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Video: Hospital volume and conditional 90-day post-cystectomy mortality

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Association of hospital volume with conditional 90-day mortality after cystectomy: an analysis of the National Cancer Data Base

Matthew E. Nielsen*†‡, Katherine Mallin§, Mark A. Weaver, Bryan Palis§, Andrew Stewart§, David P. Winchester§ and Matthew I. Milowsky*,**

*University of North Carolina Lineberger Comprehensive Cancer Center, †Department of Urology, and Divisions of General Medicine and Clinical Epidemiology and **Hematology and Oncology, University of North Carolina School Something like this?of Medicine, ‡Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, and §American College of Surgeons, National Cancer Data Base, Chicago, IL, USA

This research was presented at the Society of Urologic Oncology 2012 Annual Meeting, 29 November 2012, Bethesda, MD, USA

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OBJECTIVE

To examine the association of hospital volume and 90-day mortality after cystectomy, conditional on survival for 30 days.

PATIENTS AND METHODS

The National Cancer Data Base was used to evaluate 30- and 90-day mortality for 35 055 patients who underwent cystectomy for bladder cancer at one of 1118 hospitals.

Patient data were aggregated into hospital volume categories based on the mean annual number of procedures (low-volume hospital: <10 procedures; intermediate-volume hospital: 10–19 procedures; high-volume hospital: ≥20 procedures).

Associations between mortality and clinical, demographic and hospital characteristics were analysed using hierarchical logistic regression models. To assess the association between hospital volume and 90-day mortality independently of shorter-term mortality, 90-day mortality conditional on 30-day survival was assessed in the multivariate modelling.

RESULTS

Unadjusted 30- and 90-day mortality rates were 2.7 and 7.2% overall, 1.9 and 5.7% among high-volume hospitals, and 3.2 and 8.0% among low-volume hospitals, respectively.

Compared with high-volume hospitals, the adjusted risks among low-volume hospitals (odds ratio [95% CI]) of 30- and 90-day mortality, conditional on having survived for 30 days, from the hierarchical models were 1.5 (1.3–1.9), and 1.2 (1.0–1.4), respectively.

CONCLUSIONS

A low hospital volume was associated with greater 30- and 90-day mortality. These data support the need for further research to better understand the relatively high mortality rates seen between 30 and 90 days, which are high and less variable across hospital volume strata.

The stronger association between volume and 30-day mortality suggests that quality-reporting efforts should focus on shorter-term outcomes.

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Article of the week: A protocol for transperineal sector biopsies of the prostate

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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 prominent members 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.

Indications, results and safety profile of transperineal sector biopsies (TPSB) of the prostate: a single centre experience of 634 cases

Lona Vyas, Peter Acher, Janette Kinsella, Ben Challacombe, Richard T.M. Chang, Paul Sturch, Declan Cahill, Ashish Chandra and Richard Popert

The Urology Centre, Guy’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

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OBJECTIVE

• To describe a protocol for transperineal sector biopsies (TPSB) of the prostate and present the clinical experience of this technique in a UK population.

PATIENTS AND METHODS

• A retrospective review of a single-centre experience of TPSB approach was undertaken that preferentially, but not exclusively, targeted the peripheral zone of the prostate with 24–38 cores using a ‘sector plan’. Procedures were carried out under general anaesthetic in most patients.

• Between January 2007 and August 2011, 634 consecutive patients underwent TPSB for the following indications: prior negative transrectal biopsy (TRB; 174 men); primary biopsy in men at risk of sepsis (153); further evaluation after low-risk disease diagnosed based on a 12-core TRB (307).

RESULTS

• Prostate cancer was found in 36% of men after a negative TRB; 17% of these had disease solely in anterior sectors.

• As a primary diagnostic strategy, prostate cancer was diagnosed in 54% of men (median PSA level was 7.4 ng/mL).

• Of men with Gleason 3+3 disease on TRB, 29% were upgraded and went on to have radical treatment.

• Postoperative urinary retention occurred in 11 (1.7%) men, two secondary to clots. Per-urethral bleeding requiring hospital stay occurred in two men. There were no cases of urosepsis.

CONCLUSIONS

• TPSB of the prostate has a role in defining disease previously missed or under-diagnosed by TRB. The procedure has low morbidity.

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Editorial: Is zero sepsis alone enough to justify transperineal prostate biopsy?

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The landscape of infectious complications after TRUS-guided biopsy of the prostate has changed dramatically. While sepsis after TRUS-guided prostate biopsy has always been a concern for urologists performing this very common procedure, in the past couple of years a number of factors have added to these pre-existing concerns for urologists and patients alike.

First, key papers have reported the true incidence of sepsis and hospital re-admission after TRUS biopsy and have shown that these rates are increasing. Loeb et al. [1] reported that the 30-day re-admission rate in a Surveillance, Epidemiology and End Results (SEER)-Medicare population was 6.9% and that this rate is increasing. Nam et al. [2] similarly reported a 3.5-fold increase in hospital admissions after prostate biopsy in the previous 10 years, principally attributable to infection-related complications. These reports have been replicated around the world and there is consensus that this is a growing problem.

Second, there are increasing concerns about the emergence of resistant organisms, in particular, extended spectrum beta lactamase (ESBL), in regions where antibiotic use has contributed to the emergence of these strains [3]. Media attention has focused on this issue and has led to increased concerns among urologists and patients alike. It has also led to a requirement for extra precautions when assessing patients for prostate biopsy such that in some regions, rectal swabs are being taken to identify ESBL-carriers ahead of time. In a contemporary series, Taylor et al. [4] report that 19% of men undergoing transrectal prostate biopsy in Canada carry ciprofloxacin-resistant coliforms in rectal swabs. The thought of passing a needle through this flora into the prostate is somewhat disturbing; rectal swabs may become mandatory when offering a TRUS-guided biopsy to any patient and should absolutely be taken if planning a TRUS biopsy in someone who has travelled to South-East Asia in the preceding 6 months.

The Bloomberg News, in a well-researched report into antibiotic use in India and the emergence of resistant strains of Escherichia coli, reported some startling statistics about the overuse of antibiotics in that country, and described how the ‘perfect storm’ of antibiotic overuse, poverty and poor sanitation (half of the country’s 1.2 billion residents defaecate in the open), is contributing to the emergence of superbugs colonizing the gut of dwellers and visitors to India [5]. It is clear that even walking through a puddle in New Delhi puts a visitor at high risk of harbouring ESBL organisms in the rectum for many months after.

In this month’s BJUI, Vyas et al. [6] describe a consecutive series of 634 patients undergoing prostate biopsy at Guy’s Hospital in London using a transperineal template-guided approach, and report a sepsis rate of zero. They also report other notable factors including a 36% cancer detection rate in men who had previously undergone transrectal prostate biopsy with no evidence of malignancy and, in men on active surveillance for Gleason 6 prostate cancer, they observed upgrading to Gleason ≥7 cancer in 29% of cases after immediate re-staging biopsy using a transperineal approach. An even larger contemporary study from Pepe et al. [7] reports zero sepsis in a consecutive series of 3000 men undergoing transperineal prostate biopsy.

It is quite impossible to imagine such large series of prostate biopsies with no episodes of sepsis if performed using a transrectal approach. The documented increasing levels of ESBL and high levels of asymptomatic gut colonization, especially for those resident or travelling through South-East Asia, mean that adequate risk assessment and counselling of patients before TRUS biopsy is more important than ever before. A careful history regarding recent antibiotic use is also essential as previous recent use of quinolones is also a risk factor for infection after a transrectal biopsy [8].

While widespread adoption of a transperineal approach to prostate biopsy would have considerable resource and logistic issues, and inevitably would not be accepted by all urologists, the rising rate of infectious complications and of resistant organisms colonizing the rectum may mean that continuing with a transrectal approach becomes too risky and therefore unacceptable to patients and clinicians alike. While a transperineal approach also appears to add value in terms of more accurate staging and also facilitates the emerging interest in MRI fusion-guided biopsies and focal therapy, zero sepsis alone may be enough to convince many that a transrectal approach should no longer be preferred.

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Declan G. Murphy*†, Mahesha Weerakoon† and Jeremy Grummet‡

*Division of Cancer Surgery, University of Melbourne, Peter MacCallum Cancer Centre, †Australian Prostate Cancer Research Centre, Epworth Richmond Hospital, and ‡Department of Urology, The Alfred Hospital, Melbourne, VIC, Australia

References

  1. Loeb S, Carter HB, Berndt SI, Ricker W, Schaeffer EM. Complications after prostate biopsy: data from SEER-Medicare. J Urol 2011; 186: 1830–1834
  2. Nam RK, Saskin R, Lee Y et al. Increasing hospital admission rates for urological complications after transrectal ultrasound guided prostate biopsy. J Urol 2010; 183: 963–968
  3. Williamson DA, Masters J, Freeman J, Roberts S. Travel-associated extended-spectrum beta-lactamase-producing Escherichia coli bloodstream infection following transrectal ultrasound-guided prostate biopsy. BJU Int 2012; 109: E21–22
  4. Taylor S, Margolick J, Abughosh Z et al. Ciprofloxacin resistance in the faecal carriage of patients undergoing transrectal ultrasound guided prostate biopsy. BJU Int 2013; 111: 946–953
  5. Gale JN, Narayan A. Drug-defying germs from India speed post-antibiotic era. 2012; Available at: https://www.bloomberg.com/news/2012-05-07/drug-defying-germs-from-india-speed-post-antibiotic-era.html. Accessed June 2014
  7. Pepe PA, Aragona F. Morbidity after transperineal prostate biopsy in 3000 patients undergoing 12 vs 18 vs more than 24 needle cores. Urology 2013; 81: 1142–1146
  8. Patel U, Dasgupta P, Amoroso P, Challacombe B, Pilcher J, Kirby R. Infection after transrectal ultrasonography-guided prostate biopsy: increased relative risks after recent international travel or antibiotic use. BJU Int 2012; 109: 1781–1785

 

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Article of the month – Good vibrations: better erectile function with penile vibratory stimulation

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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 prominent members 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. Fode discussing his paper.

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

Penile vibratory stimulation in the recovery of urinary continence and erectile function after nerve-sparing radical prostatectomy: a randomized, controlled trial

Mikkel Fode*, Michael Borre†, Dana A. Ohl‡, Jonas Lichtbach§ and Jens Sønksen*

*Department of Urology, Herlev University Hospital, Herlev, †Department of Urology, Aarhus University Hospital, Aarhus, Denmark, ‡Department of Urology, University of Michigan, Ann Arbor, MI, USA, and §Department of Physiotherapy, Herlev University Hospital, Herlev, Denmark

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OBJECTIVE

• To examine the effect of penile vibratory stimulation (PVS) in the preservation and restoration of erectile function and urinary continence in conjunction with nerve-sparing radical prostatectomy (RP).

PATIENTS AND METHODS

• The present study was conducted between July 2010 and March 2013 as a randomized prospective trial at two university hospitals which we already determined with the physiotherapy system with the professional and affordable physiotherapy merrylands  has to offer for the trials. Eligible participants were continent men with an International Index of Erectile Function-5 (IIEF-5) score of at least 18, scheduled to undergo nerve-sparing RP.

• Patients were randomized to a PVS group or a control group. Patients in the PVS group were instructed in using a PVS device (FERTI CARE® vibrator).

• Stimulation was performed at the frenulum once daily by the patients in their own homes for at least 1 week before surgery. After catheter removal, daily PVS was re-initiated for a period of 6 weeks.

• Participants were evaluated at 3, 6 and 12 months after surgery with the IIEF-5 questionnaire and questions regarding urinary bother. Patients using up to one pad daily for security reasons only were considered continent. The study was registered at https://clinicaltrials.gov/ (NCT01067261).

RESULTS

• Data from 68 patients were available for analyses (30 patients randomized to PVS and 38 patients randomized to the control group).

• The IIEF-5 score was highest in the PVS group at all time points after surgery with a median score of 18 vs 7.5 in the control group at 12 months (P = 0.09), but the difference only reached borderline significance.

• At 12 months, 16/30 (53%) patients in the PVS group had reached an IIEF-5 score of at least 18, while this was the case for 12/38 (32%) patients in the control group (P = 0.07).

• There were no significant differences in the proportions of continent patients between groups at 3, 6 or 12 months. At 12 months 90% of the PVS patients were continent, while 94.7% of the control patients were continent (P = 0.46).

CONCLUSION

• The present study did not document a significant effect of PVS. However, the method proved to be acceptable for most patients and there was a trend towards better erectile function with PVS. More studies are needed to explore this possible effect further.

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Editorial: Penile vibratory stimulation (PVS) a novel approach for penile rehabilitation post nerve sparing radical prostatectomy

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The reported incidence of erectile dysfunction (ED) after nerve-sparing radical prostatectomy (NS-RP) varies in the literature from 30 to 80% [1]. This can be explained by the state of neuropraxia which affects the cavernosal nerves, even if the nerves are anatomically intact. During this period there is a lack of nocturnal tumescence which leads to tissue hypoxia and ischaemic damage to the cavernosal smooth muscles leading to smooth muscle necrosis and fibrosis, which in turn causes veno-occlusive dysfunction (VOD). A study by Mulhall et al. [2] showed that, at 12 months after NS-RP, 50% of patients will have VOD and ED. The role of penile rehabilitation, therefore, is to maintain adequate tissue oxygenation until the cavernosal nerves recover with the return of the spontaneous nocturnal tumescence; thus, penile rehabilitation should not be confused with ED treatment. If you see yourself as religious, addiction may make you feel guilty or get you to feel isolated among your friends at your religious organization. A spiritual Christian rehab center in Orlando may be the right choice for you. Not only do you get to meet like-minded people to share your experiences in your journey to sobriety, but the process may also help you to rediscover your faith in God. Legacy Healing Center Tampa offer programs that make spiritual guidance an important part of every type of addiction treatment. Orange County law enforcement has taken steps to make sure the drugs are not as easily available as they once were. This has helped manage Orlando’s drug problem and kept it from turning worse. As important as prevention is to saving lives, however, to the hundreds who are already addicted, rehab is what helps. If you are religious or spiritual, faith-based drug rehab can be the answer to the challenges that you face. It’s important to remember that faith-based rehab only works well for those who are deeply spiritual or religious. Trying faith-based rehab when you are ambivalent about religion can work against you. You may find that you aren’t able to accept what you’re asked to practice, and you may find yourself rebelling. It’s important to choose a treatment approach that you can go along with in good conscience.

Several lines of treatment, including phosphodiesterase 5 inhibitors, intracavernous injection of alprostadil and vacuum pump therapy, have been used in penile rehabilitation but an agreed rehabilitation programme in terms of agents used, timing and duration of therapy does not yet exist [1].

The present study by Fode et al. [3] reports a novel approach to penile rehabilitation using penile vibratory stimulation (PVS). The study looked into the effect of PVS on postoperative erection and continence. The Ferticare® vibrator (Fig. 1) was used at an amplitude of 2 mm and a vibration frequency of 100 Hz and applied to the frenulum once daily, with a sequence consisting of 10 s of stimulation followed by a 10-s rest and repeated 10 times.

The results showed a trend towards better erection in the PVS group (n = 30) compared with the control group (n = 38) as evidenced by the higher International Index of Erectile Function (IIEF) score, but the difference was not significant (P = 0.09). After 1 year, 16 patients (53%) in the PVS group had an IIEF score ≥18 compared with 12 (32%) patients in the control group (P = 0.07). The results did not show any effect of treatment on continence; at 12 months, 90% of the PVS group achieved continence compared with 94.7% of the control group (P = 0.46), although the PVS group had a significantly higher preoperative LUTS score which may explain the results.

The theory postulated is that application of PVS activates the parasympathetic erectile spinal centre (S2–S4), which in turn leads to activation of the cavernosal nerves, enhancing the healing process, and recovery from neuropraxia and restoration of spontaneous erections. Also this would lead to stimulation of the somatic S2–S4 spinal centre, which controls the pelvic floor muscles via the pudendal nerve, leading to the recovery of continence. Although this has been shown in patients with spinal cord injury as the authors mentioned; this may not be the case in post NS-RP with the nerves in a state of neurapraxia, whereas in patients with spinal cord injury the nerves are intact. It would have been of great value to conduct neurophysiological tests on these patients to demonstrate that, despite the cavernosal nerves being in a state of neurapraxia, nerve activity in response to PVS was actually present.

The rehabilitation protocol used in the present study started early but only continued for 6 weeks postoperatively. Studies have shown that the potential recovery time of erectile function after NS-RP is 6–36 months, with the majority recovering within 12–24 months [1,4]. The results might have shown statistical significance in favour of PVS, had treatment continued for a longer period. Starting PVS treatment in the early postoperative period may not be suitable in all patients; in this study six out of 36 patients (16.6%) were non-compliant with the protocol; four had prolonged catheterization and two experienced pain. Furthermore, neurophysiological testing is required to show that in the early postoperative period the cavernosal nerves are actually intact and therefore respond to PVS.

Although the results of the present study did not reach significance, they are encouraging, as there was a trend in favour of treatment with regard to erectile function. Further studies involving larger numbers of patients are warranted to investigate this new line of rehabilitation.

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Amr Abdel Raheem*† and David Ralph†
*Andrology Department, Cairo University Hospital, Cairo, Egypt, and †St. Peter’s Andrology Centre, Institute of Urology, London, UK

References

  1. Mulhall JP, Bivalacqua TJ, Becher EF. Standard operating procedure for the preservation of erectile function outcomes after radical prostatectomy. J Sex Med 2013; 10: 195–203
  2. Mulhall JP, Slovick R, Hotaling J et al. Erectile dysfunction after radical prostatectomy: hemodynamic profiles and their correlation with the recovery of erectile function. J Urol 2002; 167: 1371–5
  3. Fode M, Borre M, Ohl D, Lichtbach J, Sønksen J. Penile vibratory stimulation in the recovery of urinary continence and erectile function after nerve-sparing radical prostatectomy: a randomized, controlled trial. BJU Int 2014; 114: 111–7
  4. Rabbani F, Schiff J, Piecuch M et al. Time course of recovery of erectile function after radical retropubic prostatectomy: does anyone recover after 2 years? J Sex Med 2010; 7: 3984–90
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Video: Penile vibratory stimulation after radical prostatectomy

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Penile vibratory stimulation in the recovery of urinary continence and erectile function after nerve-sparing radical prostatectomy: a randomized, controlled trial

Mikkel Fode*, Michael Borre†, Dana A. Ohl‡, Jonas Lichtbach§ and Jens Sønksen*

*Department of Urology, Herlev University Hospital, Herlev, †Department of Urology, Aarhus University Hospital, Aarhus, Denmark, ‡Department of Urology, University of Michigan, Ann Arbor, MI, USA, and §Department of Physiotherapy, Herlev University Hospital, Herlev, Denmark

Read the full article
OBJECTIVE

• To examine the effect of penile vibratory stimulation (PVS) in the preservation and restoration of erectile function and urinary continence in conjunction with nerve-sparing radical prostatectomy (RP).

PATIENTS AND METHODS

• The present study was conducted between July 2010 and March 2013 as a randomized prospective trial at two university hospitals. Eligible participants were continent men with an International Index of Erectile Function-5 (IIEF-5) score of at least 18, scheduled to undergo nerve-sparing RP.

• Patients were randomized to a PVS group or a control group. Patients in the PVS group were instructed in using a PVS device (FERTI CARE® vibrator).

• Stimulation was performed at the frenulum once daily by the patients in their own homes for at least 1 week before surgery. After catheter removal, daily PVS was re-initiated for a period of 6 weeks.

• Participants were evaluated at 3, 6 and 12 months after surgery with the IIEF-5 questionnaire and questions regarding urinary bother. Patients using up to one pad daily for security reasons only were considered continent. The study was registered at https://clinicaltrials.gov/ (NCT01067261).

RESULTS

• Data from 68 patients were available for analyses (30 patients randomized to PVS and 38 patients randomized to the control group).

• The IIEF-5 score was highest in the PVS group at all time points after surgery with a median score of 18 vs 7.5 in the control group at 12 months (P = 0.09), but the difference only reached borderline significance.

• At 12 months, 16/30 (53%) patients in the PVS group had reached an IIEF-5 score of at least 18, while this was the case for 12/38 (32%) patients in the control group (P = 0.07).

• There were no significant differences in the proportions of continent patients between groups at 3, 6 or 12 months. At 12 months 90% of the PVS patients were continent, while 94.7% of the control patients were continent (P = 0.46).

CONCLUSION

• The present study did not document a significant effect of PVS. However, the method proved to be acceptable for most patients and there was a trend towards better erectile function with PVS. More studies are needed to explore this possible effect further.

Read more articles of the week

 

Article of the week: Mirabegron is an effective treatment for OAB

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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.

Phase III, randomised, double-blind, placebo-controlled study of the β3-adrenoceptor agonist mirabegron, 50 mg once daily, in Japanese patients with overactive bladder

Osamu Yamaguchi, Eiji Marui*, Hidehiro Kakizaki†, Yukio Homma‡, Yasuhiko Igawa§, Masayuki Takeda, Osamu Nishizawa**, Momokazu Gotoh††, Masaki Yoshida‡‡, Osamu Yokoyama§§, Narihito Seki¶¶, Yasushi Ikeda*** and Sumito Ohkawa***

Division of Bioengineering and LUTD Research, School of Engineering, Nihon University, Koriyama, *Department of Human Arts Sciences, University and Graduate School of Human Arts Sciences, Saitama, †Department of Urology, Asahikawa Medical University, Asahikawa, ‡Department of Urology, The University of Tokyo Graduate School of Medicine, Tokyo, §Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Department of Urology, University of Yamanashi, Yamanashi, **Department of Urology, Shinshu University, Matsumoto, ††Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, ‡‡Department of Urology, National Center 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

Registered at clinicaltrials.gov (NCT00966004)

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OBJECTIVE

• To evaluate the efficacy and safety of the β3-adrenoceptor agonist mirabegron, in a Japanese population with overactive bladder (OAB).

PATIENTS AND METHODS

• This randomised, double-blind, placebo-controlled phase III study enrolled adult patients experiencing OAB symptoms for ≥24 weeks. Patients with ≥ 8 micturitions/24 h and ≥1 urgency episode/24 h or ≥1 urgency incontinence episode/24 h were randomised to once-daily placebo, mirabegron 50 mg or tolterodine 4 mg (as an active comparator, without testing for non-inferiority of efficacy and safety) for 12 weeks.

• The primary endpoint was the change in the mean number of micturitions/24 h from baseline to final assessment. Secondary endpoints included micturition variables related to urgency and/or incontinence and quality-of-life domain scores on the King’s Health Questionnaire.

• Safety assessments included adverse events (AEs), post-void residual urine volume, laboratory variables, vital signs and 12-lead electrocardiogram.

RESULTS

• A total of 1139 patients were randomised to receive placebo (n = 381), mirabegron 50 mg (n = 380) or tolterodine 4 mg (n = 378). Demographic and baseline characteristics were similar among the treatment groups.

• At final assessment, mirabegron was significantly superior to placebo in terms of mean [sd] change from baseline in number of micturitions/24 h (–1.67 [2.212] vs -0.86 [2.354]; P < 0.001) and mean [sd] change from baseline in number of urgency episodes/24 h (–1.85 [2.555] vs –1.37 [3.191]; P = 0.025), incontinence episodes/24 h (–1.12 [1.475] vs –0.66 [1.861]; P = 0.003), urgency incontinence episodes/24 h (–1.01 [1.338] vs –0.60 [1.745]; P = 0.008), and volume voided/micturition (24.300 [35.4767] vs 9.715 [29.0864] mL; P < 0.001).

• The incidence of AEs in the mirabegron group was similar to that in the placebo group. Most AEs were mild and none were severe.

CONCLUSIONS

• Mirabegron 50 mg once daily is an effective treatment for OAB symptoms, with a low occurrence of side effects in a Japanese population.

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Editorial: Mirabegron the first β3-adrenoceptor agonist for OAB: a summary of the phase III studies

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The study reported in this edition of BJUI details the results of a large phase III study conducted in Japan contrasting 50 mg mirabegron, the new β3-adrenoceptor agonist, to placebo with tolterodine as an active comparator [1]. This adds to the body of knowledge already provided by phase III evaluations reported from Europe [2], where tolterodine was also used as an active comparator and North America [3], where the efficacy of 25–100 mg was compared with placebo [4]. As the first in this new class of compounds with a mechanism of action that is distinct from that of the antimuscarinic agents, which are the mainstay of overactive bladder (OAB) therapy to date, there is clearly interest in the efficacy and in particular the safety of this new class of compound. This has been evaluated in a long-term safety study [5].

This paper [1] confirms the findings evident in these other publications, which suggest a favourable short- and long-term tolerability profile for mirabegron in patients with OAB. In particular, excluding typical anticholinergic side-effects, such as dry mouth, which occurred with a similar incidence with mirabegron as placebo, but was reported in 13.3% of tolterodine patients, there was no evidence of any cardiotoxicity with mirabegron, which is consistent with a previous pooled analysis of the European and North American studies [6]. In this pooled analysis, mirabegron was associated with mean increases of 0.4–0.6 mmHg in blood pressure and ≈1 beat/min in heart rate, both reversible upon treatment discontinuation. In the long-term study, the changes in heart rate seen with mirabegron 50 mg were less than those seen with tolterodine. Changes in vital signs did not result in more cardiovascular-related adverse events in patients treated with mirabegron compared with those treated with placebo or tolterodine in both the pooled 12-week and the 1-year long-term studies. In addition, there was one case of urinary retention with mirabegron in the pooled 12-week studies; the incidence being less than placebo or tolterodine. Clearly from the evidence now available, mirabegron has an efficacy similar to that seen with tolterodine and significantly better than placebo for most of the symptoms of the OAB symptom complex. In conclusion, mirabegron is well-tolerated and as efficacious as anticholinergic therapy. Further analyses of the phase III data has shown that mirabegron is effective in both naïve patients and those that have failed to either tolerate or respond to a previous anticholinergic therapy [7].

Future work should include an adequately powered direct comparison to antimuscarinic therapy. Furthermore, data on the combination of mirabegron and an antimuscarinic have already shown potential benefit in a phase II study, and this should be explored further [8]. Other interesting areas to explore will be the use of this therapy in both male patients and patients with neurogenic bladder dysfunction.

Read the full article
Christopher Chapple
Department of Urology, The Royal Hallamshire Hospital, Sheffield Teaching Hospitals, Sheffield, UK

 

References

  1. Yamaguchi O, Marui E, Kakizaki H et al. Phase III, randmised, double-blind, placebo-controlled study of the β3 -adrenoceptor agonist mirabegron, 50 mg once daily, in Japanese patients with overactive bladder. BJU Int 2014; 113: 951–960.
  2. Khullar V, Amarenco G, Angulo JC et al. Efficacy and tolerability of mirabegron, a β(3)-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European-Australian phase 3 trial. Eur Urol 2013; 63: 283–295
  3. Nitti VW, Auerbach S, Martin N, Calhoun A, Lee M, Herschorn S. Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J Urol 2013; 189: 1388–1395
  4. Herschorn S, Barkin J, Castro-Diaz D et al. A phase III, randomized, double-blind, parallel-group, placebo-controlled, multicentre study to assess the efficacy and safety of the β3 adrenoceptor agonist, mirabegron, in patients with symptoms of overactive bladder. Urology 2013; 82: 313–320
  5. Chapple CR, Kaplan SA, Mitcheson D et al. Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a β(3)-adrenoceptor agonist, in overactive bladder. Eur Urol 2013; 63: 296–305
  6. Nitti VW, Khullar V, van Kerrebroeck P et al. Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies. Int J Clin Pract 2013; 67: 619–632
  7. Khullar V, Cambronero J, Angulo JC et al. Efficacy of mirabegron in patients with and without prior antimuscarinic therapy for overactive bladder: a post hoc analysis of a randomized European-Australian Phase 3 trial. BMC Urol 2013; 13: 45
  8. Abrams P, Kelleher C, Staskin D et al. Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (symphony). Eur Urol 2014. doi: 10.1016/j.eururo.2014.02.012

 

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Article of the week: Pilot study of EGFR-targeted therapies in men with penile SCC shows promising initial results

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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.

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. Pagliaro discussing his paper.

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

Epidermal growth factor receptor-targeted therapy in locally advanced or metastatic squamous cell carcinoma of the penis

Bradley C. Carthon*§, Chaan S. Ng†, Curtis A. Pettaway‡ and Lance C. Pagliaro*

Departments of *Genitourinary Medical Oncology, †Radiology, and ‡Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
§Current address: Winship Cancer Institute, Emory University,Atlanta, Georgia, USA

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OBJECTIVE

• To evaluate the safety and efficacy of epidermal growth factor receptor (EGFR)-targeted therapy in patients with advanced penile or scrotal cancer.

PATIENTS AND METHODS

• We retrospectively reviewed the charts of patients with penile or scrotal squamous cell carcinoma who had visited our tertiary cancer centre between 2002 and 2009, including their subsequent treatment and follow-up.

• We collected details of EGFR-targeted therapy and clinical outcomes. Treatment-associated time-to-disease-progression (TTP), overall survival (OS), responses to therapy and toxicity were evaluate

RESULTS

• A total of 24 patients had received EGFR-targeted therapies, including cetuximab, erlotinib and gefitinib. The most common treatment given (to 67% of patients) was cetuximab combined with one or more cytotoxic drugs.

• The most common adverse effect was skin rash (71%). The median (range) TTP and OS were 11.3 (1–40) and 29.6 (2–205) weeks, respectively. The OS time for patients with visceral or bone metastases was significantly shorter than it was for those without (24.7 vs 49.9 weeks, P = 0.013).

• Among 17 patients treated with cetuximab alone or in combination with cisplatin, there were four partial responses (23.5%) including two patients with apparently chemotherapy-resistant tumours.

CONCLUSIONS

• Our results suggest that cetuximab has antitumour activity in metastatic penile cancer, and may enhance the effect of cisplatin-based chemotherapy.

• Prospective studies of EGFR-targeted therapies in men with these tumours are warranted

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Editorial: Squamous cell carcinoma of the penis: therapeutic targeting of the EGFR

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Squamous cell carcinoma of the penis is a rare genitourinary malignancy. There are wide variations in its incidence, ranging from 0.1 to 0.9/100 000 men in Europe, where it accounts for 1% of male malignancies, to as high as 4.4 and 4.2/100 000 men in Uganda and Paraguay, where it accounts for up to 10% of male malignancies.

The management of patients with advanced squamous cell carcinoma of the penis, including those patients with node-positive disease and metastatic disease, remains challenging. The beneficial effects of chemotherapy and radiotherapy are not established, partly because of the small numbers of patients within studies, but also because of the multiple regimens used for treatment, combined with relatively low response rates and high toxicities.

The presence and extent of lymph node metastasis is the single most common factor predictive of survival in men with penile carcinoma, with 5-year survival rates of 88% in men with minimal or no metastases (one to two nodes), compared with ∼25% in those men with two or more inguinal nodes involved. In men with extra nodal spread of the cancer and pelvic metastases, 5-year survival rates fall as low as 5–10%.

The most important aetiological factors for the development of squamous cell cancer of the penis appear to be the presence of a foreskin, immunosuppression and smoking. In addition to this, human papillomavirus (HPV) has been shown to have a central role in tumorogenesis [1]. HPV DNA can be identified in up to 80% of tumour specimens. The commonest subtypes expressed are the 16/18 subtypes (high risk) and the 6/11 subtypes (low risk). The virus exerts its tumorogenic effect via expression of viral oncogenes E6 and E7, which inhibit the activity of tumour suppressor genes p53 and RB. Whilst a number of potential biomarkers have been identified as prognostic indices of survival, translational research to date is limited [2].

A recent study from the UK has reported that survival rates in men with node-positive penile carcinoma have not improved significantly in the last 20 years [3]. In view of the poor response rates from chemotherapeutic agents, combined with their high toxicity and the poor survival rates in men with node-positive disease, it is imperative that more novel treatment methods, including targeted therapies, are developed to treat this devastating tumour.

A potential biological target in all squamous cell cancers, including the penis, is the epidermal growth factor family of receptors. A number of trials have been conducted to evaluate the safety profile and activity of a combination of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, including cetuximab, with schedules of platinum-based chemotherapy in a number of tumour sites. These combinations have shown good tolerability. The addition of cetuximab to platinum-based chemotherapy prolongs survival in patients with recurrent or metastatic squamous cell tumours of the head and neck.

Penile squamous cell tumours and their metastases also highly express EGFRs with ∼90 to 100% of tumours expressing the EGFR. The EGFR is a cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands. The EGFR is a member of the ErbB family of receptors, which consist of a sub-family of four closely related tyrosine kinases (EGFR [ErbB-1], HER2/c-neu [ErbB-2], Her 3 [ErbB-3] and Her 4 [ErbB-4]). EGFR can be activated by binding its specific ligands, including EGF and TGF-α. Dimerization of the EGFR stimulates tyrosine kinase activity and autophosphorylation of a number of tyrosine residues in the C-terminal domain of the EGF receptor, which downstream initiates a number of signal transduction cascades, ultimately resulting in cell migration and proliferation.

Cetuximab and panitumumab are monoclonal antibody inhibitors of the EGFR, which block the extracellular ligand-binding domains on the EGFR receptor. Furthermore, cetuximab induces the internalization of EGFR leading to downregulation of the EGFR. It also targets cytotoxic immune effector cells towards EGFR-expressing tumour cells (antibody-dependent cell-mediated cytotoxicity). Drugs, such as gefitinib are EGFR tyrosine kinase inhibitors, which bind and inhibit the EGFR tyrosine kinase by binding to the ATP-binding site of the enzyme. In lung tumours, patients who are EGFR-positive have shown relatively high response rates to tyrosine kinase inhibitors, although many patients develop resistance.

Two studies have analysed the expression of the EGFR receptor status in penile cancer [4, 5]. In both studies, the EGFR receptor was overexpressed in tumour tissue. In one study [4], 40 out of 44, i.e. 91% of patients, showed a positive EGFR expression in the primary tumour as well as in metastases. Importantly, a correlation between EGFR receptor expression and survival was not demonstrated.

In the present study by Carthon et al. [6], the authors evaluate the safety and efficacy of EGFR-targeted therapy using both cetuximab and tyrosine kinase inhibitors, including gefitinib. This pilot study evaluated 24 patients receiving EGFR-targeted therapies. Among 17 patients treated with cetuximab alone, or in combination with cisplatin, there were four partial responses. Whilst the presence of visceral metastases at the start of EGFR-based therapy was associated with poor time to progression and overall survival, several patients in that study were shown to have regression of predominantly inguinal and pelvic tumours. Interestingly, there were no objective responses to the small molecule inhibitors gefitinib or erlotinib. This pilot study would suggest that further prospective studies of EGFR-targeted therapies in men with squamous cell carcinoma of the penis are warranted and these initial results are promising; however, the number of regimens and agents used in the study is varied. This variation and the small number of patients and the retrospective nature of the study represent study limitations. Nevertheless, the concept of targeted therapies for squamous cell carcinoma of the penis should certainly be evaluated further, as it is clear that surgery alone is insufficient to improve survival in patients with N+ or M1 disease.

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Suks Minhas
Department of Urology, University College Hospital, London, UK

  1. Minhas S, Manseck A, Watya S, Hegarty PK. Penile cancer. Prevention and premalignant conditions. Urology 2010; 76 (2 Suppl. 1): S24–35
  2. Kayes O, Ahmed HU, Arya M, Minhas S. Molecular and genetic pathways in penile cancer. Lancet Oncol 2007; 8: 420–429
  3. Kayes O, Freeman A, Lau D et al. Longitudinal analysis of outcomes for men with node positive penile cancer – are we improving? BJU Int 2013; 111 (S3): P19
  4. Börgermann C, Schmitz KJ, Sommer S, Rübben H, Krege S. Characterization of the EGF receptor status in penile cancer: retrospective analysis of the course of the disease in 45 patients. Urologe A 2009; 48: 1483–1489
  5. Lavens N, Gupta R, Wood LA. EGFR overexpression in squamous cell carcinoma of the penis. Curr Oncol 2010; 17: 4–6
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