Special Report on Prostatitis Initiatives and Future Research

Second International Prostatitis Collaborative Network Meeting

MEETING REVIEW Special Report on Prostatitis Initiatives and Future Research Highlights of the Second International Prostatitis Collaborative Network Meeting November 3-5, 1999, Bethesda, Md. [Rev Urol. 2000;2(3):158-166] Key words: Antibiotic therapy • Epidemiology • Etiology • Physical therapy • Prostatitis T he First International Prostatitis Collaborative Network (IPCN) met in Washington, DC, in November 1998. Its purpose was to determine the feasibility of developing an international collaborative network of researchers, supported by patient advocacy groups, industry and, most important, the NIH. The participants of the first IPCN meeting reviewed the new NIH definition and classification of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) that were developed at the pivotal Prostatitis Workshop convened by the NIH in December 1995. The 1998 meeting of the IPCN was an overwhelming success. The definition and classification system (Table) was confirmed as the optimal approach to define this syndrome in both research studies and clinical practice.1 The group also developed Consensus Guidelines for Future Research in CP/CPPS.2 A unanimous decision was made to continue and expand the IPCN framework. At the Second IPCN meeting in 1999, sponsored jointly by the NIH and the Prostatitis Foundation, more than 100 prostatitis researchers (representing almost a dozen countries), patients, and industry representatives participated in a series of state-of-theart lectures, panels, original research Reviewed by J. Curtis Nickel, MD, FRCSC, Queen’s University, Kingston, Ontario, for the participants of the Second International Prostatitis Collaborative Network meeting. 158 REVIEWS IN UROLOGY presentations, and breakout workshops. The most important aspects of CP/CPPS were reviewed, discussed, argued, and agreed on. The meeting was jointly chaired by Leroy Nyberg, Mike Hennenfent, and J. Curtis Nickel, representing the NIH, the Prostatitis Foundation, and the international prostatitis research community, respectively. The most important points that arose during this collaborative interaction follow. National Institutes of Health Initiatives A progress report of the NIH-funded initiative, the Chronic Prostatitis Collaborative Research Network (CPCRN), was presented by J. Kusek (NIH/National Institute of Diabetes, Digestive and Kidney Disease). The CPCRN consists of 6 North American research centers, including Northwestern University in Chicago (A. Schaeffer), Harvard University in Boston (M. O’Leary), the University of Maryland in Baltimore (A. Alexander), the University of California at Los Angeles (M. Litwin), Temple University in Philadelphia (M. Pontari), and Queen’s University in Kingston, Canada (J. C. Nickel), and a data coordinating center at the University of Pennsylvania in Philadelphia (R. Landis). The CPCRN has developed, validated, and published a CP/CPPS outcomes index, the Chronic Prostatitis Symptom Index (NIH-CPSI),3 which is being translated and validated in a number of languages. The group also SUMMER 2000 has developed and instituted the Chronic Prostatitis Cohort (CPC) study. More than 200 patients have been enrolled in the 3-year study during its first year. A Control Population Study, similar to the CPC, will be completed this year. A multicenter socioeconomic study is presently under way. The CPCRN will begin randomized, placebo-controlled treatment trials by mid2000. In addition, each participating research center provided an inventory of its epidemiologic, basic science, and clinical research projects in progress. State-of-the-Art Lectures/Panel Discussions Epidemiology (chaired by R. Roberts; panelists included T. Moon, A. Mehik, and J. Garst). Results of epidemiologic studies confirm that prostatitis is a very important and common medical condition. It is one of the most common conditions seen by urologists, with an estimated prevalence of between 5% and 9% of men at risk. Etiology (chaired by J. Krieger; panelists included D. Neal, R. Anderson, H. Kumon, and D. Bolles). The etiology of CP/CPPS is unknown. There is evidence that the following mechanisms may be involved: microbial, immunologic, neurologic, chemical, psychological, and anatomic. There may be multiple causes for the syndrome in various categories or individuals, or the condition may be multifactorial in nature. Treatment (chaired by W. Weidner; Prostatitis panelists included A. Doble, F. Lowe, R. Berger, and B. Gushchin). Antimicrobials have been compared with one another in the rare category of chronic bacterial prostatitis (category II) in controlled clinical trials, but the eradication of bacteria (as the primary end point) is not always achieved, and the effect on symptoms, even in this category of defined prostatic infection, is not known. The major treatments for patients with CP/CPPS appear to be antimicrobials, -blockers, anti-inflammatory agents, phytotherapies, heat therapy, and various physical therapies, but there is a paucity of evidence in the form of well-designed, randomized, placebo-controlled (or sham) studies in the literature to support one treatment over another. Original Research Presentations This was the largest collection of original research in prostatitis ever presented at a scientific meeting. Fortyfour abstracts, accepted for poster/podium presentation, were grouped as epidemiology-, etiology-, or treatment-related. Summary points from the 3 categories are: Epidemiology • Of men at risk, 9% suffer from prostatitis-like symptoms in a population-based study. (Nickel et al, Kingston, Canada) • The health care profession is not resolving the concerns of patients with CPPS. (Rothman et al, Seattle) • CPPS may be part of a more generalized pain disorder. (Berger et al, Seattle) • Repetitive perineal trauma from rough-riding motor vehicles may be implicated in CPPS. (Rabon, Florence, SC) • Is female prostatitis a clinical entity? (Ablin et al, Suffern, NY) • Leukocytosis was identified in the expressed prostatic secretions (EPS) of the majority of men who presented with voiding symptoms. (Wheeler, Durango, Colo) Main Points • The etiology of chronic prostatitis/chronic prostatitis pain syndrome (CP/CPPS) is still an enigma. • There is a lack of controlled studies to support 1 treatment option over another for CP/CPPS. • The significance of leukocytosis in expressed prostatic secretions in men with pelvic pain and voiding symptoms has yet to be defined. • There may be a greater tendency for prostatitis to be associated with benign prostatic hyperplasia than with prostate cancer. • -Blocking agents and fluoroquinolones can be effective in treating patients with CP, as can anti-inflammatory agents, phytotherapy, heat therapy, and physical therapy. • More research is needed in the areas of normal prostate function and immunobiology of the prostate. • Inflammation does not register an objective effect on traditional fertility parameters. (Ludwig et al, Giessen, Germany) • Semen specimens from men with CPPS exhibit oxidative stress irrespective of their leukocyte status. (Potts et al, Cleveland) • Use of a hemocytometer is more accurate than the traditional cover slip method in detecting EPS inflammation. (Muller et al, Seattle) • Counting of leukocytes in the third midstream voided bladder specimen is a reliable method, compared with evaluation of leukocytes in EPS. (Ludwig et al, Giessen, Germany) • Diagnosing and managing category IV prostatitis in patients with elevated prostate-specific antigen (PSA) levels before deciding to perform biopsy may be safe and effective. (Potts, Cleveland) • Prostatitis has a greater tendency to be associated with benign prostatic hyperplasia (BPH) than with prostate cancer. (Seftel et al, Cleveland) • • • • • • Etiology • Host response contributes to pathogen-mediated damage. (Dimitrakov et al, Plovdiv, Bulgaria) • Fungal prostatitis may be a distinct clinical entity. (Dimitrakov et al, Plovdiv, Bulgaria) • Helicobacter pylori was noted in the • • prostates of 3 of 30 patients who had CP. (Dimitrakov et al, Plovdiv, Bulgaria) Matrix metalloprotease activities secondary to the inflammatory response in CP may help mediate epithelial atrophy and proliferation of fibromuscular stroma in the rat prostate. (Wilson et al, Minneapolis) CP/CPPS is associated with increased blood flow to the prostate. (Cho et al, Seoul, Korea) Men with CPPS have more abnormal pelvic floor and abdominal muscular pathologic findings than do control patients. (Hetrick et al, Seattle) Interleukin-8 (IL-8) levels are elevated in the EPS of men with categories II, IIIA, or IV CP/CPPS. (Hochreiter et al, Chicago) Using the technique of polymerase chain reaction (PCR), no bacterial presence was detected in prostatectomy tissue of men who did not have clinical prostatitis. (Hochrieter et al, Chicago) Measurement of bacteria-specific antibodies in EPS is helpful for etiologic and treatment considerations. (Kumon, Okayama, Japan) Men with CPPS have an altered sensation of perineal pain. (Lee et al, Seattle) Bacteria are more common in biopsy tissue specimens of men with CP SUMMER 2000 REVIEWS IN UROLOGY 159 Prostatitis continued Table NIH Consensus Classification of Prostatitis Syndromes Category I II III IV • • • • • • • • • Type Acute bacterial prostatitis Chronic bacterial prostatitis Chronic pelvic pain syndrome A. Inflammatory B. Noninflammatory Asymptomatic inflammatory prostatitis than in controls, but there is no correlation to the degree of inflammation in the EPS. (Lee et al, Seattle) PCR detected sexually transmitted disease organisms in 20% of patients with abacterial prostatitis. (Mazzoli et al, Florence, Italy) Estradiol-enhanced CP in rats increases sensory nerve fiber density and inflammation, which can be prevented by depletion of sensory peptides. (Moon et al, Madison, Wis) Inflammation in the rat prostate is sustained by stress. (Robinette et al, Raleigh, NC) Prostatic inflammatory aggregates may be pathognomonic for prostatic inflammation. (Vega et al, Tucson) Chronic prostatic urethritis may be a separate but related disease entity with CP. (Vega et al, Tucson) Fungi do not appear to play a major role in CP, but Chlamydia and Corynebacterium may be important. (Polacheck et al, Tucson) PSA is a candidate antigen in CP/CPPS. (Ponniah et al, Baltimore) T2 cytokines (IL-10) are dominant in seminal plasma in CP. (Underwood et al, Farmington, Conn) Dominance of T2 (IL-10) to T1 (IL-2) cytokines promotes mast cell activity in CP. (Wong et al, Farmington, Conn) Treatment • Internal myofascial release therapy may reduce pain and resting pelvic tension levels in patients with CPPS. (Anderson et al, Stanford, Calif) • Pelvic floor physical therapy may benefit selected patients with CPPS. (Potts et al, Cleveland) • Use of α-blockers is justified for management of prostatodynia as well as bacterial and abacterial prostatitis. (Barbalias et al, Patras, Greece) • Self-treatment (including self-prostatic massage) is a viable option for the patient with prostatitis. (Bolles et al, Tucson) • Combination prostatic massage and antibiotics benefited about one third of the North American patients treated in the Philippines. (Feliciano et al, Manila, Philippines) • When performed properly, prostatic massage relieved symptoms of CPPS. (Hickman et al, St Louis) • Endosurgical management may be indicated for patients with prostate stones, BPH, or bladder neck fibrosis. (Gushchin et al, Moscow) • Dietary changes may benefit men with CP. (Krisiloff, Santa Monica, Calif) • Prostat demonstrated benefits in some patients with CP in an uncontrolled clinical trial. (Michael et al, Shanghai) • Lomefloxacin is comparably effective and as tolerated as ciprofloxacin for treating patients with CP (category II). (Naber, Straubing, Germany) • Ciprofloxacin is an excellent antimicrobial agent for treatment of patients with CP (category II); however, eradication of the pathogen is unpredictable. (Weidner et al, Geissen, Germany) Working Groups An important aspect of the Second IPCN meeting was the breakout working groups that collaboratively decided on a strategy for further endeavors in the fields of education, funding, etiology, and treatment for patients with CP/CPPS. The reports from the chairs of the working groups are briefly summarized: Education (chaired by M. McNaughton-Collins) • Objective: To determine ways to raise public awareness of CP. • Recommendations: 1. Prepare a 1-page fact sheet on CP. a. Request that government organizations, such as the NIH, give the CP fact sheet to their public affairs/relations department for dissemination. b. Request that private organizations, such as the Prostatitis Foundation, disseminate the same fact sheet. 2. Interact with the media (attempt to identify a celebrity with CP who would act as a spokesperson). 3. Request financial support from pharmaceutical and device companies associated with prostatitis treatment to establish a CP newsletter and/or public affairs campaign. Funding (chaired by J. Krieger) • Objective: To explore funding issues in prostatitis research. • Recommendations: 1. There is a need to fund clinicianinvestigators. Any basic science must be closely allied with clinical work. 2. There is a need to educate the FDA so that CP/CPPS will become an acceptable indication for drug and device therapies. 3. Research in prostatitis needs to be stimulated by the injection of more funding from the NIH. Etiology (chaired by R. Alexander) • Objective: To explore areas for basic investigation. continued on page 166 160 REVIEWS IN UROLOGY SUMMER 2000 Prostatitis continued continued from page 160 • Recommendations: 1. Normal function of the prostate in animals and humans. • Anatomy. • Secretory function. • Expressed prostatic fluid. • Neurophysiology. • Immunology. • Bacterial flora. • Blood-prostate barrier. • Role of corpora amylacea. • Microbiology of normal prostate. • Physiology of ejaculation and prostate function. 2. Animal models, directed to develop insights into the etiology of CP/CPPS. • Inflammatory infiltrates in the prostate. • Behavioral studies in chronic pain. • Bacteriology of animal gland. 3. Immunobiology of the prostate. • Immunologic function. • Role of inflammation (Why is his tologic inflammation so common in the prostate?) • Blood-prostate barrier (Is the gland an immune-privileged site?) • Does the gland have a barrier function for microbes in the genital tract? Treatment (chaired by D. Shoskes) • Objective: To recommend the most important and promising areas for research into the treatment of CP. • Recommendations: CP/CPPS likely represents clinical syndromes that may have diverse causes and that respond to diverse treatment ap- 166 REVIEWS IN UROLOGY SUMMER 2000 proaches. Few of the therapies advocated have been supported by prospective placebo-controlled trials with appropriately validated symptom or quality-of-life end points. The following avenues of research should be explored in randomized, controlled clinical trials employing validated outcomes measures: 1. Antimicrobial therapy—particularly the fluoroquinolones. 2. Anti-inflammatory therapies—including anti-inflammatory drugs, immunosuppressive therapy, and selected phytotherapy. 3. BPH therapies—including α-blockers and finasteride. 4. Neuromuscular therapies—including pelvic floor physiotherapy, biofeedback, and systemic medications (gabapentin, tricyclic antidepressants, and striated muscle relaxants). 5. Interstitial cystitis therapies— including pentosan polysulfate and other therapies used in interstitial cystitis management. 6. Surgery—including radical transurethral resection of the prostate, radical open prostatectomy, and bladder neck surgery; and minimally invasive therapies, such as microwave thermotherapy. 7. Psychological/psychiatric support—including psychological, psychiatric, and stress reduction therapies. Summary The Second IPCN meeting was an important breakthrough in the field of prostatitis research. A unified approach to the definition, classification, and outcomes measurements and a need for randomized, placebo-controlled trials in prostatitis were confirmed. There is now a forum for researchers to present their research and interact with clinicians, patients, scientists, and industry in a constructive atmosphere. The creation of the IPCN will stimulate research and funding in the field, disseminate the results of subsequent research to the international research community, allow patients a voice in developing and supporting research in the field, and educate industry about the potential of this large untapped patient market. The IPCN concept was successful, and follow-up meetings are planned. An important objective of the Third IPCN meeting, scheduled for October 23-25, 2000, will be to establish an international database of patients with prostatitis and to initiate a collaborative international study on CP/CPPS.■ References 1. Krieger JN, Nyberg L, Nickel JC. NIH consensus definition and classification of prostatitis. JAMA. 1999;282:236-237. 2. Nickel JC, Nyberg L, Hennennfent M. Research guidelines for chronic prostatitis: a consensus report from the first National Institutes of HealthInternational Prostatitis Collaborative Network (NIH-IPCN). Urology. 1999;54:229-233. 3. Litwin SM, McNaughton-Collins M, Fowler FJ, et al. The NIH Chronic Prostatitis Symptom Index (NIH-CPSI): development and validation of a new outcomes measure. J Urol. 1999;162:369-375.