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Re: Diagnosis and treatment of chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome: a consensus guideline

Letter to the Editor

Dear Sir

Fluoroquinolones must not be used inappropriately when treating chronic prostatitis (CP) and chronic pelvic pain syndrome (CPPS).

Clinical guidelines from the Prostatitis Expert Reference Group (PERG) on chronic bacterial prostatitis (CBP), chronic prostatitis and chronic pelvic pain syndrome [1] — which have been propagated by other guideline providers such as NICE Clinical Knowledge Summaries and the primary care resource, Guidelines — include the following recommendation:

For patients with early-stage CBP and CP/CPPS, offer a quinolone (e.g. ciprofloxacin or ofloxacin) for 4–6 weeks as first-line therapy.’

While the PERG guidelines do mention diagnostic tests for a bacterial cause, readers will be left with the impression that a course of fluoroquinolone without a diagnostic workup is acceptable for the initial management of CP and CPPS. This impression may be reinforced by PERG’s subsequent recommendations, in particular the second one:

A repeated course of antibiotic therapy (4–6 weeks) should be offered only if a bacterial cause is confirmed or if there is a partial response to the first course.

‘If a bacterial cause is excluded (e.g. via urine dipstick or culture) and symptoms do not improve after antibiotic therapy, a different treatment method or referral to specialist care should be considered.’

Recent recommendations [2] from the European Medicines Agency (EMA) make it clear that fluoroquinolones should be reserved for treating bacterial prostatitis. EMA’s review of fluoroquinolones was prompted by reports of serious, disabling and permanent side effects after fluoroquinolone use.

To reach its recommendations, EMA’s safety committee (Pharmacovigilance Risk Assessment Committee, PRAC) reviewed all available evidence, brought together EU experts in the field, and heard patients’ and healthcare professionals’ testimonies at a public hearing. Many patients who had developed long-lasting serious disability reported receiving a fluoroquinolone for chronic prostatitis despite the lack of evidence of a bacterial cause.

EMA’s new recommendations restrict the indications and have led to an update of the prescribing information for all systemic fluoroquinolones to prevent further unnecessary cases of rare but life-changing side effects; the narrow indications also help to reduce antibiotic selection pressure. Guidelines on chronic prostatitis should therefore be revised to clarify that fluoroquinolones are not appropriate for the empirical treatment of chronic prostatitis or chronic pelvic pain syndrome. The European Association of Urology emphasises use of appropriate culture techniques to demonstrate bacterial infection [3].

And when treating bacterial prostatitis with a fluoroquinolone, healthcare professionals should discuss with their patients the risks, including the potential for permanent musculoskeletal and neurological side effects. Details of these effects are set out in the updated prescribing information for fluoroquinolone antibacterials.

It is vital to communicate the changes in the fluoroquinolones prescribing information to all healthcare professionals involved in the management of men with prostatitis or chronic pelvic pain syndrome. Promoting this crucial change in practice will ultimately lead to more rational use of antibiotics and limit the unnecessary exposure of patients to potentially persistent and seriously disabling side effects.

Gernot Bonkat, alta uro AG, Merian Iselin Klinik, Center of Biomechanics & Calorimetry, University of Basel; Chairman, European Association of Urology (EAU) Urological Infections Guidelines

Juan Garcia Burgos, Head of Public Engagement Department, European Medicines Agency (EMA)

Martin Huber, Co-rapporteur, quinolone and fluoroquinolone review by the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC)

Eva Jirsová, Rapporteur, quinolone and fluoroquinolone review by the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC)

Florian Wagenlehner, Clinic of urology, pediatric urology and andrology, Justus Liebig University Giessen, Germany; Chairman, European Section of Infections in Urology (ESIU) of the European Association of Urology (EAU)

Correspondence: Juan Garcia Burgos, European Medicines Agency, Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands

email: [email protected]

References

  1. Rees J, Abrahams M, Double, A, Cooper A. Diagnosis and treatment of chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome: a consensus guideline. BJU Int 2015; 116: 509–525
  2. EMA. Disabling and potentially permanent side effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics, 2018. Available at: https://www.ema.europa.eu/en/medicines/human/referrals/quinolone-fluoroquinolone-containing-medicinal-products. Accessed January 2020
  3. Bonkat G, Bartoletti RR, Bruyère F, Cai T, Geerlings SE, Köves B, Schubert S, Wagenlehner F, Guidelines Associates: Mezei T, Pilatz A, Pradere B, Veeratterapillay R. EAU guidelines on urological infections 2019: 28–32. ISBN/EAN:978-94-92671-04-2. Available at: https://uroweb.org/guideline/urological-infections. Accessed January 2020

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

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

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.

Article of the week: A longitudinal analysis of urological chronic pelvic pain syndrome flares in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network

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 editorial written by a prominent member of the urological community. These are 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.

A longitudinal analysis of urological chronic pelvic pain syndrome flares in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network

Siobhan Sutcliffe*, Robert Gallop, Hing Hung Henry Lai§, Gerald L. Andriole, Catherine S. Bradley**††, Gisela Chelimsky‡‡, Thomas Chelimsky§§, James Quentin Clemens¶¶, Graham A. Colditz*, Bradley Erickson††, James W. Griffith***, Jayoung Kim†††, John N. Krieger‡‡‡, Jennifer Labus§§§, Bruce D. Naliboff§§§, Larissa V. Rodriguez¶¶¶, Suzette E. Sutherland‡‡‡, Bayley J. Taple*** and John Richard Landis

 

*Division of Public Health Sciences, Department of Surgery and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, Division of Urologic Surgery, Department of Surgery, §Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, Department of Obstetrics and Gynecology, Carver College of Medicine University of Iowa, **Department of Epidemiology, College of Public Health, ††Department of Urology, Carver College of Medicine, University of Iowa, Iowa City, IA, ‡‡Department of Pediatrics, Division of Pediatric Gastroenterology, §§Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, ¶¶Division of Neurourology and Pelvic Reconstructive Surgery, Department of Urology, University of Michigan, Ann Arbor, MI, ***Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, †††Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, ‡‡‡Department of Urology, University of Washington, Seattle, WA, §§§Oppenheimer Center for Neurobiology of Stress and Resilience and Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, and ¶¶¶Institute of Urology, University of Southern California, Beverly Hills, CA, USA

Abstract

Objective

To describe the frequency, intensity and duration of urological chronic pelvic pain syndrome symptom exacerbations (‘flares’), as well as risk factors for these features, in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Epidemiology and Phenotyping longitudinal study.

Participants and Methods

Current flare status (‘urological or pelvic pain symptoms that are much worse than usual’) was ascertained at each bi‐weekly assessment. Flare characteristics, including start date, and current intensity of pelvic pain, urgency and frequency (scales of 0–10), were assessed for participants’ first three flares and at three randomly selected times when they did not report a flare. Generalized linear and mixed effects models were used to investigate flare risk factors.

Results

Of the 385 eligible participants, 24.2% reported no flares, 22.9% reported one flare, 28.3% reported 2–3 flares, and 24.6% reported ≥4 flares, up to a maximum of 18 during the 11‐month follow‐up (median incidence rate = 0.13/bi‐weekly assessment, range = 0.00–1.00). Pelvic pain (mean = 2.63‐point increase) and urological symptoms (mean = 1.72) were both significantly worse during most flares (60.6%), with considerable within‐participant variability (26.2–37.8%). Flare duration varied from 1 to 150 days (94.3% within‐participant variability). In adjusted analyses, flares were more common, symptomatic, and/or longer‐lasting in women and in those with worse non‐flare symptoms, bladder hypersensitivity, and chronic overlapping pain conditions.

Conclusion

In this foundational flare study, we found that pelvic pain and urological symptom flares were common, but variable in frequency and manifestation. We also identified subgroups of participants with more frequent, symptomatic, and/or longer‐lasting flares for targeted flare management/prevention and further study.

Article of the Week: Diagnosis and treatment of CBP and CP/CPPS – a consensus guideline

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.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Jon Rees discussing his paper. 

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

Diagnosis and treatment of chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome: a consensus guideline

Jon Rees, Mark Abrahams*, Andrew Doble† and Alison Cooper‡ for the Prostatitis Expert Reference Group (PERG) 

 

Backwell and Nailsea Medical Group, Bristol, *Department of Pain Medicine, Department of Urology, AddenbrookeHospital, Cambridge, and Evidence Team, Prostate Cancer UK, London, UK

 

OBJECTIVES

To improve awareness and recognition of chronic bacterial prostatitis (CBP) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) among non-specialists and patients. To provide guidance to healthcare professionals treating patients with CBP and CP/CPPS, in both non-specialist and specialist settings. To promote efficient referral of care between non-specialists and specialists and the involvement of the multidisciplinary team (MDT).

PATIENTS AND METHODS

The guideline population were men with CBP or CP/CPPS (persistent or recurrent symptoms and no other urogenital pathology for ≥3 of the previous 6 months). Consensus recommendations for the guidelines were based on a search to identify literature on the diagnosis and management of CBP and CP/CPPS (published between 1999 and February 2014). A Delphi panel process was used where high-quality, published evidence was lacking.

RESULTS

CBP and CP/CPPS can present with a wide range of clinical manifestations. The four main symptom domains are urogenital pain, lower urinary tract symptoms (LUTS – voiding or storage symptoms), psychological issues and sexual dysfunction. Patients should be managed according to their individual symptom pattern. Options for first-line treatment include antibiotics, α-adrenergic antagonists (if voiding LUTS are present) and simple analgesics. Repeated use of antibiotics, such as quinolones, should be avoided if there is no obvious symptomatic benefit from infection control or cultures do not support an infectious cause. Early use of treatments targeting neuropathic pain and/or referral to specialist services should be considered for patients who do not respond to initial measures. An MDT approach (urologists, pain specialists, nurse specialists, specialist physiotherapists, general practitioners, cognitive behavioural therapists/psychologists, and sexual health specialists) is recommended. Patients should be fully informed about the possible underlying causes and treatment options, including an explanation of the chronic pain cycle.

CONCLUSION

Chronic prostatitis can present with a wide variety of signs and symptoms. Identification of individual symptom patterns and a symptom-based treatment approach are recommended. Further research is required to evaluate management options for CBP and CP/CPPS.

Editorial: Chronic prostatitis – how to give our best without apposite vagueness

A patient with chronic prostatitis poses a significant challenge to the urologist in everyday practice. We are certain that all readers will be familiar with the effort required to manage a man with chronic prostatitis, not only in diagnostic and therapeutic interventions but also personal and psychological support. This is particularly true, when you consider that chronic prostatitis affects men of all ages and can significantly impair their quality of life and social functioning. Starting with medical considerations, the symptomatic, chronic forms of prostatitis, as defined by the USA National Institutes of Health (NIH) are chronic bacterial prostatitis (CBP; NIH category II) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS; NIH category III) [1]. These chronic conditions present with a wide range of clinical manifestations, but the four main primarily recognised symptoms are: urogenital pain, lower urinary tract symptoms (voiding or storage symptoms), alteration of the psychological status, and sexual dysfunction [2].

Prevalence rates are estimated at 2–10%, with some as high as 15–16% in Asian, European and North American samples [3]. Both CBP and CP/CPPS present with no one identified underlying cause, although infectious, genetic, anatomical, physiological, neurological, and immunological factors may be involved. For whatever reason, the underlying factor(s) of chronic prostatitis are likely to trigger tissue inflammation and immune responses which, in turn, induce bladder and pelvic pain leading to LUTS, ejaculatory pain, and pain in other regions, including the lower back and abdomen. The lack of a distinct aetiology has made making a specific diagnosis and effectively treating the disorder very arduous, presenting a serious challenge to urologists. In this respect, the difficulty for us is to do our best in trying to solve the problem, without apposite vagueness! [4]. In the obscurity of actual knowledge about the pathophysiology, diagnosis and treatment of CBP and CP/CPPS, it seems that recent insights can be favourably identified.

The consensus guideline on the diagnosis and treatment of chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome, published in BJUI by Rees et al. [5], indeed represents an important tool to provide guidance to urologists and healthcare professionals treating patients with CBP and CP/CPPS. Starting from a literature review of the most updated evidence-based information in the field of CBP and CP/CPPS, the consensus guideline provides new and useful recommendations in signs and symptoms evaluation, and clinical assessment and diagnosis of CBP and CP/CPPS. In this regard, reliable instruments, e.g. the NIH-Chronic Prostatitis Symptoms index (NIH-CPSI), IPSS and UPOINT (Urinary, Psychosocial, Organ-specific, Infection, Neurological/systemic, and Tenderness) scales [5], have been suggested to assess initial symptom severity, evaluate phenotypic differences, and monitor patients’ response to therapeutic intervention. In addition, psychological screening to evaluate the presence of psychological disorders, e.g. depression and anxiety, has been strongly recommended. What is most important is the detailed information about treatment approaches for each individual patient, according to history, physical examination, investigations, and stage of the disease. Specifically, levels of evidence and different recommendations are provided for α-blockers, antimicrobial therapy, phytotherapy, and pain management. This guideline also has the merit of being simple and easily understandable for non-specialists and patients in showing the most appropriate way in following a patient with CBP and CP/CPPS. We are sure that this consensus guideline represents a step forward to a more adequate approach in diagnosing and treating patients with chronic prostatitis. It can be a tool to improve awareness and recognition of these conditions, and for uniformity among different specialists involved in the field.

Antonella Giannantoni and Silvia Proietti*

 

Department of Surgical and Biomedical Sciences, Urolog y and Andrology Section, Ospedale S. Maria della Misericordia, University of Perugia, Perugia, and *Human itas Clinical and Research Centre, Department of Urology, Rozzano, MilanItaly

 

References

 

1 Murphy AB, Macejko A, Taylor A, Nadler RB. Chronic prostatitis: management strategies. Drugs 2009; 69: 7184

 

2 Krieger JN, Lee SW, Jeon J, Cheah PY, Liong ML, Riley DEEpidemiology of prostatitis. Int J Antimicrob Agents 2008; 31 (Suppl. 1): S8590

 

3 Habermacher GM, Chason JT, Schaeffer AJ. Prostatitis/chronic pelvic pain syndrome. Annu Rev Med 2006; 57: 195206

 

4 Twain M. My Late Senatorial Secretaryship (written about 1867). In: Sketches New and Old. Hartford, CT, and Chicago, IL: The American Publishing Company, 1882. Available at: https://www.gutenberg.org/les/ 3189/old/orig3189-h/p3.htm. Accessed May 2015.

 

5 Rees J, Abrahams M, Doble A, Cooper A. Prostatitis Expert Reference Group (PERG). Diagnosis and treatment of chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome: a consensus guideline. BJU Int 2015; 116: 50925

 

Video: CP and CPPS – a consensus guideline

Diagnosis and treatment of chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome: a consensus guideline

Jon Rees, Mark Abrahams*, Andrew Doble† and Alison Cooper‡ for the Prostatitis Expert Reference Group (PERG) 

 

Backwell and Nailsea Medical Group, Bristol, *Department of Pain Medicine, Department of Urology, AddenbrookeHospital, Cambridge, and Evidence Team, Prostate Cancer UK, London, UK

 

OBJECTIVES

To improve awareness and recognition of chronic bacterial prostatitis (CBP) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) among non-specialists and patients. To provide guidance to healthcare professionals treating patients with CBP and CP/CPPS, in both non-specialist and specialist settings. To promote efficient referral of care between non-specialists and specialists and the involvement of the multidisciplinary team (MDT).

PATIENTS AND METHODS

The guideline population were men with CBP or CP/CPPS (persistent or recurrent symptoms and no other urogenital pathology for ≥3 of the previous 6 months). Consensus recommendations for the guidelines were based on a search to identify literature on the diagnosis and management of CBP and CP/CPPS (published between 1999 and February 2014). A Delphi panel process was used where high-quality, published evidence was lacking.

RESULTS

CBP and CP/CPPS can present with a wide range of clinical manifestations. The four main symptom domains are urogenital pain, lower urinary tract symptoms (LUTS – voiding or storage symptoms), psychological issues and sexual dysfunction. Patients should be managed according to their individual symptom pattern. Options for first-line treatment include antibiotics, α-adrenergic antagonists (if voiding LUTS are present) and simple analgesics. Repeated use of antibiotics, such as quinolones, should be avoided if there is no obvious symptomatic benefit from infection control or cultures do not support an infectious cause. Early use of treatments targeting neuropathic pain and/or referral to specialist services should be considered for patients who do not respond to initial measures. An MDT approach (urologists, pain specialists, nurse specialists, specialist physiotherapists, general practitioners, cognitive behavioural therapists/psychologists, and sexual health specialists) is recommended. Patients should be fully informed about the possible underlying causes and treatment options, including an explanation of the chronic pain cycle.

CONCLUSION

Chronic prostatitis can present with a wide variety of signs and symptoms. Identification of individual symptom patterns and a symptom-based treatment approach are recommended. Further research is required to evaluate management options for CBP and CP/CPPS.

A new treatment option for prostatitis/prostatodynia?

The management of patients with chronic pelvic pain attributed to chronic prostatitis has long been rather unsatisfactory. Even prolonged treatment with an aminoquinolone, such as ciprofloxacin, and an anti-inflammatory agent, or, alternatively an alpha blocker, seldom results in rapid resolution of the symptoms, and is commonly completely ineffective.

We recently encountered a patient, effectively disabled by prostatodynia, unresponsive to standard treatment, who had been taking morphine to control the pain from 2001 – 2008. He was unable to tolerate non-steroidal anti-inflammatory analgesics. In 2008 he was prescribed initially 10 mgs, then 20 mgs daily, of the phosphodiesterase type 5 (PDE5) inhibitor tadalafil, with immediate marked improvement of his symptoms. On cessation of the medication on 4 separate occasions, his symptoms returned; recommencement of treatment each time, with 5 mgs tadalafil daily, has resulted in similar persisting improvement of his symptoms, and he has been able to discontinue treatment with morphine. As a direct consequence of the conversation with this individual we have prescribed tadalafil 5 mgs daily in several of our patients with prostatitis; so far with uniformly beneficial results. Of course, we should point out that this is an off-label indication for this medication.  

However, in addition to the symptom of pelvic pain, many men suffering from chronic abacterial prostatitis/prostatodynia also complain of associated lower urinary tract symptoms and ejaculatory discomfort. Consequently treatment with tadalafil at a dose of 5 mgs per day for a period of time would seem logical. It could be surmised that many of its beneficial effects might stem from an improvement of blood flow to pelvic organs as a consequence of its anti-inflammatory and vasodilatory activity, as well as a relaxant effect on smooth muscle, as has been previously suggested in the case of lower urinary tract symptoms by Karl-Eric Andersson and others.

Clearly the hypothesis that daily treatment with a PDE5 inhibitor might be beneficial in men suffering from the prevalent condition of chronic abacterial prostatitis/prostatodynia needs to be formally tested in the context of a randomized controlled trial. If the results of such a study were to prove positive the quality of life of very many sufferers of this disorder might be significantly improved. One might also speculate that it could provide a concomitant benefit to the partners of these often very unhappy men. 

Roger Kirby, The Prostate Centre
Culley Carson III
, The University of North Carolina
Prokar Dasgupta
The Prostate Centre, Guy’s Hospital, King’s College London

 

Article of the week: Rethinking inflammation in PCa

Every week the Editor-in-Chief selects the 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.

Histological inflammation and risk of subsequent prostate cancer among men with initially elevated serum prostate-specific antigen (PSA) concentration in the Finnish prostate cancer screening trial

Tytti H. Yli-Hemminki*, Marita Laurila*, Anssi Auvinen, Liisa Määttänen§, Heini Huhtala, Teuvo L.J. Tammela and Paula M. Kujala*

*Department of Pathology, Fimlab Laboratories, Tampere University Hospital, Tampere, Department of Pathology, Seinäjoki Central Hospital, Seinäjoki, School of Health Sciences, University of Tampere, Tampere, §Finnish Cancer Registry, Helsinki, and Department of Urology, Tampere University Hospital and University of Tampere, Tampere, Finland

T. H. Y.-H. and M. L. contributed equally to this study.

OBJECTIVE

• To assess whether histological signs of inflammation are associated with an increased risk of subsequent prostate cancer (PCa) in men with elevated serum prostate-specific antigen (PSA) concentrations and benign initial biopsy.

MATERIALS AND METHODS

• Study subjects were men aged 54–67 years with an elevated PSA (≥4 ng/mL or 3–4 ng/mL and free to total PSA ratio ≤0.16 or positive digital rectal examination), but a benign biopsy result within the Finnish population-based randomised screening trial for PCa, which started in 1996.

• A total of 293 prostate biopsies without PCa or suspicion of malignancy from the first screening round in the Tampere centre were re-evaluated by a uropathologist to assess histological inflammation.

• Results of the subsequent screening rounds were obtained from the trial database and PCa diagnoses made outside the screening were obtained from the Finnish Cancer Registry.

• The median length of follow-up was 10.5 years.

• Cox regression analysis was used to assess PCa risk after the initial benign biopsy.

RESULTS

• Histological inflammation was found in 66% of the biopsies.

• Subjects with inflammation at the biopsy had a slightly lower PCa risk in the second screening round (18 vs 27%, rate ratio 0.69, 95% confidence interval [CI] 0.35–1.34) relative to men without inflammation. In further follow-up, the PCa risk remained nonsignificantly lower (hazard ratio [HR] 0.71, CI 0.46–1.10; P = 0.13). The risk was not appreciably affected by adjustment for age, PSA, prostate volume and family history of PCa (HR 0.67, CI 0.42–1.07; P = 0.092).

CONCLUSIONS

• Histological inflammation in a prostate biopsy among men with an initial false-positive screening test was not associated with an increased risk of subsequent PCa, but instead with a decreased risk which was of borderline significance.

• Inflammation in prostate biopsy is not a useful risk indicator in PCa screening.

 

Read Previous Articles of the Week

 

Editorial: Does inflammation reduce the risk of prostate cancer?

Chronic inflammation is thought to play an aetiological role in tumorigenesis in several cancers including bladder, oesophagus and liver [1]. Molecular studies show that it plays a critical role in several stages of the carcinogenic process including tumour initiation, promotion, metastases and response to therapy. However the role in prostate cancer is less clear and to date, clinical studies are inconclusive.

The article in this issue of BJUI by Yli-Hemminki et al. [2] appears to show an inverse association with histological inflammation and the risk of prostate cancer. Using data from the Finnish subgroup of the European Randomised Study of Prostate Cancer Screening (ERSPC) study they examined 293 patients with previous negative biopsies over a 10.5-year period and reported an 18% risk of prostate cancer in men with inflammation on initial biopsy (34 of 101 men) as opposed to 27% in those without inflammation (51 of 192 men). Perhaps somewhat surprisingly, histological inflammation did not appear to be significantly associated with PSA concentration, although it did appear that the free/total PSA ratio was higher in men with inflammation.

One potential confounding factor is that inflammation may also play a role in the pathogenesis of BPH. A large scale study showed that the odds ratio for BPH was 8.0 with a history of prostatitis [3]. Furthermore, the Medical Therapy of Prostatic Symptoms (MTOPS) study showed that men with inflammation had a significantly higher risk of BPH progression and acute urinary retention. These factors may impact on PSA levels and the chance of a subsequent prostate biopsy. However, the authors report that the inverse association of prostate cancer and inflammation did not alter when corrected for prostate volume, PSA level and age.

Significantly, those patients who screened positive at first biopsy were already excluded as were those with a suspicion of prostate cancer, such as a small atypical focus. Despite this, the study group probably represents high-risk patients, as they had all previously met the criteria for the first round of biopsies. This is borne out by the fact that the risk of prostate cancer was significantly increased when the men with inflammation on biopsy were compared with the initially screened negative men (hazard ratio 4.3). Unfortunately, we do not know what the rate of inflammation was in the control arm as they were screened negative and hence no biopsies were taken.

The significance of PSA level or prostatic intraepithelial neoplasia was not specifically investigated, although the reported rates were 32.1% and 7.5% respectively. Overall the incidence of inflammation was reported as 65%, but this included both acute and chronic inflammation. A smaller number of patients were given grade 2/3 chronic inflammation (80 and 20 patients, respectively) and only 14 patients had grade 2/3 acute, indicating most had milder degrees of inflammation. Whether this is a representative sample is not entirely clear. As the authors comment, published rates of histological inflammation do vary significantly from 8 to 99% and this does appear to vary according to detection method.

Several case-control studies and a meta-analysis [4] have shown that there is a significant increase in the relative risk of prostate cancer in men with prostatitis; however, these epidemiological studies all suffer from selection bias, in that men with clinical symptoms are more likely present and to be investigated and followed up by a Urologist. This study [2] only examines the role of histological inflammation and, at least partially, removes the selection bias associated with clinical symptoms, although it could still be argued that men with clinical prostatitis may be more likely to present for screening. This study represents a highly selected group of patients that are high risk for prostate cancer and no firm conclusions can be drawn on the general population. As inflammation is so common in prostate specimens, further high-quality large-scale studies are needed with similar long-term follow-up.

Miles A. Goldstraw and Roger S. Kirby
The Prostate Centre, London, UK

References

  1. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420: 860–867
  2. Yli-Hemminski T, Laurila M, Auvinen A et al. Histological inflammation and risk of subsequent prostate cancer among men with initially elevated serum prostate-specific antigen (PSA) concentration in the Finnish prostate cancer screening trial. BJU Int 2013; 112: 735–741
  3. Alcarez A, Hammerer P, Tubaro A, Schroder FH, Castro R. Is there evidence of a relationship between benign prostatic hyperplasia and prostate cancer? Findings of a literature review. Eur Urol 2009; 55: 864–875
  4. Dennis LK, Lynch CF, Torner JC. Epidemiologic association between prostatitis and prostate cancer. Urology 2002; 60: 78–83
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