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Valentine’s Day PSA

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A few years ago Barrack Obama, the President of the USA, is supposed to have said on Valentine’s Day – “Gentlemen – do not forget!”

He was apparently speaking “from experience”. Not remembering that important day can have catastrophic consequences for many men. On that occasion, PSA stood for public service announcement.

The headline, however, could easily have been mistaken for Prostate Specific Antigen. One could argue whether the PSA test is as important to men as Valentine’s Day. Most men probably do not bother, especially if they are less than 40 years old. The PSA debate swings around like a sine wave. Despite the best possible randomised controlled trials for and against PSA screening, there seem to be no clear answers with deep divisions amongst men and their urologists.

This February, the BJUI adds to the PSA debate by publishing the Melbourne Consensus Statement [1]. It was an attempt to bring some sense to a thorny subject. When published as a blog on www.bjui.org, most of our readers liked it, but certainly not all. The usual heated debate was inevitable. Earlier last summer Bal Carter, one of our BJUI Executive Members, chaired the AUA panel that recommended shared decision making for asymptomatic men between 55–69 years as far as PSA screening was concerned. They carefully analysed over 300 studies to make these recommendations [2]. I congratulated Bal on this milestone on the very morning this made headline news. However, such was the controversy that he had to present the findings twice – one appearance on the AUA podium was just not enough.

In a well-informed man, over diagnosis is not necessarily a problem as long as it does not lead to over treatment. I find myself treating a number of men in their 40s with strong family histories of prostate cancer. It is very difficult to deny them a PSA test when they seek it. This discussion is likely to become redundant in years to come when better risk stratification with genomic tools and improved imaging will complement the PSA test, rather than relying on it alone. In the meantime I leave it to our knowledgeable readers to make up their own minds.

Not everyone is interested in the PSA test in the month of February. If you belong to this category, perhaps we could grab your attention with a multi-institutional collaborative study showing disease free and overall survival rates of over 90% following LESS partial nephrectomy, a challenging procedure, even for technically accomplished surgeons [3]. Khurshid Guru’s group also present data to show that urinary and bowel domains take about 6 months to recover after robotic cystectomy; sexual domains even longer [4].

I have no illusions that none of the above may be of the slightest importance to some readers. In which case you may wish to head to the best florist in town. Forget that at your peril …

Prokar Dasgupta, Editor in Chief, BJUI
Guy’s Hospital, King’s College London

 

References

  1. Murphy DG, Ahlering T, Catalona WJ et al. The Melbourne Consensus Statement on the Early Detection of Prostate Cancer. BJU Int 2014; 113: 186–188
  2. Carter HB. American Urological Association (AUA) Guideline on prostate cancer detection: process and rationale. BJU Int 2013;112: 543–547
  3. Springer C, Greco F, Autorino R et al. Analysis of oncological outcomes and renal function after laparoendoscopic single site partial nephrectomy: a multi-institutional outcome analysis. BJU Int 2014; 113: 266–274
  4. Poch MA, Stegemann AP, Rehman S et al. Short-term patient reported health-related quality of life (HRQL) outcomes after robot-assisted radical cystectomy (RARC). BJU Int 2014; 113: 260–265
 

Editorial: The evolution of robotic cystectomy

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A decade has passed since the publication of the first series of robot-assisted radical cystectomies in the BJUI by Menon et al. [1]. New technologies are fascinating, and many surgeons who aspire to leave a mark in history take the lead in pioneering new procedures. Others follow without waiting for any evidence to justify the adoption of new procedures. In this race, the opinion of the most important stakeholder, the patient, gets ignored.

Although their study has many methodological flaws, Guru et al. [2] have made the effort to collect data on patients’ health-related quality of life (HRQL) after robot-assisted radical cystectomy for bladder cancer. Radical cystectomy is a morbid procedure with a serious impact on patients’ HRQL, no matter how it is performed. Loosing an organ which is responsible for the storage and evacuation of urine several times a day and replacing it with alternatives of continent or incontinent diversion has a serious impact on quality of life, as is evident from this study.

Robotic cystectomy is still evolving. With more experience, a few experts have ventured to perform intracorporeal reconstruction of the urinary diversion. While we await the long-term functional outcomes of this switch over in surgical approach, Guru et al. report the short-term HQRL outcomes in a series of 43 patients undergoing robot-assisted radical cystectomy and intracorporeal urinary diversion at their institution. Most patients (n = 38) had ileal conduit urinary diversion. The authors went on to compare the postoperative outcomes of this cohort with another group of 70 patients who only completed the questionnaire after having undergone robot-assisted radical cystectomy and extracorporeal urinary diversion.

It is interesting to note that there was no significant difference in HRQL between those undergoing extracorporeal and those undergoing intracorporeal reconstruction. These outcomes reinforce the need to gather robust scientific evidence from properly conducted multi-centre, multinational randomized trials before the introduction of new procedures, instead of evaluation with retrospective studies. The urological community has embraced new technologies and patients have benefited a great deal from these innovative approaches; however, it is incumbent upon us to develop a culture of independent, unbiased data collection on outcomes. In this regard we must make the HQRL one of the most important quality indicators in assessment of the new procedures. Such an approach will enable us to justify the extra cost which society has to bear for our innovative trends in the management of old problems [3].

Read the full article

Muhammad Shamim Khan
Guy’s and St Thomas’s Hospital and King’s College London, London, UK

References

  1. Menon M, Hemal AK, Tewari A et al. Nerve-sparing robot-assisted radical cystoprostatectomy and urinary diversion. BJU Int 2003; 92: 232–236
  2. Poch MA, Stegemann AP, Rehman S et al. Short-term patient reported health-related quality of life (HRQL) outcomes after robot-assisted radical cystectomy (RARC). BJU Int 2014; 113: 260–265
  3. Wang TT, Ahmed KA, Khan MS et al. Quality-of-care framework in urological cancers: where do we stand? BJU Int 2011; 109: 1436–1443

 

Editorial: How should we best manage obesity in urology?

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Abdul-Muhsin et al. [1] are to be congratulated on an excellent study involving >3000 patients undergoing robot-assisted radical prostatectomy over a 4-year period. In their study they demonstrate that the morbidly obese patient can be managed in a just about equal way to the non-morbidly obese patient for removal of the prostate. The complications and recovery characteristics in morbidly obese patients are reviewed and it is concluded that, in this single-operator single-centre study, the morbidly obese male with prostate cancer should not be overlooked as a candidate for radical surgery.

We are all faced with more obese patients presenting to our clinical care; in the UK 20% of the adult population are obese and >3% are morbidly obese. There are an increasing number of studies looking at the outcome of surgery in the obese and morbidly obese populations. These studies have drawn mixed conclusions, with some suggesting an increased risk and morbidity and others suggesting no difference when compared with a non-obese population. This is confusing: perhaps the use of body mass index alone to assess obesity is limited and misleading [2]. This is because the distribution of fat varies considerably among individuals, with the most at-risk patients being those with a centripetal fat distribution producing a large abdominal girth. In middle-aged men, a waist size of >102 cm is the best predictor of metabolic syndrome with all its concomitant risk factors [3]. It is these patients who represent the greatest risk for surgery and it is these same patients who urgently need to improve their lifestyle and shed weight in order to achieve a normal life expectancy both to aid surgery and thereafter. Factors such as hypoventilation, hypertension and the risk of thromboembolism are greatly increased in this group. Diabetes, abnormal lipids, bone and joint diseases and reflux are common. These factors will probably contribute to multiple potential peri-operative complications. Cardiopulmonary exercise testing is very useful in detecting the patients most at risk and likely to require most intensive care postoperatively. There are too few studies to date that include this test and that specifically looking at the morbidly obese population, but results are encouraging and will very probably detect those patients most likely to require critical care facilities [4].

While the surgical results in the Abdul-Muhsin et al. study are excellent, one would not wish to dilute the key message to our patients that preparation for major surgery with weight loss is vital. Addressing nutrition and exercise activity in the preoperative period is extremely beneficial and highly successful. Achieving a 10% weight loss within weeks before surgery is entirely achievable with significant benefits to the medical comorbidities and, in particular, breathing and muscle activity [5]. One great advantage of prostate cancer surgery is the often slow-growing nature of the tumour and we can, therefore, often take the opportunity to postpone major surgery for just a matter of weeks to improve fitness and nutrition. This window of opportunity is more than enough to transform a high-risk patient to one with a much lower risk profile.

If we inspire our patients to join in the aim of the whole surgical team to safely cure prostate cancer using weight reduction and improved fitness then long-term life benefits will surely follow in addition to the immediate gains for surgery and anaesthesia.

Peter Amoroso
The London Clinic, 20 Devonshire Place, London W1G 6BW

Read the full article

References

  1. Abdul-Muhsin H, Giedelman C, Samavedi S et al. Perioperative and early oncological outcomes after robot-assisted radical prostatectomy (RARP) in morbidly obese patients: a propensity score-matched study. BJU Int 2014; 113: 84–91
  2. Mullen JT, Moorman DW, Davenport DL. The obesity paradox body mass index and outcomes in patients undergoing non-bariatric general surgery. Ann Surg 2009; 250: 166–172
  3. Balentine CJ, RobInson CN, Marshall CR et al. Waist circumference predicts increased complications in rectal cancer surgery. J Gastrointest Surg 2010; 14: 1669–1679
  4. Hennis PJ, Meale PM, Hurst RA et al. Cardiopulmonary exercise testing predicts post operative outcome in patients undergoing gastric bypass surgery. Br J Anaesth 2012; 109: 566–571
  5. Benotti PN, Still CD, Wood GC et al. Preoperative weight loss before bariatric surgery. Arch Surg 2009; 44: 1150–1155

 

Editorial: The age old question: who benefits from prostate cancer treatment?

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Widespread PSA-based screening has dramatically altered the profile of newly diagnosed prostate cancer in many countries. Although screening effectively decreases the rates of metastatic disease and prostate cancer death [1], the increasing proportion of low-risk disease necessitates a critical assessment of the need for aggressive therapy.

Active surveillance and watchful waiting are potential alternatives to delay or avoid the need for treatment in carefully selected patients. The key issue is determining which patients are appropriate for conservative management. Although these approaches are often targeted toward elderly men, such men are more likely to be diagnosed with high-risk disease. A recent study by Scosyrev et al. [2] raised concern about excess prostate cancer mortality attributable to under-treatment in the elderly.

Overall, there is very little Level 1 evidence to guide prostate cancer treatment selection. One such trial, the Swedish Prostate Cancer Group 4 (SPCG-4), showed that radical prostatectomy significantly improved survival compared with watchful waiting [3]; however, that study examined a primarily clinically detected population from the 1990s. Subsequently, the Prostate Cancer Intervention versus Observation Trial (PIVOT) randomized US male veterans diagnosed with prostate cancer from 1994 to 2002 to radical prostatectomy vs observation [4]. At 10 years, they reported no significant difference in overall survival between the two arms in the intent-to-treat analysis (hazard ratio 0.88; 95% CI 0.71–1.08, P = 0.22). However, that study was smaller than anticipated owing to difficulty with recruitment and there was a high rate of crossovers between the intervention and observation arms. Per-protocol analysis was not reported for PIVOT and the prostate cancer landscape has continued to change in the past decade, raising unanswered questions over what the results would be if we compared contemporary men who were actually treated to those who were not.

This is the knowledge gap addressed by Aizer et al. [5] who used Surveillance, Epidemiology and End Results (SEER) data for 27 969 US men diagnosed with low-risk prostate cancer from 2004 to 2007. Overall, 67.1% of these men received radical prostatectomy or radiation therapy, while >30% underwent active surveillance or watchful waiting. Using competing risks regression, they showed that both age and non-curative treatment were associated with a significantly higher short-term prostate cancer-specific mortality. These results should be interpreted with caution, however, since they comprise observational data with great potential for confounding. Interestingly, at a short median follow-up of only 2.75 years, 5.4% of these men with presumed low-risk disease died from prostate cancer. Recently, there has been debate over whether Gleason 6 disease should really be considered a cancer [6], but these data highlight the limitations of current clinical staging, such that even presumed low-risk disease may be understaged. The authors suggest that use of a more extended biopsy scheme before active surveillance might reduce the risk of early progression due to undersampling. MRI represents another potential non-invasive treatment method to improve clinical staging and patient selection for active surveillance in the future [7].

Stacy Loeb
Department of Urology, New York University, New York, NY, USA

Read the full article

References

  1. Schroder FH, Hugosson J, Roobol MJ et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 2012; 366: 981–990
  2. Scosyrev E, Messing EM, Mohile S et al. Prostate cancer in the elderly: frequency of advanced disease at presentation and disease-specific mortality. Cancer 2012; 118: 3062–3070
  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. Wilt TJ, Brawer MK, Jones KM et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012;367: 203–212
  5. Aizer AA, Chen MH, Hattangadi J, D’Amico AV. Initial management of prostate-specific-antigen-detected, low-risk prostate cancer and the risk of death from prostate cancer. BJU Int 2014; 113: 43–50
  6. Carter HB, Partin AW, Walsh PC et al. Gleason score 6 adenocarcinoma: should it be labeled as cancer? J Clin Oncol 2012; 30:4294–4296
  7. Vargas HA, Akin O, Afaq A et al. Magnetic Resonance Imaging for Predicting Prostate Biopsy Findings in Patients Considered for Active Surveillance of Clinically Low Risk Prostate Cancer. J Urol 2012; 188: 1732–1738

 

Editorial: Does performing LND at nephrectomy give a survival benefit or not?

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We read with interest the article by Sun et al. [1] in this issue of the BJU International. We were pleased to see another research group interested in this important aspect of the management of patients with lymph-node-positive non-metastatic RCC. The question of the benefits of lymphadenectomy in such patients could not be answered by the European Organization for Research and Treatment of Cancer randomized trial [2], as only 4% of clinically node-negative patients had micrometastatic disease.

Given some of the complexities involved in the analysis of Surveillance, Epidemiology and End Results data and the particular statistical analysis we used in showing a benefit to increasing nodal yield in patients with positive nodes [3], we were reassured that Sun et al. were able to validate our findings when replicating our data extraction and analysis. They performed two additional analyses and the four results are shown in Table 1.

 

While Sun et al. concluded that multiple imputation introduces bias into the findings, inspection of the estimates of the impact of lymph node dissection (the hazard ratio) appear identical. If bias is a deviation of an estimate from the truth [4], we would argue that Sun et al. found no evidence of bias introduced by the multiple imputation method. This is not to say that all four analyses are free from potential bias – the reported hazard ratios may in fact still be biased results – but that there is no more bias in the multiple imputation model than in the others. In addition, we were somewhat surprised to see the use of a missing indicator approach proposed as less likely than multiple imputation to introduce bias as studies have shown the opposite [5].

Furthermore, the CIs show that the benefit to extent of lymphadenectomy may be as great as a 34% reduction in cancer-related death, with exclusion of all but a 5% increase in death associated with the procedure. CIs provide extremely valuable information, particularly in the setting of marginally significant or nonsignificant P values. Sun et al. could have strengthened their paper on statistical considerations by discussing this further. In fact, we would argue that their additional analyses lend further support to the potential benefit of the extent of lymphadenectomy.

The most notable difference across the analyses is a drift in the P value. We would argue that this mirrors the loss in power associated with the censoring of almost 3000 patients (28%) with missing grades. In addition, grade does not appear to be missing at random, as patients with missing tumour grades were associated with larger tumours, higher local stage, increased probability of nodal involvement and increased risk of kidney cancer death. The censoring of such patients may in and of itself introduce bias, although again the hazard ratios do not seem to reflect this. The devaluation of the P value continues to be an active area of biostatistical research, although in general journals have not foregone its inclusion in favour of an entirely Bayesian approach [6]. We believe that, in this case, Sun et al. have taken a far too traditional approach to interpretation of small differences in P values, particularly in the setting of changing sample sizes.

We agree with Sun et al. that consideration of another randomized trial focused on patients at high risk of nodal involvement or with clinically apparent nodes on CT is warranted based upon our combined results.

Jared M. Whitson and Maxwell Meng
Department of Urology, Kaiser Permanente South Sacramento Medical Center, Sacramento, CA, USA

Read the full article

References

  1. Sun M, Trinh Q-D, Bianchi M et al. Extent of lymphadenectomy does not improve survival of patients with renal cell carcinoma and nodal metastases: biases associated with handling of missing data. BJU Int 2014; 113: 36–42
  2. Blom JH, van Poppel H, Marechal JM et al. Radical nephrectomy with and without lymph-node dissection: final results of European Organization for Research and Treatment of Cancer (EORTC) randomized phase 3 trial 30881. Eur Urol 2009; 55: 28–34
  3. Whitson JM, Harris CR, Reese AC, Meng MV. Lymphadenectomy improves survival of patients with renal cell carcinoma and nodal metastases. J Urol 2011; 185: 1615–1620
  4. Grimes DA, Schulz KF. Bias and causal associations in observational research. Lancet 2002; 359: 248–252
  5. Greenland S, Finkle WD. A critical look at methods for handling missing covariates in epidemiologic regression analyses. Am J Epidemiol 1995; 142: 1255–1264
  6. Goodman SN. Toward evidence-based medical statistics. 2: the Bayes factor. Ann Intern Med 1999; 130: 1005–1013
 

Quality has no boundaries

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The new year has arrived bringing with it new expectations of success. It gives us the opportunity to reflect on 2013 and plan for the year ahead. We hope you enjoyed the new web journal www.bjui.org that we have introduced. It has certainly increased our full paper downloads each month which means that our readers do care. Thank you! Your loyalty makes the many hours of hard work – 24/7 – all worthwhile. We have an international team which allows someone, somewhere to be making constant improvements to the BJUI for your reading pleasure.

Many of our readers while congratulating us, commented that perhaps we had focussed on being of greater relevance to the younger generation. Imagine my surprise when at a recent Men’s Health meeting in London, my old chief came up to me for a discussion about the controversies of PSA testing following publication of the AUA guidelines [1] and a consensus statement from down under on blogs@BJUI [2]. He had read it all on the web much earlier than when these articles eventually make it to the print journal. Like him, many of our readers see and read an article or blog online but do not necessarily comment on it. As a new metric, we will start indicating the number of times an article is read in addition to the number of comments it receives.

At the BJUI we do not make New Years resolutions. It is much easier to act. During our editorial board meeting last October it became obvious that we were receiving high quality papers from all over the world. In this issue, we have the great pleasure of showcasing a superb article on circumcision from Uganda [3]. Men with or without HIV, which is highly prevalent in Africa, tend to heal well after circumcision. This does not appear to be affected by their CD4 counts. This is a large study, relevant to all urologists and I would urge you to read it and the accompanying editorial from Paul Hegarty [4].

This article also gave us the idea of highlighting the geographical location of the article of the month on the front cover. Another inspirational concept from Tet Yap our associate editor for design. More about that in coming editions.

Finally Maxine Sun is back with a SEER study showing that the extent of lymphadenectomy during radical nephrectomy in patients with nodal metastasis, does not affect survival. Like any database, missing entries may have confounded the results and it is critical from a scientific standpoint to understand the resultant bias [5]. For those wishing to learn health services research a good starting point is to read the Sun Blog on SEER at our web journal.

Here’s looking forward to interacting with you in 2014.

Prokar Dasgupta
Editor in Chief, BJUI

Guy’s Hospital, King’s Health Partners

References

  1. Ballentine Carter H. American Urological Association (AUA) Guideline on prostate cancer detection: process and rationale. BJU Int 2013; 112: 543–547
  2. Murphy D. The Melbourne Consensus Statement on Prostate Cancer Testing. blogs@BJUI. Available at: https://www.bjuinternational.com/bjui-blog/the-melbourne-consensus-statement-on-prostate-cancer-testing/. Accessed 20 November 2013
  3. Kigozi G, Musoke R, Kighoma N et al. Male circumcision wound healing in HIV-negative and HIV-positive men in Rakai, Uganda. BJU Int 2014; 113: 127–132
  4. Hegarty P. Circumcision – follow up or not? BJU Int 2014; 113: 2
  5. Sun M, Trinh Q-D, Bianchi M et al. Extent of lymphadenectomy does not improve the survival of patients with renal cell carcinoma and nodal metastases: biases associated with the handling of missing data. BJU Int 2014; 113: 36–42

Original publication of this editorial can be found at: BJU Int 2014; 113: 1. doi: 10.1111/bju.12575

Editorial: Circumcision – follow-up or not?

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There is an excellent study from Uganda in this issue of the BJUI [1]. It looks at the rate of healing of men undergoing prophylactic circumcision. Some had HIV; others not. What they termed ‘complete wound healing’ was an intact scar without a scab, sutures or a sinus – effectively a ‘sealed’ wound. There are several useful data therein:

  • all men had healed by 6 weeks; the median being 4 weeks.
  • HIV status did not appear to delay wound healing, even with low CD4 counts.
  • the patient was 95% likely to judge wound healing correctly himself.
  • routine circumcision can be safely carried out by trained medical officers.
  • a complication rate of 0.5% was reported.

So what follow-up, if any, is necessary after circumcision? Based on this population it would appear that a well instructed/consented patient can be relied on to judge healing after prophylactic circumcision. They probably do not need follow-up provided their expectations are managed well, and there is ease of access to return should problems arise.

However, this may not be generalizable to men having circumcision for phimosis or other abnormality of foreskin. These patients may have delayed healing, meatal issues or a urethral stricture upstream. Histopathological examination of abnormal foreskins is sensible also as further treatment/follow-up may indicated.

I recommend a read of this superb paper.

Paul K. Hegarty
Consultant Urological Surgeon, Mater Private, Cork, Ireland

Read the full article

Editorial: Too many men still undergo needless prostate biopsy

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Multiple studies have shown that only one in three or four men with a raised PSA level prove to have prostate cancer and many men suffer potentially life-threatening complications from transrectal prostate biopsy. There is an urgent need for better risk stratification of men with elevated PSA levels. Any such test should have a high negative predicative value (NPV; small number of significant cancers missed) but also a high positive predictive value (PPV; i.e. the yield would be high and there would be very few false positives) to diminish the number of unnecessary biopsies. Multiparametric MRI (mpMRI) of the prostate, especially with a stronger 3 T magnet, has been advocated for this purpose. The parameters refer to the separate MRI sequences used, typically at least three. Sequences can not only study the anatomy of the gland (standard T2-weighted MRI), but there is also a measure of the tissue cellularity (diffusion-weighted MRI), vascularity (dynamic contrast-enhanced MRI) or biochemistry (magnetic resonance spectroscopy). Initial data have shown promise but the changes seen on these various sequences can be subtle and interpretation is subjective. Naturally observer experience plays a large part but a standardised scoring system, the so called Prostate Imaging Reporting and Data System (PIRADS) system, has been proposed to improve reporting performance [1]. Each parameter is scored on a scale of 1–5 according to the likelihood of cancer. Scoring systems are always a compromise between the NPV and PPV, and so far there is no agreement where the threshold for each parameter should be set. In the original document, the authors proposed that a score of 4 or 5 signifies a high likelihood or almost certainty of cancer, whilst scores of 1 or 2 denote a high likelihood of benign tissue. A score of 3 is evens. The paper by Kuru et al. [2] shows a high NPV only when the threshold was set at the low level of 2 for each parameter. Predictably, at this threshold the PPV was extremely low, and therefore many men would still undergo unnecessary biopsy. Another similar paper advocated a mean threshold of 3, but even then the PPV was 38% with a NPV of 95% [3]. Both these papers are retrospective studies, in particular the MRI readings were done retrospectively. Nevertheless, the low PPV is disappointing. The results of prospective studies with multiple readers are keenly awaited and I hope that that these will find a higher PPV for mpMRI, and we can to move to an era when fewer men undergo needless prostate biopsy.

Uday Patel
St George’s Hospital, London, UK

Read the full article

References

  1. Barentsz JO, Richenberg J, Clements R et al. ESUR prostate MR guidelines 2012. Eur Radiol 2012; 22: 746–757
  2. Kuru T, Roethke M, Rieker P et al. Histology core-specific evaluation of the European Society of Urogenital Radiology (ESUR) standardised scoring system of multiparametric magnetic resonance imaging (mpMRI) of the prostate. BJU Int 2013; 112:1080–1087
  3. Portalez D, Mozer P, Cornud F et al. Validation of the European Society of Urogenital Radiology scoring system for prostate cancer diagnosis on multiparametric magnetic resonance imaging in a cohort of repeat biopsy patients. Eur Urol 2012; 62: 986–996

Editorial: Diabetes mellitus and non-muscle-invasive bladder cancer: not just a coincidence?

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Urologists are familiar with the plethora of comorbidities affecting patients with bladder cancer. Many are smoking-related, such as respiratory disease, ischaemic heart disease and peripheral vascular disease. Other conditions are associated with an ageing, increasingly obese population. Rieken et al. [1], present intriguing observations suggesting an association between diabetes mellitus (DM), its treatment and the prognosis of non-muscle-invasive bladder cancer (NMIBC). In a retrospective, multicentre cohort study of 1117 patients diagnosed with NMIBC, the authors conclude that patients taking metformin have better recurrence-free survival compared with patients with diabetes who did not take metformin. The Kaplan–Meier curves even hint at improved outcomes for patients taking metformin compared with the population without diabetes, although the difference did not reach statistical significance. Only 125 patients (out of 1117) had DM, of whom 43 were prescribed metformin. Outcome measures were recurrence and progression, with comparison of cancer-specific mortality not possible because of the low frequency of events. The study population was treated between 1996 and 2007, so re-resection was not routine, and rates of postoperative intravesical chemotherapy and adjuvant chemotherapy/immunotherapy were low. Treatment for some patients was therefore suboptimal by current standards, and there may have been differences between the multinational institutions.

The association between type 2 diabetes and the incidence of several cancer types (e.g. breast, colorectal and pancreatic) is well documented. The biological mechanisms responsible are unclear [2], and a causal relationship is debated. Postulated mechanisms include the effects of hyperinsulinaemia, hyperglycaemia and signalling pathways involving the IGF receptors. The protective effect of metformin is similarly unclear, although the authors cite studies indicating anti-proliferative properties.

A number of large cohort studies have endeavoured to show there is a higher risk of cancers in populations with diabetes. The challenge for such studies is the relatively low incident rate of bladder cancer in the population (17.1 per 100 000) [3]. Additionally, studies using general practice databases encounter problems obtaining data relating to bladder cancer characteristics. The increased detection of bladder cancer in the population with diabetes is a potential confounder, as monitoring using urine analysis is more likely.

Rieken et al. [1], in taking the opposite approach by identifying their cohorts on the basis of confirmed diagnosis of NMIBC, present accurate data regarding cancer characteristics but accept there is a potential for lack of accuracy in the recording of DM and treatment using chart review. We are not able to draw any conclusions regarding the severity of DM, its complications or compliance with prescribed medication. Future studies would be strengthened by incorporating tests such as HbA1c concentration as a marker for glycaemic control. Additionally, they do not specify the type of diabetes, although the reader can speculate that patients treated with metformin had type 2 DM. It is important to recognize that the pattern of cancer risk appears to be different for type 1 diabetes [4].

Whilst detailed discussion of the management of DM is outside the remit of a urological study, there are some important factors to be considered. Metformin is frequently recommended as a first-line agent in the management of type 2 DM [5]. It follows, therefore, that patients treated with metformin may be different from those requiring second- or third-line drugs and drug combinations; thus the cohort treated with metformin may be younger, exhibit better glycaemic control, and have improved renal function compared with those treated with other drugs and exogenous insulin. An important consideration is that rather than a protective effect being exerted by metformin, it may be that other hypoglycaemic agents have an adverse effect on NMIBC outcomes. Pioglitazone has recently been associated with an increased incidence of urothelial cancer when taken for >2 years, although effects on prognosis are not established [6]. Were the patients with diabetes not taking metformin in fact treated with hypoglycaemic agents implicated in the aetiology of bladder cancer? When considering the plausibility of biological mechanisms, the time-lag between exposure to carcinogen and the development of bladder cancer is pertinent. There is a prolonged time-lag between exposure to cigarette smoking and the development of bladder cancer, so are we ready to accept that drug exposure for a short time-scale is protective or causative? Finally, we must consider the clinical relevance of these findings. As metformin is the current first-line therapy, it may be contraindicated in those not prescribed it and conversion may not be possible.

Notwithstanding the above caveats, when treating patients with NMIBC we are often embarking on a lifelong process of treatment and surveillance. We are obliged as doctors to consider the implications of common comorbidities in order to tailor treatment. In much the same way that we now consider metabolic syndrome when evaluating erectile dysfunction, in the future we may need to consider NMIBC and DM together, and work collaboratively with other healthcare professionals to optimize the management of both conditions.

Joanne Cresswell
Department of Urology, James Cook University Hospital, Middlesbrough, UK

Read the full article

References

  1. Rieken M, Xylinas E, Kluth L et al. Association of diabetes mellitus and metformin use with oncological outcomes of patients with non-muscle-invasive bladder cancer. BJU Int 2013; 112: 1105–1112
  2. Johnson JA, Carstensen B, Witte D et al. Diabetes and cancer (1). Evaluating the temporal relationship between type 2 diabetes and cancer incidence. Diabetologica 2012; 55: 1607–1618
  3. Cancer Research UK. Bladder cancer, average number of new cases per year and age-specific incidence rates, 2006–2008. Cancer Research UK, 2012
  4. Zendehdel K, Nyren O, Ostenson CG, Adami HO, Ekbom A, Ye W. Cancer incidence in patients with type 1 diabetes mellitus: a population-based cohort study in Sweden. J Natl Cancer Inst 2003; 95: 1797–1800
  5. NICE. NICE Clinical Guideline, 66, 2008
  6. Azoulay L, Yin H, Filion K et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ 2012; 344: e3645

Editorial: Minimally invasive surgical training: do we need new standards?

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The pan-European survey conducted by Furriel et al. [1] in this issue of BJUI is a timely address of a hot topic in urology.

More than 20 years have passed since the first laparoscopic nephrectomy was performed by Clayman et al. [2] in 1991, and now all urological major interventions have been performed with one or more different minimally invasive techniques (standard, single-site or robot-assisted laparoscopy); some of them have passed the judgment of time becoming ‘gold standard’ treatments, while others are still under evaluation. Specifically, the European Association of Urology (EAU) guidelines recommend laparoscopic radical nephrectomy as the ‘standard of care’ over open surgery, report favorable outcomes for robot-assisted laparoscopic radical prostatectomy, and propose as optional treatments laparoscopic or robot-assisted partial nephrectomy and radical cystectomy [3].

Obviously, this surgical revolution brings two major new issues: (i) Starting from academic and training centres, hundreds of Urology Departments throughout Europe need to update their surgical knowledge and expertise, making senior urologists perform up-to-date procedures; (ii) Residents and young urologists require adequate and possibly standardised training in minimally invasive surgery, learning at least the basic laparoscopic skills. The study by Furriel et al. [1] correctly highlights both problems.

First, according to the survey, penetration of laparoscopy in the most important urological training centres is unexpectedly low. In fact, more than one out of four centers (26%) do not perform minimally invasive surgery, even for the ‘standards of care’, such as laparoscopic radical nephrectomy. Moreover, as the survey was conducted specifically on the topic of minimally invasive surgery, it is probable that unexposed residents were less interested in responding, making the data of penetration probably even worse than reported. This fact reflects a serious problem present in most training centres. While previously surgery slowly evolved, laparoscopy and technology brought sudden innovations, putting several senior urologists ‘out of the game’. Hence, today, training is needed not only for residents, but also for consultants. In the meantime, it is important that residents are trained in centres were minimally invasive surgery is already widely available. In this perspective, European educational authorities should endeavour to certificate the residents’ training centres, for example on the basis of adherence to EAU guidelines. Academic or non-academic training centres not adherent to guidelines (and thus not performing minimally invasive surgery) should therefore be deprived of residents.

Secondly, training residents in minimally invasive surgery can be approached in different ways, from low-cost self-made dry laboratories to expensive virtual reality or robotic three-dimensional simulators. According to the survey, >40% of centres have no training facilities available. It has been shown that self-built, cheap, dry laboratories are as efficient in training as the industrial ones [4], so that it is not a matter of costs but a matter of interest. We strongly believe that watching surgical videos, observing live surgeries and using (low-cost or not) dry laboratories are fundamental steps in acquiring the basic skills in laparoscopy, while the modular training proposed by Stolzenburg et al. [5] for laparoscopic radical prostatectomy is the best live training model and can be exported to other kinds of surgery, such as radical or partial nephrectomy. In the centres where robot-assisted surgery is available, working as a table-side assistant is another good way to acquire laparoscopic skills.

A great debate is currently ongoing about credentialing in minimally invasive surgery training [6]. Pragmatically, when the European training centres are certificated for adherence to the EAU guidelines, there will be no need for a specific credentialing in laparoscopic skills, because it will be included in the standard training path, together with endoscopic and open surgery.

In conclusion, the survey by Furriel et al. [1] shows that times are changed: the old axiom ‘big cut, big surgeon’ is not valid anymore. The emerging urological generations know it, and ask to be adequately trained. Training centres must evolve, because in 2013 minimally invasive surgery has formally to be considered as part of the standard urological armoury.

Antonio Galfano and Aldo Massimo Bocciardi
Department of Urology, Ospedale Niguarda Ca’ Granda, Milan, Italy

Read the full article

References

  1. Furriel F, Laguna MP, Figueiredo A, Nunes P, Rassweiler JJ. Training of European urology residents in laparoscopy: results of a pan-European survey. BJU Int 2013; 112: 1223–1228
  2. Clayman RV, Kavoussi LR, Soper NJ et al. Laparoscopic nephrectomy. N Engl J Med 1991; 324: 1370–1371
  3. EAU Guidelines, edition presented at the 28th EAU Annual Congress, Milan 2013. ISBN 978-90-79754-71-7. EAU Guidelines Office, Arnhem, The Netherlands. Available at: https://www.uroweb.org/guidelines/online-guidelines/. Accessed September 2013
  4. Beatty JD. How to build an inexpensive laparoscopic webcam-based trainer. BJU Int 2005; 96: 679–682
  5. Stolzenburg JU, Schwaibold H, Bhanot SM et al. Modular surgical training for endoscopic extraperitoneal radical prostatectomy. BJU Int 2005; 96: 1022–1027
  6. Lee JY, Mucksavage P, Sundaram CP, McDougall EM. Best practices for robotic surgery training and credentialing. J Urol 2011;185: 1191–1197
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