Richard Sylvester

European Association of Urology Guidelines on Upper Urinary Tract Urothelial Cell Carcinoma: 2015 Update

CONTEXTnThe European Association of Urology (EAU) guidelines panel on upper urinary tract urothelial cell carcinoma (UTUC) has prepared updated guidelines to aid clinicians in the current evidence-based management of UTUC and to incorporate recommendations into clinical practice.nnnOBJECTIVEnTo provide a brief overview of the EAU guidelines on UTUC as an aid to clinicians.nnnEVIDENCE ACQUISITIONnThe recommendations provided in the current guidelines are based on a thorough review of available UTUC guidelines and articles identified following a systematic search of Medline. Data on urothelial malignancies and UTUC were searched using these keywords: urinary tract cancer; urothelial carcinomas; upper urinary tract, carcinoma; renal pelvis; ureter; bladder cancer; chemotherapy; nephroureterectomy; adjuvant treatment; instillation; neoadjuvant treatment; recurrence; risk factors; and survival. References were weighted by a panel of experts.nnnEVIDENCE SYNTHESISnDue to the rarity of UTUC, there are insufficient data to provide strong recommendations (ie, grade A). However, the results of recent multicentre studies are now available, and there is a growing interest in UTUC. The 2009 TNM classification is recommended. Recommendations are given for diagnosis and risk stratification as well as radical and conservative treatment, and prognostic factors are discussed. A single postoperative dose of intravesical mitomycin after nephroureterectomy reduces the risk of bladder tumour recurrence. Recommendations are also provided for patient follow-up after different therapeutic strategies.nnnCONCLUSIONSnThese guidelines contain information on the management of individual patients according to a current standardised approach. Urologists should take into account the specific clinical characteristics of each patient when determining the optimal treatment regimen, based on the proposed risk stratification of these tumours.nnnPATIENT SUMMARYnUrothelial carcinoma of the upper urinary tract is rare, but because 60% of these tumours are invasive at diagnosis, an appropriate diagnosis is most important. A number of known risk factors exist.

Randomized trial of Bleomycin, Etoposide, and Cisplatin compared with Bleomycin, Etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer : a multiinstitutional medical research council/European organization for research and treatment of cancer trial

PURPOSEThis prospective randomized multicenter trial was designed to evaluate the efficacy of carboplatin plus etoposide and bleomycin (CEB) versus cisplatin plus etoposide and bleomycin (BEP) in first-line chemotherapy of patients with good-risk nonseminomatous germ cell tumors.PATIENTS AND METHODSBetween September 1989 and May 1993, a total of 598 patients with good-risk nonseminomatous germ cell tumors were randomized to receive four cycles of either BEP or CEB. In each cycle, the etoposide dose was 120 mg/m2 on days 1, 2, and 3, and the bleomycin dose was 30 U on day 2. BEP patients received cisplatin at 20 mg/m2/d on days 1 to 5 or 50 mg/m2 on days 1 and 2. For CEB patients, the carboplatin dose was calculated from the glomerular filtration rate to achieve a serum concentration x time of 5 mg/mL x minutes. Chemotherapy was recycled at 21-day intervals to a total of four cycles.RESULTSOf patients assessable for response, 253 of 268 (94.4%) of those allocated to receive BEP achieved a complete response...

What Is the Negative Predictive Value of Multiparametric Magnetic Resonance Imaging in Excluding Prostate Cancer at Biopsy? A Systematic Review and Meta-analysis from the European Association of Urology Prostate Cancer Guidelines Panel

CONTEXTnIt remains unclear whether patients with a suspicion of prostate cancer (PCa) and negative multiparametric magnetic resonance imaging (mpMRI) can safely obviate prostate biopsy.nnnOBJECTIVEnTo systematically review the literature assessing the negative predictive value (NPV) of mpMRI in patients with a suspicion of PCa.nnnEVIDENCE ACQUISITIONnThe Embase, Medline, and Cochrane databases were searched up to February 2016. Studies reporting prebiopsy mpMRI results using transrectal or transperineal biopsy as a reference standard were included. We further selected for meta-analysis studies with at least 10-core biopsies as the reference standard, mpMRI comprising at least T2-weighted and diffusion-weighted imaging, positive mpMRI defined as a Prostate Imaging Reporting Data System/Likert score of ≥3/5 or ≥4/5, and results reported at patient level for the detection of overall PCa or clinically significant PCa (csPCa) defined as Gleason ≥7 cancer.nnnEVIDENCE SYNTHESISnA total of 48 studies (9613 patients) were eligible for inclusion. At patient level, the median prevalence was 50.4% (interquartile range [IQR], 36.4-57.7%) for overall cancer and 32.9% (IQR, 28.1-37.2%) for csPCa. The median mpMRI NPV was 82.4% (IQR, 69.0-92.4%) for overall cancer and 88.1% (IQR, 85.7-92.3) for csPCa. NPV significantly decreased when cancer prevalence increased, for overall cancer (r=-0.64, p<0.0001) and csPCa (r=-0.75, p=0.032). Eight studies fulfilled the inclusion criteria for meta-analysis. Seven reported results for overall PCa. When the overall PCa prevalence increased from 30% to 60%, the combined NPV estimates decreased from 88% (95% confidence interval [95% CI], 77-99%) to 67% (95% CI, 56-79%) for a cut-off score of 3/5. Only one study selected for meta-analysis reported results for Gleason ≥7 cancers, with a positive biopsy rate of 29.3%. The corresponding NPV for a cut-off score of ≥3/5 was 87.9%.nnnCONCLUSIONSnThe NPV of mpMRI varied greatly depending on study design, cancer prevalence, and definitions of positive mpMRI and csPCa. As cancer prevalence was highly variable among series, risk stratification of patients should be the initial step before considering prebiopsy mpMRI and defining those in whom biopsy may be omitted when the mpMRI is negative.nnnPATIENT SUMMARYnThis systematic review examined if multiparametric magnetic resonance imaging (MRI) scan can be used to reliably predict the absence of prostate cancer in patients suspected of having prostate cancer, thereby avoiding a prostate biopsy. The results suggest that whilst it is a promising tool, it is not accurate enough to replace prostate biopsy in such patients, mainly because its accuracy is variable and influenced by the prostate cancer risk. However, its performance can be enhanced if there were more accurate ways of determining the risk of having prostate cancer. When such tools are available, it should be possible to use an MRI scan to avoid biopsy in patients at a low risk of prostate cancer.

Oncologic Outcomes of Kidney-sparing Surgery Versus Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Systematic Review by the EAU Non-muscle Invasive Bladder Cancer Guidelines Panel

CONTEXTnThere is uncertainty regarding the oncologic effectiveness of kidney-sparing surgery (KSS) compared with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).nnnOBJECTIVEnTo systematically review the current literature comparing oncologic outcomes of KSS versus RNU for UTUC.nnnEVIDENCE ACQUISITIONnA computerised bibliographic search of the Medline, Embase, and Cochrane databases was performed for all studies reporting comparative oncologic outcomes of KSS versus RNU. Approaches considered for KSS were segmental ureterectomy (SU) and ureteroscopic (URS) or percutaneous (PC) management. Using the methodology recommended by the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, we identified 22 nonrandomised comparative retrospective studies published between 1999 and 2015 that were eligible for inclusion in this systematic review. A narrative review and risk-of-bias (RoB) assessment were performed using cancer-specific survival (CSS) as the primary end point.nnnEVIDENCE SYNTHESISnSeven studies compared KSS overall (n=547) versus RNU (n=1376). Information on the comparison of SU (n=586) versus RNU (n=3692), URS (n=162) versus RNU (n=367), and PC (n=66) versus RNU (n=114) was available in 10, 5, and 2 studies, respectively. No significant difference was found between SU and RNU in terms of CSS or any other oncologic outcomes. Only patients with low-grade and noninvasive tumours experienced similar CSS after URS or PC when compared with RNU, despite an increased risk of local recurrence following endoscopic management of UTUC. The RoB assessment revealed, however, that the analyses were subject to a selection bias favouring KSS.nnnCONCLUSIONSnOur systematic review suggests similar survival after KSS versus RNU only for low-grade and noninvasive UTUC when using URS or PC. However, selected patients with high-grade and invasive UTUC could safely benefit from SU when feasible. These results should be interpreted with caution due to the risk of selection bias.nnnPATIENT SUMMARYnWe reviewed the studies that compared kidney-sparing surgery versus radical nephroureterectomy for upper tract urothelial carcinoma. We found similar oncologic outcomes for favourable tumours when using ureteroscopic or percutaneous management, whereas indications for segmental ureterectomy could be extended to selected cases of aggressive tumours.

Prognostic Performance and Reproducibility of the 1973 and 2004/2016 World Health Organization Grading Classification Systems in Non–muscle-invasive Bladder Cancer: A European Association of Urology Non-muscle Invasive Bladder Cancer Guidelines Panel Systematic Review

CONTEXTnTumour grade is an important prognostic indicator in non-muscle-invasive bladder cancer (NMIBC). Histopathological classifications are limited by interobserver variability (reproducibility), which may have prognostic implications. European Association of Urology NMIBC guidelines suggest concurrent use of both 1973 and 2004/2016 World Health Organization (WHO) classifications.nnnOBJECTIVEnTo compare the prognostic performance and reproducibility of the 1973 and 2004/2016 WHO grading systems for NMIBC.nnnEVIDENCE ACQUISITIONnA systematic literature search was undertaken incorporating Medline, Embase, and the Cochrane Library. Studies were critically appraised for risk of bias (QUIPS). For prognosis, the primary outcome was progression to muscle-invasive or metastatic disease. Secondary outcomes were disease recurrence, and overall and cancer-specific survival. For reproducibility, the primary outcome was interobserver variability between pathologists. Secondary outcome was intraobserver variability (repeatability) by the same pathologist.nnnEVIDENCE SYNTHESISnOf 3593 articles identified, 20 were included in the prognostic review; three were eligible for the reproducibility review. Increasing tumour grade in both classifications was associated with higher disease progression and recurrence rates. Progression rates in grade 1 patients were similar to those in low-grade patients; progression rates in grade 3 patients were higher than those in high-grade patients. Survival data were limited. Reproducibility of the 2004/2016 system was marginally better than that of the 1973 system. Two studies on repeatability showed conflicting results. Most studies had a moderate to high risk of bias.nnnCONCLUSIONSnCurrent grading classifications in NMIBC are suboptimal. The 1973 system identifies more aggressive tumours. Intra- and interobserver variability was slightly less in the 2004/2016 classification. We could not confirm that the 2004/2016 classification outperforms the 1973 classification in prediction of recurrence and progression.nnnPATIENT SUMMARYnThis article summarises the utility of two different grading systems for non-muscle-invasive bladder cancer. Both systems predict progression and recurrence, although pathologists vary in their reporting; suggestions for further improvements are made.

Oncological Outcomes of Laparoscopic Nephroureterectomy Versus Open Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: An European Association of Urology Guidelines Systematic Review

CONTEXTnMost series have suggested better perioperative outcomes of laparoscopic radical nephroureterectomy (RNU) over open RNU. However, the oncological safety of laparoscopic RNU remains controversial.nnnOBJECTIVEnTo systematically review all relevant literature comparing oncological outcomes of open versus laparoscopic RNU.nnnEVIDENCE ACQUISITIONnA systematic literature search using the Medline, Embase, and Cochrane databases and clinicaltrial.gov was performed in December 2014 and updated in August 2016. Randomised controlled trials (RCTs) and prospective or retrospective nonrandomised comparative studies comparing the oncological outcomes of any laparoscopic RNU with those of open RNU were included. The primary outcome was cancer-specific survival. The risk of bias (RoB) was assessed using Cochrane RoB tools. A narrative synthesis of the evidence is presented.nnnEVIDENCE SYNTHESISnOverall, 42 studies were included, which accounted for 7554 patients: 4925 in the open groups and 2629 in the laparoscopic groups. Most included studies were retrospective comparative series. Only one RCT was found. RoB and confounding were high in most studies. No study compared the oncological outcomes of robotic RNU with those of open RNU. Bladder cuff excision in laparoscopic groups was performed via an open approach in most studies, with only three studies reporting laparoscopic removal of the bladder cuff. Port-site metastasis rates ranged from 0% to 2.8%. No significant difference in oncological outcomes was reported in most series. However, three studies, including the only RCT, reported significantly poorer oncological outcomes in patients who underwent laparoscopic RNU, especially in the subgroups of patients with locally advanced (pT3/pT4) or high-grade upper tract urothelial carcinoma (UTUC), as well as in instances when the bladder cuff was excised laparoscopically.nnnCONCLUSIONSnThe current available evidence suggests that the oncological outcomes of laparoscopic RNU may be poorer than those of open RNU when bladder cuff is excised laparoscopically and in patients with locally advanced high-risk (pT3/pT4 and/or high-grade) UTUC.nnnPATIENT SUMMARYnWe reviewed the literature comparing the outcomes of two different surgical procedures for the treatment of upper tract urothelial carcinoma. Open radical nephroureterectomy is a surgical procedure in which the kidney is removed through a large incision in the abdomen, while in laparoscopic radical nephroureterectomy, the kidney is removed through a number of small incisions. Our findings suggest that the outcomes of laparoscopic radical nephroureterectomy may be poorer than those of open radical nephroureterectomy, particularly when the bladder cuff is also required to be removed. Laparoscopic radical nephroureterectomy may also be less effective in patients with locally advanced (pT3/pT4) or high-grade upper tract urothelial carcinomas.

Potential Benefit of Lymph Node Dissection During Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Systematic Review by the European Association of Urology Guidelines Panel on Non–muscle-invasive Bladder Cancer

CONTEXTnThe oncological efficacy of routine lymphadenectomy (lymph node dissection [LND]) at the time of radical nephroureterectomy (RNU) remains controversial.nnnOBJECTIVEnTo systematically review the available literature assessing the impact of LND in upper tract urothelial carcinoma (UTUC) patients.nnnEVIDENCE ACQUISITIONnEmbase, Medline, and Cochrane databases were searched for all studies comparing outcomes of patients undergoing RNU without LND versus any form of LND. We identified nine retrospective studies eligible for inclusion in this systematic review. We took cancer-specific survival (CSS) as the primary end point, and performed a narrative review and risk of bias assessment.nnnEVIDENCE SYNTHESISnSix studies compared outcomes of no LND versus LND. Three studies compared complete LND versus incomplete LND versus no LND. The incidence of pN+ in patients with high-stage (≥pT2) tumours ranged from 14.3% to 40%. Pre- and postoperative characteristics differed among the study groups, potentially biasing the results, as demonstrated by the risk of bias assessment, potentially favouring the LND group. Oncological outcomes such as cancer-specific, overall, recurrence-free, and metastasis-free survival were reviewed, demonstrating a survival benefit with LND in high-stage disease of the renal pelvis.nnnCONCLUSIONSnTemplate-based and complete LND improves CSS in patients with high-stage (≥pT2) UTUC and reduces the risk of local recurrence. The impact of LND in ureteral tumours remains uncertain.nnnPATIENT SUMMARYnStudies comparing radical nephroureterectomy with or without the removal of nodes (lymph node dissection [LND]) were analysed. LND improves survival in patients with high-stage disease of the renal pelvis, if it is performed according to an anatomical template-based approach.

Reply to Harry Herr's Letter to the Editor re: Marko Babjuk, Andreas Böhle, Maximilian Burger, et al. EAU Guidelines on Non–muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol 2017;71:447–61

The definition of failure of bacillus Calmette-Guérin (BCG) intravesical immunotherapy has been controversial for many years. As consequence, different definitions are used in the literature [1]. One of the most controversial issues is the definition of the interval after initiation of BCG treatment when we can say that BCG has failed and patients are unlikely to respond to further BCG instillations. The importance of the correct definition is driven by the danger of muscle-invasive progression, which is associated with extremely poor prognosis [2]. However, many patients are unwilling to undergo radical cystectomy without exhausting all the less aggressive options. Several analyses have demonstrated unfavourable prognosis in patients with tumour persistence immediately after an induction course of BCG. Solsona et al [3] showed that the 3-mo response was the only independent factor predictive of invasive progression. In a SWOG study, patients who achieved a complete response at 3 mo had 5-yr survival probability of 77%, compared to 62% for patients who did not [4]. In an analysis of CUETO trials, tumour presence at 3-mo cystoscopy was associated with a higher risk of progression in multivariate analysis [5]. In analysis published in 2003, Herr and Dalbagni [6] favoured 6-mo over 3-mo response in prediction of further recurrences. Unfortunately, a similar analysis for progression was not presented, probably because of a low number of events. As tumour progression and survival, in contrast to further recurrences, are the main issue for patients with high-risk non–muscle-invasive bladder cancer (NMIBC) after BCG, the EAU guidelines panel decided to set status at 3 mo as crucial for the definition of BCG failure for highgrade papillary tumours. We greatly appreciate the thorough analysis presented by Dr. Herr [7]. In spite of small discrepancies in numbers (789 vs 784 patients with no tumour at 3 and 6 mo), it is based on previously published data for patients with high-risk NMIBC treated with BCG without maintenance [8]. The letter by Dr. Herr contains an additional analysis of

Grading of Urothelial Carcinoma and The New “World Health Organisation Classification of Tumours of the Urinary System and Male Genital Organs 2016”

CONTEXTnIn the management of urothelial carcinoma, determination of the pathological grade aims at stratifying tumours into different prognostic groups to allow evaluation of treatment results, and optimise patient management. This article reviews the principles behind different grading systems for urothelial bladder carcinoma discussing their reproducibility and prognostic value.nnnOBJECTIVEnThis paper aims to show the evolution of the World Health Organisation (WHO) grading system, discussing their reproducibility and prognostic value, and evaluating which classification system best predicts disease recurrence and progression. The most optimal classification system is robust, reproducible, and transparent with comprehensive data on interobserver and intraobserver variability. The WHO published an updated tumour classification in 2016, which presents a step forward, but its performance will need validation in clinical studies.nnnEVIDENCE ACQUISITIONnMedline and EMBASE were searched using the key terms WHO 1973, WHO/International Society of Urological Pathology 1998, WHO 2004, WHO 2016, histology, reproducibility, and prognostic value, in the time frame 1973 to May 2016. The references list of relevant papers was also consulted, resulting in the selection of 48 papers.nnnEVIDENCE SYNTHESISnThere are still inherent limitations in all available tumour classification systems. The WHO 1973 presents considerable ambiguity for classification of the G2 tumour group and grading of the G1/2 and G2/3 groups. The 2004 WHO classification introduced the concept of low-grade and high-grade tumours, as well as the papillary urothelial neoplasm of low malignant potential category which is retained in the 2016 classification. Furthermore, while molecular markers are available that have been shown to contribute to a more accurate histological grading of urothelial carcinomas, thereby improving selection of treatment for a given patient, these are not (yet) part of standard clinical practice.nnnCONCLUSIONSnThe prognosis of patients diagnosed with urothelial carcinoma greatly depends on correct histological grading of the tumour. There is still limited data regarding intraobserver and interobserver variability differences between the WHO 1973 and 2004 classification systems. Additionally, reproducibility remains a concern: histological differences between the various types of tumour may be subtle and there is still no consensus amongst pathologists. The recent WHO 2016 classification presents a further improvement on the 2004 classification, but until further data becomes available, the European Association of Urology currently recommends the use of both WHO 1973 and WHO 2004/2016 classifications.nnnPATIENT SUMMARYnBladder cancer, when treated in time, has a good prognosis. However, selection of the most optimal treatment is largely dependent on the information your doctor will receive from the pathologist following evaluation of the tissue resected from the bladder. It is therefore important that the classification system that the pathologist uses to grade the tissue is transparent and clear for both urologists and pathologists. A reliable classification system will ensure that aggressive tumours are not misinterpreted, and less aggressive cancer is not overtreated.

Indication for a Single Postoperative Instillation of Chemotherapy in Non–muscle-invasive Bladder Cancer: What Factors Should Be Considered?

An early single instillation of intravesical chemotherapy (SICI) used immediately after transurethral resection of the bladder (TURB) can significantly reduce the recurrence rate in selected patients with non-muscle-invasive bladder cancer (NMIBC). SICI should be used in patients with low-risk and with selected intermediate-risk tumours, in particular for multiple primary small papillary tumours, single primary papillary tumours >3cm, and single recurrent papillary tumours recurring >1yr after the previous resection. The available data do not support any recommendation to reduce the role of SICI in patients after fluorescence cystoscopy-guided TURB or en bloc TURB. SICI can even provide some benefit in patients with intermediate-risk tumours subsequently treated with further instillations. During instillation, contraindications should be taken into account and safety measures should be applied. PATIENT SUMMARY: An early single instillation of intravesical chemotherapy immediately after transurethral resection of the bladder can significantly reduce the recurrence rate in selected patients with non-muscle-invasive bladder cancer. It should be used in patients with low-risk and selected intermediate-risk tumours.