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Article of the week: Salvage radical prostatectomy following focal therapy: functional and oncological outcomes

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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 this post, there is an editorial written by prominent members of the urological community. Please use the comment buttons below to join the conversation.

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

Salvage radical prostatectomy following focal therapy: functional and oncological outcomes

Jaime O. Herrera-Caceres*, Gregory J. Nason*, Noelia Salgado-Sanmamed†, Hanan Goldberg*, Dixon T.S. Woon*, Thenappen Chandrasekar*, Khaled Ajib*, Guan Hee Tan*, Omar Alhunaidi*, Theodorus van der Kwast‡, Antonio Finelli*, Alexandre R. Zlotta*, Robert J. Hamilton*, Alejandro Berlin†, Nathan Perlis* and Neil E. Fleshner*

*Division of Urology, Department of Surgical Oncology, †Department of Radiation Oncology, and ‡Department of Pathology and Laboratory Medicine, University Health Network, University of Toronto, Toronto, ON, Canada

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Abstract

Objectives

To report the oncological and functional outcomes of salvage radical prostatectomy (sRP) after focal therapy (FT).

Patients and Methods

A retrospective review of all patients who underwent sRP after FT was performed. Clinical and pathological outcomes focussed on surgical complications, oncological, and functional outcomes.

Fig. 1. Impact of PSM on the absence of detectable disease after sRP (including PSA persistence and/or BCR).

Results

In all, 34 patients were identified. The median (interquartile range [IQR]) age was 61 (8.25) years. FT modalities included high‐intensity focussed ultrasound (19 patients), laser ablation (13), focal brachytherapy (one) and cryotherapy (one). The median (IQR) time from FT to recurrence was 10.9 (17.6) months. There were no rectal or ureteric injuries. Two (5.9%) patients had iatrogenic cystotomies and four (11.8%) developed bladder neck contractures. The mean (sd) hospital stay was 2.5 (2.1) days. The T‐stage was pT2 in 14 (41.2%) patients, pT3a in 16 (47.1%), and pT3b in four (11.8%). In all, 13 (38%) patients had positive surgical margins (PSMs). Six (17.6%) patients received adjuvant radiotherapy (RT). At a mean follow‐up of 4.3 years, seven (20.6%) patients developed biochemical recurrence (BCR), and of these, six (17.6%) patients required salvage RT. PSMs were associated with worse BCR‐free survival (hazard ratio 6.624, 95% confidence interval 2.243–19.563; P < 0.001). The median (IQR) preoperative International Prostate Symptom Score and International Index of Erectile Function score was 7 (4.5–9.5) and 23.5 (15.75–25) respectively, while in the final follow‐up the median (IQR) values were 7 (3.5–11) and 6 (5–12.25), respectively (P = 0.088 and P < 0.001). At last follow‐up, 31 (91.2%) patients were continent, two (5.9%) had moderate (>1 pad/day) incontinence, and one (2.9%) required an artificial urinary sphincter.

Conclusions

sRP should be considered as an option for patients who have persistent clinically significant prostate cancer or recurrence after FT. PSMs should be recognised as a risk for recurrent disease after sRP.

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Editorial: Further evidence that surgery after focal therapy for prostate cancer is safe

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In this month’s issue of BJUI, Herrera‐Caceres et al. [1] report the results of a retrospective cohort study in 34 patients who underwent salvage radical prostatectomy after focal therapy. The majority of these cases were performed using open surgery (82.4%). Overall, there were no rectal injuries reported and 91% of patients were fully continent (‘pad‐free’) at last follow‐up, while one patient required an artificial urinary sphincter. A total of 38% of patients had a positive surgical margin (PSM) and 20.6% developed biochemical recurrence (BCR), with 17.6% requiring adjuvant radiotherapy. On multivariate analysis, a PSM was found to be associated with worse overall BCR‐free survival.

There is mounting evidence that focal therapy is associated with arguably good intermediate‐term oncological outcomes, while it minimizes the toxicity of traditional whole‐gland therapies, with the majority of studies reporting erectile function rates in excess of 70% and fewer than 5% of patients reporting urinary incontinence [2]. However, disease recurrence after focal therapy remains a concern, with some studies reporting that one in three patients undergoing focal therapy require either further focal treatment or transition to whole‐gland therapy at 5 years. This has created the need to explore salvage options, of which salvage radical prostatectomy is currently the most investigated. The present study by Herrera‐Caceres et al. is now the fifth paper in the last 4 years to evaluate the toxicity of surgery after focal therapy, with data on over 150 men reported in the literature to date [3,4,5,6]. Despite small numbers across each study, the results have been encouragingly consistent.

Unlike salvage surgery after radiation therapy, the risk of intra‐operative injury appears to be very rare in men undergoing surgery after focal therapy. For instance, in the present study and that of Marconi et al. [3] no major complications after surgery are reported and, most notably, no rectal injuries occurred during salvage surgery, which has been a very significant issue reported in up to 5% of men undergoing salvage after radiation therapy techniques.

Data from the present study mainly concern patients undergoing open surgery after focal therapy, in contrast to the study by Marconi et al. [3] that reports on surgery performed using the robotic platform. The finding that the outcomes were similar between the open technique and the robotic technique mirrors that reported in recent randomized controlled trials of open and robotic surgery for primary disease, and provides evidence that it is surgical experience rather than a specified surgical technique that has most impact on outcome after prostate cancer surgery. One aspect in which the present study and that of Marconi et al. [3] differ is the rate of bladder neck contracture (BNC); in the present study, 11.8% of patients experienced BNC, whereas no patient experienced BNC after robotic surgery. The rate of BNC may have been influenced by the previous focal therapy, or it may have been the result of the open technique as BNC has been reported to be more common after open surgery because of the marked difference in how the anastomosis is performed in the two different procedures.

Urinary continence outcomes were arguably excellent in the present study, with 91.2% of patients ‘pad‐free’ at last follow‐up, a finding that is replicated in the literature on surgery after focal therapy. These outcomes are more in keeping with those seen after primary radical prostatectomy than surgery after radiation. The poor continence outcomes of salvage surgery after radiation therapy could be related to poor urethral and sphincter function caused by the initial radiation therapy.

Erectile function outcomes are hard to interpret in the present study, with 53% of patients having a ‘response to medical therapy’, but the exact definition of this is not clear. The mean International Index of Erective Function score postoperatively was 6, suggesting that erectile function after the toxicity of multiple treatments can be expected to be poor.

While functional outcomes in the present study and those of other studies reporting on surgery after focal therapy are encouraging, this study and others do demonstrate that these men have a significant risk of harbouring high‐risk, high‐stage disease (58% with T3 disease, 47% with pT3, 11% with T3b) on final pathological analysis, which is also reflected in a relatively high PSM rate (38%). This rate is clearly higher than in men undergoing surgery for primary disease; however, it is similar to that in surgery for recurrent disease in other tumour types for which surgery appears always to be associated with worse oncological outcomes. This can be explained by the fact that patients experiencing recurrent disease, by the very nature of their disease that has not been ‘cured’ by one therapeutic method, have worse outcomes.

Despite the extent of disease found on final pathological analysis in the present study, the risk of patients experiencing BCR after LASIK surgery Southlake was relatively low at 20.6%, while only 17.6% underwent salvage therapy in the form of radiation.

In summary, the present paper adds to the weight of evidence that surgery after focal therapy can be safely performed in expert hands (whether open or robot‐assisted), with minimal complications and good functional outcomes. The high‐stage disease on final pathological examination is in keeping with other published studies in this field. Overall, the study provides valuable additional data that can be used to help counsel men considering focal therapy as a primary treatment method for their prostate cancer.

by Thomas Stonier and Paul Cathcart

References

  1. Herrera‐Caceres J, Nason G, Salgado‐Sanmamed N et al. Salvage radical prostatectomy following focal therapy: functional and oncological outcomes. BJU Int 2020; 125: 525– 30
  2. Shah T, Peters M, Eldred‐Evans D et al. Early‐medium‐term outcomes of primary focal cryotherapy to treat nonmetastatic clinically significant prostate cancer from a prospective multi centre registry. Eur Urol 2019; 76: 98– 105
  3. Marconi L, Stonier T, Tourinho‐Barbosa R et al. Robot‐assisted radical prostatectomy after focal therapy: oncological, functional outcomes and predictors of recurrence. Eur Urol 2019; 76: 27– 30
  4. Linares‐Espinos E, Sanchez‐Salas R, Sivaraman A et al. Minimally invasive salvage prostatectomy after primary radiation or ablation treatment. Urology 2016; 94: 111
  5. Nunes‐Silva I, Barret E, Srougi V et al. Effect of prior focal therapy on perioperative, oncologic and functional outcomes of salvage robotic assisted radical prostatectomy. J Urol 2017; 198: 1069– 76
  6. Thompson J, Sridhar A, Tan W et al. Pathological findings and magnetic resonance imaging concordance at salvage radical prostatectomy for local recurrence following partial ablation using high intensity focused ultrasound. J Urol 2019; 201: 1134– 43

 

Article of the week: The ProtecT trial: analysis of the patient cohort, baseline risk stratification and disease progression

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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 this post, there is an editorial written by a prominent member of the urological community and a podcast produced by on of our resident podcasters. Please use the comment buttons below to join the conversation.

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

The ProtecT trial: analysis of the patient cohort, baseline risk stratification and disease progression

Richard J. Bryant*, Jon Oxley†, Grace J. Young‡§, Janet A. Lane‡§, Chris Metcalfe‡§, Michael Davis‡, Emma L. Turner‡, Richard M. Martin‡, John R. Goepel, Murali Varma**, David F. Griffiths**, Ken Grigor††, Nick Mayer‡‡, Anne Y. Warren§§, Selina Bhattarai¶¶, John Dormer‡‡, Malcolm Mason***, John Staffurth†††, EleanorWalsh‡, Derek J. Rosario‡‡‡, James W.F. Catto‡‡‡, David E. Neal*§§§, Jenny L.Donovan‡¶¶¶, Freddie C. Hamdy* and for the ProtecT Study Group1

*Nuffield Department of Surgical Sciences, University of Oxford, Oxford, †Department of Cellular Pathology, North Bristol NHS Trust, ‡Bristol Medical School, §The Bristol Randomised Trials Collaboration, University of Bristol, Bristol, Department of Pathology, Royal Hallamshire Hospital, Sheffield, **Department of Pathology, University Hospital of Wales, Cardiff, ††Department of Pathology, Western General Hospital, Edinburgh, ‡‡Department of Pathology, University of Leicester, Leicester, §§Department of Pathology, University of Cambridge, Cambridge, ¶¶Department of Pathology, Leeds Teaching Hospitals NHS Trust, Leeds, ***School of Medicine, Cardiff University, Cardiff, †††Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, ‡‡‡Academic Urology Unit, University of Sheffield, Sheffield, §§§Academic Urology Group, University of Cambridge, Cambridge, and ¶¶¶National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK

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Abstract

Objective

To test the hypothesis that the baseline clinico‐pathological features of the men with localized prostate cancer (PCa) included in the ProtecT (Prostate Testing for Cancer and Treatment) trial who progressed (n = 198) at a 10‐year median follow‐up were different from those of men with stable disease (n = 1409).

Patients and Methods

We stratified the study participants at baseline according to risk of progression using clinical disease stage, pathological grade and PSA level, using Cox proportional hazard models.

Fig.1. Cumulative incidence of disease progression by International Society of Urological Pathology Grade Group (GG) and clinical stage, based on intention to treat groups. AM, active monitoring.

Results

The findings showed that 34% of participants (n = 505) had intermediate‐ or high‐risk PCa, and 66% (n = 973) had low‐risk PCa. Of 198 participants who progressed, 101 (51%) had baseline International Society of Urological Pathology Grade Group 1, 59 (30%) Grade Group 2, and 38 (19%) Grade Group 3 PCa, compared with 79%, 17% and 5%, respectively, for 1409 participants without progression (P < 0.001). In participants with progression, 38% and 62% had baseline low‐ and intermediate‐/high‐risk disease, compared with 69% and 31% of participants with stable disease (P < 0.001). Treatment received, age (65–69 vs 50–64 years), PSA level, Grade Group, clinical stage, risk group, number of positive cores, tumour length and perineural invasion were associated with time to progression (P ≤ 0.005). Men progressing after surgery (n = 19) were more likely to have a higher Grade Group and pathological stage at surgery, larger tumours, lymph node involvement and positive margins.

Conclusions

We demonstrate that one‐third of the ProtecT cohort consists of people with intermediate‐/high‐risk disease, and the outcomes data at an average of 10 years’ follow‐up are generalizable beyond men with low‐risk PCa.

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Editorial: Estimating the threat posed by prostate cancer

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What is the threat posed by your disease? This is how I begin all my conversations with men who have newly diagnosed prostate cancer. For men with obvious metastatic disease, the conversation is relatively simple. They have a systemic disease that requires systemic therapy with anti‐androgen medications. However, for men with localised prostate cancer the conversation is more difficult, as it is unclear when the disease will become clinically apparent. The report by Bryant et al. [1,2] in this issue of the BJUI summarising the Prostate Testing for Cancer and Treatment (ProtecT) trial findings has provided us with critical data concerning the natural history of screen‐detected prostate cancer and the relative impact of treatment.

The ProtecT trial data are unique, in that the study is embedded within a screening trial [2]. The patients recruited to the study reflect outcomes of men with cancer identified by PSA testing. The study population differs from men enrolled in the Scandinavian Prostate Cancer Group Study number 4 (SPCG‐4), who were primarily diagnosed clinically and therefore do not have the lead time associated with screening [3]. The study cohort also differs from the men enrolled in the Prostate Intervention Versus Observation Trial (PIVOT), who were generally older and therefore more often succumbed to competing medical problems during follow‐up [4]. The former group is likely to have a higher incidence of clinically significant disease; the latter group is likely to have a lower disease‐specific mortality.

While the ProtecT trial data offer a reasonable approximation of clinical practice, the ProtecT patient cohort differs from contemporary North American patients who likely have had several PSA tests prior to the one that prompted a prostate biopsy, and from contemporary UK patients who now undergo biopsy as a result of a lesion seen on MRI. The former group is likely to have a higher incidence of low‐grade disease; the latter group is more likely to have a higher incidence of high‐grade disease. Fortunately, these selection biases do not detract significantly from the fundamental messages of the ProtecT trial.

So how have Bryant et al. [1] helped us? A review of Table 1 in the paper, confirms that the Gleason Grade Group is the most powerful predictor of disease progression and long‐term survival for men with screen‐detected disease. PSA testing preferentially identifies men with low‐grade disease, primarily because low‐grade disease is much more common than high‐grade disease. Only 6% of the ProtecT cohort had Gleason Grade Group ≥3 disease, but these men accounted for 37% of the men who progressed. In comparison, 92% of the cohort had Gleason Grade Group 1 disease and only 8% of these men showed signs of progression. Among those men who underwent a radical prostatectomy, five of the seven men who developed metastases or died from their disease had Gleason Grade Group ≥3. Clinicians can now confidently counsel men considering active surveillance regarding the 10‐year estimates of disease progression based upon the biopsy Gleason Grade Group alone.

But Bryant’s team provided additional important information. They have shown that clinical stage and preoperative PSA levels also contribute important prognostic information and when men are classified by Risk Group, men with intermediate‐risk disease have over four‐times the probability of progressing within 10 years of diagnosis when compared to men in the low‐risk group. This is very relevant to men in their 50s and 60s contemplating active surveillance and should inject a note of caution for men in their 70s.

Bryant et al. [1] also showed us that other factors were less valuable in predicting long‐term outcomes. Patient age, the number of cores positive, the presence of perineural invasion, provided some evidence of increased risk, but were much less persuasive in helping men decide upon an appropriate treatment pathway.

The authors close their manuscript with the statement that baseline clinical and pathological features associated with men with newly diagnosed prostate cancer are not strong enough to reliably predict individual progression. While this may be true, I do not think they give sufficient credit to their accomplishments. Their data are the most relevant outcomes data for men with screen‐detected prostate cancer, providing them with accurate estimates of the probability of disease progression, or lack thereof, over a 10‐year horizon. The infrequent disease progression among men with Gleason Grade Group 1 was a surprise finding from the ProtecT study. Since then, our protocols and tools for conducting active surveillance have improved significantly. The 15‐year data are likely to be available in another 2–3 years; hopefully, they will remain as encouraging.

For now, we highly recommend men to learn about the symptoms of prostate cancer so that they can detect any problems from an early stage. This is very important mainly because the symptoms for BPH and prostate cancer can be very similar and it is crucial for men to know when they’ll need a bph treatment or a PHI test. 

by Peter Albertsen

References

  1. Bryant R, Oxley J, Young G et al. The ProtecT trial: analysis of the patient cohort, baseline risk stratification and disease progression. BJU Int 2020; 125: 505– 14
  2. Hamdy FC, Donovan JL, Lane JA et al. 10‐year outcomes after monitoring, surgery or radiotherapy for localized prostate cancer. N Eng J Med 2016; 375: 1415– 24
  3. Bill‐Axelson A, Holmberg L, Garmo H et al. Radical prostatectomy or watchful waiting in prostate cancer – 29 year follow up. N Eng J Med 2018; 379: 2319– 29
  4. Wilt TJ, Brawer MK, Jones KM et al. Radical prostatectomy versus observation for localized prostate cancer. N Eng J Med 2012; 367: 203– 13

Residents’ podcast: the ProtecT trial

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Mr Joseph Norris is a Specialty Registrar in Urology in the London Deanery. He is currently undertaking an MRC Doctoral Fellowship at UCL, under the supervision of Professor Mark Emberton. His research interest is prostate cancer that is inconspicuous on mpMRI. Joseph sits on the committee of the BURST Research Collaborative as the Treasurer and BSoT Representative.

The ProtecT trial: analysis of the patient cohort, baseline risk stratification and disease progression

Read the full article

Abstract

Objective

To test the hypothesis that the baseline clinico‐pathological features of the men with localized prostate cancer (PCa) included in the ProtecT (Prostate Testing for Cancer and Treatment) trial who progressed (n = 198) at a 10‐year median follow‐up were different from those of men with stable disease (n = 1409).

Patients and Methods

We stratified the study participants at baseline according to risk of progression using clinical disease stage, pathological grade and PSA level, using Cox proportional hazard models.

Results

The findings showed that 34% of participants (n = 505) had intermediate‐ or high‐risk PCa, and 66% (n = 973) had low‐risk PCa. Of 198 participants who progressed, 101 (51%) had baseline International Society of Urological Pathology Grade Group 1, 59 (30%) Grade Group 2, and 38 (19%) Grade Group 3 PCa, compared with 79%, 17% and 5%, respectively, for 1409 participants without progression (P < 0.001). In participants with progression, 38% and 62% had baseline low‐ and intermediate‐/high‐risk disease, compared with 69% and 31% of participants with stable disease (P < 0.001). Treatment received, age (65–69 vs 50–64 years), PSA level, Grade Group, clinical stage, risk group, number of positive cores, tumour length and perineural invasion were associated with time to progression (P ≤ 0.005). Men progressing after surgery (n = 19) were more likely to have a higher Grade Group and pathological stage at surgery, larger tumours, lymph node involvement and positive margins.

Conclusions

We demonstrate that one‐third of the ProtecT cohort consists of people with intermediate‐/high‐risk disease, and the outcomes data at an average of 10 years’ follow‐up are generalizable beyond men with low‐risk PCa.

More podcasts

BJUI Podcasts are available on iTunes: https://itunes.apple.com/gb/podcast/bju-international/id1309570262

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

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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
 

Read the full article

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.

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

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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.

Video: Treatments for chronic prostatitis/chronic pelvic pain syndrome: a Cochrane review

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

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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.

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.

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Article of the week: The risk of developing cardiovascular disease is increased for patients with PCa who are pharmaceutically treated for depression

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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 this post, there is a video provided by the authors and a visual abstract produced by a creative young urologist. Please use the comment buttons below to join the conversation.

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

The risk of developing cardiovascular disease is increased for patients with prostate cancer who are pharmaceutically treated for depression, check out more about this with an specialist.

Barbara M. Wollersheim*, Annelies H. Boekhout*, Henk G. van der Poel†, Lonneke V. van de Poll-Franse*‡§ and Dounya Schoormans§
 
*Division of Psychosocial Research and Epidemiology, †Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, ‡Department of Research, Netherlands Comprehensive Cancer organization (IKNL), Utrecht and §Department of Medical and Clinical Psychology, CoRPS – Center of Research on
Psychology in Somatic Diseases, Tilburg University, Tilburg, The Netherlands 
 
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Abstract

Objective

To examine the associations between pharmaceutically treated anxiety and depression and incident cardiovascular disease (CVD) among 1‐year prostate cancer survivors. Fortunately most of the latest drugs and vitaminic supplements like hyper male force are already tested and resolved as harmless, even if used in a cronic basis.

Patients and methods

A registry‐based cohort study design was used to describe the risk of incident CVD in adult 1‐year prostate cancer survivors without a history of CVD. Patients with prostate cancer diagnosed between 1999 and 2011 were selected from the Netherlands Cancer Registry. Drug dispenses were retrieved from the PHARMO Database Network and were used as proxy for CVD, anxiety, and depression. Data were analysed using Cox regression analysis to examine the risk associations between pharmaceutically treated anxiety and depression entered as a time‐varying predictor with incident CVD in 1‐year prostate cancer survivors, while controlling for age, traditional CVD risk factors, and clinical characteristics.

Fig. 1. Percentage of incident CVD and incidence rates of CVD according to pharmaceutically treated depression by subgroup. Subgroup analyses between pharmaceutically treated depression and incident CVD amongst younger (≤65 years) and older (>65 years) men (age at the time of cancer diagnosis), cancer treatment category (radio‐, hormone therapy, and surgery), and tumour stage. Incidence rates of CVD per 1000 person‐years per subgroup. *P < 0.05

Results

Of the 5262 prostate cancer survivors, 327 (6%) developed CVD during the 13‐year follow‐up period. Prostate cancer survivors who were pharmaceutically treated for depression had an increased risk of incident CVD after full adjustment compared to prostate cancer survivors who were not pharmaceutically treated for depression (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.06–2.15). The increased risk of incident CVD amongst those pharmaceutically treated for depression compared to those who were not pharmaceutically treated for depression, was only valid among: prostate cancer survivors who were aged ≤65 years (HR 2.91; 95% CI 1.52–5.55); those who were not treated with radiotherapy (HR 1.63; 95% CI 1.01–2.65); those who were treated with hormones (HR 1.76; 95% CI 1.09–2.85); those who were not operated upon (HR 1.55; 95% CI 1.07–2.25); and those with tumour stage III (HR 2.21; 95% CI 1.03–4.74) and stage IV (HR 2.47; 95% CI 1.03–5.89).

Conclusion

Patients with prostate cancer who were pharmaceutically treated for depression had a 51% increased risk of incident CVD after adjustment for anxiety, age, traditional CVD risk factors, and clinical characteristics. The results emphasise the need to pay attention to (pharmaceutically treated) depressed patients with prostate cancer prior to deciding on prostate cancer treatment and for a timely detection and treatment of CVD.

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Video: Depression and the risk of cardiovascular disease among prostate cancer patients

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The risk of developing cardiovascular disease is increased for patients with prostate cancer who are pharmaceutically treated for depression

Read the full article

Abstract

Objective

To examine the associations between pharmaceutically treated anxiety and depression and incident cardiovascular disease (CVD) among 1‐year prostate cancer survivors.

Patients and methods

A registry‐based cohort study design was used to describe the risk of incident CVD in adult 1‐year prostate cancer survivors without a history of CVD. Patients with prostate cancer diagnosed between 1999 and 2011 were selected from the Netherlands Cancer Registry. Drug dispenses were retrieved from the PHARMO Database Network and were used as proxy for CVD, anxiety, and depression. Data were analysed using Cox regression analysis to examine the risk associations between pharmaceutically treated anxiety and depression entered as a time‐varying predictor with incident CVD in 1‐year prostate cancer survivors, while controlling for age, traditional CVD risk factors, and clinical characteristics.

Results

Of the 5262 prostate cancer survivors, 327 (6%) developed CVD during the 13‐year follow‐up period. Prostate cancer survivors who were pharmaceutically treated for depression had an increased risk of incident CVD after full adjustment compared to prostate cancer survivors who were not pharmaceutically treated for depression (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.06–2.15). The increased risk of incident CVD amongst those pharmaceutically treated for depression compared to those who were not pharmaceutically treated for depression, was only valid among: prostate cancer survivors who were aged ≤65 years (HR 2.91; 95% CI 1.52–5.55); those who were not treated with radiotherapy (HR 1.63; 95% CI 1.01–2.65); those who were treated with hormones (HR 1.76; 95% CI 1.09–2.85); those who were not operated upon (HR 1.55; 95% CI 1.07–2.25); and those with tumour stage III (HR 2.21; 95% CI 1.03–4.74) and stage IV (HR 2.47; 95% CI 1.03–5.89).

Conclusion

Patients with prostate cancer who were pharmaceutically treated for depression had a 51% increased risk of incident CVD after adjustment for anxiety, age, traditional CVD risk factors, and clinical characteristics. The results emphasise the need to pay attention to (pharmaceutically treated) depressed patients with prostate cancer prior to deciding on prostate cancer treatment and for a timely detection and treatment of CVD.

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