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Editorial: Pushing the robot-assisted prostatectomy envelope – to the safety limits? Better outcomes

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The present article by Lim et al. [1] describing the new technique for robot-assisted radical prostatectomy is provocative. It really does highlight the dramatic improvement in outcomes of prostate cancer surgery for men over the last 25 years. What used to be a 3-week hospital stay with a 50% incontinence rate and a 100% impotence rate [2, 3] now becomes a day case with a high likelihood of excellent urinary control early after surgery and a fair potential for potency preservation. Twenty-five years ago men who underwent radical prostatectomy were truly brave patients.

Lim et al. report a single series by the senior author of 50 cases performed using the so-called Retzius preservation technique. Their cohort of 50 patients treated this way was compared with a retrospective cohort of the surgeon’s patients. The patients had lower-risk disease and patients who had seminal vesicle invasion or extracapsular extension noted preoperatively, presumably on MRI, were excluded from the series. The authors report a shorter operating time and an earlier return to urinary continence in the first 6 months after surgery.

I guess where surgeons are now taking us is to an attempt to remove the prostate from the hammock of neurovascular, muscular and fascial tissue surrounding it, without disturbing the anatomy [4]. If this can be achieved then radical prostatectomy with minimal morbidity is a very compelling choice for the primary treatment of prostate cancer.

The authors’ hypothesis is that preservation of the levator fascia, puboprostatic ligaments and detrusor apron will fix the bladder somewhat like a sling would, with support at the bladder neck during increased intra-abdominal pressure.

It should be noted, however, that the present paper represents a single series of patients selected after a long learning curve by a very experienced surgeon. These excellent outcomes may simply reflect the fact that the surgeon is now extremely technically capable. It is contentious to assume that a propensity score matching of a retrospective cohort would represent a true comparator to contemporary outcomes. These excellent outcomes probably reflect technical improvements achievable with more risky and innovative surgery – after many cases. The authors should be congratulated on pushing the envelope to achieve even better outcomes for patients undergoing this operation, but the exclusion of patients with high-risk disease is probably the major negative aspect of their report. It has become increasingly obvious that patients with high-risk disease are those who benefit most from radical prostatectomy surgery. Surgery for patients with very-low-risk disease (Gleason 6) is probably unnecessary. Nevertheless, with continued insights such as those provided by these surgeons, we may be able to increase the range of patients to whom Retzius-sparing surgery in higher risk cohorts can be offered.

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Anthony J. Costello
Department of Urology, Royal Melbourne Hospital, Parkville, Victoria, Australia

References

  1. Lim SK, Kim KH, Shin T-Y et al. Retzius-sparing Robot-assisted Laparoscopic Radical Prostatectomy – combining the best of retropubic and perineal approaches. BJU Int 2014; 114: 236–244
  2. Wein AJ, Kavousi LR, Novick AC, Partin AW, Peters CA. Campbell-Walsh Urology, 10th edn. Saint Louis, MO: Saunders, 2011: 5688
  3. Catalona WJ, Carvalhal GF, Mager DE, Smith DS. Potency, continence and complication rates in 1,870 consecutive radical retropubic prostatectomies. J Urol 1999; 162: 433–438
  4. Costello AJ, Brooks M, Cole OJ. Anatomical studies of the neurovascular bundle and cavernosal nerves. BJU Int 2004; 94: 1071–1076
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Editorial: Routine data expose a need for change

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Withington et al. [1], in their analysis of changes in stress urinary incontinence (SUI) surgery in England, have tapped in to a rich seam of information which, as well as holding the promise of much more, also highlights a need for changed thinking about services and training. They have produced an excellent review of the use of Hospital Episode Statistics (HES) data to establish a pattern of changing surgical practice for the treatment of urinary incontinence in England. They rightly point out the great potential of using patient-specific linked data to explore other relationships between predictors and outcome. Widespread use of powerful data of this sort could, theoretically at least, help to answer research questions, as well as to plan service design and resource allocation.

The use of routine data by the NHS is a hot topic in the UK at present. An England wide database, Care.data, has been developed that plans to link anonymised routine data, automatically drawn from community care, hospital statistics, public health and social care databases. Whilst debate rages about the confidentiality issues, and conspiracy theories abound, some strident voices promote a vision of how such a databank will be used to address big health questions and to identify relationships between social conditions, healthcare and outcomes, which have not previously been possible. Similar projects exist in Wales and Scotland enjoying the acronyms of SAIL (Secure Anonymised Information Linkage) and SPIRE (The Scottish Primary Care Information Resource), and Northern Ireland also has plans in progress. These systems do differ subtly in detail but not in aspiration [2].

The authors’ findings confirm that lesser invasive procedures now dominate the treatment of SUI in women, and that the use of Botulinum toxin A for treating refractory urgency incontinence, despite the absence until recently of a license for its use, has become commonplace. Whilst demand for SUI surgery may have levelled off, following something of a surge in recent years, the demand for Botulinum toxin A treatment inevitably increases as patients become locked in to long-term retreatment programmes. With these numbers it should be possible for a hospital serving a population of, say, 250 000 to perform at least 40–50 of each procedure per annum. This is probably enough to sustain a routine service, consistent with recommendations from the National Institute for Health and Clinical Excellence (NICE), which described how surgeons should seek to maintain expertise through, amongst other things, having an adequate caseload [3].

Sacral neuromodulation (SNS), artificial sphincter, colposuspension, tape removal and augmentation cystoplasty are procedures that occupy the complex end of a range of surgical options for incontinence. These are patients who have often failed other treatments, defy easy categorisation, and are performed in relatively small numbers. SNS has not been adopted in the UK, as widely as might have been anticipated following NICE guidance in 2006, which strongly recommended its implementation – perhaps because of local difficulties in commissioning a procedure with such high capital costs. The low figures for all these procedures strengthen the argument to focus complex work into expert centres, where adequate numbers can be maintained and the next generation of specialists can be effectively trained.

Those who commission or plan service delivery, and those who design training programmes, need to take heed of this evidence. The nature of female and urodynamic urology has changed over recent years, now being characterised by 95% very routine procedures and 5% complex difficult cases. But if we centralise the 5% of complex work and leave those working in more peripheral hospitals able to offer only mid-urethral slings and Botulinum toxin A, then we have to reconsider the basis of specialist training. There is no point training a person to high levels of competence in complex procedures that they will never use in senior practice. The UK Continence Society is currently developing a set of minimum standards for service delivery and training, which will take this information into account.

The evidence presented by Withington et al. [1] is specific to England and it remains unclear how much these trends can be extrapolated to the UK nations with devolved healthcare, or indeed to other countries. However, Withington et al. [1] must be congratulated for highlighting both the power of routine data in clinical research, and specifically for identifying the dramatic changes in surgical practice of incontinence, which require an adaptive response from both the NHS and our specialist organisations.

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Malcolm Lucas
Department of Urology, Morriston Hospital, Swansea, UK

References

  1. Withington J, Hirji S, Sahai A. The changing face of urinary continence surgery in England: a perspective from the hospital episode statistics database. BJU Int 2014; 114: 268–277
  3. National Institute for Health and Clinical Excellence. September 2013. Urinary incontinence: the management of urinary incontinence in women. Clinical guidelines CG171. Available at: https://guidance.nice.org.uk/CG171. Accessed April 2014

 

Editorial: Upper tract urothelial carcinoma: do we really need to burn down the house?

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In this issue, Simhan et al. [1] use the Surveillance, Epidemiology, and End Results (SEER) database to compare outcomes of nephron-sparing and radical extirpative therapy for upper tract urothelial carcinoma (UTUC). Their study sheds some well-needed light on a difficult clinical dilemma.

A diagnosis of low- or moderate-grade, low-stage UTUC is akin to finding a spot of suspicious green mould on your attic drywall. The scale and potential danger of the problem may not be immediately apparent and both patient and urologist must make tough choices with incomplete information. Spot treat the problem and preserve nephrons via endoscopic or segmental resection or burn down the house with radical nephroureterectomy to minimise recurrence and progression risk? With only relatively small datasets for guidance and the uncertainty of endoscopic biopsy, many urologists have a low threshold to proceed with radical therapy, perhaps unnecessarily.

Simhan et al. [1] identified 1227 patients in the SEER dataset with low- or moderate-grade, localised, non-invasive UTUC who were treated either with nephron-sparing procedures (endoscopic resection or segmental ureterectomy) or nephroureterectomy between 1992 and 2008. For this cohort, radical therapy with nephroureterectomy imparted no advantage in cancer-specific survival. Patients undergoing nephron sparing were slightly older and did experience higher non-cancer specific mortality. This may reflect an underlying bias to offer nephron sparing to older patients with a greater burden of comorbidities and shorter life expectancy. These results corroborate another large SEER study from 2010, which documented no difference in cancer-specific mortality when comparing segmental resection with nephroureterectomy for T1–T4 N0M0 urothelial carcinoma of the ureter [2].

Population-based tumour registry studies are complementary to institutional series and are particularly valuable for rare tumours like UTUC. However, they have their limitations and these are outlined clearly in the Simhan et al. [1] article. Most notable are the lack of linked comorbidity information and the inability to separate segmental resection from endoscopic management in the nephron-sparing group. We should avoid the temptation to broaden indications for endoscopic resection to all patients with low-grade, low-stage UTUC of the renal pelvis and calyces. After all, the authors present no data on: (i) local recurrence and reoperation rates, (ii) progression to radical nephroureterectomy or (iii) correlation between endoscopic biopsy results and the ultimate pathology from nephroureterectomy specimens.

Over the past decade, there has been a progressive movement toward nephron-sparing approaches for treatment of T1 RCC, even in the context of a normal contralateral kidney. This transition has been fuelled by data showing the substantial negative impact of chronic kidney disease (CKD) on cardiovascular events and overall mortality [3]. Broader application of this philosophy to the treatment of low- or moderate-grade, low-stage UTUC would be a natural next step. This is particularly true given the advantage of maximising nephrons should disease progression necessitate platinum-based chemotherapy.

However, endoscopic resection of UTUC carries a much higher burden of local recurrence (20–85%) [4], than does partial nephrectomy for RCC. Patients with UTUC often require multiple serial endoscopic resections and years of complicated and costly surveillance. More recent data also suggests that surgically induced CKD may not carry the same risk of progression and mortality as medical CKD [5]. Perhaps burning down the house is not as potentially destructive as we once thought?

With these caveats firmly in mind, the Simhan et al. [1] study does support a growing appreciation that nephron-sparing approaches to low- or moderate-grade, low-stage UTUC do not worsen cancer-specific mortality. Although these findings are encouraging, I agree with the authors that patient selection for nephron sparing should continue to be informed by clinical judgment and adherence to published treatment guidelines [6].

Richard E. Link
Associate Professor of Urology, Director, Division of Endourology and Minimally Invasive Surgery, Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

References

  2. Jeldres C, Lughezzani G, Sun M et al. Segmental ureterectomy can safely be performed in patients with transitional cell carcinoma of the ureter. J Urol 2010; 183: 1324–1329
  3. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: 1296–1305
  4. Bagley DH, Grasso M 3rd. Ureteroscopic laser treatment of upper urinary tract neoplasms. World J Urol 2010; 28: 143–149
  5. Lane BR, Campbell SC, Demirjian S, Fergany AF. Surgically induced chronic kidney disease may be associated with a lower risk of progression and mortality than medical chronic kidney disease. J Urol 2013; 189: 1649–1655
  6. Roupret M, Zigeuner R, Palou J et al. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. Eur Urol 2011; 59: 584–594

 

Editorial: Radical prostatectomy at young age

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Becker et al. [1] investigated a large sample of young patients (aged <50 years) who underwent radical prostatectomy during a 20-year period in a high-volume European centre. In this study [1], men aged <50 years had a significantly more favourable functional outcome (continence rates [0–1 pads] 97% vs 92%; International Index of Erectile Function [IIEF] score drop of 4 vs 8 points), compared with their older counterparts. Biochemical tumour control was higher in younger patients in univariate (5-year rates 81% vs 70%) but not in multivariate analysis.

In studies in the pre-PSA era, young age at prostate cancer diagnosis was often associated with adverse tumour-related outcome [2]. Possibly, the disadvantage of younger patients was attributable to rapidly growing high-grade tumours causing symptoms at a young age in the absence of a dilution by favourable early detected low-grade cancers. In contemporary patients, the opposite is observed [1]. As the impact of age vanished after controlling for tumour-related prognostic factors reflecting the presence of more favourable disease criteria in younger men, it may be considered likely that PSA-based early detection enriched favourable parameters in the younger subgroup. Altogether, prostate cancer biology is probably not meaningfully associated with age. Outcome differences, even in randomised trials [3, 4], are rather caused by age-related differences in the approach to prostate cancer diagnostics and early detection than in actual biological differences.

The relative favourable functional outcome in younger patients [1] supports early curative treatment in this population. Currently available active surveillance studies have very limited follow-up and were performed mainly in elderly patients with significant comorbidity [5]. Currently, in Germany the further life expectancy in men aged 50 years is ≈30 years [6]. In a contemporary active surveillance study, narrowly half of patients received active treatment within 10 years [5]. Therefore, most men starting active surveillance at an age of 50 years will subsequently receive active treatment. This treatment will then be performed at a greater age where the chances for satisfactory functional recovery are less favourable.

The inferior tumour control rates in patients receiving robot-assisted surgery is another remarkable finding of this study (hazard ratio 1.4, 95% CI 0.99–1.9, P = 0.06 in the multivariate analysis). Although the significance level was narrowly failed, this observation cannot be ignored. It was accompanied by an increased continence recovery rate after robot-assisted surgery suggesting that it may probably not be attributed to the learning curve. Less radical removal of the prostate with more sparing of neurovascular structures and bladder neck might be a conceivable explanation of this phenomenon. In this study [1], the prognostic impact of robot-assisted approach was in a similar range as a positive surgical margin (hazard ratio 1.5, 95% CI 1.4–1.7).

Current clinical guidelines discourage prostate cancer screening in average-risk men aged <50 years [7]. It remains to be seen in which degree these recommendations will affect clinical practice and outcome parameters in this age group in the years ahead.

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Manfred P. Wirth and Michael Froehner
Department of Urology, University Hospital ‘Carl Gustav Carus’, Dresden University of Technology, Dresden, Germany

References

  1. Becker A, Tennstedt P, Hansen J et al. Functional and oncological outcomes of patients younger than 50 years treated with radical prostatectomy for localized prostate cancer in a European population. BJU Int 2014; 114: 38–45
  2. Parker CC, Gospodarowicz M, Warde P. Does age influence the behaviour of localized prostate cancer? BJU Int 2001; 87: 629–637
  3. Bill-Axelson A, Holmberg L, Ruutu M et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011; 364: 1708–1717
  4. Froehner M, Wirth MP. Early prostate cancer – treat or watch? N Engl J Med 2011; 365: 568
  5. Selvadurai ED, Singhera M, Thomas K et al. Medium-term outcomes of active surveillance for localised prostate cancer. Eur Urol 2013; 64: 981–987
  6. Statistisches Bundesamt. Periodensterbetafeln für Deutschland 1871/1881 bis 2008/2010 [Period death tables for Germany 1871/1881 bis 2008/2010]. Wiesbaden 2012. Available at: https://www.destatis.de/DE/Publikationen/Thematisch/Bevoelkerung/Bevoelkerungsbewegung/PeriodensterbetafelnPDF_5126202.pdf?__blob=publicationFile [Website in German]. Accessed 12 July 2013.
  7. Qaseem A, Barry MJ, Denberg TD, Owens DK, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Screening for prostate cancer: a guidance statement from the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med 2013; 158: 761–769
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Editorial: High hospital volume reduces mortality after cystectomy

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In the current issue of BJUI, Nielsen et al. [1] assessed the role of hospital characteristics on the risk of short-term mortality in a contemporary cohort of patients with bladder cancer treated with radical cystectomy (RC) representing the USA population. In their investigation, the authors evaluated >35 000 undergoing RC included within the National Cancer Database. Interestingly, they showed that hospital volume represents an independent predictor of both 30- and 90-day mortality. Several studies already explored the association between hospital characteristics (i.e., hospital volume) and short- and long-term postoperative outcomes, e.g. complication, blood transfusion, readmission, and mortality rates after RC [2-5]. Although this topic has already been broadly investigated, the current study was able to determine the 90-day mortality rates conditional on survival to 30 days after RC.

From a clinical standpoint, the authors report several relevant findings. First, hospital volume represented an independent predictor of 90-day mortality after RC [1]. Particularly, patients treated in centres performing an average of >20 RC/year had significantly lower mortality rates compared with those undergoing RC in smaller volume hospitals. However, it should be noted that the magnitude of the effect was substantially greater when evaluating the 30-day period as compared with 90 days after RC. This observation leads to clinically relevant considerations. Indeed, it might be speculated that the better quality of care generally provided in high-volume tertiary referral centres has a substantial impact on perioperative outcomes and mortality. However, this effect manifests itself mainly in the immediate period after RC. This is consistent with previous studies evaluating the impact of hospital volume on perioperative outcomes in inpatient cohorts [4, 5]. For example, Trinh et al. [3] showed that this parameter was significantly associated with the risk of dying in the perioperative period when a complication occurred. In this context, tertiary referral centres might be better equipped to assist patients in the postoperative period and eventually treat them in a timely fashion [4]. Particularly, better processes of care, e.g. preoperative patient evaluation, invasive monitoring, and perioperative consultations with critical care and other units, might be at least in part responsible for this phenomenon [4]. These observations justify the referral to high-volume centres when a major surgical procedure is planned [3, 4]. On the other hand, the quality of the assistance received during hospitalisation might have a limited impact on postoperative outcomes after hospital discharge. Consequently, these findings might be used to advocate better home care in order to improve patient management after hospital discharge and, in turn, reduce the risk of perioperative morbidity and mortality.

Second, it should be noted that a substantial proportion of patients had died by the 3-month follow-up (7.2%). Moreover, up to 5% of patients who survived at 1 month after RC died in the following 2 months. These observations are consistent with previous studies and highlight the need for better perioperative patient management [1, 3, 5, 6]. Additionally, these sobering figures should be used to advocate better patient selection in order to spare the potential RC-related complications in frail patients, where alternative and less invasive treatment options might be considered.

Concluding, the study by Nielsen et al. [1] further demonstrates that patients with bladder cancer undergoing RC have a non-negligible risk of perioperative mortality at 30- and 90-days after RC. Patients treated at higher volume centres (≥20 procedures/year) experience better perioperative outcomes compared with their counterparts undergoing RC at lower volume institutions (<10 procedures/year). However, the effect of hospital volume on the risk of perioperative mortality is considerably greater in the early period after RC. Consequently, substantive efforts should be made to improve postoperative patient care even after hospital discharge.

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Giorgio Gandaglia*†, Pierre I. Karakiewicz†, Quoc-Dien Trinh‡ and Maxine Sun*

*Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Centre, Canada, †Urological Research Institute, San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy, and ‡Center for Surgery and Public Health, Division of Urologic Surgery, Brigham and Women’s Hospital, Boston, MA, USA

References

  1. Nielsen ME, Mallin K, Weaver MA et al. Association of hospital volume with conditional 90-day mortality after cystectomy: an analysis of the national cancer database. BJU Int 2014; 114: 46–55
  2. Kulkarni GS, Urbach DR, Austin PC, Fleshner NE, Laupacis A. Higher surgeon and hospital volume improves long-term survival after radical cystectomy. Cancer 2013; 119: 3546–3554
  3. Trinh VQ, Trinh QD, Tian Z et al. In-hospital mortality and failure-to-rescue rates after radical cystectomy. BJU Int 2013; 112: E20–27
  4. Sun M, Ravi P, Karakiewicz PI et al. Is there a relationship between leapfrog volume thresholds and perioperative outcomes after radical cystectomy? Urol Oncol 2014; 32: 27 e7–13
  5. Kim SP, Boorjian SA, Shah ND et al. Contemporary trends of in-hospital complications and mortality for radical cystectomy. BJU Int 2012; 110: 1163–1168
  6. Gandaglia G, Popa I, Abdollah F et al. The effect of neoadjuvant chemotherapy on perioperative outcomes in patients who have bladder cancer treated with radical cystectomy: a population-based study. Eur Urol 2014; (in press) doi: 10.1016/j.eururo.2014.01.014

 

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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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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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Research vibrations

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Here is a randomised trial from Denmark to uplift your mood this European summer. Penile vibratory stimulation may help with the recovery of erectile function after nerve-sparing radical prostatectomy [1]. However, it does not hasten recovery of continence. Building on the European theme, we were discussing alternative ways of influencing research communities and colleagues during the European Association of Urology (EAU) meeting in Stockholm. One obvious rising star is ResearchGate (Fig. 1).

ResearchGate (https://www.researchgate.net/) is a social networking site for scientists and researchers that allows them to share papers, exchange questions and find collaborators. ResearchGate has won the digital innovation of the year award from Focus Magazine in 2014. An important accolade in a world increasingly influenced and greatly amplified by the web and social media.

For a generation of scientists using Facebook, Twitter and similar social networks, ResearchGate has become a familiar site to exchange data and knowledge related to research. Similar to the other social network sites people can post comments, form groups, have profile pages and can ‘like’, ‘endorse’ and ‘follow’ other members. One can use it as an online bibliography and can even deposit published papers on the site. Members can also share negative results or experiments that are difficult to publish in peer-reviewed journals.

There is also a project section where groups can work together on projects in a secure environment. Forget Skype meetings at the last minute!

ResearchGate also introduces a new way of measuring the impact of a certain researcher on a scientific community. The ResearchGate score (RG score) is a new bibliometric tool that combines traditional parameters, such as the impact factor, with the user’s activity on the site, like posting or answering questions or the number of people that follow them. Also, the RG score of the peers that follow you will have an impact on your own RG score: the more influential your followers are, the higher your personal RG score will get.

Just as the Klout score is measuring the influence that one has in social media, ResearchGate could become an alternative measure not only of the scientific importance of a certain researcher but also of his or her interactivity. It is a measure for ‘scientific social network reputation’.

At the moment the relationship between impact factor, citation index and the RG score is difficult to establish, as the algorithm that is used to calculate the RG score is not widely known. If ResearchGate wants to establish the RG score as a respected measurement tool, some transparency will be helpful in future.

Since ResearchGate was founded in 2008 by Dr Ijad Madisch, Dr Sören Hofmayer and computer scientist Horst Fickensher, >4 million members have joined and the numbers are steadily increasing. Several other exchange platforms exist on the internet, but ResearchGate is certainly the most widespread at the moment. We think it is here to stay and claim a role as one of the tools to measure one’s scientific reputation.

Dirk De Ridder† and Prokar Dasgupta*
†BJUI Associate Editor, University Hospitals Leuven, Leuven, Belgium, and *Guy’s Hospital, KCL and Editor-in-Chief, BJUI

Reference

  1. Fode M, Borre M, Ohl DA, Lichtbach J, Sønksen J. Penile vibratory stimulation in the recovery of urinary continence and erectile function after nerve-sparing radical prostatectomy: a randomised, controlled trial. BJU Int 2014; 114: 111–7

 

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.

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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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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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