with chronic non-bacterial prostatitis/chronic pelvic pain [abstract]. J Urol. 2002;167(4 suppl):24. 19. Downey J, Nickel JC, Pontari MA, et al. Randomized placebo controlled multi-center pilot study to evaluate the safety and efficacy of finasteride in the treatment of male chronic pelvic pain syndrome: category IIIA CPPS (chronic non-bacterial prostatitis) [abstract]. J Urol. 2002;167(4 suppl):26. 20. Nickel JC, Forrest J, Tomera KM, et al. Effects of pentosan polysulfate sodium in men with chronic pelvic pain syndrome: a multi-center randomized, placebo-controlled study [abstract]. J Urol. 2002;167(4 suppl):63. 21. Chen R, Nickel JC. Acupuncture improves pain, voiding symptoms and quality of life in men with chronic pelvic pain syndrome [abstract]. J Urol. 2002; 167(4 suppl):25. 22. Leskinen MJ, Kilponen A, Lukkarinen O, Tammela T. Transurethral needle ablation (TUNA) does not relieve the symptoms of 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. chronic pelvic pain syndrome (CPPS) [abstract]. J Urol. 2002;167(4 suppl):25. Gretzer MB, Trock B, Han M, Walsh PC. A critical analysis of the interpretation of biochemical failure in surgically treated patients using the American Society for Therapeutic Radiation and Oncology criteria [abstract]. J Urol. 2002;167(4 suppl):68. Link RE, Shariat S, Nguyen CV, et al. Variation in PSA results from different assay platforms: clinical impact on 2304 patients undergoing prostate cancer screening [abstract]. J Urol. 2002;167(4 suppl):101. Van der Cruijsen-Koeter IW, Roobol MJ, Damhuis RA, et al. Comparison of screendetected and clinically diagnosed prostate cancer in the European randomized study of screening for prostate cancer [abstract]. J Urol. 2002;167(4 suppl):102. Cheli C, Bartsch G, Horninger W, et al. Final results of a multicenter prospective evaluation of complexed PSA for early detection of prostate cancer [abstract]. J Urol. 2002;167(4 suppl):207. Bartsch G, Cheli CD, Horninger W, et al. Complexed PSA for early detection of prostate cancer in men with serum levels of 2–4 ng/mL [abstract]. J Urol. 2002;167(4 suppl):208. Ulmert CB, Becker C, Bjork T, et al. Very rapid degradation of free PSA in archival serum but not in plasma following thawing [abstract]. J Urol. 2002;167(4 suppl):209. Nakashima J, Kikuchi E, Horiguchi Y, et al. Alpha-1 antichymotrypsin-PSA complex is the most useful PSA-based parameter for the prediction of lymph node metastases in patients with prostate cancer [abstract]. J Urol. 2002;167(4 suppl):227. Aboutaleb H, Bolduc S, Upadhyay J, et al. Macroplastique injection versus extravesical reimplantation in primary low grade vesicoureteral reflux: a comparative study [abstract]. J Urol. 2002;167(4 suppl):89. Lackren G, Wahlin N, Skoldenberg E, Stenberg A. Long-term follow-up of children treated with dextranomer/hyaluronic acid copolymer for vesicoureteral reflux. J Urol. 2001;166:1887–1892. Mevorach R, Rabinowitz R, Beck C, Hulbert W. Endoscopic treatment of vesicoureteral reflux with Coaptite™: the first 50 patients [abstract]. J Urol. 2002;167(suppl 4):107. Upadhay J, Farhat W, Bolduc S, et al. Natural history of neonatal reflux associated with antenatal hydronephrosis: long-term results of a prospective study [abstract] J Urol. 2002;167(4 suppl):253. Barry MJ, Williford WO, Chang Y, et al. Benign prostatic hyperplasia specific health status measures in clinical research: how much change in the American Urological Association Symptom index and the benign prostatic hyperplasia impact index is perceptible to the patients? J Urol. 1995;154:1770–1774. Lepor H, Williford WO, Barry MJ, et al. the efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. N Engl J Med. 1996;335:533–539. Savage S, Spungen A, Galea G, et al. Combination medical therapy for symptomatic benign prostatic hyperplasia. Can J Urol. 1998;5:578–584. McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY 139 AUA Annual Meeting continued 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 140 Group Study. N Engl J Med. 1998;338:557–563. Roehrborn CG, Boyle P, Bergner, et al. 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. PLESS Study Group. Urology. 1999;54:662–669. McConnell JD, for the MTOPS Steering Committee. The long-term effects of medical therapy on the progression of BPH: results from the MTOPS trial [abstract]. J Urol. 2002;167(4 suppl):265A. Roehrborn CG, Andriole G, Nickel C, et al. Effect of dutasteride, a novel dual 5-reductase inhibitor, on BPH-related signs and symptoms [abstract]. J Urol. 2002;167(4 suppl):265A. Roehrborn CG, Andriole G, Nickel C, Boyle P. Effect of the dual 5-reductase inhibitor dutasteride on endocrine parameters [abstract]. J Urol. 2002;167(4 suppl):266A. Andriole G, Roehrborn CG, Nickel C, Boyle P. Effect of the dual 5-reductase inhibitor, dutasteride, on serum total PSA, free PSA and the ratio of F/T PSA [abstract]. J Urol. 2002;167(4 suppl):209A. Boyle P, Siami P, Wachs BH, et al. Effect of dutasteride on the risk of acute urinary retention and the need for surgical treatment [abstract]. J Urol. 2002;167(4 suppl):372A. Roehrborn CG, Ramsdell J, Siami P, et al. Prostate volume at baseline predicts the margin of therapeutic response with the 5-reductase inhibitor, dutasteride [abstract]. J Urol. 2002;167(4 suppl):373A. Han KR, Lugg J, Freitas DG, et al. Treatment of organ-confined prostate cancer with third generation cryosurgery - preliminary multi-center experience [abstract]. J Urol. 2002;167(4 suppl):Late-breaking #23. Kim SC, Rubenstein J, Yap RL, et al. Laparoscopic renal cryosurgery: the Northwestern experience [abstract]. J Urol. 2002;167(4 suppl):1. Steinberg AP, Gill IS, Strzempkowski B, et al. 3-year follow-up of laparoscopic renal cryoablation in 25 patients [abstract]. J Urol. 2002;167(4 suppl):166. Su LM, Jarret TW, Kavoussi LR, Solomon SB. Percutaneous CT-guided radiofrequency ablation of small renal masses in poor surgical risk patients: preliminary results [abstract]. J Urol. 2002;167(4 suppl):1. Pautler SE, Pavlovich CP, Choyke PL, et al. Percutaneous radiofrequency ablation of renal tumors: 1-year follow-up [abstract]. J Urol. 2002;167(4 suppl):167. Michaels MJ, Rhee HK, Summerhayes IC, Silverman ML, et al. Functional and anatomic evidence of incomplete tumor necrosis in radiofrequency ablation [abstract]. J Urol. 2002;167(4 suppl): Late-breaking 23. Shingleton W, Sewell PE. Renal cryoablation performed by a percutaneous approach with magnetic resonance image guidance —18 and 24 month follow-up [abstract]. J Urol. 2002;167(4 suppl):167. Uzzo RG, Novick AC. Nephron sparing surgery for renal tumors: indications, techniques and outcomes. J Urol. 2001;166:6–18. Lerner SE, Hawkins CA, Blute ML, et al. Disease outcome in patients with low stage renal cell carcinoma treated with nephron sparing or radical surgery. J Urol. 1996;155:1868–1873. Hafez KS, Fergany AF, Novick AC. Nephron sparing surgery for localized renal cell carcinoma: impact of tumor size on patient survival, VOL. 4 NO. 3 2002 tumor recurrence and TNM staging. J Urol. 1999;162:1930–1933. 55. Lee CT, Katz J, Shi W, et al. Surgical management of renal tumors 4 cm or less in a contemporary cohort. J Urol. 2000;163:730–736. 56. Belldegrun A, Tsui KH, deKernion JB, Smith RB. Efficacy of nephron-sparing surgery for renal cell carcinoma: analysis based on the new 1997 tumor-node-metastasis staging system. J Clin Oncol. 1999;17:2868–2875. 57. Leibovich BC, Blute ML, Cheville JC, et al. Appropriate selection of renal masses 4-7 cm for renal preserving surgery [abstract]. J Urol. 2002;167 (4 suppl):167. 58. Antenor JV, Roehl KA, Catalona WJ. Relation between PSA level at initial screening and subsequent cancer detection in a prostate cancer screening study [abstract]. J Urol. 2002;167(4 suppl):99. 59. Ross KS, Carter HB, Pearson JD, Guess HA. Comparative efficiency of prostate-specific antigen screening strategies for prostate cancer detection. JAMA. 2000;284;1399–1405. 60. Grubb RL, Roehl KA, Antenor JV, Catalona WJ. Delays in cancer detection using 2 and 4 year screening intervals for prostate cancer screening in men with initial PSA < 2 ng/mL [abstract]. J Urol. 2002;167(4 suppl):99. 61. Crawford DL, Chia D, Andriole GL, et al. PSA testing interval, reduction in screening intervals: data from the PLCO cancer screening trial [abstract]. J Urol. 2002;167(4 suppl):99. 62. Mulhall JP, Lodowsky C, Ghali S, et al. Subjective and objective analysis of the prevalence of Peyronie’s disease in a population of men presenting for prostate cancer [abstract]. J Urol. 2002;167(4 suppl):204. 63. Awogu OF, Shah N, Carr TW, et al. Extracorporeal shock-wave therapy for Peyronie’s disease [abstract]. J Urol. 2002;167(4 suppl):204. 64. Neururer R, Studen M, Maneschg C and Bartsch G. ESWT for the treatment of induratio penis plastica—clinical outcome. J Urol. 2002;167(4 suppl):204. 65. Fitch WP, Easterling WJ. Topical verapamil, trifluoperazine, and magnesium sulfate for Peyronie’s disease [abstract]. J Urol. 2002;167(4 suppl):205. 66. Mulhall JP, Badwan K, Martin D, Parker M. Does transdermal verapamil applied to the penis infiltrate the tunica albuginea? [abstract]. J Urol. 2002;167(4 suppl):205. 67. Hauc EW, Hauptmann A, Bein G, et al. Prospective analysis of transforming growth factor-beta-1 (TGF-B1) polymorphisms in Peyronie’s disease [abstract]. J Urol. 2002;167(4 suppl):206. 68. Levine LA, Estrada CR, Shou W, Cole A. Tunica albuginea tissue analysis following electromotive drug administration [abstract]. J Urol. 2002;167(4 suppl):205. 69. Lahme S, Goetz T, Zimmermann R, Bichler KH. Defect coverage by collagen fleece after plaque excision in patients with Peyronie’s disease— first longterm results [abstract]. J Urol. 2002;167(4 suppl):206. 70. Carson CC, West SL, Hill C, et al. Prevalence and correlates of erectile dysfunction in a United States nationwide population-based sample: phase I results [abstract]. J Urol. 2002;167(4 suppl):29. 71. Montorsi F, Salonia A, Montorsi P, et al. May erectile dysfunction predict ischemic heart disease? [abstract]. J Urol. 2002;167(4 suppl):148. 72. Niederberger CS, Londsdale J. Erectile dysfunction—patient characteristics and attitudes based REVIEWS IN UROLOGY on a large-scale male health study conducted in US, Europe, Mexico, and Brazil [abstract]. J Urol. 2002;167(4 suppl):148. 73. Robertson C, Boyle P, Mazzetta C, et al. Benign prostatic hyperplasia, prostate volume, maximum flow and lower urinary tract symptoms in four centres: the Urepik study [abstract]. J Urol. 2002;167(4 suppl):268. 74. Althof SE, Stecher VJ, Tseng LJ. Evaluation of partner satisfaction with sildenafil citrate treatment in men with erectile dysfunction [abstract]. J Urol. 2002;167(4 suppl):280. 75. Blitz J, Ginsberg PC, Harkaway R, et al. Preliminary experience with sildenafil citrate in patients with myelomengocele [abstract]. J Urol. 2002;167(4 suppl):281. 76. Carson CC, Hill C, Siegel RL, Orazem J. Sildenafil citrate treatment for erectile dysfunction: rate of adverse events decreases over time [abstract]. J Urol. 2002;167(4 suppl):179. 77. Kloner RA, Watkins VS, Costigan T, et al. Cardiovascular profile of tadalafil, a new PDE-5 inhibitor [abstract]. J Urol. 2002;167(4 suppl):176. 78. Brock G, McMahon C, Point P, et al. Efficacy and safety of tadalafil in men with erectile dysfunction: an integrated analysis of registration trials [abstract]. J Urol. 2002;167(4 suppl):178. 79. Kloner RA, Mitchell MI, Bedding A, Emmick J. Pharmacodynamic interactions between tadalafil and nitrates compared with sildenafil [abstract]. J Urol. 2002;167(4 suppl):176. 80. Porst H, Rosen RC, Padma-Nathan H, Varanese L. Tadalafil allows men with erectile dysfunction to have successful intercourse up to 36 hours postdose [abstract]. J Urol. 2002;167(4 suppl):177. 81. Goldfischer E, Eardley I, Segerson T, et al. Vardenafil improves erectile function in men with significant comorbidities associated with erectile dysfunction (ED) [abstract]. J Urol. 2002;167(4 suppl):178. 82. Donatucci C, Eardley I, McVary KT, et al. Vardenafil improves erectile function regardless of etiology or baseline severity in men with erectile dysfunction [abstract]. J Urol. 2002;167(4 suppl):178. 83. Padma-Nathan H, Eardley I, Collins O, et al. Vardenafil restores normal functioning to me with erectile dysfunction [abstract]. J Urol. 2002;167(4 suppl):177. 84. Molinoff PB, Earle DC, Shadiack AM, et al. A double-blind placebo-controlled study to evaluate the safety, pharmacokinetics, and erectogenic effect of subcutaneously administered PT-141 in health males [abstract]. J Urol. 2002;167 (4 suppl):[CD-ROM]. 85. Chang S, Hypolite J, Changolkar A, et al. Diabetes associated erectile dysfunction: role [abstract]. J Urol. 2002;167(4 suppl):237. 86. White S, Wilkes N, Bernie J, Rajasekaran M. Role of rho-kinase inhibition in age-related male erectile dysfunction: the Brown-Norway rat model [abstract]. J Urol. 2002;167(4 suppl):238. 87. Chang JA, Gholami SS, Lin GT, et al. The effect of vascular endothelial growth factor (VEGF) on function and gene expression in the penile corpus cavernosum in a rat model of radiationinduced erectile dysfunction [abstract]. J Urol. 2002;167(4 suppl):241. 88. Ho HC, Chang JA, Gholami SS, et al. The effect of vascular endothelial growth factor (VEGF) on an animal model of severe arteriogenic erectile dysfunction [abstract]. J Urol. 2002;167(4 suppl):242.