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Best of the SIU Meeting on Prostatic Disease

Meeting Review

MEETING REVIEW Best of the SIU Meeting on Prostatic Disease Highlights from the Société Internationale d’Urologie Meeting on Prostatic Disease: Recent Advances and New Technologies, September 29–October 1, 2005, Bariloche, Patagonia, Argentina [Rev Urol. 2005;7(4):224-228] © 2005 MedReviews, LLC Key words: Prostate cancer • Prostate Cancer Prevention Trial • Prostate-specific antigen • Benign prostatic hyperplasia • Lower urinary tract symptoms • Erectile dysfunction • Prostatitis ore than 500 delegates from 48 countries met in northern Patagonia from September 29 to October 1, 2005, to present, discuss, and debate the novel and exciting developments that are changing the ways we manage prostate disease. This report discusses some of the major highlights from this important international meeting. M Controversies in Grading Prostate Cancer—Pathologic and Clinical Implications Although several grading systems have been developed over the years to measure aggressive cellular morphology in prostate cancer, the Gleason system has been more or less universally accepted worldwide as the best Reviewed by J. Curtis Nickel, MD, FRCSC, Department of Urology, Queen’s University, Kingston, Ontario, Canada 224 VOL. 7 NO. 4 2005 system available. However, as discussed by Ferran Algaba (Spain), the Gleason system’s reproducibility is not ideal; interpersonal agreement ranges from 36% to 81%, whereas intraobserver reproducibility is 42% to 78%. To improve reproducibility, educational programs, information exchange, and recognition of “problem areas” are needed. A significant problem is the apparent lack of correlation between grading of biopsy cancers and grading of the cancer on the subsequent surgical pathology specimen. It seems that there is approximately 50% exact correlation, with 38% undergrading and 12% overgrading. There are also changes related to hormone therapy and radiotherapy that can be interpreted as a Gleason score change (eg, they might change cell morphology to mimic an aggressive pattern). It has been strongly suggested that the Gleason grading REVIEWS IN UROLOGY system should not be used in patients who have been subjected to hormone manipulation (including 5-reductase inhibition). These discrepancies are important because higher Gleason grade does correlate with decreased 5- and 10-year survival. It has also become evident that any Grade 4 and 5 patterns in a specimen are important in long-term prognosis, even if they are not the predominant primary or secondary pattern (the Gleason system reports predominant primary then secondary patterns) in the specimen. New recommendations state that pathologists should report even minimal Grade 4 and 5 as a tertiary percentage of 4 and 5. Screening for Prostate Cancer: Lessons from the Prostate Cancer Prevention Trial For the last 10 to 15 years, urologists were taught that prostate-specific Best of the SIU antigen (PSA) level correlated with probability of positive biopsy (ie, PSA of 0–2 ng/mL  1% risk, PSA 2–4 ng/mL  15% risk, PSA 4–10 ng/mL  25%, and PSA 10 ng/mL  50% probability of positive biopsy). However, because few low-PSA patients (with normal results on digital rectal examination [DRE]) were biopsied, overdetection of cancer in high PSA ranges and underdetection in patients with low PSA levels resulted. In the Prostate Cancer Prevention Trial (PCPT), all subjects were scheduled for an end-of-study biopsy. Ian Thompson (United States) reviewed a secondary analysis of the placebo patients, in which end-of-study biopsy results independent of PSA assay and DRE results were evaluated. Of 5587 men in the placebo group with end-of-study PSA assay and biopsy, 1225 had cancer; 250 with a Table 1 Factors That Would Identify Risk of Prostate Cancer in a 65-Year-Old Man* Family History DRE Results PSA Level (ng/mL) Risk (%) Negative Normal 2.22 25 Positive Normal 1.61 25 Positive Abnormal 0.56 25 Negative Normal 3.5 32 Positive Normal 1.2 17 Positive Abnormal 1.2 40 DRE, digital rectal examination; PSA, prostate-specific antigen. *This is an estimation only based on the Bariloche presentation. PSA levels and more negative margin who are more likely to be cured. How do we combine risk factors of family history, DRE result, and age? With 5519 placebo patients in PCPT all having prostate biopsy and both PSA assay and DRE at biopsy, it was possible to identify patients at most Can we wait until a PSA level of 4.0 ng/mL or greater has been reached to consider biopsy in a man concerned about prostate cancer? Gleason score of 7 or greater, and 57 with a Gleason score of 8 or greater. Not only did PSA level strongly correlate with the risk of prostate cancer, but it was further confirmed that PSA level was an excellent indicator of high-grade disease, suggesting that it is more effective in identifying severe cancer than mild cancer. Thus, can we wait until a PSA level of 4.0 ng/mL or greater has been reached to consider biopsy in a man concerned about prostate cancer? Patients with a low Gleason grade (2–6) have a better posttherapy relapse rate (19%) compared with those with higher-grade disease (patients with Gleason grade 7–10 have 56% relapse), so although a PSA level greater than 4 will detect more high-grade cancer, it is the patients with lower risk of developing prostate cancer. Table 1 lists the combined risk factors that would identify risk of prostate cancer in a 65-year-old man (a 25% risk is a reasonable trigger point for consideration of biopsy). Analyses of serial PSA levels in the PCPT suggest that PSA velocity provides no predic- testing has failed as a screening test for prostate cancer. Conclusions should be based on thorough analysis more than on rhetoric. The value of the PCPT, in which 18,000 men all started with PSA levels less than 4 ng/mL, is that it eliminates the population bias of many other trials. A follow-up symposium of these PSA issues in the international community, moderated by Claude Schulman (Belgium) and involving Ubirajara Ferreira (Brazil), Remigio Vela-Navarrete (Spain), and Osvaldo Mazza (Argentina), reached basically the same conclusions. Other Prostate Cancer Topics Other important topics covered in the prostate cancer field at the meeting included radiotherapy (Luisa Rafailovici, Argentina), salvage The challenge will be to re-educate the media, who have decided that PSA testing has failed as a screening test for prostate cancer. tive value more than shown in Table 1. Therefore, the challenge will be to re-educate patients and physicians, many of whom are now totally confused, and then to re-educate the media, who have decided that PSA prostatectomy in radiotherapy failures (Edson Pontes, United States), radical prostatectomy (Horst Zinke, United States), and adjuvant hormonal and chemotherapy (Richard Fourcade, France) for locally advanced disease. VOL. 7 NO. 4 2005 REVIEWS IN UROLOGY 225 Best of the SIU continued Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia: The Management Algorithm Has Shifted Mark Speakman (United Kingdom) summarized the data confirming that benign prostatic hyperplasia (BPH) is a progressive disease of aging men. Men with BPH risk developing a deterioration of their symptoms, acute urinary retention, and surgery. To identify the 20% to 25% of BPH patients at risk of progression, we must consider the objective factors that progress over time: symptoms (especially nocturia), flow rate (2.1% per year deterioration), prostate volume (increased at a rate of 2% per year in general population, and approximately 18% over 4 years in BPH patients in clinical trials), and PSA level; acute urinary retention and surgery are poor outcome endpoints. hibitors not only modestly improve symptoms, but also favorably alter the natural progression of BPH. The key to successful management is to identify the right patient for monotherapy, combination therapy, or, alternatively, surgery or minimally invasive therapies. The Role of New Technologies for BPH: Global and Latin American Viewpoints A very important objective of this meeting was to assess the rapidly evolving field of new technologies proposed for BPH management and the role of these technologies in developed and less-developed countries. This was accomplished during 2 debates, a symposium, and poster presentations. The following invited speakers and delegates participated in this ongoing debate: Remigio PSA level seems to be the best and most robust predictor of risk of BPH progression. We now recognize factors that determine risk of progression in BPH, which include age, symptoms, bother, flow rate, residual volume, prostate volume, and PSA level. PSA level seems to be the best and most robust predictor of risk of progression (it has been called a metabolic indicator of risk). Speakman presented the Slawin nomogram, an interactive system to identify an individual patient’s risk based on these factors, in which patient data are entered and individualized risk is calculated. This nomogram is available on the Internet, on the “Nomograms” page at www. oncovance.com. Regarding medical therapy, combination therapy is clearly most effective: -blockers quickly improve symptoms and reduce symptom progression, whereas 5-reductase in- 226 VOL. 7 NO. 4 2005 Vela-Navarrete (Spain), Walter Koff (Brazil), Arturo Mendoza-Valdes (Mexico), Eiji Higashihara (Japan), Laurent Boccon-Gibod (France), Frans DeBruyne (The Netherlands), Thane Larson (United States), Claude Schulman (Belgium), Alex Te (United States), and Mostafa Elhilali (Canada). Transurethral resection of the prostate (TURP) remains the international gold standard for the treatment of bothersome BPH. Globally, medical therapy is gaining ground, and TURP rates seem to be falling. Many new technological advances that accomplish the same objectives as TURP but without the morbidity have been introduced in developing countries over the last decade. Many have been abandoned (balloon dilation) or avoided (urethral stents) or have become antiquated (old laser technol- REVIEWS IN UROLOGY ogy as new lasers are introduced). Long-term and comparative data are not always available, and therefore the dilemma for the international audience is to decide whether the new technologies result in good long-term, cost-effective results. On the basis of the discussion at the Bariloche meeting, it seems that transurethral microwave thermotherapy (TUMT), transurethral needle ablation (TUNA), and laser therapy (with Holmium or potassium-titanylphosphate [KTP] laser) technologies have weathered the test of time, whereas intraprostatic injection strategies provide the opportunity to offer lower-cost alternatives. TUMT and TUNA are outpatient procedures that ablate prostate tissues; efficacy data comparing outcomes with those of TURP and some data on long-term outcomes (including retreatment rates) are available. Both are outpatient procedures that can be done without a general or spinal anesthesia, but both have real upfront (the machine) and ongoing (catheters, radiofrequency needles) costs. Economic factors that seem to be driving these technologies in the United States might not be the same in other countries. As for laser TURP, the KTP laser (“Green Light” vaporization) and the Holmium laser (enucleation or vaporization) are the two contemporary systems that have recently undergone the most evaluation and that have the best long-term follow-up data. However, most of the studies and procedures have been performed in developed countries. The KTP laser seems to have an easier learning curve but has significant ongoing costs (laser fibers), and data from trials comparing the procedure with TURP have not yet become available. Holmium laser prostate enucleation seems to be more difficult to learn, but the ongoing costs seem to be less (laser fibers can be reused). In Best of the SIU addition, data from comparative TURP trials are available. Prostatic injection of absolute alcohol is a novel, inexpensive, and simple method of producing prostate tissue ablation. This procedure, primarily evaluated outside of North America, was Becher, Argentina). Recent community-based studies show a positive relationship between LUTS and sexual dysfunction (mainly ED), estimated as a doubled rate of sexual dysfunction, especially if a man older than 50 years has LUTS. LUTS might be an Prostatic injection of absolute alcohol is a novel, inexpensive, and simple method of producing prostate tissue ablation. received with significant interest by many international delegates looking for a simple, cost-effective, minimally invasive outpatient therapy for BPH. The problem of alcohol migration seemed to be controlled by the use of a gel preparation of absolute alcohol. Lower Urinary Tract Symptoms/ BPH and Erectile Dysfunction The relationship between erectile dysfunction (ED) and BPH-related lower urinary tract symptoms (LUTS), including their epidemiological and etiological relationships and the fact that BPH management can impact on sexuality, was discussed (Edgardo even more important risk factor for ED than diabetes and cardiac disease, which are chronic diseases associated with an accepted higher incidence of ED. Sexual dysfunction, including ED, increases with increasing severity of Prostatitis Rational management strategies for the diagnosis of acute and chronic bacterial prostatitis were presented by Daniel Shoskes (United States). Diagnosis should incorporate a simple evaluation of the bacterial and inflammatory status of the lower urinary tract, whereas management includes 2 to 4 weeks of antimicrobial therapy, optimally, a fluoroquinolone. Chronic nonbacterial prostatitis/ chronic pelvic pain syndrome (discussed by J. Curtis Nickel, Canada), a condition whose management is a significant frustration among urologists, is prevalent worldwide. The patient’s quality of life is dismal, the socioeconomic costs high, Recent community-based studies show a positive relationship between LUTS and sexual dysfunction. LUTS. It was suggested that there is a need for integrated management of BPH/LUTS and sexual dysfunction. The diagnosis of one should drive at least a baseline assessment of the other. diagnosis difficult, and management problematic. The development of an accepted classification system and outcome index and the recent completion of a number of randomized, placebo-controlled trials have Main Points • Gleason system reproducibility is not ideal; to improve reproducibility, we need to recognize “problem areas,” such as the apparent lack of correlation between grading of biopsy cancers and grading of the cancer on the subsequent surgical pathology specimen. • A secondary analysis in the Prostate Cancer Prevention Trial showed that prostate-specific antigen (PSA) level strongly correlated with the risk of prostate cancer; it was further confirmed that PSA level was an excellent indicator of high-grade disease, suggesting that it is more effective in identifying severe cancer than mild cancer. • We now recognize factors that determine risk of progression in benign prostatic hyperplasia (BPH), which include age, symptoms, bother, flow rate, residual volume, prostate volume, and PSA level. • Regarding medical therapy for BPH, combination therapy is clearly most effective: -blockers quickly improve symptoms and reduce symptom progression, whereas 5-reductase inhibitors not only modestly improve symptoms but also favorably alter the natural progression of BPH. • Prostatic injection of absolute alcohol for the treatment of BPH is a novel, inexpensive, and simple method of producing prostate tissue ablation; the problem of alcohol migration seemed to be controlled by the use of a gel preparation of absolute alcohol. • Lower urinary tract symptoms (LUTS) might be an even more important risk factor for erectile dysfunction (ED) than diabetes and cardiac disease; sexual dysfunction, including ED, increases with increasing severity of LUTS. VOL. 7 NO. 4 2005 REVIEWS IN UROLOGY 227 Best of the SIU continued allowed an evidence-based approach to treatment. Antibiotics (only in early-diagnosed, antibiotic-naïve patients but not chronic patients), -blockers (recommended therapy, but best in early-diagnosis, treatment-naïve men treated for 12 weeks), anti-inflammatories (as adjuvant rather than monotherapy), 5-reductase inhibitors (not as a monotherapy but perhaps in men with concurrent BPH), and phytotherapies (quercetin is intriguing) all have a role, whereas other neurogenic- and immunologic-based therapies, physical therapies, and minimally invasive procedures are being evaluated. Future Management of Prostate Disease An interesting aspect of the program was a presentation by an international panel of urologists who discussed what they believe prostate disease management will look like a decade from now. Bernard Lobel (France) predicted that in 2015, prostatitis would still be a major urologic problem but that we would 228 VOL. 7 NO. 4 2005 have a better evidence-based approach and, perhaps by discovery of specific biomarkers, be able to select the best therapy for each patient. Arturo Mendoza-Valdes (Mexico) examined medical therapy and showed that the recent guidelines provide solid evidence for the use of -blockers and 5-reductase inhibitors but that new, innovative medical therapies will capitalize on other metabolic pathways associated with the pathogenesis of BPH. Laurent Boccon-Gibod (France) stated that future new technologies for treating BPH would be based on the failures and successes of the last decade. He believed that long-term data will substantiate many of the minimally invasive techniques in use today and that further refinements will provide even more benefits to the patient with BPH. Will assessment by PSA assay still be around in a decade? Ian Thompson (United States) provided solid arguments that it will continue to be useful in follow-up of patients with prostate cancer, but it also will have continued utility in REVIEWS IN UROLOGY screening, detection, and prognosis of early prostate cancer. Finally, Frans Debruyne (The Netherlands) presented his opinion that a molecular diagnostic test for prostate cancer soon will be available that will improve our detection of early prostate cancer. A major highlight of the meeting was the presentation of an international collection of posters that depicted state-of-the-art research in prostate cancer, BPH, and prostatitis from the many countries represented at the meeting (abstracts are available in Urology, volume 66, number 3A, the supplement to the September 2005 issue). Nine hours of plenary session presentations, with audio, video, and synchronized slides, will be available for a year for review or reference at www.ttmed.com/ urology/SIU2005 and at www.siuurology.org. The 2005 SIU meeting “Prostatic Disease: Recent Advances and New Technologies” in Bariloche, Argentina, was truly an international meeting of urologists interested in the better management of prostate disease.

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