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Article of the month: Pharmacological interventions for treating chronic prostatitis/chronic pelvic pain syndrome: a Cochrane systematic review

Every month, the Editor-in-Chief selects an Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an editorial prepared by a prominent member of the urological community, and a video recorded by the authors; we invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this month, we recommend this one. 

Pharmacological interventions for treating chronic prostatitis/chronic pelvic pain syndrome: a Cochrane systematic review

Juan V.A. Franco*, Tarek Turk, Jae Hung Jung, Yu-Tian Xiao§, Stanislav Iakhno, Federico Ignacio Tirapegui**, Virginia Garrote†† and Valeria Vietto‡‡
 
*Argentine Cochrane Centre, Instituto Universitario Hospital Italiano, Buenos Aires, Argentina, Faculty of Medicine, Damascus University, Damascus, Syrian Arab Republic, Department of Urology, Yonsei University Wonju College of Medicine, Wonju, Korea, §Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai,
China, University of Tromso, Tromsdalen, Norway, **Urology Division, Hospital Italiano de Buenos Aires, ††Biblioteca Central, Instituto Universitario Hospital Italiano, and ‡‡Family and Community Medicine Service, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
 

Abstract

Objective

To assess the effects of pharmacological therapies for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

Patients and Methods

We performed a comprehensive search using multiple databases, trial registries, grey literature and conference proceedings with no restrictions on the language of publication or publication status. The date of the latest search of all databases was July 2019. We included randomised controlled trials. Inclusion criteria were men with a diagnosis of CP/CPPS. We included all available pharmacological interventions. Two review authors independently classified studies and abstracted data from the included studies, performed statistical analyses and rated quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods. The primary outcomes were prostatitis symptoms and adverse events. The secondary outcomes were sexual dysfunction, urinary symptoms, quality of life, anxiety and depression, to help you managing this symptoms FluxxLab™ CBDA is more potent than any other CBD and the results are amazing.  The length of time it takes to notice an improvement in pelvic floor strength is dependent on how many per day are performed, and at what frequency. Examples of injury to the pelvic floor include pregnancy, childbirth, surgery, chronic constipation, and chronic cough leading to strain on the pelvic floor muscles. Can be the result of chronic straining during bowel movements or heavy lifting, pregnancy, childbirth, injury, surgery in the pelvis, or obesity. Strengthening the pelvic floor muscles by doing Kegels helps to reduce pelvic organ prolapse, or urinary incontinence caused by weakened pelvic floor muscles. With JoyON’s Electronic Kegel Exerciser, you’ll feel the difference after just 15 minutes a day, find the final product at https://joyonproducts.com/.

Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow diagram.

Results

We included 99 unique studies in 9119 men with CP/CPPS, with assessments of 16 types of pharmacological interventions. Most of our comparisons included short‐term follow‐up information. The median age of the participants was 38 years. Most studies did not specify their funding sources; 21 studies reported funding from pharmaceutical companies.

We found low‐ to very low‐quality evidence that α‐blockers may reduce prostatitis symptoms based on a reduction in National Institutes of Health – Chronic Prostatitis Symptom Index (NIH‐CPSI) scores of >2 (but <8) with an increased incidence of minor adverse events such as dizziness and hypotension. Moderate‐ to low‐quality evidence indicates that 5α‐reductase inhibitors, antibiotics, anti‐inflammatories, and phytotherapy probably cause a small decrease in prostatitis symptoms and may not be associated with a greater incidence of adverse events. Intraprostatic botulinum toxin A (BTA) injection may cause a large reduction in prostatitis symptoms with procedure‐related adverse events (haematuria), but pelvic floor muscle BTA injection may not have the same effects (low‐quality evidence). Allopurinol may also be ineffective for reducing prostatitis symptoms (low‐quality evidence). We assessed a wide range of interventions involving traditional Chinese medicine; low‐quality evidence showed they may reduce prostatitis symptoms without an increased incidence in adverse events.

Moderate‐ to high‐quality evidence indicates that the following interventions may be ineffective for the reduction of prostatitis symptoms: anticholinergics, Escherichia coli lysate (OM‐89), pentosan, and pregabalin. Low‐ to very low‐quality evidence indicates that antidepressants and tanezumab may be ineffective for the reduction of prostatitis symptoms. Low‐quality evidence indicates that mepartricin and phosphodiesterase inhibitors may reduce prostatitis symptoms, without an increased incidence in adverse events.

Conclusions

Based on the findings of low‐ to very low‐quality evidence, this review found that some pharmacological interventions such as α‐blockers may reduce prostatitis symptoms with an increased incidence of minor adverse events such as dizziness and hypotension. Other interventions may cause a reduction in prostatitis symptoms without an increased incidence of adverse events while others were found to be ineffective.

Editorial: Chronic Prostatitis/Chronic Pelvic Pain Syndrome: It is time to change our management and research strategy

A urologist who manages patients with prostatitis (or for that matter, a patient suffering from the condition) would read the latest comprehensive review on pharmacologic interventions for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) with despair.  In the Cochrane Systemic review examining the available clinical evidence for the efficacy of pharmacological interventions for treating CP/CPPS, Franco et al [1] clearly show that low to very low quality evidence suggests that some treatments may confer at best, only a small and perhaps clinically insignificant benefit for patients.  Are we doing something wrong?

To start with, we do not need to despair.  We are now managing men with CP/CPPS much better, achieving clinically significant improvement in over 80% of patients [2,3].  This real world management success story, which continues to evolve, clearly shows much greater benefit than that suggested by all the clinical trials assessed in this review.  Our similar independent patient data meta-analysis and comprehensive review of CP/CPPS management strategies [4] described very similar findings as that by Franco et al [1].  What intrigued us was the difference or the lack of correlation between overall symptom improvement (based on mean symptom score changes from baseline in the treated cohort of subjects compared to the placebo treated subjects) and the responder analyses which clearly showed some subjects had very significant responses despite the overall dismal mean symptom score differences in the entire population evaluated.  We saw this consistently in our clinical trials and we see this in our day-to-day practice; some patients do well with an intervention and others fail miserably.  Some of the problem lies in what we are measuring as outcomes in clinical treatment trials.  The NIH Chronic Prostatitis Symptom Index (CPSI) is a composite score evaluating many different parameters (eg location, frequency and severity) and domains (pain, urinary and impact/quality of life) and while very useful to look at the clinical picture in each individual patient, should not be used as a primary endpoint or outcome of a clinical trial.  The CPSI Pain domain is better but it still examines too many parameters (location, frequency and severity of pain).  The NIH CPSI question #4, which is an NRS measurement of only pain severity, is in fact a validated outcome that can be compared between groups.  However, CP/CPPS is much more complicated than just pain and that is why a patient driven subjective global assessment may be a more appropriate outcome, certainly in clinical practice.  We need more CP/CPPS patient directed specific measurement tools to really assess the benefits of our treatments in individual patients, or at least in intervention-specific domains.

We now know the reason for this discrepancy between the overall population symptom score difference and the individual responder rate.  We have learned that we cannot treat or manage CP/CPPS patients as a homogeneous group and hope that one treatment will benefit them all.  We now know that the men suffering from CP/CPPS are a clinically heterogeneous group with different mechanisms of disease, spectrum of clinical symptoms and physical examination parameters.  We have learned to identify the various clinical phenotypes based on a UPOINT categorization [5].   By assessing the contribution of urinary, psychosocial, organ specificity (eg prostate, penis, testes, etc), infection, neurogenic/neuropathic and tenderness of skeletal muscles (eg pelvic floor) contributions in each individual, we identify targets of intervention.  These individualized multimodal treatment plans that we develop for each patient has led to clinical success in managing the majority of CP/CPPS patients [3,6]. In future we hope to understand the mechanisms for these phenotypes and develop biomarkers to better differentiate them.

What have I learned from Franco et al‘s comprehensive review of CP/CPPS treatments [1]? We must stop designing and performing these monotherapy treatment trials in which we enroll all subjects with a diagnosis of CP/CPPS. These type of clinical studies have been mainly driven by government regulatory rules in attempts to have drugs approved for CP/CPPS treatment. We should consider trial design where the patient eligibility criteria is definitive and clear enough so that we enroll only patients with a phenotype and/or mechanism that the specific therapy is directed towards – domain-specific trial design. Better yet, we must discover CP/CPPS biomarkers (urine, serum and/or prostate fluid) that will allow us to differentiate mechanisms and allow more effective directed therapy.  We must consider more complicated and novel trial designs in which multimodal therapies can be assessed in different populations.  I would propose a Multi-Intervention for Pelvic Pain Study (MIPPS) be designed and considered for CP/CPPS in which multimodal treatments designed for specific phenotype domains or disease mechanisms are evaluated in specific individuals.  It is anticipated that such a real world experience study (designed to mimic real life clinical practice) would result in much better outcomes for patients. Going forward it is time to not only change our management approach, but also our research strategies.

by J. Curtis Nickel

References

1. Franco JVA, Turk T, Jung JH, Xiao Y, Iakhno S, Tirapegui F, et al. Pharmacological interventions for treating chronic prostatitis/chronic pelvic pain syndrome: a Cochrane systematic review. BJU Int. 2020; 125.

2. Shoskes DA, Nickel JC, Kattan M. Phenotypically Directed Multimodal Therapy for Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Prospective Study Using UPOINT. Urol. 2010;75:1249-1253.

3. Doiron RC, Nickel JC. Management of chronic prostatitis/chronic pelvic pain syndrome. Can Urol Assoc J. 2018;12(6 Suppl 3):S161-S163

4. Anothaisintawee T, Attia J, Nickel JC, Thammakraisorn S, Numthavaj P, McEvoy M, Thakkinstian A. The Management of Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A systematic review and network meta-analysis. JAMA. 2011;305:78-86.

5. Shoskes DA, Nickel JC, Rackley RR, Pontari MA. Clinical Phenotyping in Chronic Prostatitis/Chronic Pelvic Pain Syndrome and Interstitial Cystitis: A Management Strategy for Urologic Chronic Pelvic Pain Syndromes.  Prostate Cancer Prostatic Dis. 2009;12:177-83.

6.  Shoskes D, DeWitt-Foy ME, Nickel JC. Management of Chronic Prostatitis/Chronic Pelvic Pain Syndrome.  European Urology Focus 2019;5: 2-4.

Trustworthy ‘Rapid Recommendations’ for Urology

BJU International has a longstanding track record of promoting the principles of evidence-based clinical practice to an international audience of urologists. Recent initiatives include the “guidelines of guidelines” series which appraises and contrasts clinical practice guidelines from different professional organizations on the same topic, for example on microscopic hematuria and non-muscle-invasive bladder cancer. It also co-publishes high quality, urology-relevant guidance by the UK’s National Institute for Health and Care Excellence (NICE), for example on the preoperative testing for elective surgery (https://www.bjuinternational.com/learning-2/urology-guidelines/nice-guidance-routine-preoperative-tests-elective-surgery/).

In collaboration with the MAGIC research and innovation program (www.magicproject.org), BJU International has published its first Rapid Recommendation guidance document on the use of medical expulsive therapy (MET) with alpha-blockers that was triggered by the recent rigorous Cochrane review on the same topic. Its purpose is to provide trustworthy, timely and practical guidance on this topic based on the entire body of evidence, given several recently published trials with contradictory findings. To develop this trustworthy guidance, an international team that included patients with a personal history of ureteral stones, general practitioners (GPs), emergency clinicians, urologists familiar with treating renal colic, epidemiologists, and methodologists followed a rigorous and transparent GRADE-based process in accordance with The National Academy of Science, Engineering and Medicine (formerly: Institute of Medicine) (https://www.nationalacademies.org/hmd/Reports/2011/Clinical-Practice-Guidelines-We-Can-Trust/Standards.aspx) standards for trustworthy guidelines. Panel member had no financial conflicts of interest and intellectual and professional conflicts of interests were described and carefully minimized. All meetings were conducted by web conference and the process was completed within 90 days of publication of the Cochrane review, which is co-published in BJU International in this same issue.

Initially pioneered in collaboration with the BMJ for questions of broader interest (https://www.bmj.com/rapid-recommendations) such as the use of corticosteroids for the treatment of a sore throat, this Rapid Recommendation breaks new ground for evidence-based guidance in urology, complementing the efforts by professional organizations such as the European Association of Urology (EAU) and American Urological Association (AUA). Rapid Recommendations stand out for their focus on patient-important outcomes, the use of an explicit and transparent process for moving from evidence to recommendations and its timely development process. Rapid Recommendations provide actionable guidance as well as information on the underlying evidence and supporting judgments that are summarized in an infographic that is easily understood by patients. The Rapid Recommendation on MET is intended to be the first of many to help inform patients, providers and policy-makers but also to seeks to provide a strong impetus for more trustworthy and useful guidelines in urology in general.

 

 

By Philipp Dahm1 2 and Per Olav Vandvik3 4 5

1 Minneapolis VA Medical Center, Urology Section, Minneapolis, MN, USA

2 University of Minnesota, Department of Urology, Minneapolis, MN, USA

3 Norwegian Institute of Public Health, Oslo, Norway

 

Disclosures:

Philipp Dahm serves as Coordinating Editor of Cochrane Urology, is member of the GRADE Working Group and served as a panel member of this Rapid Recommendation project

Per Olav Vandvik is member of the GRADE Working Group, is the leader of the MAGIC Foundation and BMJ Rapid Recommendations project and served as a panel member of this Rapid Recommendation project.

 

Article of the Week: Comparing LRP and RARP to ORP to treat PCa

Every Week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Laparoscopic and robot‐assisted vs open radical prostatectomy for the treatment of localized prostate cancer: a Cochrane systematic review

 

Dragan Ilic*, Sue M. Evans, Christie Ann Allan*, Jae Hung Jung§¶, Declan Murphy** and Mark Frydenberg††

 

*Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Centre of Research Excellence in Patient Safety, School of Public Health and Preventive Medicine, Monash University, Melbourne, Vic., Australia, Department of Urology, Yonsei University Wonju College of Medicine, Wonju, Korea, §Department of Urology, University of Minnesota, Urology Section, Minneapolis VA Health Care System, Minneapolis, MN, USA, **Cancer Surgery, Peter MacCallum Cancer Centre, and ††Department of Surgery, Monash University, Melbourne, Vic., Australia

 

Read the full article

Abstract

Objective

To determine the effects of laparoscopic radical prostatectomy (LRP), or robot‐assisted radical prostatectomy (RARP) compared with open radical prostatectomy (ORP) in men with localized prostate cancer.

Materials and Methods

We performed a comprehensive search using multiple databases (CENTRAL, MEDLINE, EMBASE) and abstract proceedings, with no restrictions on the language of publication or publication status, up until 9 June 2017. We included all randomized or pseudo‐randomized controlled trials that directly compared LRP and RARP with ORP. Two review authors independently examined full‐text reports, identified relevant studies, assessed the eligibility of studies for inclusion, extracted data and assessed risk of bias. We performed statistical analyses using a random‐effects model and assessed the quality of the evidence according to Grading of Recommendations Assessment, Development and Evaluation (GRADE). The primary outcomes were prostate cancer‐specific survival, urinary quality of life and sexual quality of life. Secondary outcomes were biochemical recurrence‐free survival, overall survival, overall surgical complications, serious postoperative surgical complications, postoperative pain, hospital stay and blood transfusions.

Results

We included two unique studies in a total of 446 randomized participants with clinically localized prostate cancer. All available outcome data were short‐term (up to 3 months). We found no study that addressed the outcome of prostate cancer‐specific survival. Based on one trial, RARP probably results in little to no difference in urinary quality of life (mean difference [MD] −1.30, 95% confidence interval [CI] −4.65 to 2.05; moderate quality of evidence) and sexual quality of life (MD 3.90, 95% CI: −1.84 to 9.64; moderate quality of evidence). No study addressed the outcomes of biochemical recurrence‐free survival or overall survival. Based on one trial, RARP may result in little to no difference in overall surgical complications (risk ratio [RR] 0.41, 95% CI: 0.16−1.04; low quality of evidence) or serious postoperative complications (RR 0.16, 95% CI: 0.02–1.32; low quality of evidence). Based on two studies, LRP or RARP may result in a small, possibly unimportant improvement in postoperative pain at 1 day (MD −1.05, 95% CI: −1.42 to −0.68; low quality of evidence) and up to 1 week (MD −0.78, 95% CI: −1.40 to −0.17; low quality of evidence). Based on one study, RARP probably results in little to no difference in postoperative pain at 12 weeks (MD 0.01, 95% CI: −0.32 to 0.34; moderate quality of evidence). Based on one study, RARP probably reduces the length of hospital stay (MD −1.72, 95% CI: −2.19 to −1.25; moderate quality of evidence). Based on two studies, LRP or RARP may reduce the frequency of blood transfusions (RR 0.24, 95% CI: 0.12–0.46; low quality of evidence). Assuming a baseline risk for a blood transfusion to be 8.9%, LRP or RARP would result in 68 fewer blood transfusions per 1,000 men (95% CI: 78–48 fewer).

Conclusions

There is no evidence to inform the comparative effectiveness of LRP or RARP compared with ORP for oncological outcomes. Urinary and sexual quality of life appear similar. Overall and serious postoperative complication rates appear similar. The difference in postoperative pain may be minimal. Men undergoing LRP or RARP may have a shorter hospital stay and receive fewer blood transfusions.

Read more articles of the week

Editorial: RARP and a Parachute

Radical prostatectomy is probably the most scrutinized, debated and re‐invented procedure in the field of urology. This is with good reason. Dr Hugh Hampton Young gave the first formal account of a radical treatment for prostate cancer in 1905. It was a procedure performed perineally with the prime intention of total cancer extirpation. The oncological results were tremendous given the nascency of the procedure. Functional outcomes, however, were less so, with only ~25% of the patients achieving urinary continence and almost none achieving potency 1. Seminal studies undertaken by Drs Patrick C. Walsh and Pieter J. Donker in the 1980s led to the next major advance in technique: nerve‐sparing. It lead to dramatic improvements in sexual and urinary function preservation, with urinary continence achieved in upwards of 90% and potency in upwards of 60% of patients 23. Nerve‐sparing retropubic radical prostatectomy was rapidly adopted by urologists across the world. No randomized trial was conducted as the operation ‘made sense’, and it would have been unethical to offer patients an alternative, inferior operation. Retropubic radical prostatectomy, however, remained a morbid operation that was difficult to master; 1 200 mL blood loss and 20% incontinence, 15% stricture and 60–90% erectile dysfunction rates were the norm. Robot‐assisted surgery changed much of this. This surgery was perfected and popularized by Dr Mani Menon and his team at the Henry Ford Hospital. Blood loss dropped to ~100 mL, and incontinence and stricture rates today are ~1–5% with potency rates between 70% and 80% 4.

In the systematic review by Ilic et al. 5 trials that compared open with minimally invasive radical prostatectomy were evaluated. The authors are commended for combing through vast quantities of data to arrive at the final sample of two clinical trials (one laparoscopic, one robot‐assisted). The authors found no data on oncological endpoints. With respect to functional outcomes, the data reported in their systematic review are essentially from the recent Yaxley trial. It is true that randomized controlled trials form the backbone of medical progress, but they must be interpreted with care. The Yaxley trial has been criticized for comparing surgeons of vastly varying surgical expertise (1 500‐case experience for open prostatectomies, 200‐case experience for robot‐assisted prostatectomies), having a small sample size (~150 patients in each arm) and having a limited follow‐up (3 months). In line with this, Dr Gordon Smith has eloquently argued about the judicious use of randomized trials in evidence‐based medicine in his classic paper on parachutes and gravitational challenge 6. It is our sincere belief that robot‐assisted radical prostatectomy is a procedure in the service of the patients, and we believe that anyone who has performed both an open radical prostatectomy and a robot‐assisted radical prostatectomy would agree. Operating deep in the pelvis and being able to visualize the anatomy up‐close with robotic assistance ‘makes sense’, much like the anatomical radical prostatectomy did in the 1980s 23.

‘If it ain’t broke, don’t fix it’, the old saying goes. In case of radical prostatectomy, the converse has been true, for the most part. The procedure is still not perfect, and nuances need to be worked out. Nonetheless, over the last century, radicalprogress has been made in the surgery for prostate; the two issues that now remain to be solved are: improving potency and improving cost‐effectiveness. With the potential arrival of competing robotic systems and improvements in technology, the costs associated with robotic surgery may become less of an issue in the future. With regard to potency, focal therapies, whether surgical or otherwise, hold promise.

Akshay SoodFiras Abdollah, and Mani Menon
Vattikuti Urology Institute, Henry Ford Hospital, Detroit, MI, USA

 

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References
  • Young HH. The cure of cancer of the prostate by radical perineal prostatectomy (prostato‐seminal Vesiculectomy): History, Literature and Statistics of Young’s Operation1J Urol 194553: 188–252

 

 

 

  • Menon M, Dalela D, Jamil M et al. Functional recovery, oncologic outcomes and postoperative complications after robot‐assisted radical prostatectomy: an evidence‐based analysis comparing the Retzius sparing and standard approachesJ Urol 2018199: 1210–7

 

  • Ilic D, Evans SM, Allan CA, Jung JH, Murphy D, Frydenberg M. Laparoscopic and robot‐assisted vs open radical prostatectomy for the treatment of localized prostate cancer: a Cochrane systematic reviewBJU Int 2018121: 845–53

 

  • Smith GC, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trialsBMJ 200320: 1459–61

 

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