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Video: Complications following AUS placement after RP and radiotherapy

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Complications following artificial urinary sphincter placement after radical prostatectomy and radiotherapy: a meta-analysis

Anthony S. Bates1,*, Richard M. Martin2 and Tim R. Terry1

1Department of Urology, Leicester General Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK 2School of Social and Community Medicine, University of Bristol, Bristol, UK

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Objective

To conduct a systematic review and meta-analysis of artificial urinary sphincter (AUS) placement after radical prostatectomy (RP) and external beam radiotherapy (EBRT).

Patients and Methods

There were 1 886 patients available for analysis of surgical revision outcomes and 949 for persistent urinary incontinence (UI) outcomes from 15 and 11 studies, respectively. The mean age (sd) was 66.9 (1.4) years and the number of patients per study was 126.6 (41.7). The mean (sd, range) follow-up was 36.7 (3.9, 18–68) months. A systematic database search was conducted using keywords, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Published series of AUS implantations were retrieved, according to the inclusion criteria. The Newcastle–Ottawa Score was used to ascertain the quality of evidence for each study. Surgical results from each case series were extracted. Data were analysed using CMA® statistical software.

Results

AUS revision was higher in RP + EBRT vs RP alone, with a random effects risk ratio of 1.56 (95% confidence interval [CI] 1.02–2.72; P < 0.050; I2 = 82.0%) and a risk difference of 16.0% (95% CI 2.05–36.01; P < 0.080). Infection/erosion contributed to the majority of surgical revision risk compared with urethral atrophy (P = 0.020). Persistent UI after implantation was greater in patients treated with EBRT (P < 0.001).

Conclusions

Men receiving RP + EBRT appear at increased risk of infection/erosion and urethral atrophy, resulting in a greater risk of surgical revision compared with RP alone. Persistent UI is more common with RP + EBRT.

 

Article of the Week: A phase I study of TRC105 anti-CD105 (endoglin) antibody in mCRPC

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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 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.

A phase I study of TRC105 anti-CD105 (endoglin) antibody in metastatic castration-resistant prostate cancer

Fatima H. Karzai, Andrea B. Apolo, Liang Cao, Ravi A. Madan, David E. Adelberg, Howard Parnes, David G. McLeod, Nancy Harold, Cody Peer, Yunkai Yu, Yusuke Tomita,,Min-Jung Lee, Sunmin Lee, Jane B. Trepel, James L. Gulley, William D. Figg and William L. Dahut

 

Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA

 

Read the full article
OBJECTIVE

TRC105 is a chimeric immunoglobulin G1 monoclonal antibody that binds endoglin (CD105). This phase I open-label study evaluated the safety, pharmacokinetics and pharmacodynamics of TRC105 in patients with metastatic castration-resistant prostate cancer (mCRPC).

PATIENTS AND METHODS

Patients with mCRPC received escalating doses of i.v. TRC105 until unacceptable toxicity or disease progression, up to a predetermined dose level, using a standard 3 + 3 phase I design.

RESULTS

A total of 20 patients were treated. The top dose level studied, 20 mg/kg every 2 weeks, was the maximum tolerated dose. Common adverse effects included infusion-related reaction (90%), low grade headache (67%), anaemia (48%), epistaxis (43%) and fever (43%). Ten patients had stable disease on study and eight patients had declines in prostate specific antigen (PSA). Significant plasma CD105 reduction was observed at the higher dose levels. In an exploratory analysis, vascular endothelial growth factor (VEGF) was increased after treatment with TRC105 and VEGF levels were associated with CD105 reduction.

CONCLUSION

TRC105 was tolerated at 20 mg/kg every other week with a safety profile distinct from that of VEGF inhibitors. A significant induction of plasma VEGF was associated with CD105 reduction, suggesting anti-angiogenic activity of TRC105. An exploratory analysis showed a tentative correlation between the reduction of CD105 and a decrease in PSA velocity, suggestive of potential activity of TRC105 in the patients with mCRPC. The data from this exploratory analysis suggest that rising VEGF level is a possible compensatory mechanism for TRC105-induced anti-angiogenic activity.

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Editorial: Is angiogenesis still an attractive target in metastatic castration-resistant prostate cancer?

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In this issue of BJU International, Karzai et al. [1] report the results of a phase I study of the anti-endoglin antibody TRC105 in patients with metastatic castration-resistant prostate cancer (mCRPC). This is a new anti-angiogenic compound with a unique mechanism of action.

Since the introduction of the concept of angiogenesis as a requirement for tumour growth and survival of solid cancers, a substantial body of research has emerged, establishing inhibition of angiogenic pathways as an important part of the armamentarium in several tumour types [2]. The idea of dynamic tumour angiogenic factors that are able to mediate neovascularisation has also been associated with tumour growth, progression and metastases in prostate cancer [1].

Some studies have revealed that microvessel density, a histological measurement of tumour angiogenesis assessed by immunohistochemical CD105 (endoglin), correlates with higher Gleason score and may predict disease progression, as well as poorer survival outcomes in patients with mCRPC. Accordingly, angiogenesis is considered an attractive target for therapeutic intervention in this disease and anti-angiogenic strategies have been studied in several clinical settings. Unfortunately, well established anti-angiogenic therapies have failed to improve survival outcomes in advanced prostate cancer. Bevacizumab or afilbercept, both combined with docetaxel, were evaluated in phase III clinical trials and no survival benefit was observed over docetaxel alone. Similarly, sunitinib was no better than placebo after chemotherapy treatment. Moreover, the recent COMET-1 trial failed to show survival benefit with cabozantinib, a dual vascular endothelial growth factor (VEGF) and MET inhibitor, in patients with mCRPC and, as a consequence, enrolment in other studies evaluating this agent has been discontinued. Strikingly, although no survival benefit has been reported, progression-free survival benefit has been observed in all of these trials.

Other anti-angionenic therapies have been investigated in patients with mCRPC. A phase II study combining thalidomide and bevacizumab with docetaxel plus prednisone showed that this is an active combination in this subset of patients. Unfortunately, the combination resulted in significant neurotoxicity and myelotoxicity, limiting its clinical use [3]. Lenalidomide was developed to have a more favourable toxicity profile compared with thalidomide and has shown activity as a single agent in patients with non-metastatic, biochemically-relapsed prostate cancer. Again, the large randomised phase III trial comparing docetaxel plus lenalidomide vs docetaxel plus placebo failed to show improvement in overall survival with the addition of this agent [4]. Finally, tasquinimod, another compound targeting angiogenesis, is under evaluation and the final results have not yet been reported. A phase III placebo-controlled study (NCT01234311), designed based on promising phase II data, is ongoing in men with mCRPC with bone metastases and is powered to detect an improvement in overall survival.

Overall, limited activity have been reported with the available agents and, until the results of the tasquinimod trial become available, additional investigations with better-targeted therapies and tools for patient selection are needed to define how this class of agents can improve survival outcome in mCRPC. In this setting, CD105 (endoglin), a homodimeric cell membrane glycoprotein that was initially identified as a human leukaemia-associated antigen, and later also found on endothelial cells, might serve as a reasonable reference point to continue research in this direction. CD105 is a TGFβ co-receptor that is essential for angiogenesis and is selectively expressed on proliferating endothelial cells of tumour vessels. All these properties make CD105 an attractive target for drug development, as targeting the vasculature of the tumour may be more effective than conventional anti-angiogenic therapy, such as anti-VEGF therapy [5].

TRC105, an antibody to CD105, caused a overall reduction in angiogenic biomarkers and reduced tumour burden in a phase I study of advanced solid tumours at doses that were well tolerated. Karzai et al. [1] report the results of a phase I study of TRC105 in patients with mCRPC. This study was designed to define the maximum tolerated dose and to access the safety and tumour activity of TRC105 in a small cohort of patients with mCRPC. Of note, given that TRC105 has a unique mechanism of action, the toxicity profile was not similar with those commonly associated with VEGF inhibition and, at 20 mg/kg, the drug was well tolerated. Although evaluating a small number of patients, the tumour activity of this agent seems to be similar to that of the other anti-angiogenic therapies, and the potential benefit will most likely be seen when combined with other therapies. In addition, exploratory analyses have identified changes in plasma VEGF and CD105 staining on endothelial cells of tumour vessels after treatment with TRC105. These findings suggest that higher levels of VEGF are a possible compensatory mechanism for TRC105-induced anti-angiogenic activity, providing a rationale for TRC105 combination with other anti-VEGF therapies.

It has been hypothesised that endoglin-expressing vessels resist treatment, with antibody targeting the VEGF receptor by allowing continued growth of human tumour xenografts. Therefore, combining anti-angiogenic strategies with agents having different mechanisms of action may be an option to overcome resistance and produce anti-tumour responses [6]. Results from the combination of TRC105 with axitinib in patients with metastatic RCC may support this concept and are now under evaluation (NCT01806064).

Over the last 5 years, treatment of mCRPC has evolved rapidly. Immunotherapy agents (sipuleucel-T), androgen inhibitors (abiraterone acetate and enzalutamide), radioisotope (Radium-223) and cytotoxic chemotherapy (cabazitaxel) have been shown to improve overall survival in randomised phase III clinical trials. However, despite these recent advances, disease progression remains a major cause of morbidity and mortality and new therapies or combinations are required to improve patient care offering them a higher chance of achieving long-term survival.

Anti-angiogenic agents are active in certain settings of prostate cancer and some significant responses have been reported. However, a deeper understanding of the biology of mCRPC is required to characterise the complex angiogenic pathways and to elucidate mechanisms of resistance to this class of agents. This, together with the development of biomarkers to predict responses to anti-angiogenic therapies, might assist in guiding novel treatment combinations and optimising clinical benefit based on patient selection.

Read the full article

 

Andre P. Fay*† and Joaquim Bellmunt*‡

 

*Dana–Farber Cancer Institute, Harvard Medical School, Boston, MA, USA, †Faculdade de Medicina, Pontifıcia Universidade Catolica do Rio Grande do Sul, Porto Alegre, Brazil and ‡University Hospital del Mar, IMIM, Barcelona, Spain

 

References

 

1 Karzai FH, Apolo AB, Cao L et al. A phase I study of TRC105 anti-CD105 (endoglin) antibody in metastatic castration-resistant prostate cancer. BJU Int 2014; 116: 546–55

 

2 Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285: 1182–6

 

3 Ning YM, Gulley JL, Arlen PM et al. Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer. J Clin Oncol 2010; 28: 2070–6

 

4 Petrylak D, Fizazi K, Sternberg CN et al. A phase 3 study to evaluate the efficacy and safety of docetaxel and prednisone with or without lenalidomide in patients with castrate-resistant prostate cancer (CRPC): the MAINSAIL trial. In 2012 ESMO Congress, Abstract LBA24, presented 30 September 2012

 

5 Horsman MR, Siemann DW. Pathophysiologic effects of vascular- targeting agents and the implications for combination with conventional therapies. Cancer Res 2006; 66: 11520–39

 

6 Gordon MS, Robert F, Matei D et al. An open label phase 1b dose escalation study of TRC105 (anti-endoglin antibody) with bevacizumab in patients with advanced cancer. Clin Cancer Res 2014; 20: 5918–26

 

Video: A phase I study of TRC105 anti-CD105 (endoglin) antibody in mCRPC

/by

A phase I study of TRC105 anti-CD105 (endoglin) antibody in metastatic castration-resistant prostate cancer

Fatima H. Karzai, Andrea B. Apolo, Liang Cao, Ravi A. Madan, David E. Adelberg, Howard Parnes, David G. McLeod, Nancy Harold, Cody Peer, Yunkai Yu, Yusuke Tomita,,Min-Jung Lee, Sunmin Lee, Jane B. Trepel, James L. Gulley, William D. Figg and William L. Dahut

 

Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA

 

Read the full article
OBJECTIVE

TRC105 is a chimeric immunoglobulin G1 monoclonal antibody that binds endoglin (CD105). This phase I open-label study evaluated the safety, pharmacokinetics and pharmacodynamics of TRC105 in patients with metastatic castration-resistant prostate cancer (mCRPC).

PATIENTS AND METHODS

Patients with mCRPC received escalating doses of i.v. TRC105 until unacceptable toxicity or disease progression, up to a predetermined dose level, using a standard 3 + 3 phase I design.

RESULTS

A total of 20 patients were treated. The top dose level studied, 20 mg/kg every 2 weeks, was the maximum tolerated dose. Common adverse effects included infusion-related reaction (90%), low grade headache (67%), anaemia (48%), epistaxis (43%) and fever (43%). Ten patients had stable disease on study and eight patients had declines in prostate specific antigen (PSA). Significant plasma CD105 reduction was observed at the higher dose levels. In an exploratory analysis, vascular endothelial growth factor (VEGF) was increased after treatment with TRC105 and VEGF levels were associated with CD105 reduction.

CONCLUSION

TRC105 was tolerated at 20 mg/kg every other week with a safety profile distinct from that of VEGF inhibitors. A significant induction of plasma VEGF was associated with CD105 reduction, suggesting anti-angiogenic activity of TRC105. An exploratory analysis showed a tentative correlation between the reduction of CD105 and a decrease in PSA velocity, suggestive of potential activity of TRC105 in the patients with mCRPC. The data from this exploratory analysis suggest that rising VEGF level is a possible compensatory mechanism for TRC105-induced anti-angiogenic activity.

Read more articles of the week

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

/by

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, Addenbrooke’s Hospital, Cambridge, and ‡Evidence Team, Prostate Cancer UK, London, UK

 

Read the full article
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.

Read more articles of the week

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

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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.

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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, Milan, Italy

 

References

 

1 Murphy AB, Macejko A, Taylor A, Nadler RB. Chronic prostatitis: management strategies. Drugs 2009; 69: 71–84

 

2 Krieger JN, Lee SW, Jeon J, Cheah PY, Liong ML, Riley DE. Epidemiology of prostatitis. Int J Antimicrob Agents 2008; 31 (Suppl. 1): S85–90

 

3 Habermacher GM, Chason JT, Schaeffer AJ. Prostatitis/chronic pelvic pain syndrome. Annu Rev Med 2006; 57: 195–206

 

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/files/ 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: 509–25

 

Video: CP and CPPS – a consensus guideline

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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, Addenbrooke’s Hospital, Cambridge, and ‡Evidence Team, Prostate Cancer UK, London, UK

 

Read the full article
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.

Read more articles of the week

Article of the Week: CCH in the Treatment of Peyronie’s disease

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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 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.

Clinical Efficacy of Collagenase Clostridium Histolyticum in the Treatment of Peyronie’s Disease by Subgroups: Results From Two Large, Double-Blind, Randomized, Placebo-Controlled, Phase 3 Studies

Larry I. Lipshultz, Irwin Goldstein*, Allen D. Seftel†, Gregory J. Kaufman‡, Ted M. Smith‡, James P. Tursi‡ and Arthur L. Burnett§

 

Scott Department of Urology, Baylor College of Medicine, Houston, TX, *San Diego Sexual Medicine, Alvarado Hospital, San Diego, CA,†Cooper University Hospital, Camden, NJ, ‡Auxilium Pharmaceuticals, Inc., Chesterbrook, PA, and §Johns Hopkins Medicine, Baltimore, MD, USA

 

Read the full article
OBJECTIVE

To examine the efficacy of intralesional collagenase Clostridium histolyticum (CCH) in defined subgroups of patients with Peyronie’s disease (PD).

PATIENTS AND METHODS

The efficacy of CCH compared with placebo, assessed from baseline to week 52, was examined in subgroups of participants from the Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies (IMPRESS) I and II. The subgroups were defined according to: severity of penile curvature deformity at baseline (30–60° [n = 492] and 61–90° [n = 120]); PD duration (1 to ≤2 [n = 201], >2 to ≤4 [n = 212] and >4 years [n = 199]); degree of plaque calcification (no calcification [n = 447], non-contiguous stippling [n = 103] and contiguous calcification that did not interfere with injection of CCH [n = 62]); and baseline erectile function (International Index of Erectile Function [IIEF] scores 1–5 [n= 22], 6–16 [n = 106] and ≥17 [n = 480]).

RESULTS

Reductions in penile curvature deformity and PD symptom bother were observed in all subgroups. Penile curvature deformity reductions were significantly greater with CCH than with placebo for the following subgroups: baseline penile curvature 30–60° and 61–90°; disease duration >2 to ≤4 years and >4 years; no calcification; and IIEF score ≥17 (high IIEF-erectile function score; P < 0.05 for all). PD symptom bother reductions were significantly greater in the CCH group for: penile curvature 30–60°; disease duration >4 years; no calcification; and IIEF score 1–5 (no sexual activity) and ≥17 (P < 0.05 for all).

CONCLUSIONS

In this analysis, clinical efficacy of CCH treatment for reducing penile curvature deformity and PD symptom bother was found across subgroups. In the IMPRESS I and II overall, adverse events (AEs) were typically mild or moderate, although treatment-related serious AEs, including corporal rupture or penile haematoma, occurred. Future studies could be considered to directly assess the efficacy and safety of CCH treatment in defined subgroups of PD patients, with the goal of identifying predictors of optimum treatment success.

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Editorial: Intralesional Collagenase injections in PD patients : do they IMPRESS and can we afford them?

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The study by Lipshultz et al. [1] is a post hoc reworking of the results of the Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies (IMPRESS) I and II phase 3 trials (each included 418 randomised patients) of intralesional injections of collagenase clostridium histolyticum (CCH) in patients with Peyronie’s disease (PD). The intention being to identify specifically, which subgroups of patients with PD might do best with CCH treatment compared with their matched placebo controls, as determined by reductions in penile curvature deformity and Peyronie’s Disease Questionnaire (PDQ) PD Symptom Bother score at study week 52 compared with baseline.

In both IMPRESS studies, CCH-treated patients showed statistically greater mean improvements vs placebo for reduction of penile curvature and PDQ PD Symptom Bother score. The current authors [1] have reassessed these previous results using four patient cohort variables, namely, baseline penile curvature, duration of PD, degree of penile calcification, and baseline erectile function severity, which were then further divided using various descriptors.

The results show that intralesional CCH significantly reduced baseline penile curvature in both the 30–60 and 61–90° curvature cohorts (P < 0.001 and P <0.008, respectively). Additionally, significant penile curvature improvements occurred with intralesional CCH when PD duration was >2 to <4 years and >4 years (P < 0.001).

CCH treatment in patients with PD with no penile calcification show statistically significant improvements in reducing baseline penile curvature and PDQ PD Symptom Bother score but this was not seen for either the noncontiguous stippling or contiguous calcification patient subgroups. Significant improvements in penile curvature occurred with intralesional CCH in patients with PD with a baseline International Index of Erectile Function (IIEF) score of >17 (P < 0.001) and the PDQ PD Symptom Bother score was also significantly reduced in these patients. Although these results are statistically meaningful, the clinical benefits are less readily discernible considering 12.5° was the largest difference in the reduction of mean penile curvature in all subgroups when comparing intralesional CCH to placebo at week 52. Similarly, although statistically significant changes in the PDQ PD Symptom Bother score were reported for intralesional CCH for the subgroups with duration of disease of >4 years, no penile calcification, and IIEF of >17, it is unclear what clinical benefit would accrue with a maximal change of 1.4 in any of the randomised subgroups.

Importantly, the IMPRESS I and II studies were not designed for subgroup analysis and despite combining these studies some of the specified PD subgroups contained in the present paper contain too few subjects to allow a valid statistical analysis of CCH efficacy. This has prompted the authors to conclude that further adequately powered prospective, randomised studies should be conducted to further clarify which PD characteristics offer optimal patient benefit with CCH treatment. The outcomes of these future studies might then optimise healthcare expenditure for a non-surgical treatment (consisting of eight penile injections and modelling), which shows therapeutic promise for patients with PD but potentially has significant consumer cost issues, which may be prohibitive unless some clinician guidelines exist for the use of CCH treatment. This has relevance as the USA Food and Drug Administration has already approved the use of intralesional CCH for the treatment of adult men with PD, who at the start of therapy have a palpable plaque and a curvature deformity of ≥30° [2].

Importantly, the outcomes of the patients with PD in the IMPRESS studies were only reported to week 52 of the study, which begs the questions as to how long any clinical benefit might last in patients who initially respond to intralesional CCH and whether these patients once having relapsed might respond to adjuvant injections.

 

Read the full article
Tim Terry
Department Urology, Leicester General Hospital, Leicester

 

References
1 Lipshultz LI, Goldstein I, Seftel AD et al. Clinical efficacy of collagenase clostridium histolyticum in the treatment of Peyronie’s disease by subgroups: results from two large, randomised, placebo-controlled, phase 3 studies. BJU Int 2015; 116: 650–56

 

2 Honig SC. Intralesional collagenase in the treatment of Peyronie’s disease. Ther Adv Urol 2014; 6: 47–53

 

Article of the Month: Safety and efficacy of mirabegron as add-on therapy in patients with solifenacin-treated OAB (MILAI study)

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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 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 Prof. Osamu Yamaguchi discussing his paper. 

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

Safety and efficacy of mirabegron as add-on therapy in patients with overactive bladder treated with solifenacin: a postmarketing, open-label study in Japan (MILAI study)

Osamu Yamaguchi, Hidehiro Kakizaki*, Yukio Homma†, Yasuhiko Igawa‡, Masayuki Takeda§, Osamu Nishizawa, Momokazu Gotoh**, Masaki Yoshida††, Osamu Yokoyama‡‡, Narihito Seki§§, Akira Okitsu¶¶, Takuya Hamada¶¶, Akiko Kobayashi¶¶ and Kentarou Kuroishi¶¶

 

Division of Bioengineering and LUTD Research, School of Engineering, Nihon University, Koriyama, *Department of Urology, Asahikawa Medical University, Asahikawa, †Department of Urology, University of Tokyo Graduate School of Medicine, Tokyo, ‡Department of Continence Medicine, University of Tokyo Graduate School of Medicine, Tokyo, §Department of Urology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, ¶Department of Urology, Shinshu University, Matsumoto, **Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, ††Department of Urology, National Centre for Geriatrics and Gerontology, Obu, ‡‡Department of Urology, University of Fukui Faculty of Medical Sciences, Fukui, §§Department of Urology, Kyushu
Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, and ¶¶Astellas Pharma Inc., Tokyo, Japan

 

Read the full article
OBJECTIVE

To examine the safety and efficacy of mirabegron as ‘add-on’ therapy to solifenacin in patients with overactive bladder (OAB).

PATIENTS AND METHODS

This multicentre, open-label, phase IV study enrolled patients aged ≥20 years with OAB, as determined by an OAB symptom score (OABSS) total of ≥3 points and an OABSS Question 3 score of ≥2 points, who were being treated with solifenacin at a stable dose of 2.5 or 5 mg once daily for at least 4 weeks. Study duration was 18 weeks, comprising a 2-week screening period and a 16-week treatment period. Patients meeting eligibility criteria continued to receive solifenacin (2.5 or 5 mg once daily) and additional mirabegron (25 mg once daily) for 16 weeks. After 8 weeks of treatment, the mirabegron dose could be increased to 50 mg if the patient’s symptom improvement was not sufficient, if he/she was agreeable to the dose increase, and the investigator judged that there were no safety concerns. Safety assessments included adverse events (AEs), laboratory tests, vital signs, 12-lead electrocardiogram, QT corrected for heart rate using Fridericia’s correction (QTcF) interval and post-void residual (PVR) volume. Efficacy endpoints were changes from baseline in OABSS total score, OAB questionnaire short form (OAB-q SF) score (symptom bother and total health-related quality of life [HRQL] score), mean number of micturitions/24 h, mean number of urgency episodes/24 h, mean number of urinary incontinence (UI) episodes/24 h, mean number of urgency UI episodes/24 h, mean volume voided/micturition, and mean number of nocturia episodes/night. Patients were instructed to complete the OABSS sheets at weeks −2, 0, 8 and 16 (or at discontinuation), OAB-q SF sheets at weeks 0, 8 and 16 (or at discontinuation) and patient voiding diaries at weeks 0, 4, 8, 12 and 16 (or at discontinuation).

RESULTS

Overall incidence of drug-related treatment-emergent AEs (TEAEs) was 23.3%. Almost all TEAEs were mild or moderate. The most common TEAE was constipation, with similar incidence in the groups receiving a dose increase to that observed in the groups maintained on the original dose. Changes in PVR volume, QTcF interval, pulse rate and blood pressure were not considered to be clinically significant and there were no reports of urinary retention. Significant improvement was seen for changes in efficacy endpoints from baseline to end of treatment (EOT) in all groups (patients receiving solifenacin 2.5 or 5 mg + mirabegron 25 or 50 mg).

CONCLUSIONS

Add-on therapy with mirabegron 25 mg once daily for 16 weeks, with an optional dose increase to 50 mg at week 8, was well tolerated in patients with OAB treated with solifenacin 2.5 mg or 5 mg once daily. There were significant improvements from baseline to EOT in OAB symptoms with combination therapy with mirabegron and solifenacin. Add-on therapy with mirabegron and an antimuscarinic agent, such as solifenacin, may provide an attractive therapeutic option.

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