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Editorial: MRI-Fusion Biopsy – Behind the Scenes

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MRI information of the prostate is increasingly used for improving the diagnostic yield of prostate biopsies [1]. However, increasing complexity of a procedure makes it prone to errors at multiple technical and human levels. Incorporating MRI information and ultrasonography (US) images for MRI-fusion biopsies is a technically challenging task. It involves various steps such as the acquisition and fusion of MRI and US images, the needle guidance during biopsy, and the diligence of the pathological evaluation of biopsy specimens. These different steps and interfaces between different medical professions influence the diagnostic performance of MRI-fusion biopsies.

For example, in daily clinical practice, MRIs from different institutions still harbour a great variance of sequences and reporting, despite the European Society of Urogenital Urology (ESUR) recently introducing acquisition and imaging protocols and a new and advanced version of the Prostate Imaging Reporting and Data System (PIRADS) version 2.0 [2]. The usefulness of such reporting schemes is evidenced by a moderate-to-good interobserver agreement between uro-radiologists for tumour lesion interpretation and corresponding κ values ranging from 0.55 to 0.80 [3]. Important pitfalls of image interpretation are benign lesions such as prostatitis, BPH and fibrosis, which might score similarly to prostate cancer lesions. This problem is further aggravated by a high proportion of patients that receive their first multiparametric MRI (mpMRI) of the prostate in the repeat-biopsy setting with a high burden of post-biopsy artefacts (haemorrhage, capsular irregularity) and lower overall cancer detection rate. Also, during MRI-fusion biopsy patient movement, prostate deformation by the US probe, and mismatch of image planes can lead to a biopsy error exceeding 4 mm. Moreover, targeting error might be aggravated by MRI underestimation of the tumour volume compared with final pathology [4]. After various authors reported the advantages and accuracy of MRI/US-fusion biopsy approaches, Cash et al. [5] address potential reasons for targeted biopsy failure to detect prostate cancer compared with random biopsy. Within their analyses the authors address potential limitations and technical considerations. Based on different technical biopsy strategies (with the patient placed within the MRI scanner (‘in-bore’) vs outside) and different technical approaches, these considerations are very important.

In contrast to cognitive fusion, most MRI/US platforms allow needle tracking by archiving the needle orientation, either by an electromagnetic, image-based or stepper-based mechanism [1]. However, lesion targeting by needle guidance is highly dependent on the dimensions of the primary lesion, numbers of relevant lesions, localisation, and overall prostate volume, making MRI-US fusion and cognitive fusion more error prone (i.e. aiming off the mark with the needle) than in-bore biopsies. Moreover, different technical fusion approaches provide different degrees of manual/automated adjustment tools, with for example either rigid or elastic image transformation to facilitate MRI/US image alignment.

Finally, due to the recent introduction of these techniques the influence of learning curve and experience of the uro-radiologist must be considered [6].

In their analyses, Cash et al. [5] found that 34% of negative targeted biopsies could be explained by initially too high estimated PIRADS scores that were downgraded at re-reading. Interestingly, the remaining lesions were without an mpMRI correlate but within this group 92.9% showed a primary Gleason 3 pattern in biopsy pathology, suggesting a high degree of invisibility on mpMRI. Subanalyses did not show an association of targeted biopsy failures in the ventral location. Therefore, the study by Cash et al. [5] is an important precursor for further analyses to address other underlying reasons for targeted biopsy failure. Moreover, it reveals the need for a tight collaboration of radiologists, urologists, and pathologists as interdisciplinary partners involved in MRI-fusion biopsy. Consequently, the optimal diagnostic performance of MRI-fusion biopsies can only be achieved through standardised MRI performance, reading and reporting of MRI findings, as well as final correlation of MRI findings with histopathological work up.

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Lars Budaus and Sami-Ramzi Leyh-Bannurah
Martini-Clinic University Hospital Hamburg-Eppendorf, Hamburg, Germany

 

References

 

1 Logan JK, Rais-Bahrami S, Turkbey B et al. Current status of magnetic resonance imaging (MRI) and ultrasonography fusion software platforms for guidance of prostate biopsies. BJU Int 2014;114:641–52

 

2 American College of Radiology. Prostate Imaging Reporting and Data System (PI-RADS), version 2.0. 2015. Available at: https://www.acr.org/ Quality-Safety/Resources/PIRADS/. Accessed November 2015

 

3 Schimmoller L, Quentin M, Arsov C et al. Inter-reader agreement of the ESUR score for prostate MRI using in-bore MRI-guided biopsies as the reference standard. Eur Radiol 2013;23:3185–90

 

4 Rud E, Klotz D, Rennesund K et al. Detection of the index tumour and tumour volume in prostate cancer using T2-weighted and diffusion-weighted magnetic resonance imaging (MRI) alone. BJU Int 2014;114: E32–42

 

5 Cash H, Gunzel K, Maxeiner A et al. Prostate cancer detection on transrectal ultrasonography-guided random biopsy despite negative real- time magnetic resonance imaging/ultrasonography fusion-guided targeted biopsy: reasons for targeted biopsy failure. BJU Int 2016; 118: 35–43

 

6 Gaziev G, Wadhwa K, Barrett T et al. Defining the learning curve for multiparametric magnetic resonance imaging (MRI) of the prostate using MRI-transrectal ultrasonography (TRUS) fusion-guided transperineal prostate biopsies as a validation tool. BJU Int 2016; 117: 80–6

 

Editorial: The Jury on Posterior Muscolofascial Reconstruction is still out

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In their systematic review and meta-analysis, Grasso et al. [1] address the question of whether posterior muscolofascial reconstruction (PMR), the so-called Rocco stitch, positively affects urinary continence after radical prostatectomy. The relevance of the question to this structured form of inquiry is that individual studies to date have been inconclusive. We recognize Sir Archie Cochrane, who gave his name to the Cochrane Collaboration that pioneered the methods for conducting systematic reviews, for emphasizing the critical importance of looking at the entire body of evidence in a structured manner when seeking to answer a clinical question [2]. In the present study, which included both randomized controlled trials (RCTs) and observational studies of variable methodological quality, a favourable impact of PMR across all postoperative time points (3–7 days, 30 days, 3 and 6 months) was observed. The effect was most pronounced early on at the time of catheter removal, when the patients undergoing PMR were nearly twice as likely as the control group (risk ratio 1.9; 95% CI 1.3–2.9) to be continent, thereby suggesting a major benefit of this approach. It should be noted, however, that this analysis was dominated by the observational studies, particularly retrospective observational studies, which offer the least degree of methodological rigor.

Even more important, therefore, than the act of pooling across studies is the rating of the quality of evidence for the body of evidence on an outcome-specific basis. Based on the GRADE approach, which has become the most widely endorsed framework for rating the quality of evidence, we would initially place a high and low level of confidence in a body of evidence drawn from RCTs and observational studies, respectively [3]. As a result, one might plan a separate analysis of those two groups of studies first, and only move to pool them if their results were similar. In this case, the results from the RCTs and observational studies were different, with prospective and retrospective studies reporting larger, probably exaggerated effect sizes; however, it is also understood that other aspects such as study limitation (risk of bias), inconsistency, impression, indirectness and risk publication bias may lower our confidence in the effect estimates from RCTs [4]. Focusing on the body of evidence from RCTs alone (Table 1) we have ‘moderate’ confidence that PMR may not improve early continence at the time of catheter removal. Similarly, the few RCTs that contributed to the assessment of continence at later timepoints do not provide evidence that continence is affected favourably, although our confidence for those outcomes is only ‘low’ or ‘very low’, suggesting that future trials may change these estimates of effect. Meanwhile, it should be noted that none of the RCTs appeared to provide information on the potential downsides of PMR, such as rates of urinary retention or bladder neck contracture. As a result, enough uncertainty remains to state that the jury on PMR is still out; this is consistent with the authors’ call for a future high-quality trial, which is reportedly ongoing. While PMR is already widely used by open and robot-assisted prostatectomy surgeons around the globe, this example sheds light on current evidentiary standards of surgical innovation. Following the IDEAL recommendations, it would be much preferred if the urological community committed to well designed trials for novel surgical approaches and device-dependent interventions up front, before moving to widespread dissemination [5].

JulEOTW2

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Philipp Dahm
Department of Urology, Minneapolis VA Health Care System, Urology Section 112D and University of Minnesota, Minneapolis, MN, USA

 

References

 

1 Grasso AAC, Mistretta FA, Sandri M et al. Posterior musculofascial reconstruction after radical prostatectomy: an updated systematic review and a meta-analysis. BJU Int 2016; 118: 20–34.

 

2 Hajebrahimi S, Dahm P, Buckingham J. Evidence-based urology in practice: the cochrane library. BJU Int 2009; 104: 1048–9

 

3 Canfield SE, Dahm P. Rating the quality of evidence and the strength of recommendations using GRADE. World J Urol 2011; 29: 311–7

 

4 Guyatt GH, Oxman AD, Vist GE et al. GRADE: what is “quality of evidence” and why is it important to clinicians? BMJ 2008; 336: 995–8

 

5 McCulloch P. The IDEAL recommendations and urological innovation. World J Urol 2011; 29: 331–6

 

Editorial: Analysis of Genetics to Identify Susceptibility to Secondary Malignancies in Patients with BCa

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A study by Muller et al. [1] evaluated a cohort of 10 047 patients diagnosed with a first invasive (≥T1) bladder cancer and found that independent of gender and age, the risk of subsequent lung cancer was increased. This is not surprising considering the strong association of both bladder and lung cancer with tobacco, which is the main risk factor for both malignancies. While the authors limited their analysis to patients with invasive disease, the same association of bladder and lung cancer probably holds true for patients with non-invasive disease. An important question this raises is whether urologists should be more proactive in screening for lung cancer in their patients with bladder cancer. While chest radiographs are commonly used to monitor patients who undergo cystectomy, they are not routinely used for patients with non-invasive disease. Furthermore, the recommendations for screening for lung cancer based on the National Lung Cancer Screening Trial (NLST) involve use of low-dose chest CT, which is rarely done routinely by urologists [2]. In the Muller et al. [1] study, despite the large cohort and median follow-up of 3.1 years, there were still only 295 cases of lung cancer. This was three-times the expected incidence but overall a low rate.

One interesting consideration is whether use of genetic factors may be useful to identify which patients might be at higher risk at baseline for subsequent secondary cancers. Currently, single nucleotide polymorphism (SNP) analysis is not used clinically in screening but other genetic abnormalities such as BRCA (BReast Cancer gene) mutations and Lynch syndrome have been used to identify secondary malignancies. However, identifying individuals at higher risk of developing cancer may inform clinicians and allow for a more targeted screening strategy, even in patients of increased baseline risk.

The USA National Cancer Institute performed genome-wide association studies (GWAS) for 49 492 patients with cancer and 34 131 controls to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers [3]. They calculated that at least 24% and 7% of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Only four pairs of cancers had marginally statistically significant correlations including bladder and lung.

While tobacco is the major cause of lung cancer, only ≈10% of smokers develop lung cancer in their lifetime indicating there is significant individual variation in susceptibility to lung cancer. The International Lung Cancer Consortium pooled genotype data for SNPs at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case-control studies for 11 645 patients with lung cancer and 14 954 control subjects [4]. Associations between 15q25 and the risk of lung cancer were replicated in White ever-smokers (rs16969968) but there was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, they confirmed statistically significant associations in Whites for both rs2736100 and rs402710 and identified similar associations in Asians. Zhang et al. [5] undertook a gene–smoking interaction analysis in a GWAS of lung cancer in Han Chinese population of 5 408 subjects (2 331 patients and 3 077 controls) using a two-phase designed case-control study. They identified two SNPs associated with lung cancer and smoking, including one with a synergistic interaction (rs4589502) and one with an antagonistic interaction (rs131629).

There have also been several studies evaluating SNPs and risk of bladder cancer. A study of 1 595 patients and 1 760 controls, stratified for smoking habits, found that different SNP combinations were relevant in smokers and non-smokers [6]. In smokers, polymorphisms involved in detoxification of cigarette smoke carcinogens were most relevant (GSTM1 [glutathione S-transferase μ1], rs11892031), in contrast to those in non-smokers where MYC (v-myc avian myelocytomatosis viral oncogene homolog) and APOBEC3A (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A) near polymorphisms (rs9642880, rs1014971) were the most influential. A study of genome-wide interaction of smoking and bladder cancer risk based on data from 3 002 patients and 4 411 controls with validation in a separate dataset identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use [7]. These studies of genetic polymorphisms add evidence regarding the impact of gene–environment interactions, which influence the detrimental effects of tobacco on risk of bladder cancer.

There are other genetic polymorphisms that have been found to increase risk of tobacco-related malignancies. A study of polymorphisms inNAT2 (N-acetyltransferase 2 [arylamine N-acetyltransferase]), GSTM1, NAT1, GSTT1 (GST θ1), GSTM3, and GSTP1 (GST π1) in 1 150 patients with bladder cancer and 1 149 controls found that compared with NAT2 rapid or intermediate acetylators, NAT2 slow acetylators had an increased overall risk of bladder cancer (odds ratio 1.4, 95% CI 1.2–1.7), which was stronger for cigarette smokers than for never smokers. No significant associations were found with the other polymorphisms [8]. The overall association for GSTM1 was also robust (P < 0.001) but was not modified by smoking status (P = 0.86).

While it may be too early to apply GWAS to all patients who smoke, a trial focusing on those with other tobacco-related malignancies may identify cohorts where screening for other malignancies is not only effective but also practical.

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Yair Lotan, Professor of Urology
Department of Urology, UT Southwestern Medical Center at Dallas, Dallas, TX, USA

 

References

 

1 Muller J, Grosclaude P, Lapotre-Ledoux B et al. Trends in the risk of second primary cancer among bladder cancer survivors: a population-based cohort of 10 047 patients. BJU Int 2016; 118: 53–9

 

2 National Lung Screening Trial Research Team, Aberle DR, Adams AM et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365: 395–409

 

3 Sampson JN, Wheeler WA, Yeager M et al. Analysis of heritability and shared heritability based on genome-wide association studies for thirteen cancer types. J Natl Cancer Inst 2015; 107: pii: djv279. doi: 10.1093/jnci/djv279

 

4 Truong T, Hung RJ, Amos CI et al. Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. J Natl Cancer Inst 2010; 102: 959–71

 

5 Zhang R, Chu M, Zhao Y et al. A genome-wide gene-environment interaction analysis for tobacco smoke and lung cancer susceptibility. Carcinogenesis 2014; 35: 1528–35

 

6 Schwender H, Selinski S, Blaszkewicz M et al. Distinct SNP combinations confer susceptibility to urinary bladder cancer in smokers and non-smokers. PLoS One 2012; 7: e51880

 

7 Figueroa JD, Han SS, Garcia-Closas M et al. Genome-wide interaction study of smoking and bladder cancer risk. Carcinogenesis 2014; 35: 1737–44

 

8 Garcia-Closas M, Malats N, Silverman D et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet 2005; 366: 649–59

 

Editorial: EAU guidelines – do we care? Reflections from the EAU Impact Assessment of Guidelines Implementation and Education group

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There is increasing evidence in the literature that androgen deprivation therapy (ADT) is overused among practising urologists in the setting of localized, and even locally advanced, prostate cancer (PCa) [1, 2]. Morgia et al. [1] report a misuse of ADT prescriptions among Italian urologists in roughly a quarter of cases, mainly in the setting of low-risk/localized disease where ADT may harm patients without proven benefit with regard to disease-specific outcomes [3]. Such clinical practice behaviours are even more unjustifiable given the high level of evidence upon which the current European Association of Urology (EAU) guidelines recommendations on ADT use are based [4].

Morgia et al. [1] should be congratulated for highlighting the magnitude of the problems the urological community currently face in terms of the gap between evidence and practice. Unfortunately, while the authors report significant geographical differences in ADT prescriptions within the same country (Italy), the methods they used in their study do not allow an understanding of the reasons for the discrepancy. It is currently unknown whether the gap between evidence and practice is attributable to physician or patient attitude or to the national health system structure. The inclusion of qualitative methods, such as semi-structured interviews, would have been ideal to probe clinician reasoning for discordant adherence. This is crucial because knowledge of possible barriers to the application of guidelines represents a key step in their implementation process. Indeed, once the issue is raised, the next logical questions to pose would be: how can we reduce such variation in urological practice especially where there is a real risk of causing harm to patients and how can we improve and implement the use of guideline recommendations when clearly underpinned by high-quality evidence?

It is indeed intuitive that any huge evidence–practice gap may have profound implications not only in the process of patient care optimization but also in the context of national healthcare efficiency.

Certainly the issue of ADT overuse raised by Morgia et al. [1] can be considered the perfect setting to scale up and prioritize efforts aimed at improving current urological practice for three main reasons: (i) the high prevalence of the disease studied (namely, PCa); (ii) the availability of an up-to-date evidence-based guideline showing the impact of ADT in terms of patient side effects and costs; and (iii) the now known gap between evidence and practice patterns.

Given this setting, it should then be mandatory to promote ways not only to assess the use of guideline recommendations but also to increase dissemination among users (not only healthcare professionals, but also patients and policy makers) and to evaluate their impact. The aim of this highly articulated process of knowledge translation is eventually to move research findings into clinical practice. Ideally, this approach should be based on the following five crucial questions: (i) What should be transferred? (ii) To whom should research knowledge be transferred? (iii) By whom should research knowledge be transferred? (iv) How should research knowledge be transferred? and (v) To what effect should research knowledge be transferred? [5]. Each of these questions represents a crucial step in any knowledge translation process. To optimize this approach, it is critical to identify barriers to knowledge implementation and to choose the optimum interventions to limit or to overcome them. This ‘global process’ is much more complicated than commonly thought, given the significant cultural, social, economic and health system differences not only between countries but also within the same country, as shown by Morgia et al. [1]. It is likely, therefore, that any knowledge implementation approach should be tailored according to each country and should be based on key steps, such as: selection of a credible ‘messenger’; development of the appropriate technological and organizational instruments to facilitate access to disseminate and use existing high-quality evidence; and the setting up of education programmes to improve clinical research literacy skills.

Finally, we believe that the paper by Morgia et al. [1] strongly supports the notion that ‘evidence-based medicine should be complemented by evidence-based implementation’ [6]. It is indeed likely that creating a knowledge translation setting where the gap between evidence and practice is eventually bridged is as important as producing accurate, scientifically sound and meticulous guidelines that can be trusted by all stakeholders.

Tackling the crucially important problem of discordant guideline adherence is the remit of the recently established EAU Guidelines Office ‘IMAGINE’ project (IMpact Assessment of Guidelines Implementation and Education) which aims to: ascertain adherence to prioritized guideline recommendations; elucidate the barriers and facilitators to change; design bespoke knowledge transfer interventions; and evaluate the impact of the EAU guidelines, thereby optimizing adherence, with the ultimate goal of improving patient care.

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Alberto Briganti*, Steven MacLennan†, Lorenzo Marconi‡, Karin Plass§ and James N’Dow †on behalf of EAU Guidelines Office ‘IMAGINE’ project
*Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy, †Academic Urology Unit, University of Aberdeen, Aberdeen, UK, ‡Department of Urology, Coimbra University Hospital, Coimbra, Portugal and §EAU Central Office, Guidelines Office, Arnhem, The Netherlands

 

References

 

1 Morgia G, Russo GI, Tubaro A et al. Patterns of prescription and adherence to European Association of Urology guidelines on androgen deprivation therapy in prostate cancer: an Italian multicentre cross- sectional analysis from the Choosing Treatment for Prostate Cancer (CHOICE) study. BJU Int 2016; 117: 867–73

 

2 Lycken M, Garmo H, Adolfsson J, Stattin P, Holmberg L, Bill-Axelson A. Patterns of androgen deprivation therapies among men diagnosed with localised prostate cancer: a population-based study. Eur J Cancer 2014; 50: 1789–98

 

3 Lu-Yao GL, Albertsen PC, Moore DF et al. Survival following primary androgen deprivation therapy among men with localized prostate cancer. JAMA 2008; 300: 173–81

 

4 Heidenreich A, Bastian PJ, Bellmunt J et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 2014; 65: 467–79

 

5 Grimshaw JM, Eccles MP, Lavis JN, Hill SJ, Suires JE. Knowledge translation of research findings. Implement Sci 2012; 7: 50

 

6 Grol R. Beliefs and evidence in changing clinical practice. BMJ 1997; 315: 418–21

 

The PROMIS of MRI

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Hashim AhmedThe prostate cancer pathway is controversial and views are often polarized. For a researcher, this is the perfect melting pot for innovation and practice-changing studies. It is clear that we need to reduce the harms of treatment, not only by treating very few low-risk cancers but also by innovations in surgery. It is pleasing to see Grasso et al. [1] systematic review of surgical innovation that may potentially lead to improvements in urinary incontinence after radical prostatectomy. This was a diligently conducted systematic review and points to the need for a randomized trial, which the authors tell us is currently being conducted.

The era of multiparametric MRI (mpMRI) for prostate cancer diagnosis is upon us. Few of us will live through such a wholesale change in the entire pathway for diagnosis and treatment of a cancer, and a common one at that. Whilst a few of us have been using mpMRI prior to first biopsy, there can be no doubting that we now have level 1b evidence to support the adoption of mpMRI prior to a first prostate biopsy as the standard care. The NIHR-HTA/MRC-CTU/UCL PROstate MR Imaging Study (or PROMIS) has been long awaited, and its initial results were presented at ASCO last month [2]. mpMRI performed better than expectations in a multicentre setting across 11 NHS trusts and just over a dozen radiologists. Sensitivity was 93% (95% CI 88–96) and the negative predictive value was 89% (95% CI 83–94). Although the focus, quite rightly, has been on mpMRI, equally significant has been the discovery of how bad a test TRUS-guided biopsy really was, with a sensitivity for clinically significant prostate cancer of only 48% (95% CI 42–55).

These findings answer several criticisms of mpMRI. First, that it is not as accurate as retrospective data suggest. It is, provided you do not expect it to find every millimetre of significant disease. Second, it is not reproducible outside of expert centres. It is, provided you quality assure every scanner, optimize the sequences iteratively, quality control scans and have robust training for radiologists. Third, it cannot be carried out on 1.5-Tesla scanners. It can; all the PROMIS scans were 1.5 Tesla without an endorectal coil. Fourth, it misses lots of clinically significant prostate cancers. It does not, but this depends on your definition of clinical significance. In this respect, the study by Cash et al. [3] is pertinent. They evaluated the rates of subsequent cancer found on ‘negative’ mpMRIs and, using the very conservative Epstein definition, found a high rate of missed ‘significant’ cancers. The rate of Gleason 7 disease missed was lower and some missed cancers were attributable to interobserver variability in mpMRI reporting. All centres should evaluate their own data to determine where their own negative predictive value sits and then strive to improve upon this through a constant iterative dialogue between urology and radiology. PROMIS shows that mpMRI has very high performance characteristics that should be possible across the board.

There is considerable work still to be done. Cost-effectiveness analyses are under way; with these data, NICE will need to consider their clinical recommendations, having laboured the point that they wished to await PROMIS. The challenge of dissemination and maintenance of quality standards is not to be underestimated. Work on determining what is out there, who is capable of performing such scans and reporting them, whether there is enough capacity in the NHS and whether all centres are capable of carrying out targeted biopsies are all legitimate health policy issues.

Similar to mammography standards laid down centrally, we will need to insist on: independent (not self-) accreditation; independent scan and report audits, with outliers (too many negatives, too many positives, too many equivocals) reviewed to determine whether further standardization training is required; rates of clinically significant and insignificant cancers detected on subsequent biopsy; rates of repeat biopsies; and rates of unnecessary radical therapy on low risk cases. We should all look within our centres to ensure we can meet these expectations.

 

Hashim U. Ahmed, BJUI Consulting Editor – Imaging Division of Surgery and Interventional Sciences, UCL, and
Department of Urology, UCL Hospital NHS Foundation Trust, London, UK

References

1. Grasso AAC, Mistretta FA, Sandri M et al. Posterior musculofascial reconstruction after radical prostatectomy: an updated systematic review and a meta-analysis. BJU Int 2016; 118: 20–34 Wiley Online Library

2. Ahmed HU. The PROMIS study: a paired-cohort, blinded confirmatory study evaluating the accuracy of multi-parametric MRI and TRUS biopsy in men with an elevated PSA. J Clin Oncol 2016; 34: (suppl; abstr 5000)

3. Cash H, Günzel K, Maxeiner A et al. Prostate cancer detection on transrectal ultrasonography-guided random biopsy despite negative real-time magnetic resonance imaging/ ultrasonography fusion-guided targeted biopsy: reasons for targeted biopsy failure. BJU Int 2016; 118: 35–43 Wiley Online Library

 

Editorial: SRMs – Where is the Wisdom We Have Lost in Knowledge?

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The perceived wisdom that a small enhancing mass in the kidney represents a surgical lesion that automatically requires excision without the need for a preoperative biopsy has been challenged by Fernando et al. [1] in this issue of BJUI.

The authors are to be congratulated in bringing these data to publication to provoke debate on the treatment paradigm for small renal masses (SRMs) by reviewing nationally collected data on the main therapeutic surgical option: nephron-sparing surgery. As anyone who has attended a renal multidisciplinary meeting can testify, the predominant presentation of renal cancer is the incidentally detected SRM, often in elderly patients with significant comorbidity.

As the authors emphasize, these data are unique in representing a national picture encompassing both high- and low-volume centres, as opposed to the majority of the studies in the literature, which report data from high-volume tertiary referral centres.

Drawing conclusions from data requires a clear understanding of the source and quality. Most importantly, as these data only refer to patients undergoing nephron-sparing surgery, we need to be cautious about extrapolating to infer information on the management of SRMs in general.

For instance, a striking finding of the present study is the high incidence of benign lesions in the younger age groups. We have no knowledge of the numbers of patients with SRMs within the study period who had biopsy-proven benign disease and thus avoided surgery. It is probable that the true incidence of benign disease would be even higher if these cases had been recorded and included in the analysis.

An inherent difficulty with self-reported data is the issue of compliance, and this is clearly evident in the present study, with, for example, almost a third of cases missing data on surgical margin results. It would perhaps be helpful for future audits if the BAUS dataset had a clear definition of positive surgical margin in recognition of the surgical drift to enucleation rather than excision with a margin of renal parenchyma.

The variation in caseload between reporting centres raises important questions, as does the finding that two fifths of patients with T1a tumours underwent radical nephrectomies. As the authors concede, with the numbers involved and the absence of any measure of tumour complexity, it is difficult to draw firm conclusions; however, the study does highlight the need to examine this issue in future analyses and to consider including some form of renal scoring system in future audits.

Where do we go from here and what can we do with this information? First, we need to rethink our discussion with patients with SRMs. Can we justify performing major surgery with a one in 20 chance of a significant complication for a possible benign lesion without at least a pragmatic discussion of the role of renal biopsy with the patient? Indeed, one may argue, could it really be an ‘informed’ decision without it?

Second, we need to improve the quality of the data by encouraging robust data reporting, increasing the completion rate and considering adding data fields which will allow us to draw clearer conclusions on surgical margin and surgical outcome and volume relationships.

Third, we need to recognize that nephron-sparing surgery is only one component of the management of SRMs, which represents a major contemporary challenge in terms of health resources and, most importantly, in deciding the best treatment paradigm for our patients. If BAUS can carry out this audit, could we not extend this to all patients with SRMs, whether they have surgery, ablation or surveillance, and establish greater clarity on these treatment methods?

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Michael Aitchison, Consultant Urological Surgeon and Maxine Tran, Senior Lecturer in Renal Cancer Surgery and Honorary Consultant Urological Surgeon

 

Renal Cancer Service, Royal Free NHS Foundation Trust, London, UK

 

Reference
1 Fernando A, Fowler S, O’Brien T. Nephron-sparing surgery across a nation—outcomes from the British Association of Urological Surgeons 2012 national partial nephrectomy audit. BJU Int 2016; 117: 874–82

 

Editorial: One Day Protocol for Early Penile Cancer – The Way to Go

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The present article by Dimopoulos et al. [1] has some useful lessons on the development of new services. The authors have kept a detailed database of all patients going through their super-regional network, and have designed the protocol around the patient, whereby the primary and regional lymph nodes are dealt with in one visit. Previously, bilateral inguinal lymph node dissection (ILND) was so fraught with complications that it would not be combined routinely with organ-sparing surgery of the penis [2]; however, the significantly lower complication rate of dynamic sentinel node biopsy (DSNB) has allowed the more streamlined approach. The ‘only handle it once’ (OHIO) philosophy is surely not only preferable for the patient, but also reduces the risk of patients not receiving ideal management. In most cases, a biopsy at the time of presentation, along with physical examination/imaging, can determine those requiring DSNB instead of waiting for final pathology from the primary tumour. The controversy surrounding DSNB compared with ILND has been the false-negative rates. The pioneering group from the Netherlands reported four deaths in six patients with false-negative results [3]. In the present paper, the overall false-negative rate was 5.8%, but the smaller and newer cohort of patients underwent a same-day protocol and had zero false-negatives. This may be attributable to the fact that biopsies were taken from a total sample of 65 or that slightly more nodes were taken in this group. We expect the one-day protocol to become standard, and future independent reports will be welcome. Should there truly be a 0% false-negative rate then the controversy is resolved and prophylactic ILND will become a historical procedure. Finally, the lower morbidity of the present study cohort allowed the authors to move the intermediate-risk group from surveillance to nodal biopsy, which proved justified because some of these cases had micrometastatic disease. We congratulate the group for their scientific approach to improving the quality of care for patients and for bringing their data to publication.

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Paul K. Hegarty and Peter E. Lonergan
Urology, National Penile Cancer Centre, Mater Misericordiae University Hospital, Dublin, Ireland

 

References

 

1 Dimopoulos P, Christopoulos P, Shilito S et al. Dynamic sentinel lymph node biopsy for penile cancer: a comparison between 1- and 2-day protocols. BJU Int 2016; 117: 890–6

 

2 Hegarty PK, Eardley I, Heidenreich A et al. Penile cancer: Organ-sparing techniques. BJU Int 2014; 114: 799–805

 

3 Kroon BK, Horenblas S, Meinhardt W et al. Dynaminc sentinel node biopsy in penile cancer: evaluation of 10 years experience. Eur Urol 2005; 47: 601–6

 

Editorial: Cost-effectiveness of robotic surgery; what do we know?

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The introduction of the daVinci robotic surgical system (Intuitive Surgical, Sunnyvale, CA, USA) has led to a continuous discussion about the cost-effectiveness of its use. The capital costs and extra costs per procedure for robot-assisted procedures are well known, but there are limited data on healthcare consumption in the longer term. In this issue of BJUI, a retrospective study investigated the NHS-registered, relevant care activities up to three years after surgery comparing robot-assisted, conventional laparoscopic, and open surgical approaches to radical prostatectomy and partial nephrectomy [1].

The robotic system is particularly useful in difficult to perform laparoscopic surgeries, which are easier to perform with the daVinci system due to improved three-dimensional vision, ergonomics, and additional dexterity of the instruments. Because the use of the robotic system is more costly, to justify its use the outcomes for patients should be improved. Therefore, more detailed information about the clinical and oncological outcomes, as well as the incidence of complications after surgery with the daVinci system, is needed.

Lower rates of positive surgical margins for robot-assisted radical prostatectomy (RARP) vs open and laparoscopic RP have been reported [2]. There also is evidence of an earlier recovery of functional outcomes, such as continence. RARP is associated with improved surgical margin status compared with open RP and reduced use of androgen-deprivation therapy and radiotherapy after RP, which has important implications for quality of life and costs. Ramsay et al. [3] reported that RARP could be cost-effective in the UK with a minimum volume of 100–150 cases per year per robotic system.

Centralisation of complex procedures will not only result in better outcomes, but also facilitate optimal economical usage of expensive medical devices. Furthermore, the skills learned to perform the RARP procedure can be used during other procedures, such as robot-assisted partial nephrectomy (RAPN) and radical cystectomy (RARC). The recent report by Buse et al. [4] confirms that RAPN is cost-effective in preventing perioperative complications in a high-volume centre, when compared with the open procedure. Minimally invasive techniques for complex procedures, such as a RC, take more time to perform, but result in less blood loss. A systematic review by Novara et al. [5] showed a longer operation time for RARC, but fewer transfusions and fewer complications compared with open surgery. However, there is no solid evidence about the cost-effectiveness of this technique to date. The RAZOR trial (randomised trial of open versus robot assisted radical cystectomy, DOI: 10.1111/bju.12699) is likely to provide some answers about differences in cost, complications, and quality of life when the results of the study become available later this year.

Additionally, the robotic system has been shown to shorten the learning curve of complex laparoscopic procedures in simulation models [6]. Recently, a newly structured curriculum to teach RARP has been validated by the European Association of Urology-Robotic Urology Section [7]. The effect of the shorter learning curve on the cost of the procedures has not yet been well studied for cost-effectiveness. However, due to the shorter learning curves, patients have lower risks of complications, which from the patients’ perspective is more important than any increased costs.

The study reported in this issue [1]; however, does not include the ‘out of pocket’ expenses of patients, it does not report on the differences in patient and tumour characteristics, and outcomes such as complications and oncological safety. These issues are all challenges to be addressed in a thorough prospective (randomised) trial on the cost-effectiveness of the use of robot-assisted surgery, including quality-of-life measurements and complications of the surgical procedures. In the Netherlands the RACE trial (comparative effectiveness study open RC vs RARC, www.racestudie.nl) started in 2015 and the results are expected in 2018–2019.

Read the full article
Carl J. Wijburg
Department of Urology, Robotic Surgery , Rijnstate Hospital, Arnhem, The Netherlands

 

References

 

1 Hughes D, Camp C, O’Hara J, Adshead J. Health resource use after robot-assisted surgery vs open and conventional laparoscopic techniques in oncology: analysis of English secondary care data for radical prostatectomy and partial nephrectomy. BJU Int 2016; 117: 940–7

 

2 HuJC, Gandaglia G, Karakiewicz PI et al. Comparative effectiveness of robot-assisted versus open radical prostatectomy. Eur Urol 2014; 66: 666–72

 

3 Ramsay C, Pickard R , Soomro N et al. Systematic review and economic modelling of the relative clinical benefit and cost-effectiveness of laparoscopic surgery and robotic surgery for removal of the prostate in men with localised prostate cancer. Health Technol Assess 2012; 16: 1–313

 

4 Buse S, Hach CE, Klumpen P et al. Cost-effectiveness of robot-assisted partial nephrectomy for the prevention of perioperative complications. World J Urol 2015; [Epub ahead of print]. DOI:10.1007/s00345-015-1742-x

 

5 Novara G, Catto JW, Wilson T et al. Systematic review and cumulative analysis of perioperative outcomes and complications after robot-assisted radical cystectomy. Eur Urol 2015; 67: 376–401

 

6 Moore LJ, Wilson MR, Waine E, Masters RS, McGrath JS, Vine SJ. Robotic technology results in faster and more robust surgical skill acquisition than traditional laparoscopy. J Robot Surg 2015; 9: 67–73

 

7 Ahmed K, Khan R, Mottrie A et al. Development of a standardised training curriculum for robotic surgery: a consensus statement from an international multidisciplinary group of experts. BJU Int 2015; 116: 93–101

 

Consensus guidelines for reporting prostate cancer Gleason Grade

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Prokar_v2The International Society of Urologic Pathology (ISUP) has endorsed modifications to the Gleason grading system for prostate cancer [1]. Five Grade Groups have been defined with tumors of Grade Group 1 being the least aggressive and having the lowest likelihood of progression, whereas those of Grade Group 5 have the highest likelihood of early systemic spread. This new system provides clearer guidance for pathologists to classify cancers on the basis of gland morphology, and it aligns better with contemporary management including active surveillance.

The editors of the major uro-oncology journals believe this is a helpful change for clinicians, researchers, and patients alike and are eager to help this system establish itself in the reporting of pathologic grade. To that end we are now asking investigators to use the new system in the reporting of prostate cancers in their publications. As the Grade Groups correspond to current Gleason scores 6, 3+4, 4+3, 8, 9 and 10, the translation should be relatively simple. Over the next one to two years, side-by-side reporting of old and new histology may temporarily be necessary. We do recognize that some institutional and national databases are not set up to make the translation and exceptions will be granted in these cases.

Anthony Zietman, Editor-in-Chief*, Joseph Smith, Editor†, Eric Klein , Editor-in-Chief‡, Michael Droller, Editor-in-Chief§, Prokar Dasgupta, Editor-in-Chief¶ and James Catto, Editor-in-Chief**

 

*International Journal of Radiation Oncology Biology Physics, †Journal of Urology, ‡Urology, §Urologic Oncology, BJUI and **European Urology

Reference

1 Epstein JI, Egevad L, Amin MB et al. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference of Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol 2016; 40: 244–52

 

Editorial: Current Gleason score 3 + 4 = 7: has it lost its significance compared with its historical counterpart?

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Berg et al. [1] report that patients classified as Gleason score 7 (3 + 4) according to the revised grading system published in 2005 are to some extent similar to patients with pre-2005 Gleason score 6, at least in terms of risk of biochemical recurrence. The logical but not necessarily correct conclusion is that current patients with Gleason score 7 on biopsy are appropriate candidates for active surveillance.

What must be kept in mind is that, using the post-2005 revised grading system, approximately 25% of men with Gleason score 3 + 4 = 7 on biopsy have either 3 + 4 = 7 with tertiary pattern 5 or >4 + 3 = 7 in the corresponding radical prostatectomy [1]. With the exception of men with a limited life expectancy, these men need definitive therapy for their potentially life-threatening cancer. Numerous studies have shown that extended biopsies, whether they are >10- or 12-core, are associated with less upgrading than sextant biopsies [2]. In the report by Berg et al. [1], the median number of cores sampled before 2005 was 6 with an interquartile range (IQR) of 6–6 compared with a median (IQR) of 10 (10–12) cores after 2005. Consequently, in their cohorts, the pre-2005 group of men with Gleason score 3 + 3 = 6 were more likely to have unsampled higher grade cancer and a correspondingly worse prognosis more closely approximating post-2005 better-sampled Gleason score 3 + 4 = 7 cancers.

Berg et al. [1] further claim that the prognostic and clinical value of Gleason score 7 has been weakened since the 2005 modifications. In fact, the revised grading system more accurately reflects prostate cancer biology than the pre-2005 Gleason system. The major consequence of the modification, as Berg et al. [3] illustrate, has been the better prognosis associated with post-2005 Gleason score 6 cancer because patterns associated with more aggressive behaviour have been shifted to Gleason score 7. Historically, a diagnosis of Gleason score 6 cancer, even at radical prostatectomy, was not as predictive of ‘good’ behaviour, and had a higher rate of progression with some men even dying from prostate cancer [4]. Currently, Gleason score 6 cancer at radical prostatectomy has a 96% cure rate at 5 years, even including cases with extraprostatic extension and positive margins [3]. Several studies have shown that post-2005 pure Gleason score 6 cancers at radical prostatectomy are incapable of metastasizing to lymph nodes [4]. Berg et al. are correct, however, that men with a post-2005 grade of Gleason Score 3 + 4 = 7 have a better prognosis than those graded prior to 2005. As a consequence, it has been recommended that pathologists should record the percent pattern 4 in cases with Gleason score 7 on biopsy for men being considered for active surveillance [5]. For the appropriate patient, depending on age, comorbidity, extent of cancer, MRI findings, patient desire, etc., could be a candidate for active surveillance with Gleason score 3 + 4 = 7 if the pattern 4 is limited. Currently, this information is not transparent in most pathology reports.

A new grading system, first proposed in BJUI by this author, and verified in a large multi-institutional study, resulted in a simplified five-grade group system that more accurately reflects the biology of prostate cancer than the pre-2005 grading system [3, 6]. Men with Gleason score 6 cancers need to be reassured that their cancer is the lowest grade that is currently assigned, despite Gleason scores ranging from 2 to 10. In addition, I have talked to some patients with Gleason score 3 + 4 = 7 who think that they are going to die in the near future because their score of 7 was closer to highest grade of 10 than the lowest grade of 2. With the new grading system, patients can be reassured that they have a Grade group 1 (3 + 3 = 6) out of 5, which is the lowest grade, or a Grade group 2 (Gleason score 3 + 4 = 7) out of 5, which is still a relatively low grade.

Read the full article
Jonathan I. Epstein
Departments of Pathology, Urology and Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

 

References

 

1 Berg KD, Thomsen FB, Nerstrom C et al. The impact of the 2005 International Society of Urological Pathology consensus guidelines on Gleason grading – a matched pair analysis. BJU Int 2016; 117: 883–9

 

2 Epstein JI, Feng Z, Trock BJ , Pierorazio PM. Upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: incidence and predictive factors using the modified Gleason grading system and factoring in tertiary grades. Eur Urol 2012; 61: 1019–24

 

3 Epstein JI, Zelefsky MJ, Sjoberg DD et al. A contemporary prostate cancer grading system: a validated alternative to Gleason score. Eur Urol 2016; 69: 428–35

 

4 RossHM, Kryvenko ON, Cowan JE, Simko JP, Wheeler TM, Epstein JI. Do adenocarcinomas of the prostate with Gleason score (GS) ≤ 6have the potential to metastasize to lymph nodes? Am J Surg Pathol 2012; 36: 1346–52

 

5 Kryvenko ON, Epstein JI. Prostate cancer grading: a decade after the 2005 modified Gleason grading system. Arch Pathol Lab Med 2016; [Epub ahead of print]

 

6 Pierorazio PM, Walsh PW, Partin AW, Epstein JI. Prognostic Gleason grade grouping: data based on the modified Gleason scoring system. BJU Int 2013; 111: 753–60

 

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