Male Abstracts

PREVALENCE AND CORRELATES OF ERECTILE DYSFUNCTION IN A UNITED STATES NATIONWIDE POPULATION-BASED SAMPLE: PHASE I RESULTS
Culley C Carson*, Suzanne L West, Chapel Hill, NC; Dale B Glasser, New York, NY; Edward O Laumann, Chicago, IL; John M Flack, Detroit, MI; Eric Rimm, Boston, MA; Raymond C Rosen, Piscataway, NJ; Herman A Taylor, Jackson, MS; Richard H Grimm, Minneapolis, MN
This first national study of erectile dysfunction (ED) in men 40 years old and older with no upper age limit was designed to provide future prevalence estimates for black, white and Hispanic men. Only 1 previous epidemiological study of ED in the United States (National Health and Social Life Survey) included a nationally representative sample and the upper age limit was 59 years. In our earlier phase I study, we estimated the age specific prevalence of ED and evaluated the associations between ED and other co-morbidities. In the current cross-sectional study, we performed computer assisted and automated self-interviews via telephone in a nationally representative sample of nonHispanic white, nonHispanic black and Hispanic men 40 years old and older. Men were classified with ED if they were sometimes or never able to get and keep an erection that was satisfactory for sexual intercourse. Over the 5 months of the study, 491 nonHispanic white, 134 nonHispanic black and 195 Hispanic men were contacted through random-digit telephone dialing and interviewed. Overall, 49 percent of the men were always, 29 percent were usually, 14 percent were sometimes and 8 percent were never able to get and keep a satisfactory erection. ED estimates increased with increasing age. There was ED in 8 percent of 40 to 49-year-old men, in 19 percent of 50 to 59-year-old men and in 39 percent of men 60 years old and older. In addition to its association with age, ED was associated with diabetes. However, in this series ED was not related to ischemic heart disease, high cholesterol or hypertension. ED is common, since 22 percent of men 40 years old and older reported sometimes or never being able to get and keep an erection satisfactory for sexual intercourse; while 29 percent reported usually being able to do so. Thus, ED is significantly associated with increasing age as well as with diabetes.

IS ETHNICITY A PREDICTOR OF PROSTATE CANCER RECURRENCE FOLLOWING RADICAL PROSTATECTOMY? DATA FROM CAPSURE.
Gary D Grossfeld*, David M Latini, Deborah P Lubeck, San Francisco, CA; Shilpa S Mehta, Lake Forest, IL; Peter R Carroll, San Francisco, CA
Prostate cancer incidence and mortality are higher in African-American than Caucasian men. We determined whether ethnicity is an independent predictor of disease recurrence in men who undergo radical prostatectomy. We studied age, race, prostate specific antigen (PSA) at diagnosis, clinical stage, biopsy Gleason score and the percent of positive biopsies at diagnosis in 1,468 men who underwent radical prostatectomy at the University of California, San Francisco or as part of the database of CaPSURE, a longitudinal disease registry of patients with prostate cancer. Disease recurrence was defined as a PSA of 0.2 ng./ml. or greater on 2 occasions after prostatectomy or cancer re-treatment at least 6 months after surgery. To control for pretreatment characteristics simultaneously, the men were assigned to previously described risk groups based on clinical stage, PSA at diagnosis and biopsy Gleason score. We assessed the likelihood of recurrence for each risk group according to ethnicity. Disease recurred in 304 of the 1,468 patients (21 percent). Age and clinical stage were not significant predictors of prostate cancer recurrence. African-American ethnicity was an independent predictor of recurrence when the men were stratified into risk groups. Ethnicity was most important in high risk patients. In high risk Caucasian men median survival was 6.27 years, while it was 4.27 years in high risk African-American men. Ethnicity appears to be an independent predictor of recurrence in community patients who undergo prostatectomy. This predictor appears to be particularly important in men with high risk disease.

UROLOGY SALVAGE OF SILDENAFIL FAILURES FROM PRIMARY CARE PHYSICIANS
Geoffrey N Sklar, Michael J Szostak*, Baltimore, MD
Sildenafil citrate is effective first line therapy for erectile dysfunction. Approximately 65 percent of initial prescriptions are not written by urologists, but by primary care physicians. In many of these patients sildenafil therapy is considered to fail and they are subsequently referred to urologists for alternative treatment. It is often thought that sildenafil was ineffective, when in actuality failure was due to inadequate patient education. We examined these so-called sildenafil failures and reeducated patients in a urology setting to determine how many failures could be converted to sildenafil responders. Of the 622 consecutive patients referred to a single urologist from primary care physicians with the diagnosis of erectile dysfunction between October 1999 and September 2001, 253 were considered sildenafil failures by the primary care physician. These patients were reeducated on correct sildenafil use with videotapes and instruction sheets. Patients were followed at 3-month intervals to determine long-term efficacy in sildenafil responders. Efficacy was measured using a sexual health questionnaire and a global assessment question. Ninety-eight of the original 253 sildenafil failures (38 percent) were converted to sildenafil responders. During extended followup, 89 percent of the salvaged responders continued to use the drug with good results for a long-term salvage rate of 31 percent. Sildenafil citrate is efficacious first line therapy for erectile dysfunction. Many factors determine drug efficacy, including age, vasculogenic risk factors, and the etiology and severity of underlying erectile dysfunction. A factor that has been difficult to quantitate is the success of medical counseling. We showed that the cause of many sildenafil failures is poor education. Many patients in whom sildenafil failed initially tried the drug only once and never noticed any sexual stimulation. Our study shows the profound positive impact of proper urological counseling on the outcome of sildenafil therapy.

VARDENAFIL IMPROVES ERECTILE FUNCTION REGARDLESS OF ETIOLOGY OR BASELINE SEVERITY IN MEN WITH ERECTILE DYSFUNCTION
Craig Donatucci*, Durham, NC; Ian Eardley, Leeds, UK; Kevin T McVary, Chicago, IL; Marc Thibonnier, West Haven, CT
Erectile dysfunction (ED) arises from many etiologies and may be mild to severe. A recent phase IIb trial showed that vardenafil improved erectile function regardless of etiology or baseline severity. We determined the efficacy and safety of vardenafil with respect to etiology and baseline severity in a pooled analysis of data from 2 randomized, double-blind, phase III trials. Men who had had ED for less than 6 months received 5, 10 or 20 mg. vardenafil, or placebo for 12 weeks. The International Index of Erectile Function (EF Domain) was analyzed within subgroups defined by etiology, including organic ED in 672 men, psychogenic ED in 185 and mixed ED in 500. Baseline severity according to the EF domain score was severe in 533 men, moderate in 415, mild to moderate in 298 and mild in 8. Regardless of etiology or dose, vardenafil improved ED in statistically significantly fashion. ED was also statistically significantly improved by vardenafil regardless of baseline severity. Most significantly, after vardenafil treatment, severe ED improved to the mild-to-moderate range. Vardenafil was well tolerated. The most common drug related adverse events, namely headache, vasodilatation, rhinitis and dyspepsia, were related to the dosage and mostly mild to moderate. Vardenafil significantly improved ED regardless of etiology or severity, especially in men with severe ED.

PHYSICAL CHARACTERISTICS OF TISSUE-ENGINEERED PROSTHESIS FOR THE TREATMENT OF ERECTILE DYSFUNCTION
Byungsoo Kim, James J Yoo*, Anthony Atala, Boston, MA
We previously reported that autologous chondrocytes seeded on rod shaped polymer scaffolds can form cartilage penile prostheses within rabbit corpus cavernosa. In the current study, we investigated the feasibility of engineering biomechanically adequate, large autologous human cartilage rods that could be used clinically as penile prostheses. Chondrocytes were isolated from human auricular cartilage and expanded in vitro. They were seeded onto pre-formed, rod-shaped, biodegradable polymer scaffolds and maintained in a cell culture bioreactor for 1 month. The cell-seeded scaffolds were then implanted into the subcutaneous space of athymic rats. Specimens were retrieved 3 months after initial seeding for histomorphological and biomechanical analyses. We compared the biomechanical properties of the cartilage prostheses, including tension, bending and elasticity, with those of 2 currently available silicone penile prostheses, namely the AMS 700 inflatable and Jonas silicone rod prostheses. Chondrocytes seeded on polymer scaffolds formed cartilaginous rods that maintained the same size and shape as the initial implants. Histological analyses revealed mature and well formed chondrocytes in retrieved implants 2 months after implantation. Tensile tests showed that the engineered rods were readily elastic and withstood high tensile force. This finding was not significantly different for the Jonas or AMS 700 inflatable prosthesis. Dynamic bending tests showed that the rods were flexible and durable. No rod ruptured during the continuous, strenuous mechanical tests. These results indicate that autologous human auricular cartilage tissue can serve as a cell source for engineering cartilaginous penile prostheses. Human chondrocytes seeded on pre-formed polymers can form large dimension prostheses that may be placed in adult corporeal spaces. The tissue engineered rods are flexible, elastic and able to withstand high degrees of compressive forces. Prosthesis engineering using this technology may be useful in patients with erectile dysfunction.

TISSUE ENGINEERED TESTICULAR PROSTHESES WITH PROLONGED TESTOSTERONE RELEASE
Atlantida Raya-Rivera*, James J Yoo, Anthony Atala, Boston, MA
Congenital or acquired bilateral anorchia often requires testicular prosthesis placement and testosterone supplementation. Several types of testosterone compounds and various hormone delivery modes are currently used clinically, although their pharmacokinetic properties are not ideal. We explored the possibility of creating hormone releasing testicular prostheses to supply and maintain continuous, physiological levels of testosterone in vivo over time. Chondrocytes harvested from bovine articular cartilage were seeded on testis-shaped polymer scaffolds, which were maintained in a bioreactor for 4 weeks to form cartilage tissue. Testosterone enanthate was then injected into the central hollow space of each testicular prosthesis and maintained for 40 weeks. A sample of medium was collected every 2 days for testosterone assays. Other ex vivo engineered testicular prostheses were implanted into the scrotal space of 10 castrated athymic mice. Testosterone enanthate was injected in intratesticular fashion in each prosthesis. Controls included 8 castrated mice and 5 that underwent sham operation. Testosterone was measured for up to 14 weeks and the engineered testicular prostheses were then retrieved for analysis. Cartilage testicular prostheses formed by 4 weeks. Ex vivo prostheses showed an initial testosterone burst effect, followed by a broad plateau for 16 weeks of greater than 500 ng./dl. before testosterone decreased through week 40. Testosterone levels were physiological throughout the 40-week period. Circulating testosterone in prosthesis implanted mice had a maximum peak on day 1 and a continued physiological range throughout the study period. Histologically, the retrieved testicular implants showed mature chondrocytes with a hollow prosthesis center. This study demonstrates that engineered testicular prostheses can be created in bioreactors. When implanted in vivo, they can release a physiological level of testosterone for a prolonged period. Periodic re-injection may potentially provide permanent physiological hormonal replacement. This novel technology may be beneficial in patients who require testicular prostheses and chronic hormone supplementation

AN ANALYSIS OF DEFERRED THERAPY FOR PATIENTS WITH LOCALIZED PROSTATE CANCER.
Manish I Patel*, New York, NY; Dino DeConcini, Santa Monica, CA; Ernesto Lopez-Corona, Makoto Ohori, Peter T Scardino, New York, NY

Introduction and Objectives:
Patients with localized prostate cancer are being offered deferred therapy with increasing frequency. This is particularly so with patients suitable for definitive treatment but with minimal disease. Our objective is to determine whether these patients will progress, as assessed by currently available means.

Methods:
Retrospective review, of prospectively entered database records. Patients studied were eligible for radical prostatectomy but elected deferred therapy between 1985 and 2001. Patients were defined as low risk if they initially had a PSA<10, no Gleason pattern 4/5, PSA density (PSAD) <0.1and stage T1a or c. Patients were evaluated for progression by DRE, TRUS, biopsy and PSA. All progression factors were scored and strict progression was defined as achieving a sum of 3 factors. Patients with strict progression were recommended to have definitive treatment.

Results:
70 consecutive patients comprised the cohort. Mean age:65.8 (44-79)years, PSA:5.9(0.21-30.2), PSADensity:0.15(0.01-0.8). Stage:T1a=14, T1b=1, T1c=42, T2=14. Gleason sum:3-4=25, 5-6=43, 7=2. Mean followup(FU) was 38 months(m). 18 patients met the criteria for strict progression, at a median of 26.3m. FU. Factors that predicted non progression on univariate analysis were low risk group (p=0.000), PSA<6 (p=0.003),T1a (p=0.055), Gleason sum<6 (p=0.059). 82% of patients with a Kattan nomogram PFP of >90% did not progress, compared to 45% progression if the PFP was <90% (p=0.02). Multivariate analysis showed low risk group (p=0.0003) as the only factor significant. Only 9.8% in the low risk group progressed vs 68% in the high risk group. 30 patients had treatment during FU. 16 had RRP, 12 had XRT and 2 had androgen deprevation. 6 of these patients were treated because of anxiety not progression and 9 patients had some factors of progression but did not reach the strict definition. Actuarial 1 and 5 year, definitive treatment free survival was 79% and 51%. Treatment free survival was significantly better for those with PSA<6 (p=0.042) and stage T1a(p=0.053).

Conclusions:
Progression rates in deferred therapy cohorts are low but not negligible. Patients fitting the criteria for low risk have a very low risk of progression and can be safely placed on watchful waiting. Those with higher risk should be cautioned or assessed more frequently.

OPEN VERSUS LAPAROSCOPIC RADICAL PROSTATECTOMY : A PROSPECTIVE COMPARATIVE STUDY
Thierry Roumeguere, Renaud Bollens, Marc Vanden Bossche*, Claude Schulman, Alexandre Zlotta, Brussels, Belgium

Introduction and Objectives:
Laparoscopic radical prostatectomy is gaining increased attention but its results have never been compared appropriately to the gold standard open procedure. We prospectively compared, within the same center and during the same period of time the peroperative and postoperative parameters, oncological and functional results of both open retropubic (ORP) and laparoscopic radical prostatectomy (LRP).

Methods:
From September 1999 to September 2001, 162 patients with biopsy proven prostate cancer were treated with radical prostatectomy, 77 using an open retropublic technique, and 85 by laparoscopic extraperitoneal approach. We prospectively created a database including pre-, per- and postoperative parameters, recorded morbidity and complications, and evaluated carcinologic and functional results comparing both approaches. Patients were treated using either technique according to their preference.

Results:
There were no statistically significant differences in the preoperative characteristics of patients between the two groups except the greater incidence of clinical T3 cases treated by ORP (14.1% vs 1.3%). Mean operative time was statistically longer with LRP than by ORP (288 ± 67 min vs 168 ± 52 min). Median blood loss (400 vs 1300ml), per and postoperative transfusions (8% vs 38%), bladder catheterization time (6 vs 14 days) and hospital stay (8 vs 16 days) were significantly lower with LRP than ORP. Major complications occurred in similar number of cases (5% vs 2.4%, NS) while minor complications occurred more frequently with ORP (24.6% vs 11.8%). Pathological examination revealed similar distribution of Gleason score and pathological stages in the two groups. Positive surgical margins in pT2 cases occurred in 7.8% of LRP and 9.5% of ORP. There was no difference in terms of PSA progression at 1 year between both groups. Continence rates (no pad at all) were similar (83.9% in ORP vs 80.7% in LRP) but continence recovery was quicker with open surgery. Potency rates were similar at one year in patients undergoing bilateral nerve sparing (55% ORP vs 65% LRP). However, patients operated by LRP had more spontaneous erections than those operated by ORP who required more frequently oral medication.

Conclusions:
This prospective comparative study shows that laparoscopic radical prostatectomy, when performed in specialized centres, gives oncological and functional results comparable to open surgery. At the price of an increased operative time, LRP results in reduced blood loss, bladder catheterization time and hospital stay.

LONG-TERM SURVIVAL IN MEN WITH CLINICALLY LOCALIZED HIGH GRADE PROSTATE CANCER MANAGED CONSERVATIVELY COMPARED WITH DEFINITIVE RADIATION OR RADICAL PROSTATECTOMY
Benjamin J Leak*, Farmington Hills, MI; Ashutosh Tewari, Mani Menon, Detroit, MI

Introduction and Objectives:
The debate between definitive therapy and conservative management for clinically localized prostate cancer has been waged for many years. In past studies a trend toward improved outcomes has been demonstrated in men with Grade 3 (poorly differentiated, Gleason score 8-10) cancers receiving definitive therapy. Our study's objective was to determine if any long-term survival benefit over conservative therapy can be gained by undergoing definitive therapy for high grade clinically localized prostate cancer.

Methods:
We studied 3159 patients with biopsy confirmed, clinically localized prostate cancer diagnosed between 1980 and 1997. 470 of these men had biopsy grade 3 (Gleason score 8-10) prostate cancer. Our analysis was restricted to men 75 years of age and younger. After adjusting for age, race, grade of tumor, co-morbidity, income status, and year of diagnosis which could influence survival,a Cox proportional hazards model was used to compare long term survival between men with grade 3 prostate cancer treated conservatively with those treated with either radiotherapy or radical prostatectomy.

Results:
Radical prostatectomy reduced 15 year mortality by 65% for patients with grade 3 tumors and gave a 10.4 year survival advantage over conservative therapy. Patients with grade 1 and 2 tumors had a reduction in 15 year mortality of 47% and 60%, respectively. Radiation therapy conferred a 1.7 year increase in the length of survival for patients with grade 3 tumors as compared to conservative therapy. Patients with grade 1 and 2 tumors had a 4.7 and 4.4 year improvement in survival by undergoing radiation therapy in lieu of conservative management. The fifteen year cancer- specific risk ratio for patients with grade 3 prostate cancer undergoing radical prostatectomy was 0.40, while those undergoing radiation therapy had a risk ration of 0.60.

Conclusions:
Although decreases in mortality occurred in all subsets of patients undergoing definitive treatment, the reduction in mortality was greatest in patients with poorly differentiated tumors undergoing radical prostatectomy.

TRANSDERMAL ESTROGEN THERAPY FOR ADVANCED PROSTATE CANCER- FORWARD TO THE PAST?
Jeremy Ockrim*, El-Nasir Lalani, Marc E Laniado, Simon S Carter, Paul D Abel, London, UK

Introduction and Objectives:
Conventional androgen deprivation for advanced prostate cancer (CaP) is associated with significant morbidity. Evidence suggests estrogen therapy is equivalent to orchiectomy and maximal androgen blockade, but oral estrogens were abandoned because of cardiovascular toxicity. By contrast, recent data suggest parenteral estrogens reduce cardiovascular mortality by >90%. We report preliminary data on the effects of transdermal estradiol on hormones, PSA and quality of life (QoL) in men with advanced CaP.

Methods:
Twenty patients with locally advanced (n=10) or metastatic (n=10) CaP were enrolled. Six transdermal estradiol (7.8mg) patches were applied weekly for 8 weeks, and then adjusted to maintain castrate levels. Hormones, PSA and thrombophilic assays were performed before treatment and at regular intervals thereafter. Vascular flow studies, CT and isotope bone scanning, and bone densitometry were performed 6 monthly to monitor for thrombosis, disease progression and osteoporosis respectively. All patients completed the cancer and prostate specific QoL questionnaires.

Results:
Median follow up is currently 10 months (range 6 to 14). Patches were well tolerated. Estradiol levels greater than 1000pmol/l were achieved using 4 patches and even higher levels by increasing the number of patches. Both LH (<0.5units/l) and FSH (<1.7units/l) were suppressed. All patients reached castrate levels of testosterone (<3nmol/l) within 3 weeks and had biochemical evidence of disease regression with an average reduction in PSA of 95.1% (range 84.2-99.8%). One patient has biochemical relapse at 14 months. No cardiovascular or vascular flow (thromboembolic) complications have occurred and clotting times have not been extended. Early data show bone density is maintained. Mild (grade I) or moderate (grade II) gynecomastia occurred in 70% of patients, but no patient had hot flushes. All other functional and symptomatic QoL domains improved or stabilized.

Conclusions:
Transdermal estrogens are an effective treatment for advanced CaP, producing castrate levels of testosterone and objective clinical response. They are acceptable to patients with minimal morbidity (gynecomastia). Transdermal estrogen therapy costs less than one-tenth of LHRH agonists, potentially saving over $100,000,000 annually in the USA. Randomised trials are warranted to determine the place of parenteral (transdermal) estrogens in the management of CaP.