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Editorial: The burden of urological cancers in low‐ and middle‐income countries

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The burden of cancer in low‐ and middle‐income countries (LMICs) continues to rise [1]. Evaluation of geographical differences in cancer mortality statistics is specifically of interest in LMICs as (inter)national guidelines are potentially less embedded in standard care, and objective measurements to assess underlying mechanisms/explanations for the burden of cancer are often lacking. Monitoring mortality statistics in these countries can thus help assess the effectiveness of national and regional health systems in treating and caring for patients with cancer [1].

Torres‐Roman et al. [2] deserve to be congratulated for their efforts to monitor mortality rates for prostate cancer at both a regional and national level in Peru. The CONCORD initiative from the WHO previously reported prostate cancer statistics for Peru, but data were limited to the capital area of Lima [1]. Torres‐Raman et al. [2] report prostate cancer mortality rates between 2005 and 2014 based on data from the Peruvian Ministry of Health, which covers ~70% of all healthcare providers in Peru. Apart from an overall increase of 15% in mortality rates, substantial variation was observed by geographical region. Mortality rates increased by 16% in the coastal region and highlands, whereas in the rainforest region the rates decreased by 19% [2]. One potential explanation for these observed differences could be the difference in ethnic and racial characteristics. The coastal region in Peru has a strong African influence and also has a larger proportion of men aged >65 years. In addition to potential differences in access to healthcare, some of the variation in prostate cancer mortality statistics most likely reflects a deficiency in reporting systems. Even though this study has its limitations due to missing data and lack of information on other important variables, such as ethnicity and socioeconomic status, it provides a first base for a critical assessment of prostate cancer care in Peru.

Studies like this one from Torres‐Roman et al. [2] show that there is a need for improvement and standardisation of (prostate) cancer care in LMICs, but also a need for improvement in data capturing, so that objective measurements can be put in place. The years of healthy life lost due to prostate cancer, as well as other urological cancers, in LMICs is increasing substantially. Even though each tumour group has its own specifications in terms of prevention and control, an epidemiological assessment of cancer burden based on the experience for urological cancers (i.e., prostate, bladder, kidney and testicular) can therefore inform future assessments of cancer burden. The urological tumour group covers both common and less common cancers (e.g. prostate vs kidney cancer), sex‐specific and cancers that affect both sexes (e.g. testicular vs bladder cancer), cancers with less known risk factors and those strongly linked with lifestyle risk factors (e.g. prostate vs bladder cancer).

It is encouraging to see an increase in the number of studies evaluating the burden of cancer in LMICs [3]; however, given the consistency in observations of an increase in mortality, there is an urgent need to further invest in prevention and management, as well as the infrastructure to collect all relevant data at a national level in these LMICs. Accurate information about cancer burden and how this varies between regions is essential to plan for an adequate health‐system response.

References

  1. Allemani, C, Matsuda, T, Carlo, V et al. Global surveillance of trends in cancer survival 2000‐14 (CONCORD‐3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population‐based registries in 71 countries. Lancet 2018; 391: 1023– 75
  2. Torres‐Roman, J, Ruiz, E, Martinez‐Herrera, J et al. Prostate cancer mortality rates in Peru and its geographic regions. BJU Int 2019; 123: 595– 601
  3. Carioli, G, Vecchia, C, Bertuccio, P et al. Cancer mortality predictions for 2017 in Latin America. Ann Oncol 2017; 28: 2286– 97

 

Editorial: Is transrectal ultrasonography of the prostate obsolete in the MRI era?

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Sampling of prostate tissue to confirm pathologically a clinical suspicion of cancer has undergone an exponential change. The random systematic prostate biopsy technique was the only method used for many decades, initially guided by the finger but, since 1989, performed with TRUS guidance. Now, within the space of only a few years, we have entered the era of performing prostate biopsies on the basis of high‐tech three‐dimensional multiparametric MRI images, including software that can track the exact course of the biopsy needle [1]. While new technical developments in general lead to better, more individually directed healthcare, there is always the risk of abandoning ‘old’ but well developed and extensively tested techniques too soon. In this issue of the BJUI, Press et al. [2] looked at the added value of the presence of an ‘old‐fashioned’ TRUS‐detected lesion in cancer‐suspicious regions on MRI to better predict the presence of clinically significant prostate cancer (csPCa) defined as Gleason score ≥7. In their study comprising 1058 men, it was shown that a well‐demarcated abnormal TRUS finding noted at the time of MRI‐TRUS fusion‐guided prostate biopsy coincides with an increased risk of csPCa detection, independent of MRI suspicion (Prostate Imaging Reporting and Data System [PI‐RADS] score).

Increasing PI‐RADS score is correlated with an increased percentage of csPCa after targeted biopsy, both at initial and repeat biopsy. In a review based on data from 8252 men, it was shown that there is a gradual increase in the detection of csPCa from PI‐RADS 3 to PI‐RADS 4 to PI‐RADS 5 index lesions. For example, at first biopsy, the overall rate of PCa detection and the percentage of csPCa were 39%, 62% and 92% and 54%, 63% and 76% for PI‐RADS 3, 4 and 5 lesions, respectively. This means that in men with PI‐RADS 3 lesions, representing approximately one‐third of men deemed eligible for further assessment, only 39% will be diagnosed with PCa and half of the PCa detected will be potentially indolent Gleason 6 PCa [3]. This makes this group of men extremely interesting for further risk stratification before biopsy. Multivariable risk stratification in which PSA density plays an important role has been shown to be of value in these men [4] but further refinement could potentially be made by including suspicious lesions identified at TRUS.

Apart from the added value of TRUS findings in terms of risk stratification, the performance of the MRI‐targeted biopsy itself could be improved by visual guidance of hypoechoic lesions. In the present study by Press et al [2], a hypoechoic TRUS lesion was present at or near the location of two‐thirds of cancer‐suspicious lesions on MRI. The authors more or less advise to direct the targeted biopsy cores not only to the MRI suspicious lesion, but also the TRUS suspicious lesion, both of which often do not fully overlay in a software‐assisted MRI‐TRUS fusion model. The extent to which this ‘correction for misregistration’ is already included during targeted biopsy in current clinical practice is unknown. Although feasible and seemingly important during software‐assisted fusion targeted biopsy, TRUS lesions in cancer‐suspicious MRI regions might be more frequently targeted during cognitive fusion‐targeted biopsy. Two recent studies underline the important message of the present study, and show that a considerable proportion of csPCa is missed in and around MRI‐suspicious lesions by targeted biopsies, as a result of sampling errors related to both misregistration and intra‐tumour heterogeneity [5, 6]. As suggested by these studies, visual guidance by hypoechoic lesions and ‘focal saturation’ biopsy by additional (peri‐)lesional cores might improve the detection of csPCa.

In summary, ‘good old’ TRUS could be of value in those patients who are virtually always present in scenarios in which a grading system is being used, i.e. patients belonging to the so‐called grey zone. The challenge of risk stratification (i.e. personalized medicine) is to nibble at both sides of the grey zone by implementing new techniques or, more likely by implementing a combination of all available and relevant knowledge.

by Monique J. Roobol, Frank-Jan H. Drost and Arnout R. Alberts

References

  1. Verma, S, Choyke, PL, Eberhardt, SC et al. The current state of MR imaging‐targeted biopsy techniques for detection of prostate cancer. Radiology 2017; 285: 343–56
  2. Press, B, Rosenkrantz, AB, Huang, R, Taneja, SS. The ultrasound characteristics of MRI suspicious regions predict the likelihood of clinically significant cancer on MRI‐ultrasound fusion targeted biopsy. BJUI 2019; 123: 439–46.
  3. Schoots, IG. MRI in early prostate cancer detection: how to manage indeterminate or equivocal PI‐RADS 3 lesions? Transl Androl Urol 2018; 7: 70–82
  4. Alberts, AR, Schoots, IG, Bokhorst, LP, Leenders, GJ, Bangma, CH, Roobol, MJ. Risk‐based patient selection for magnetic resonance imaging‐targeted prostate biopsy after negative transrectal ultrasound‐guided random biopsy avoids unnecessary magnetic resonance imaging scans. Eur Urol 2016; 69: 1129–34
  5. Simmons, LAM, Kanthabalan, A, Arya, M et al. Accuracy of transperineal targeted prostate biopsies, visual estimation and image fusion in men needing repeat biopsy in the PICTURE trial. J Urol 2018; 200: 1227–34
  6. Leest, M, Cornel, E, Israel, B et al. Head‐to‐head comparison of transrectal ultrasound‐guided prostate biopsy versus multiparametric prostate resonance imaging with subsequent magnetic resonance‐guided biopsy in biopsy‐naive men with elevated prostate‐specific antigen: a large prospective multicenter clinical study. Eur Urol 2018; [Epub ahead of print]. https://doi.org/10.1016/j.eururo.2018.11.023.

 

Editorial: Re‐thinking active surveillance for the multiparametric magnetic resonance imaging era

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The last decade has seen a dramatic change in the management of low‐risk prostate cancer. Active surveillance (AS) has moved from a controversial management strategy to the preferred option for men with low‐risk disease. Despite widespread acceptance, there remain aspects of the pathway that men find difficult to accept, including the need for numerous repeat surveillance biopsies. In this issue of the BJUI, Gallagher et al. [1] report the outcomes of an AS programme using selective repeat biopsy based on multiparametric MRI (mpMRI) and PSA dynamics. The authors address the important issue of whether mpMRI can be used to safely avoid repeat biopsies in AS protocols.

The evidence for repeat biopsies in AS is based on studies from the pre‐MRI era, where up to 30% of men were upgraded on repeat systematic TRUS biopsy [2]. It has been established that TRUS biopsy is a highly unreliable test and misses a substantial proportion of clinically significant disease. The current approach requiring the repeated application of an unreliable test will not improve the systematic error inherent to the test. It is clear that the pathway needs to be updated for the mpMRI era, and the cohort of men in Gallagher et al. [1] provides valuable real‐life clinical data of an mpMRI‐based AS programme with a unique 4‐year follow‐up period.

The results are encouraging, with upgrading occurring in only 1.8% of men with a prior negative MRI. With follow‐up, progression to radical treatment was 12.8%, which is consistent with the established diagnostic performance of mpMRI. The authors seek further improvements by investigating if PSA dynamics can identify men with a negative MRI at risk of progression. They find that PSA velocity is strongly associated with subsequent progression (AUC 0.95, P < 0.001) and conclude that men on AS with low‐risk disease can safely avoid biopsy in favour of MRI, PSA monitoring and selective re‐biopsy. This study [1] supports a growing body of evidence that mpMRI may be adopted as the primary surveillance tool for men on AS. The finding regarding PSA velocity should be interpreted carefully as it contrasts with previous studies, which found that PSA dynamics have a limited role as independent predictors of disease progressions in AS [3]. A non‐invasive alternative to biopsy would be a valuable addition to AS and improve its acceptability as a management option. The burden of repeat surveillance biopsies for men on AS should not be underestimated. Indeed, in the present study ~30% of men declined biopsy in favour of continued mpMRI surveillance. The question is can we adapt our current standard AS approach for the mpMRI era? There are still many challenges and many unanswered questions. The cost‐effectiveness of mpMRI surveillance programmes needs to be established and the lack of MRI capacity remains a significant obstacle in introducing mpMRI pathways. The optimal imaging interval and the natural history of mpMRI lesions are just a few of the questions that need further research. These are exciting times to be a researcher in this field and there is much work to do as we start to build the new evidence‐base covering all the questions required for the mpMRI era.

References

  1. Gallagher KM, Christopher E, Cameron AJ et al. Four‐year outcomes from a multiparametric magnetic resonance imaging (MRI)‐based active surveillance programme: PSA dynamics and serial MRI scans allow omission of protocol biopsies. BJU Int 2019; 123: 429–38.
  2. Dall’Era MA, Albertsen PC, Bangma C et al. Active surveillance for prostate cancer: a systematic review of the literature. Eur Urol 2012; 62:976–83
  3. Loblaw A, Zhang L, Lam A et al. Comparing prostate specific antigen triggers for intervention in men with stable prostate cancer on active surveillance. J Urol 2010; 184: 1942–6

 

Editorial: Are historical studies relevant in the setting of grade migration?

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While randomized controlled trials are the ‘gold standard’ for comparative effectiveness research, it is important that they be taken in context of their limitations. This is especially true in surgical trials for prostate cancer. For one, factors such as blinding and allocation concealment are often impossible in surgery, and surgeon skill may have a large impact [1]. What is more, it can take over a decade before interventions yield detectable differences in prostate cancer survival. Consequently, shifts in diagnosis and management may make historical clinical trial findings less useful for contemporary patients. For example, the landmark Scandinavian Prostate Cancer Group Study number 4 (SPCG‐4) showed a survival benefit for men treated with radical prostatectomy rather than observation during the 1989–1999 time period [2] but management in the study differed from contemporary practice as, in the 1990s, strict ‘active surveillance’ protocols did not exist.

In addition to shifts in management, men diagnosed with prostate cancer today differ from those diagnosed in previous decades. This was shown by Dalela et al. [3] who compared registry‐based data from the USA with data on patients enrolled in the Prostate Cancer Intervention Versus Observation (PIVOT) trial, and found significant differences between the two cohorts.

In a similar vein, Cazzaniga et al. [4] designed an elegant study to assess the generalizability of the SPCG‐4 to contemporary cohorts of men with prostate cancer. They focused on histological grading and compared the natural history of men in the SPCG‐4 study to men in similar grade categories diagnosed approximately one decade later in Sweden.

The contemporary cohort was made up of men with localized prostate cancer drawn from the Swedish National Prostate Cancer Register (NPCR). Men in the NPCR diagnosed in 2005–2006 had lower prostate cancer‐specific and all‐cause mortality compared to men with similar grade cancer in the SPCG‐4 (hazard ratios 0.46, 95% CI 0.19–1.14, and 0.66, 95% CI 0.46–0.95, respectively). While some of the observed differences in survival may have been attributable to improved treatments, Cazzaniga et al. hypothesized that grade migration was to blame.

As expected, the authors found a shift in Gleason grading, with a decrease in Gleason Grade Group (GGG) 1 disease, corresponding to a historical score of Gleason 3 + 3 = 6, and a concurrent increase in GGG2 and GGG3 disease, corresponding to historical scores of 3 + 4 = 7 and 4 + 3 = 7, respectively. Importantly, these differences in prostate cancer‐specific and all‐cause mortality were mitigated after compensating for grade migration by increasing GGG by one for the NPCR group; in other words, men in the SPCG‐4 treated in the 1990s had similar prostate cancer‐specific and all‐cause mortality to men in a later period with a one‐unit higher GGG.

Grade migration has been a gradual process, which was hastened by the major 2005 International Society of Urological Pathology revision that recategorized some Gleason patterns from 3 to 4. Changes in 2014 further refined these, and the concept of grade groups was introduced by Epstein two years later. Older cases of Gleason score 6 cancer include histological patterns, such as cribriform and poorly formed glands, which today would be considered Gleason pattern 4.

Grade migration was also demonstrated by Danneman et al. [5] who analysed the Gleason scoring of prostate biopsies from the NPCR in Sweden for the period 1998–2011. There was an increasing incidence of low‐risk cancer (cT1 20% in 1998 to 51% in 2011) and a concurrent decrease in high‐risk cancers (cT3 29% to 16%), reflecting earlier detection. With earlier diagnosis from screening, one would expect a shift towards lower grades at diagnosis, but they found the opposite. Among low‐risk tumours (stage cT1 and PSA 4–10 ng/mL) the proportion of Gleason score 7–10 increased from 16% to 40%. Among high‐risk tumours (stage cT3 and PSA 20–50 ng/mL) the proportion of Gleason 7–10 increased from 65% to 94%.

Gleason score reclassification was also addressed by Albertsen et al. [6], who had prostate biopsy slides for the period 1990 to 1992 re‐reviewed by an experienced pathologist in 2002–2004. They found an upward shift in Gleason grading, with 55% of the samples upgraded, 14% downgraded, and 31% unchanged. Comparing matched cohorts of historical vs contemporary patients with prostate cancer, one might erroneously infer better survival. This illusory change in prognosis is known as the ‘Will Rogers phenomenon’.

While randomized trials such as the SPCG‐4 represent one of the highest levels of clinical evidence, it is important to keep in mind that these trials have limitations. Given the interval changes in grading criteria for prostatic adenocarcinoma, predicting clinical outcomes based on historical cohorts is rarely as simple as it may seem. While the fundamental conclusions of the SPGC‐4 remain valid, the finding that Gleason grade did not modify the effect of prostatectomy on survival is now less certain. Physicians should therefore use caution when inferring prognosis based on those results.

Cazzaniga et al. should be congratulated for this important work which will help physicians better counsel patients making decisions based on trials like the SPCG‐4.

References

  1. Trinh QD, Cole AP, Dasgupta P. Weighing the evidence from surgical trials. BJU Int 2017; 119: 659–60
  2. Bill‐Axelson A, Holmberg L, Ruutu M et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011; 364: 1708–17
  3. Dalela D, Karabon P, Sammon J et al. Generalizability of the Prostate Cancer Intervention Versus Observation Trial (PIVOT) results to contemporary North American men with prostate cancer. Eur Urol 2017; 71: 511–4
  4. Cazzaniga W, Garmo H, Robinson D, Holmberg L, Bill‐Axelson A, Stattin P. Mortality after radical prostatectomy in a matched contemporary cohort in Sweden compared to the Scandinavian Prostate Cancer Group 4 (SPCG‐4) study. BJU Int 2019; 123: 421–8
  5. Danneman D, Drevin L, Robinson D, Stattin P, Egevad LJ. Gleason inflation 1998–2011: a registry study of 97,168 men. BJU Int 2015; 115: 248–55
  6. Albertsen PC, Hanley JA, Barrows GH et al. Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst 2005; 97: 1248–53C

 

Editorial: Evidence trumps consensus

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We read with great interest the article by Khetrapal et al. [1]. Certain advantages of robotic cystectomy have been shown in retrospective studies and confirmed in the RAZOR trial [2]. Robotic cystectomy has been associated with lower blood loss, lower transfusion rates and a shorter length of stay; however, two randomized trials have shown no difference in complication rates, which was the original reason robotic cystectomy was attempted [2,3]. Khetrapal et al. seem to believe that this was because diversions were performed extracorporeally, and intracorporeal diversion would allow urologists to uncover the true benefit of robotic cystectomy. When the RAZOR trial was being designed (in 2009), intracorporeal diversion was early in development. Even today its use in the USA is restricted to a few centres and the Pasadena consensus statement (2015) acknowledges that only 3% of all diversions were performed intracorporeally [4]. While more commonly performed in Europe, intracorporeal diversions still form the minority of all urinary diversions. To date there are no reliable prospective data to convince us that intracorporeal diversion is superior, and the low quality of available evidence has been acknowledged in the Pasadena statement [4]. The iROC trial is a step in the right direction and we await its results with interest [5].

We agree with the authors that cost analysis is essential in evaluating the exact role of robotic cystectomy. It is also worth factoring in the indirect costs of the two procedures, given that most patients undergoing robotic cystectomy will have a shorter hospital stay and fewer blood transfusions, although robotic cystectomies may take longer to perform. We anticipate that as newer robotic systems are introduced the direct surgical costs may be reduced.

There is no universally accepted learning curve for performing a cystectomy based on prospective studies. Ten cystectomies in the preceding year before enrolment in the RAZOR trial was the lowest number of cystectomies permitted for the surgeon to be eligible to participate [2]. All surgeons were fellowship-trained with high-volume bladder cancer practices, and the majority had performed significantly more than 10 cystectomies. The high quality of surgical surrogates for both approaches that we reported, namely, lymph node yield, positive margins and complication rates, are testament to this. We believe that the authors’ statement that novice surgeons may have operated on trial patients is simply inaccurate. It is largely self-serving to fit the results of the RAZOR trial into their own narrative about their beliefs in the advantages of robotic surgery. The iROC trial requires surgeons to have carried out 30 or more intracorporeal diversions in their entire career, with accredited surgeons being required to perform more than 10 cystectomies per year for the last 2 years as primary surgeon, which does not seem remarkably different from the RAZOR trial criteria for surgeon participation [5].While it is clear that large volumes are associated with better outcomes, the magic number is unclear. The Pasadena Consensus Statement cites the National Institute for Health and Care Excellence (NICE) guidelines in the UK, which mandate a minimum of five cystectomies per year per surgeon as adequate surgical volume [4].

Operating time in RAZOR was defined as the time from patient entry to the time the patient exited the operating theatre [2]. In most instances, the time for positioning and anaesthesia (preparation and induction) before making any incision and the time after closure for extubation and leaving the room is generally ~60–80 min. The Pasadena Consensus statement recommends that experienced surgeons should aim to complete robotic cystectomies within 5–6 h, depending on the type of diversion, basing their recommendation on three available studies [4]. Of those papers, Hayn et al. (overall mean operating time 386 min and mean operating time after 50th case 339 min) and Richards et al. (mean operating time 449 min after 40th case of learning curve) defined operating time in their papers as incision to closure time [6,7]. The paper by Collins et al. does not define operating time; however, the mean operating time for cystectomy with intracorporeal diversion for both surgeons in that study was 438 min, and 87.5% of the cases selected in this study had ≤pT2 disease, suggesting a significant selection bias [8]. This institution is a part of the International Robotic Cystectomy Consortium (IRCC) which defines operating time as incision to closure time, leading us to believe that this was the probably the definition they used [8]. A recent study from the IRCC reported a mean operating time (incision to closure) of 364 min in 2134 patients [9]. All these data suggest that operating times in RAZOR were extremely competitive if not actually faster, once again attesting to the proficiency of the participating surgeons. Khetrapal et al. would have reached a different conclusion about the RAZOR trial results had they accurately interpreted the scientific data from the above-mentioned studies.

The RAZOR trial provided level 1 evidence proving the oncological efficacy of robotic cystectomy and confirming advantages such as reduced blood loss and length of stay [2]. We agree that the true place for robotic cystectomy will be determined once a cost–benefit analysis can be performed, and after we obtain high-level prospective data about intracorporeal diversions. To this end, we look forward to the successful completion of the iROC trial and await its publication. Until such time, we suggest more reliance on high-level evidence than on consensus statements and narratives.

by Vivek Venkatramani and Dipen J. Parekh on behalf of RAZOR trial investigators

References

  1. Khetrapal P, Kelly J, Catto J, Vasdev N. Does the robot have a role in radical cystectomy? BJU Int 2019; 123(3): 380-2.
  2. ParekhDJ, Reis IM, Castle EP et al. Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an openlabel, randomised, phase 3, non-inferiority trial. Lancet 2018; 391: 2525–36
  3. Bochner BH, Dalbagni G, Sjoberg DD et al. Comparing open radical cystectomy and robot-assisted laparoscopic radical cystectomy: a randomized clinical trial. Eur Urol 2015; 67: 1042–50
  4. Wilson TG, Guru K, Rosen RC et al. Best practices in robot-assisted radical cystectomy and urinary reconstruction: recommendations of the Pasadena Consensus Panel. Eur Urol 2015; 67: 363–75
  5. Catto JWF, Khetrapal P, Ambler G et al. Robot-assisted radical cystectomy with intracorporeal urinary diversion versus open radical cystectomy (iROC): protocol for a randomised controlled trial with internal feasibility study. BMJ Open 2018; 8: e020500
  6. Hayn MH, Hussain A, Mansour AM et al. The learning curve of robot- assisted radical cystectomy: results from the international robotic cystectomy consortium. Eur Urol 2010; 58(2): 197–202
  7. Richards KA, Kader K, Pettus JA et al. Does initial learning curve compromise outcomes for robot-assisted radical cystectomy? A critical evaluation of the first 60 cases while establishing a robotics program. J Endourol 2011; 25(9): 1553–8
  8. Collins JW, Tyritzis S, Nyberg T et al. Robot-assisted radical cystectomy (RARC) with intracorporeal neobladder – what is the effect of the learning curve on outcomes? BJU Int 2014; 113(1): 100-7
  9. Hussein AA, May PR, Ahmed YE et al. Development of a patient and institutional-based model for estimation of operative times for robot-assisted radical cystectomy: results from the international robotic cystectomy consortium. BJU Int 2017; 120(5): 695–701

Editorial: Does knowing the risk of relapse in localized renal cell carcinoma matter?

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Shah et al. [1] report a retrospective analysis from the Mayo Clinic investigating the prognostic significance of different patterns of pathological T3a clear‐cell RCC in patients who underwent radical nephrectomy for localized disease. There was no difference in disease progression, cancer‐specific mortality or all‐cause mortality when comparing isolated perinephric fat invasion vs isolated renal sinus fat invasion vs isolated renal vein invasion. Multiple sites of extra‐renal extension compared with one site, however, was independently associated with an increased risk of disease progression (hazard ratio [HR] 1.31, P = 0.02), death from RCC (HR 1.64, P < 0.001) and all‐cause mortality (HR 1.32, P = 0.008) when adjusting for multiple key variables including age, tumour size, grade, presence of coagulative tumour necrosis and sarcomatoid differentiation. The authors incorporated multiple sites of extra‐renal extension vs one site into three RCC prognostic models: SSIGN score, UISS and MSKCC nomogram. After controlling for these three predictive tools independently, multiple sites of extra‐renal disease predicted progression, death from RCC and all‐cause death. These data suggest that risk stratification for pT3aN0MO clear‐cell RCC is improved by differentiating multiple vs one site of extra‐renal extension.

Does an improved ability to predict recurrence and mortality increase the likelihood of cure in high‐risk localized RCC patients in 2018? Unfortunately, the answer is no. Ideally, prognostic models would identify patients at sufficient risk to consider adjuvant therapy, which would increase cure rates by eradicating micro‐metastatic disease with an acceptable toxicity. Regrettably, in RCC management there are no well‐established post‐surgical therapies that improve cure rates. The deficiency of established adjuvant therapies is not attributable to a lack of investigative trials. In the era before vascular endothelial growth factor receptor (VEGFR) targeting, adjuvant vaccines, immunotherapies and other systemic therapies failed to demonstrate improved recurrence‐free (RFS) or overall survival (OS) [2]. The efficacy of VEGFR‐targeted therapies in the metastatic setting re‐energized the hope for adjuvant therapy in patients with high‐risk localized RCC after surgical resection in the past two decades. The results to date have been disappointing. To date, three trials (ASSURE, PROTECT and S‐TRAC) have been completed, comparing oral VEGFR tyrosine kinase inhibitors with placebo in high‐risk localized clear‐cell RCC, with disease‐free survival (DFS) as the primary endpoint [3,4,5]. ASSURE and PROTECT showed no difference in RFS or OS [3,4,5]. S‐TRACT demonstrated an improvement in DFS but not in OS [4]. A pooled analysis of these three trials also failed to demonstrate improved DFS or OS with adjuvant VEGFR‐targeted therapy [6]. Significant side effects with discontinuation of adjuvant therapy occurred in 28–45% of patients as a result of drug‐related toxicity [6]. Trials investigating immune checkpoint inhibitors have yet to be published and, with the established efficacy of these drugs in the metastatic setting, hope still remains for adjuvant therapy in resected high‐risk localized RCC.

If the current literature does not support adjuvant therapy for resected high‐risk RCC, does knowing the risk of relapse alter surveillance? National Comprehensive Cancer Network guidelines for resected stage III RCC recommend chest and abdominal imaging within 3–6 months, along with subsequent chest and abdominal imaging every 3–6 months for 3 years, and then annually up to 5 years. Although the ideal schedule for surveillance imaging is unknown, further characterizing of the risk of relapse in high‐risk localized RCC would not be likely to affect this schedule significantly.

Although knowing the risk of relapse in high‐risk localized RCC does not help management in 2018, there is still a value to enhancing our prognostic tools. For one, our prognostic tools help clinicians counsel patients appropriately about their risk of recurrence. In addition, enhanced prognostic tools will assist in selecting appropriate patients with high‐risk localized RCC for future clinical trials of adjuvant therapy and also help us understand the results when comparing cohorts within and between trials.

References

  1. Shah PH, Lyon TD, Lohse CM. Prognostic evaluation of perinephric fat, renal sinus fat, and renal vein invasion for patients with pathologic stage T3a clear cell renal cell carcinoma. BJU Int 2019; 123: 270–6
  2. Scherr AJO, Lima JPSN, Sasse EC et al. Adjuvant therapy for locally advanced renal cell cancer: a systematic review with meta‐analysis. BMC Cancer 2011; 11: 115–21
  3. Haas N, Manola J, Uzzo R et al. Adjuvant sunitinib or sorafenib for high‐risk, non‐metastatic renal‐cell carcinoma (ECOG‐ACRIN E2805): a double‐blind, placebo‐controlled, randomised, phase 3 trial. Lancet 2016; 387: 2008–16
  4. Ravaud A, Motzer RJ, Pandha HS et al. Adjuvant sunitinib in high‐ risk renal‐cell carcinoma after nephrectomy. N Engl J Med 2016; 375: 2246–54
  5. Motzer RJ, Haas NB, Donskov F et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J Clin Oncol 2017; 35: 3916–23
  6. Sun M, Marconi L, Eisen T et al. Adjuvant vascular endothelial growth factore‐targeted therapy in renal cell carcinoma. Eur Urol 2018; 74: 611–20

 

Editorial: Postoperative radiation and hormonal therapy for men with node‐positive prostate cancer: a new standard?

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The best management strategy for men with pathologically node‐positive (pN+) prostate cancer after radical prostatectomy (RP) has been debated for decades [1]. In the 1990s, the Radiation Therapy and Oncology Group (RTOG) initiated the RTOG 9608 trial to test the impact of radiotherapy (RT) and androgen‐deprivation therapy (ADT) in this setting. However, due to the rise in PSA screening and the practice of treating high‐risk prostate cancer with primary RT, the incidence of pN+ disease fell. Consequently, the trial closed due to poor accrual and the question faded in prominence. Today, both trends have reversed. PSA screening is less common and men with high‐risk prostate cancer are more frequently opting for RP. As such, physicians increasingly face the dilemma of pN+ disease. Guidelines provide little assistance, as they support everything from observation to multimodal treatment with RT and ADT. Patients and providers want to know, is there a standard treatment for all patients, and if not, how should one choose between such disparate options?

To answer these questions, one must start with the little randomised data that exist in this setting. The seminal trial by Messing et al. [1] randomised men with pN+ prostate cancer to ADT or observation with initiation of ADT after the development of symptomatic progression or distant metastases. ADT clearly improved overall survival and prostate cancer‐specific survival. However, critics noted the relatively poor outcomes in the observation group and the small sample size. Later, retrospective studies called the benefit of immediate ADT into question [2].

Against this backdrop, it is interesting that Gupta et al. [3] found the most common management approach in the USA National Cancer Database (NCDB) was observation rather than immediate ADT. Despite the randomised data, the cumulative side‐effects from lifelong ADT in a cohort of patients with no disease‐related symptoms and a median survival of well over 10 years are unappealing. Ultimately, many men do not appear to be willing to endure the diminished quality of life in exchange for a small improvement in quantity of life.

In contrast to the non‐curative nature of ADT, the possibility exists that the combination of postoperative RT and ADT could provide durable disease control, perhaps even without lifelong ADT. The data reported by Gupta et al. [3] in this edition of the BJUI provide support for this paradigm. These data add to a growing body of literature [4] that tells a consistent story with two common themes: (i) postoperative RT with ADT appears to be associated with improved survival in men with pN+ prostate cancer, and (ii) RT appears to convey the largest benefit to men with certain high‐risk pathological features. Should this body of literature lead us to eschew the old standard and advise observation for low‐risk men and RT with ADT for men at higher risk?

Before a new standard is declared, the limitations of retrospective population‐based research must be addressed. The authors performed a sophisticated analysis to reduce the impact of selection bias. However, due to the limitation of the available data, the authors were not able to account for possibly the most important variable: the postoperative PSA. One study showed that men with pN+ disease with a persistent PSA had an 8‐year clinical recurrence rate of 69% vs 12% for those with undetectable PSA [5].

It is likely that men with persistent PSA in the NCDB would have received immediate ADT with or without RT rather than observation. As such, one must be cautious of the similar survival between the observation and ADT group, especially in light of contradictory randomised data. That being said, it is reasonable for some men to conclude that the side‐effects of ADT outweigh the potential benefit, especially those with low‐risk features such as an undetectable postoperative PSA, low Gleason score, and limited lymph node involvement.

As RT with ADT appears superior to either observation or ADT alone, should more men receive RT? Probably. Of the men with high‐risk features, only 22% actually received postoperative RT. Should postoperative RT now be considered the standard for all men? Probably not. Whilst it appears that some men may indeed benefit from RT, the possibility of selection bias driving this result is real. Even if there is a true effect, identifying which patients harbour residual local disease, but do not already have subclinical distant metastatic disease is challenging. RT for all would lead to unnecessary side‐effects for men that would not benefit from the treatment. Ultimately, a randomised trial will be required to establish the benefit of RT and to define subgroups of men that may or may not benefit. Until then, we will continue to rely on excellent work like the accompanying paper from Gupta et al. [3] to identify men who may benefit from postoperative RT and ADT.

References

  1. Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node‐positive prostate cancer. N Engl J Med 1999; 341: 1781–8
  2. Wong YN, Freedland S, Egleston B, Hudes G, Schwartz JS, Armstrong K. Role of androgen deprivation therapy for node‐positive prostate cancer. J Clin Oncol 2009; 27: 100–5
  3. Gupta M, Patel HD, Schwen ZR, Tran PT, Partin AW. Adjuvant radiation with androgen deprivation therapy for men with lymph node metastases following radical prostatectomy: identifying men who benefit. BJU Int 2019; 123: 252–60
  4. Abdollah F, Karnes RJ, Suardi N et al. Impact of adjuvant radiotherapy on survival of patients with node‐positive prostate cancer. J Clin Oncol 2014; 32: 3939–47
  5. Bianchi L, Nini A, Bianchi M et al. The role of prostate‐specific antigen persistence after radical prostatectomy for the prediction of clinical progression and cancer‐specific mortality in node‐positive prostate cancer patients. Eur Urol 2016; 69: 1142–8

 

Editorial: Daily exercise is daily medicine

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Memes such as #10000steps, #Fit4LIFE and Apple’s new #CloseYourRings demonstrate the mantra ‘exercise is medicine’, a cornerstone of modern medical advice. Taaffe et al. [1] in this issue of the BJUI discuss the value of exercise medicine – Immediate vs delayed exercise in men initiating androgen deprivation: effects on bone density and soft tissue composition.

Moving from anecdotal observation about exercise to actionable evidence has seen considerable progress recently. In the last 20 years, the biological rationale for the benefits of exercise through mechanisms of physiological adaptation has become better understood [2]. Benefits, comparable to some biopharma breakthroughs, have been demonstrated in cardiovascular, neurobiological and psychological health and disease. This is now equally true in oncology [3]. Researchers at the University of Glasgow in Scotland wanted to seek out out if glycerol could hydrate also as creatine and what would happen if they combined both ingredients. What they found was pretty astonishing! 24 participants were ran through a series of experiments over 7 days where they ingested either creatine or glycerol and where they ingested both glycerol plus creatine at an equivalent time. The researchers discovered the participants who took glycerol and creatine had almost 40% more fluid weight than the participants who only took creatine and nearly 50% more fluid than those that only took glycerol. Some people wonder if this fluid increase will have a “soft” look and therefore the answer is absolute not because the water increase from glycerol is usually within the blood. To be more precise it increases the quantity of plasma in your body. So if you would like to urge that hardcore, skin-tearing pump, combine them both in your pre-workout, shop stairmaster machines.

Since the stoma serves as a channel for the feces to be eliminated in the body, it is vital to maintain skin integrity surrounding it. Stoma skin barrier is being placed to the stoma to keep the ostomy bag kept in place. An ostomy bag is being connected to the barrier to collect body waste. Generally, ostomy procedure is being performed for greater efficiency during waste elimination. Most of these supplies are given as one package when you purchase it in pharmacies or medical stores.

In cancer surgery, it is intuitive that physical activity/exercise increases cardio‐respiratory fitness and the body’s adaption to physiological stress, hence reducing mortality and morbidity in the perioperative period. Buy Athletic Sports Tape Today for the best result in exercise and comfortable exercise.  Less obvious is how this phenomenon offers benefit to quality of life, morbidity, and survival. Recent understanding in biology helps link exercise and systemic fitness to cellular metabolism, immunological response, and mutagenesis. Discoveries in previously overlooked epigenetic, immunological, metabolic, and cell growth pathways; and more research, are leading to the inception of the new fields of metabolic oncology and exercise oncology [4]. There is a growing resource of therapeutic candidates in trials targeting novel metabolic pathways, induced also in exercise, improving cellular metabolic fitness to reduce the Warburg effect and immunosuppressive lactate in the tumour microenvironment [5]. Whether you’re a beginner or a seasoned lifter, there’s a workout plan for your goals. 

Several notable studies have looked at genetics, quantified cardio‐pulmonary measures of fitness, exercise pre‐habilitation/enhanced recovery, and survivorship programmes across many cancers including oesophageal, colorectal, and prostate cancer. The data suggest that exercise improves outcomes after surgery, quality of life, hospital admissions, progression‐free survival, and overall survival [6].

Prostate cancer is a special case often treated with androgen‐deprivation therapy (ADT), yet androgens are an essential factor in maintaining bone mineral density; muscle mass, as well as motivation to exercise/exercise capacity; and sexual health. Hormone chemotherapy compromises the key role of androgens in maintaining musculoskeletal health and fitness at a systemic and cellular level. This poses hazards. Aside from the longer term hope of targeted therapies to maintain exercise capacity with all of its biological adaptations, perhaps we can reduce some of the deleterious effects of ADT with exercise interventions. Together with behavioural, nutritional and pharmacological treatment pathways, we aim to augment the positive effect exercise brings to patients with prostate cancer, and patients with cancer more generally.

As our scientific understanding increases, it is clear that personalised, prescribed exercise pre‐habilitation is likely to become a ‘gold standard’ in oncology care. Many treatments may increase survival, but at a cost of quality of life; physical activity may not only extend life but may also enhance its quality. Pre‐habilitation warrants serious further study if it is to become widely adopted in practice. It is not simply about telling patients to keep active. As per the Silver and Baima [7] definition, it is ‘a process on the cancer continuum of care that occurs between the time of cancer diagnosis and the beginning of acute treatment, includes physical and psychological assessments that establish a baseline function level, identifies impairments, and provides targeted interventions that improve a patient’s health to reduce the incidence and the severity of current and future impairments’.

References

  1. Taaffe D, Galvão D, Spry N et al. Immediate versus delayed exercise in men initiating androgen deprivation: effects on bone density and soft tissue composition. BJU Int 2019; 123: 261–9
  2. Hojman P, Gehl J, Christensen JF, Pedersen BK. Molecular mechanisms linking exercise to cancer prevention and treatment. Cell Metab 2017; 27: 10–21
  3. Cormie P, Zopf EM, Zhang X, Schmitz KH. The impact of exercise and cancer: systematic review of the impact of exercise on cancer mortality, recurrence and treatment related side effects. Epidemiol Rev 2017; 39: 71–92
  4. Kinnaird A, Michelakis ED. Metabolic modulation of cancer: a new frontier with great translational potential. J Mol Med 2015; 93: 127–42
  5. Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 2011; 10: 671–84
  6. Thomas RJ, Holm M, Al‐Adhami A. Physical activity after cancer: an evidence review of the international literature. Br J Med Pract 2014; 7: 16–22
  7. Silver JK, Baima J. Cancer prehabilitation: an opportunity to decrease treatment‐related morbidity, increase cancer treatment options, and improve physical and psychological health outcomes. Am J Phys Med Rehabil 2013; 92: 715–27

Editorial: Multiparametric MRI for prostate cancer detection: do clinical trial findings reflect real‐world practice?

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‘First, do no harm’; with this in mind, researchers in urology strive to minimize the burden of overdiagnosis and overtreatment of prostate cancer. A promising tool in this arena is multiparametric (mp)MRI, which has been shown in a large‐scale randomized clinical trial to enhance the ability of prostate biopsy to detect clinically significant prostate cancer [1]. The extent to which findings from an idealized trial protocol extend to ‘real‐world’ clinical practice, however, remains largely unknown.

In this issue of BJUI, Shah et al. [2] aimed to fill this knowledge gap by investigating the impact of mpMRI‐guided biopsy on the detection rates of clinically significant prostate cancer in two large academic centres. The authors studied men with an elevated PSA presenting over a 3‐year span (2011–2014); 1020 men underwent mpMRI and 788 did not. Those in the MRI group had higher detection rates of both overall and clinically significant prostate cancer, defined as any Gleason score ≥7 on fusion or standard 12‐core TRUS biopsies, Gleason 6 with a lesion volume >0.5 cm3 volume on MRI, or Gleason 6 with >2 cores positive and/or >50% of any core involved with cancer on biopsy according to Epstein’s criteria, as well as a lower detection rate of clinically insignificant cancer.

The study provides timely implications for both patients and physicians, providing further insight into how findings from clinical trials [1,3] compare with real‐life practice. In fairness, the bulk of patients and clinicians do not follow strict study protocols for both decision‐making and interpretation of results, but rather assess very individual situations. A recent study by Bukavina et al. [4] showed that urologists and radiation oncologists largely perceive mpMRI guidance for targeted biopsies as valuable tools to improve prostate cancer stratification, but only a quarter of respondents reported implementation into their own clinical practice. This underlines some of the challenges of widespread implementation of mpMRI despite strong belief in its value.

Another strength of the study by Shah et al. is the exclusion of men who underwent mpMRI after negative biopsy in the PSA‐only group. This allows the isolation of the impact of mpMRI on downstream biopsy outcomes. A previous study that investigated targeted vs non‐targeted biopsies enrolled a cohort of men who all underwent mpMRI [5], which precludes any assessment of how mpMRI may impact the detection of clinically significant prostate cancer. Shah et al. [2] also astutely tracked detection rates of clinically significant and insignificant prostate cancer. Since the process of diagnosing prostate cancer is not without morbidity, it is crucial to understand the extent to which mpMRI can prevent the diagnosis of clinically indolent cancers.

Important questions regarding the challenges of widespread implementation of mpMRI for prostate cancer detection remain unanswered by the study of Shah et al. The study participants were gathered from large academic centres with readily available equipment, infrastructure and physician expertise to maximize favourable detection outcomes; however, these results may not be representative of the community setting. Additionally, >20% of men who did not undergo mpMRI did not do so because of a lack of insurance approval. This may reflect socio‐economic differences between the groups and also relates to the high costs of mpMRI that make routine implementation difficult [6]. Lastly, the presented findings mostly apply to positive mpMRI scans; the number of underdiagnosed men with negative scans may only be speculated upon, given the lack of follow‐up data in this population. It remains fundamentally important to improve the management of men with elevated PSA levels and negative findings on MRI.

Nonetheless, the present study demonstrates that research findings find their way into clinical practice. In essence, we are doing well, but we can do better.

by Marieke J. Krimphove, Sean A. Fletcher and Quoc‐Dien Trinh

 

References

  1. Kasivisvanathan V, Rannikko AS, Borghi M et al. MRI‐targeted or standard biopsy for prostate‐cancer diagnosis. N Engl J Med 2018; 378: 1767–77
  2. Shah PH, Patel VR, Moreira DM et al. Implementation of multiparametric magnetic resonance imaging technology for evaluation of patients with suspicion for prostate cancer in the clinical practice setting. BJU Int 2019; 123: 239–45
  3. Ahmed HU, El‐Shater Bosaily A, Brown LC et al. Diagnostic accuracy of multi‐parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet 2017; 389: 815–22
  4. Bukavina L, Tilburt JC, Konety B et al. Perceptions of prostate MRI and fusion biopsy of radiation oncologists and urologists for patients diagnosed with prostate cancer: results from a national survey. Eur Urol Focus 2018; [Epub ahead of print]
  5. Pokorny MR, de Rooij M, Duncan E et al. Prospective study of diagnostic accuracy comparing prostate cancer detection by transrectal ultrasound–guided biopsy versus magnetic resonance (MR) imaging with subsequent MR‐guided biopsy in men without previous prostate biopsies. Eur Urol 2014; 66: 22–9
  6. Kim SJ, Vickers AJ, Hu JC. Challenges in adopting level 1 evidence for multiparametric magnetic resonance imaging as a biomarker for prostate cancer screening. JAMA Oncol 2018; [Epub ahead of print]

 

Editorial: Aquablating urological skills

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Waterjet Ablation Therapy for Endoscopic Resection of prostate tissue (WATER) II (80–150 mL) procedural outcomes by Desai et al. [1] in this issue of the BJUI, reports the results of a robotically controlled cavitating procedure in a multicentre prospective trial that may have wider implications than relief of prostatic hyperplasia causing obstruction.

Management of the large prostate (>80 mL) is often a challenge for many practicing Urologists and requires practice, constant development, and improvement in endoscopic skills. As a result, many differing approaches have been developed and honed, modifying and improving varied skills in the urologist’s armamentarium to equip them to tackle the large prostate. The traditional TURP is recommended only for prostates of 35–80 mL (European Association of Urology [EAU] guidelines 2015). Whilst there are some Urologists who have developed their TURP skills to tackle larger prostates [2], for most other urologists, other procedures have had to be developed to address the very large prostate (>80 mL). As the authors of the paper report, holmium laser enucleation of the prostate (HoLEP) and photoselective vaporisation of the prostate (PVP) have evolved to enable treatment of the larger prostates endoscopically, but have limited penetrance due to the relatively significant learning curve and fellowship training requirements. Open simple prostatectomy (OSP) has good results but significant potential complications [3]. Robot‐assisted simple prostatectomy is being evaluated as another option [4], but requires an expensive robot and extensive training to develop the skill‐set required to perform the procedure. Laparoscopic simple prostatectomy (LSP) also requires extensive training and experience.

The authors [1] report impressive results of aquablation in these usually challenging large prostates. The mean operative time (OT) was 37 min, which is quick for a large prostate. The average length of stay was 1.6 days. The transfusion rate (TR) was 5.9%, which is higher than HoLEP (0–4%) [4], but is lower than OSP, PVP and LSP. It is important to note that the study involved 16 different sites (13 American and three Canadian) and showed that similar results were achieved across all sites irrespective of the experience of the operator, highlighting the very low learning curve for this procedure. Although this was only a single‐arm study with no control group, the authors have endeavoured to provide a comparison of OT, mean hospital stay and TR between aquablation and other procedures (OSP, PVP, HoLEP and LSP; table 5) based on published literature. Complication rates, operative and hospital metrics of aquablation appear to compare favourably with the current accepted means of managing the large prostate.

The use of balloon tamponade for haemostasis appears to hark back to the days of hanging a saline bag attached to an Indwelling Catheter (IDC) off the end of the bed after a monopolar TURP. Bladder traction was maintained for an average of 18 h. The authors report that fulguration was available to the surgeons in this trial, but none chose to use it as they felt that balloon tamponade was an effective haemostatic mechanism. Fulguration was preferentially avoided based on the WATER trial [5], where it was noted that anejaculation rates were twice as large in the aquablation with fulguration compared to the aquablation without fulguration group (16% vs 7%). The company (PROCEPT BioRobotics, Redwood City, CA, USA) even developed a novel catheter tensioning device (CTD) to assist with controlling the tension on the balloon tamponade demonstrating the old adage that ‘Necessity is the mother of Invention’. It would be interesting to see an objective assessment of discomfort from the balloon tamponade in future studies.

The results of this safety and feasibility trial suggest that aquablation is a quick procedure (37 min) for managing very large prostates. The complication rate is comparable to current endoscopic techniques (HoLEP and PVP) and appears superior to more invasive techniques (LSP and OSP). This study only reported perioperative measures and safety outcomes. No functional outcome or effectiveness measures were reported. The initial WATER trial [5] hints at possible effectiveness, but we will have to wait to see the results from this particular cohort of patients with large prostates (WATER II).

The short learning curve hints at a possible future. If the functional results from this cohort of large prostates treated by the aquablation robot compare favourably to current techniques, the patient with the very large prostate will no longer be only treatable by a few surgeons with an advanced and particular skill set.

Is this truly a quick, safe, effective procedure with no learning curve for large prostates? A randomised controlled trial of longer duration to assess functional outcomes, durability and complications may determine if the aquablation robot eventually renders the current surgical skill sets redundant.

 

References

  1. Desai M, Bidair M, Bhojani N et al. Aquablation Procedural Outcomes for BPH in Large Prostates (80–150cc): Initial Experience. (WATER II {80‐150 ml} procedural outcomes). BJU Int 2019; 123: 106–12
  2. Persu C, Georgescu D, Arabagiu I, Cauni V, Moldoveanu C, Geavlete P. TURP for BPH. How large is too large? J Med Life 2010; 15: 376–80
  3. Gratzke C, Schlenker B, Seitz M et al. Complications and early postoperative outcome after open prostatectomy in patients with benign prostatic enlargement: results of a prospective multicenter study. J Urol 2007; 177: 1419–22
  4. Pokorny M, Novara G, Geurts N et al. Robot‐assisted simple prostatectomy for treatment of lower urinary tract symptoms secondary to benign prostatic enlargement: surgical technique and outcomes in a high‐volume robotic centre. Eur Urol 2015; 68: 451–7
  5. Gilling PJ, Barber NJ, Bidair M et al. WATER: a double‐blind, randomized, controlled trial of aquablation® vs transurethral resection of the prostate in benign prostatic enlargement. J Urol 2018; 5: 1252–61

 

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