J.C. NICKEL, J. DOWNEY, M.A. PONTARI*, D.A. SHOSKES

Transcription

1 Original Article FINASTERIDE TREATMENT OF CHRONIC PELVIC PAIN SYNDROME J.C. NICKEL et al. A randomized placebo-controlled multicentre study to evaluate the safety and efficacy of finasteride for male chronic pelvic pain syndrome (category IIIA chronic nonbacterial prostatitis) J.C. NICKEL, J. DOWNEY, M.A. PONTARI*, D.A. SHOSKES and S.I. ZEITLIN Queen s University, Kingston, ON, Canada, *Temple University, Philadelphia, PA, Cleveland Clinic Florida, Weston, FL, University of California at Los Angeles, Los Angeles, CA, USA Accepted for publication 5 December 2003 OBJECTIVE To determine if finasteride can reduce symptoms in men with a clinical diagnosis of chronic nonbacterial prostatitis (National Institutes of Health, NIH, category IIIA chronic pelvic pain syndrome, CPPS) compared with placebo. PATIENTS AND METHODS Men (76) with category IIIA CPPS enrolled in four North American prostatitis research centres were randomized after a 2-week placebo run-in to finasteride or placebo for 6 months. The primary efficacy variable was a subjective overall assessment (SOA); the secondary efficacy variables included the NIH chronic prostatitis symptom index (NIH-CPSI) and safety data. Patients were assessed at screening, baseline (after the 2-week placebo run-in), 3 and 6 months. RESULTS Sixty-four patients had at least one assessment on medication (31 placebo, 33 finasteride); 75% of the finasteride and 54% of the placebo group had at least a mild improvement (defined as >25% improvement in SOA), and 44% and 27%, respectively, a moderate or marked improvement (>50% improvement in SOA). The trend was similar in the NIH-CPSI scores. Five patients in the finasteride and seven in the placebo group reported medication-related adverse events. CONCLUSION This randomized placebo-controlled pilot study suggests that finasteride was of benefit for some men with category IIIA CPPS, but the results do not justify recommending finasteride as monotherapy, except for men who also have benign prostatic hyperplasia. A larger, properly powered study, possibly evaluating combination with other therapies or specifically in men with prostatitis and benign prostatic hyperplasia, is required to confirm any clinical benefit. KEYWORDS prostatitis, chronic nonbacterial prostatitis, chronic pelvic pain syndrome, finasteride, 5a-reductase inhibitors INTRODUCTION There are no standard confirmed therapies indicated for treating male chronic pelvic pain syndrome (chronic nonbacterial prostatitis and/or prostatodynia, CP/CPPS). Most traditional therapies were based on small case series, uncontrolled studies and anecdotal experience [1]. This is changing as more evidence from controlled studies is reported. Most patients with the clinical diagnosis of CP/CPPS are treated at least once with antibiotics, and although some guidelines [2] recommend a short course of antibiotics for chronic nonbacterial prostatitis (inflammatory CP/CPPS category IIIA), recent evidence comparing the efficacy of antibiotic therapy in CP/CPPS with placebo [3] does not substantiate this suggestion. Recent randomized controlled studies comparing tamsulosin [4], terazosin [5] and alfuzosin [6] with placebo have also suggested that a- blockers may be helpful, particularly if the treatment is for >12 weeks. Similarly, a randomized controlled pilot study comparing a cyclooxygenase-2 inhibitor, rofecoxib, with placebo [7] suggested benefits of antiinflammatory therapy in patients with CP/CPPS. Quercetin [8] and pentosan polysulphate [9] have been shown in small placebo-controlled trials to have some efficacy in CP/CPPS. There is a significant need, and more recently an increased interest, in evaluating medical therapies for CP/CPPS. The results of several clinical trials currently underway by the National Institutes of Health (NIH) Chronic Prostatitis Collaborative Research Network [10] and others will soon be available. Finasteride, a specific type II 5a-reductase inhibitor, was approved for clinical use worldwide for treating symptomatic BPH in the early 1990s [11]. As physicians have become familiar with finasteride for treating BPH and have identified improvements in LUTS in these patients, many have used finasteride to treat their patients with prostatitis who were refractory to other forms of therapy. Many such anecdotal reports have been published [12]. Three small independent studies undertaken in Denmark [13], the USA [14] and Finland [15], respectively, suggested that the anecdotal report may have merit and that finasteride may benefit some men with CP. We undertook a pilot study to determine whether finasteride reduces symptoms in men with a clinical diagnosis of NIH category IIIA CPPS (chronic nonbacterial prostatitis), compared with placebo. PATIENTS AND METHODS Patients with a diagnosis consistent with NIH CP/CPPS IIIA [16] were enrolled in four North 2004 BJU INTERNATIONAL 93, doi: /j x x 991

2 J.C. NICKEL ET AL. American university prostatitis research centres. The definition of NIH category IIIA CP/ CPPS and the inclusion/exclusion criteria were compatible with guidelines suggested by the first International Prostatitis Collaborative Network report [17] and the associated first randomized placebo-controlled study design [10]. To be eligible to enter the study, patients were aged 18 years and had symptoms of discomfort or pain in the pelvic region for 3 months during the 6 months before entry. The exclusion criteria are shown in the Appendix. TABLE 1 The results of finasteride therapy at baseline, 3 and 6 months vs placebo in men diagnosed with Category IIIA CP/CPPS Placebo (31 men) Finasteride (33 men) Variable Baseline 3 6 Baseline 3 6 SOA 25%*, % SOA 50%, % Mean (SD): total NIH-CPSI 22.5 (1.6) 21.7 ( (1.7) 20.1 (1.4) 19.1 (1.5) 17.1 (1.7) 25% decrease, % *mild, moderate or marked response; moderate or marked response. The study was a 6-month, double-blind, randomized, placebo-controlled, multicentre study with a 2-week placebo run-in. After the placebo run-in the patients were randomized to receive finasteride 5 mg/day or identical looking placebo tablets. Ethics review and approval was obtained from each institution, and written and informed consent from all patients. A complete medical history included the time since the first diagnosis of prostatitis and all specific prostatitis treatments. The physical examination included vital signs, a DRE and a standard four-glass test [18] to determine whether the patient met the criteria for category IIIA CP/CPPS. For purposes of the study, category IIIA was defined as the presence of any white blood cells per highpower microscopic field in the expressed prostatic secretion (EPS) or in the sediment of the post-prostatic massage urine sample (VB3) [19]. The primary end-point was a subjective overall assessment (SOA) [20], which graded the patient s improvement as none ( 25% improvement), mild (25 50% improvement), moderate (50 75% improvement) or marked improvement (>75%) in SOA. This patientdirected SOA or similar overall response assessments have been responsive in previous studies in CP [7,9,10,20,21]. Responders were pre-defined as those who indicated that they had a marked (>75%) or moderate (>50%) improvement in their overall symptoms. Secondary end-points were the mean total scores and subscores of NIH-Chronic Prostatitis Symptom Index (NIH-CPSI) [22]. This specific assessment questionnaire has also been responsive in previous studies in CP. The NIH-CPSI consists of nine questions, exploring the three major domains of prostatitis, i.e. pain (scored 0 21), voiding disturbances (scored 0 10) and quality of life/ impact (scored 0 12); the total NIH-CPSI score is For the purposes of the present study patients were categorized as having a treatment response if they had a 25% decrease in total NIH-CPSI score. Selfadministered patient questionnaires were completed at screening, baseline (after 2 weeks of placebo run-in), 3 and 6 months. The efficacy of treatment was measured by the change from baseline to the last observed value during the 6-month treatment. The last value carried forward method was used to estimate missing data at 6 months. The statistical analysis included a t-test, and where data were not distributed normally the Mann Whitney rank-sum test and the Z-test for proportions. When multiple differences were determined, a one-way ANOVA was used with the Tukey test; two-tailed significance was assigned at P The sample size was estimated using the SD data from the validation of the NIH-CPSI [22]. A sample size of 30 patients in each treatment group was necessary to detect a 6-point difference between treatment groups with 80% power using a two-sided a level of RESULTS In all, 76 patients were enrolled in the study and 64 had at least one assessment on medication (31 placebo, 33 finasteride). The finasteride group was slightly older (mean age 46.9, SD 1.7, range 27 63) and had had symptoms for longer, at 9.4 (1.4) years, than the placebo group (mean age 41.7, SD 2.1, range 26 71; duration 7.1, SD 1.2 years). The difference was not statistically different. Table 1 describes the baseline and follow-up assessment of each treatment group. The placebo group was more symptomatic at baseline than the men randomized to the finasteride group, but the difference was not significant. Over the 6 months the mean (SD) total NIH-CPSI decreased from the baseline by -0.8 points in the placebo and 3.0 points in the finasteride group. At six months, 16% of the placebo group had a >25% decrease in total NIH-CPSI (defined as a responder) compared with 33% of the finasteride group. Although more patients had an improvement in the SOA, total NIH-CPSI and responder subgroups in the finasteride than in the placebo group the results were not statistically significant (P > 0.05 for all variables). Finasteride and placebo were generally well tolerated. Five patients in the finasteride group (decreased libido in two, mood change, fatigue, gastrointestinal discomfort) and seven in the placebo group (decreased libido, decreased ejaculatory volume, rash, dry mouth, throat constriction, increase in acne, weight gain) reported possible medication induced adverse events. DISCUSSION Finasteride, an orally active, specific inhibitor of the type II 5a-reductase isoenzyme, reduces the level of the testosterone metabolite dihydrotestosterone, decreasing the volume of hyperplastic tissue, primarily the glandular component, in BPH and to a lesser extent in prostate cancer [11]. Finasteride therapy also promotes a significant decrease in vascular endothelial growth factor [23], resulting in a decrease in local prostatic blood flow. This factor may be important in treating BPH, BPH-related haematuria and possibly even prostate cancer. There is a possibility that prostatic inflammation may be also directly influenced BJU INTERNATIONAL

3 FINASTERIDE TREATMENT OF CHRONIC PELVIC PAIN SYNDROME by its hormonal milieu and manipulation of androgen levels may have similar ramifications for therapy in patients with prostatitis as those encountered in other prostate diseases. The growth and function of the prostate is tightly regulated by circulating and tissue androgens. There is evidence in animal models of CP that some form of imbalance between androgens and oestrogens may influence the development, persistence and severity of chronic nonbacterial prostatitis [24]. The latter is believed by some to result from a combination of high-pressure dysfunctional voiding and intraprostatic ductal reflux of urine [25]. Others have recently reported a greater intraprostatic tissue pressure in patients with category IIIA CP/CPPS than in normal control patients [26]. Regression of glandular mass (prostatic ducts and acini) as a consequence of hormonally induced changes may theoretically result in improved voiding and a decrease in intraprostatic ductal reflux and perhaps also intraprostatic pressure. Prostatic inflammation begins as an inflammatory disease of the prostatic ducts and acini, progressing to peri-glandular inflammation with subsequent disruption of the ducts and glands, and spreading of the inflammatory process into the stromal tissue [27]. Regression of prostatic glandular tissue, the specific area where the prostatic inflammation is located, may result in regression of prostatic inflammation. The recently published Prostate Cancer Prevention Trial [28], which showed that finasteride prevents or delays the appearance of prostate cancer (25% reduction in the prevalence of prostate cancer over the 7-year trial period), indicated that men on finasteride had a 28% reduction (6.1% in placebo group vs 4.4% in the finasteride group) in the prevalence of prostatitis. Holm and Meyhoff [13] noted that finasteride was successful in alleviating symptoms in four patients with CPPS secondary to CP/ prostatodynia. Golio [14] used finasteride therapy (for 1 year) in 33 patients with chronic nonbacterial prostatitis and found a significant reduction in prostatitis and urinary symptom scores, subjective prostate tenderness and leukocytosis in the EPS compared with baseline values. Leskinen et al. [15] randomized 41 patients with chronic idiopathic (nonbacterial prostatitis and prostatodynia) prostatitis to treatment with placebo (10) or finasteride (31) for 1 year. Symptom severity scores (including voiding symptoms) and pain scores decreased significantly in the finasteride group from baseline. The finasteride-treated patients had a >60% decrease in pain scores and about half the prostatitis-related symptom severity. The lack of any significant difference between the finasteride and placebo group was explained by noting that the baseline characteristics of the two groups were not compatible in numbers and symptom severity before therapy. Kaplan et al. [29] randomized 64 men with CP/CPPS to 1 year of therapy with finasteride or saw palmetto extract (phytotherapy). Finasteride therapy resulted in significantly more symptom amelioration than saw palmetto, but the trial was difficult to interpret because of the lack of a placebo arm. In the present study there was a numerically greater treatment-related improvement in the finasteride than in the placebo group in SOA (44% vs 27% responders, respectively), mean total NIH-CPSI (decrease of 3.0 and 0.8 points, respectively) and proportion of NIH-CPSI responders (33% vs 16%) but the magnitude of the treatment effect and the variation precluded statistically significant differences. The NIH-CPSI was used to power the study, but at the time the study was designed there were no previous placebo-controlled data using the NIH-CPSI in prostatitis. Subsequent studies [3 7,9,10] confirmed that the present statistical premise and estimate of a clinically important difference between treatment groups (a 3- or 4-point difference would have been clinically acceptable) was flawed and that the study was grossly underpowered. A larger study could also determine if the efficacy was more pronounced in patients with higher degrees of prostatic inflammation, older patients or perhaps those with associated BPH. a-blockers, an effective therapy for BPH symptoms, were also recently evaluated as therapy for CP/CPPS [4 6]. The efficacy of a- blockers in CP/CPPS was reported in all these studies but the clinical effect was modest and a-blockers cannot be recommended as a monotherapy. A recent study reporting the effect of combining finasteride with an a- blocker in BPH [30] showed an additive treatment effect for the combined therapy compared with either agent alone. A similar effect might be detected by combining a 5areductase inhibitor and a-blocker therapy in CP/CPPS. In conclusion, finasteride may benefit some patients with CP/CPPS but based on the present results we cannot currently recommend finasteride as a monotherapy for men with CP/CPPS. A larger, properly powered, multicentre randomized placebocontrolled trial (possibly evaluating combined therapy or in men with CP/CPPS and BPH) is necessary to confirm this perceived beneficial effect and determine for whom it is indicated. At present finasteride might perhaps be considered as one agent in a multimodal therapeutic algorithm or in men with CP/CPPS and BPH. ACKNOWLEDGEMENTS This study was funded by the University Grants Program (Merck Inc.) as an independent investigator initiated research project. All the authors Prostatitis Research Centers are funded by grants from the NIH/ NIDDK CONFLICT OF INTEREST J.C. Nickel is a study investigator/consultant; D.A. Shoskes is a study investigator. Source of funding: Investigator Initiated Independent Research Grant from Merck. REFERENCES 1 McNaughton-Collins M, MacDonald R, Wilt TJ. Diagnosis and treatment of chronic abacterial prostatitis: a systematic review. Ann Intern Med 2000; 133: Bjerklund Johansen T, Gruneberg RN, Guibert J et al. The role of antibiotics in the treatment of chronic prostatitis: a consensus statement. Eur Urol 1998; 34: Nickel JC, Downey J, Clark J et al. Levofloxacin treatment for chronic prostatitis/chronic pelvic pain syndrome in men: a randomized placebo controlled multicenter trial. Urology 2003; 62: Nickel JC, Narayan P, McKay J, Doyle C. Treatment of chronic prostatitis/chronic pelvic pain syndrome with tamsulosin: a randomized double-blind trial. J Urol 2004; 171: Cheah PY, Liong ML, Yuen KH et al. Terazosin therapy for chronic prostatitis/ 2004 BJU INTERNATIONAL 993

4 J.C. NICKEL ET AL. chronic pelvic pain syndrome: a randomized, placebo controlled trial. J Urol 2003; 169: Mehik A, Alas P, Nickel JC, Sarpola A, Helstrom PJ. Alfuzosin treatment for syndrome: A prospective, randomized, double-blind, placebo-controlled, pilot study. Urology 2003; 62: Nickel JC, Pontari M, Moon T et al. A randomized, placebo controlled, multicenter study to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial prostatitis. J Urol 2003; 169: Shoskes DA, Zeitlin SI, Shahed A, Rajfer J. Quercetin in men with category III chronic prostatitis: a preliminary prospective, double-blind, placebo control trial. Urology 1999; 54: Nickel JC, Forrest J, Tomera KM et al. Effects of pentosan polysulfate sodium in men with chronic pelvic pain syndrome: a multi-center randomized, placebocontrolled study. J Urol 2002; 167 (Suppl.): 63, A Propert KJ, Alexander RB, Nickel JC, Kusek JW, Litwin MS. The design of a multi-center randomized clinical trial for syndrome. Urology 2002; 59: McConnel JD, Wilson JD, George FW, Geller J, Pappas F, Stoner E. Finasteride, an inhibitor of 5-alpha-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia. J Clin Endocrinol Metab 1992; 74: Evans DTP. Medical management of chronic nonbacterial prostatitis. In Nickel JC ed. Prostatitis. Oxford: Isis Medical Media Inc, 1999: Holm M, Meyhoff HH. Chronic prostatic pain; a new treatment option with finasteride? Scand J Urol Nephrol 1996; 31: Golio G. The use of finasteride in the treatment of chronic nonbacterial prostatitis. In Abstracts of the 49th Annual Meeting of the Northeastern Section of the AUA. Litchfield, Arizona: October 23 26, 1997: Leskinen M, Lukkarinen O, Marttilla T. Effects of finasteride in patients with inflammatory chronic pelvic pain syndrome: a double-blind, placebo controlled, pilot study. Urology 1999; 53: Krieger JN, Nyberg LJ, Nickel JC. NIH consensus definition and classification of prostatitis. JAMA 1999; 282: Nickel JC, Nyberg LM, Hennenfent M. Research guidelines for chronic prostatitis. consensus report from the first National Institutes of Health International Prostatitis Collaborative Network. Urology 1999; 54: Meares EM Jr, Stamey TA. Bacteriologic localization patterns in bacterial prostatitis and urethritis. Invest Urol 1968; 5: Krieger JN, Jacobs R, Ross SO. Does the chronic prostatitis/pelvic pain syndrome differ from non-bacterial prostatitis and prostatodynia? J Urol 2000; 64: Nickel JC, Sorensen R. Transurethral microwave thermotherapy for nonbacterial prostatitis: a randomized double blind sham controlled study using new prostatitis specific assessment questionnaires. J Urol 1996; 155: Chen R, Nickel JC. Acupuncture ameliorates symptoms in men with syndrome. Urology 2003; 61: Litwin MS, McNaughton-Collins M, Fowler FJ Jr et al. The National Institutes of Health chronic prostatitis symptom index: development and validation of a new outcome measure. J Urol 1999; 162: Pareek G, Shevchuk M, Armenakas NA, Vasjovic L, Hochberg DA, Basillote JB. The effect of finasteride on the expression of vascular endothelial growth factor and microvessel density: a possible mechanism for decreased prostatic bleeding in treated patients. J Urol 2003; 169: Nickel JC. The role of the animal model in the study of prostatitis. In Bergan T ed. Urinary Tract Infection. Basel: Karger, 1997: Kirby RS, Lowe D, Bultitude MI, Shuttleworth KE. Intraprostatic urinary reflux: An aetiological factor in abacterial prostatitis. Br J Urol 1982; 54: Mehik A, Hellstrom P, Nickel JC et al. Chronic prostatitis/chronic pelvic pain syndrome can be characterized by prostatic tissue pressure measurements. J Urol 2001; 167: Nickel JC, True LD, Kreiger JN, Berger RE, Baog AH, Young ID. Consensus development of a histopathological classification system for chronic prostatic inflammation. Br J Urol Int 2001; 87: Thompson IM, Goodman PJ, Tangen CM et al. The influence of finasteride on the development of prostate cancer. NEJM 2003; 349: Kaplan SA, Volpe MA, Te AE. A prospective, 1-year trial using saw palmetto versus finasteride in the treatment of category III prostatitis/ chronic pelvic pain syndrome. J Urol 2004; 171: McConnell JD, Roehrborn CG, Bautista OM et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. NEJM 2003; 349: Correspondence: J. Curtis Nickel, Department of Urology, Kingston General Hospital, Kingston, Ontario, K7L 2V7, Canada. jcn@post.queensu.ca Abbreviations: CP, chronic prostatitis; CPPS, chronic pelvic pain syndrome; NIH(-CPSI), National Institutes of Health (Chronic Prostatitis Symptom Index); SOA, subjective overall assessment; EPS, expressed prostatic secretion. APPENDIX Exclusion criteria; any patient satisfying any one of the following criteria was NOT eligible for the study. Patients with a history of cystitis with a positive (uropathogen) urine culture or previous positive culture of expressed prostatic secretion or semen specimen within the last year Patients with a history of prostate, bladder or urethral cancer. Patients with a history of genital herpes within the last year. Patients with inflammatory bowel disease. Patients who had had intravesical chemotherapy. Patients with a history of pelvic radiation or chemotherapy. Patients treated for unilateral orchialgia with no pelvic symptoms BJU INTERNATIONAL

5 FINASTERIDE TREATMENT OF CHRONIC PELVIC PAIN SYNDROME Patients with an active urethral stricture. Patients with a neurological disease or disorder affecting the bladder. Patients with a neurological impairment or psychiatric disorder preventing his understanding of consent and his ability to comply with the protocol. Patients with a history of any sexually transmitted disease in the past 3 months. Patients with a history of TURP, or other transurethral intervention (e.g. incision, bladder neck, thermotherapy), balloon dilation of the prostate, open prostatectomy, or any other prostate surgery or treatment such as cryotherapy or thermal therapy. Patients who had previously or concurrently received 5a-reductase therapy BJU INTERNATIONAL 995