Richard Zigeuner

EAU Guidelines on Non–Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016

CONTEXT The European Association of Urology (EAU) panel on Non-muscle-invasive Bladder Cancer (NMIBC) released an updated version of the guidelines on Non-muscle-invasive Bladder Cancer. OBJECTIVE To present the 2016 EAU guidelines on NMIBC. EVIDENCE ACQUISITION A broad and comprehensive scoping exercise covering all areas of the NMIBC guidelines published between April 1, 2014, and May 31, 2015, was performed. Databases covered by the search included Medline, Embase, and the Cochrane Libraries. Previous guidelines were updated, and levels of evidence and grades of recommendation were assigned. EVIDENCE SYNTHESIS Tumours staged as TaT1 or carcinoma in situ (CIS) are grouped as NMIBC. Diagnosis depends on cystoscopy and histologic evaluation of the tissue obtained by transurethral resection of the bladder (TURB) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TURB is essential for the patients prognosis. If the initial resection is incomplete, there is no muscle in the specimen, or a high-grade or T1 tumour is detected, a second TURB should be performed within 2-6 wk. The risks of both recurrence and progression may be estimated for individual patients using the European Organisation for Research and Treatment of Cancer (EORTC) scoring system and risk tables. The stratification of patients into low-, intermediate-, and high-risk groups is pivotal to recommending adjuvant treatment. For patients with a low-risk tumour and intermediate-risk patients at a lower risk of recurrence, one immediate instillation of chemotherapy is recommended. Patients with an intermediate-risk tumour should receive 1 yr of full-dose bacillus Calmette-Guérin (BCG) intravesical immunotherapy or instillations of chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for 1-3 yr is indicated. In patients at highest risk of tumour progression, immediate radical cystectomy (RC) should be considered. RC is recommended in BCG-refractory tumours. The long version of the guidelines is available at the EAU Web site (www.uroweb.org/guidelines). CONCLUSIONS These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice. PATIENT SUMMARY The European Association of Urology has released updated guidelines on Non-muscle-invasive Bladder Cancer (NMIBC). Stratification of patients into low-, intermediate-, and high-risk groups is essential for decisions about adjuvant intravesical instillations. Risk tables can be used to estimate risks of recurrence and progression. Radical cystectomy should be considered only in case of failure of instillations or in NMIBC with the highest risk of progression.

GuidelinesEAU Guidelines on Non–Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2013

CONTEXT The first European Association of Urology (EAU) guidelines on bladder cancer were published in 2002 [1]. Since then, the guidelines have been continuously updated. OBJECTIVE To present the 2013 EAU guidelines on non-muscle-invasive bladder cancer (NMIBC). EVIDENCE ACQUISITION Literature published between 2010 and 2012 on the diagnosis and treatment of NMIBC was systematically reviewed. Previous guidelines were updated, and the levels of evidence and grades of recommendation were assigned. EVIDENCE SYNTHESIS Tumours staged as Ta, T1, or carcinoma in situ (CIS) are grouped as NMIBC. Diagnosis depends on cystoscopy and histologic evaluation of the tissue obtained by transurethral resection (TUR) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TUR is essential for the patients prognosis. Where the initial resection is incomplete, where there is no muscle in the specimen, or where a high-grade or T1 tumour is detected, a second TUR should be performed within 2-6 wk. The risks of both recurrence and progression may be estimated for individual patients using the EORTC scoring system and risk tables. The stratification of patients into low-, intermediate-, and high-risk groups is pivotal to recommending adjuvant treatment. For patients with a low-risk tumour, one immediate instillation of chemotherapy is recommended. Patients with an intermediate-risk tumour should receive one immediate instillation of chemotherapy followed by 1 yr of full-dose bacillus Calmette-Guérin (BCG) intravesical immunotherapy or by further instillations of chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for 1-3 yr is indicated. In patients at highest risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is recommended in BCG-refractory tumours. The long version of the guidelines is available from the EAU Web site: http://www.uroweb.org/guidelines/. CONCLUSIONS These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice. PATIENT SUMMARY The EAU Panel on Non-muscle Invasive Bladder Cancer released an updated version of their guidelines. Current clinical studies support patient selection into different risk groups; low, intermediate and high risk. These risk groups indicate the likelihood of the development of a new (recurrent) cancer after initial treatment (endoscopic resection) or progression to more aggressive (muscle-invasive) bladder cancer and are most important for the decision to provide chemo- or immunotherapy (bladder installations). Surgical removal of the bladder (radical cystectomy) should only be considered in patients who have failed chemo- or immunotherapy, or who are in the highest risk group for progression.

Outcomes of radical nephroureterectomy: A series from the Upper Tract Urothelial Carcinoma Collaboration

The literature on upper tract urothelial carcinoma (UTUC) has been limited to small, single center studies. A large series of patients treated with radical nephroureterectomy for UTUC were studied, and variables associated with poor prognosis were identified.

European Guidelines on Upper Tract Urothelial Carcinomas: 2013 Update

CONTEXT The European Association of Urology (EAU) guideline group for upper tract urothelial carcinoma (UTUC) has prepared updated guidelines to aid clinicians in assessing the current evidence-based management of UTUC and to incorporate present recommendations into daily clinical practice. OBJECTIVE To provide a brief overview of the EAU guidelines on UTUC as an aid to clinicians in their daily clinical practice. EVIDENCE ACQUISITION The recommendations provided in the current guidelines are based on a thorough review of available UTUC guidelines and articles identified using a systematic search of Medline. Data on urothelial malignancies and UTUCs in the literature were searched using Medline with the following 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; nomogram; and survival. References were weighted by a panel of experts. EVIDENCE SYNTHESIS There is a lack of data in the current literature to provide strong recommendations (ie, grade A) due to the rarity of the disease. A number of recent multicentre studies are now available, and there is a growing interest in UTUC in the recent literature. Overall, 135 references have been included here, but most of these studies are still retrospective analyses. The TNM 2009 classification is recommended. Recommendations are given for diagnosis as well as radical and conservative treatment (ie, imperative and elective cases); additionally, prognostic factors are discussed. Recommendations are also provided for patient follow-up after different therapeutic options. CONCLUSIONS These guidelines contain information for the management of individual patients according to a current standardised approach. Physicians must take into account the specific clinical characteristics of each individual patient when determining the optimal treatment regimen including tumour location, grade, and stage; renal function; molecular marker status; and medical comorbidities.

European Guidelines for the Diagnosis and Management of Upper Urinary Tract Urothelial Cell Carcinomas: 2011 Update

CONTEXT The European Association of Urology (EAU) Guideline Group for urothelial cell carcinoma of the upper urinary tract (UUT-UCC) has prepared new guidelines to aid clinicians in assessing the current evidence-based management of UUT-UCC and to incorporate present recommendations into daily clinical practice. OBJECTIVE This paper provides a brief overview of the EAU guidelines on UUT-UCC as an aid to clinicians in their daily practice. EVIDENCE ACQUISITION The recommendations provided in the current guidelines are based on a thorough review of available UUT-UCC guidelines and papers identified using a systematic search of Medline. Data on urothelial malignancies and UUT-UCCs in the literature were searched using Medline with the following keywords: urinary tract cancer, urothelial carcinomas, upper urinary tract, carcinoma, transitional cell, renal pelvis, ureter, bladder cancer, chemotherapy, nephroureterectomy, adjuvant treatment, neoadjuvant treatment, recurrence, risk factors, and survival. A panel of experts weighted the references. EVIDENCE SYNTHESIS There is a lack of data in the current literature to provide strong recommendations due to the rarity of the disease. A number of recent multicentre studies are now available, whereas earlier publications were based only on limited populations. However, most of these studies have been retrospective analyses. The TNM classification 2009 is recommended. Recommendations are given for diagnosis as well as for radical and conservative treatment; prognostic factors are also discussed. Recommendations are provided for patient follow-up after different therapeutic options. CONCLUSIONS These guidelines contain information for the diagnosis and treatment of individual patients according to a current standardised approach. When determining the optimal treatment regimen, physicians must take into account each individual patients specific clinical characteristics with regard to renal function including medical comorbidities; tumour location, grade and stage; and molecular marker status.

Multi-Institutional Validation of a New Renal Cancer–Specific Survival Nomogram

PURPOSE We tested the hypothesis that the prediction of renal cancer-specific survival can be improved if traditional predictor variables are used within a prognostic nomogram. PATIENTS AND METHODS Two cohorts of patients treated with either radical or partial nephrectomy for renal cortical tumors were used: one (n = 2,530) for nomogram development and for internal validation (200 bootstrap resamples), and a second (n = 1,422) for external validation. Cox proportional hazards regression analyses modeled the 2002 TNM stages, tumor size, Fuhrman grade, histologic subtype, local symptoms, age, and sex. The accuracy of the nomogram was compared with an established staging scheme. RESULTS Cancer-specific mortality was observed in 598 (23.6%) patients, whereas 200 (7.9%) died as a result of other causes. Follow-up ranged from 0.1 to 286 months (median, 38.8 months). External validation of the nomogram at 1, 2, 5, and 10 years after nephrectomy revealed predictive accuracy of 87.8%, 89.2%, 86.7%, and 88.8%, respectively. Conversely, the alternative staging scheme predicting at 2 and 5 years was less accurate, as evidenced by 86.1% (P = .006) and 83.9% (P = .02) estimates. CONCLUSION The new nomogram is more contemporary, provides predictions that reach further in time and, compared with its alternative, which predicts at 2 and 5 years, generates 3.1% and 2.8% more accurate predictions, respectively.

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

CONTEXT The 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. OBJECTIVE To provide a brief overview of the EAU guidelines on UTUC as an aid to clinicians. EVIDENCE ACQUISITION The 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. EVIDENCE SYNTHESIS Due 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. CONCLUSIONS These 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. PATIENT SUMMARY Urothelial 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.

Prognostic Factors in Upper Urinary Tract Urothelial Carcinomas: A Comprehensive Review of the Current Literature

CONTEXT The heterogeneity of upper tract urothelial carcinoma (UTUC) biology and prognosis, as well as the presence of different treatment options, makes the clinical decision-making process extremely challenging. OBJECTIVE Provide an overview of the currently available prognostic factors for UTUC, focusing on clinical and pathologic characteristics, as well as on molecular markers. EVIDENCE ACQUISITION A systematic literature search was conducted using the PubMed, Scopus, and Embase databases to identify original articles, review articles, and editorials regarding prognostic factors in patients with UTUC. Keywords included urothelial carcinoma, renal pelvis, ureter, upper urinary tract urothelial carcinoma, upper urinary tract transitional cell carcinoma, prognosis, prognostic factors, markers, and survival. Articles published between 2000 and 2011 were reviewed and selected with the consensus of all the authors. EVIDENCE SYNTHESIS Prognostic factors can be divided into four different categories: preoperative/clinical factors, intraoperative/surgical factors, postoperative/pathologic factors, and molecular markers. Because of the rarity of the disease, only a small amount of level 1 evidence information from prospective randomized trials is available. Conversely, several single-institutional and multi-institutional studies have been published providing level 3 evidence information on various prognostic factors. Tumor stage and grade represent the best-established predictors of prognosis in patients with UTUC, but controversies still exist regarding the prognostic impact of tumor location and tumor necrosis. Several promising biomarkers have also been evaluated, but further studies evaluating their prognostic role are still needed. Finally, few prognostic models have been developed to provide clinicians with accurate estimates of the outcome of interest. CONCLUSIONS In the past few years, several prognostic factors have been identified to help clinicians dealing with patients with UTUC in the decision-making process. However, well-designed multi-institutional studies are still needed to provide stronger evidence and to promote the use of these prognostic factors in clinical practice.

Adjuvant chemotherapy for high risk upper tract urothelial carcinoma: results from the Upper Tract Urothelial Carcinoma Collaboration.

PURPOSE There is relatively little literature on adjuvant chemotherapy after radical nephroureterectomy in patients with upper tract urothelial carcinoma. We determined the incidence of adjuvant chemotherapy in high risk patients and the ensuing effect on overall and cancer specific survival. MATERIALS AND METHODS Using an international collaborative database we identified 1,390 patients who underwent nephroureterectomy for nonmetastatic upper tract urothelial carcinoma between 1992 and 2006. Of these cases 542 (39%) were classified as high risk (pT3N0, pT4N0 and/or lymph node positive). These patients were divided into 2 groups, including those who did and did not receive adjuvant chemotherapy, and stratified by gender, age group, performance status, and tumor grade and stage. Cox proportional hazard modeling and Kaplan-Meier analysis were used to determine overall and cancer specific survival in the cohorts. RESULTS Of high risk patients 121 (22%) received adjuvant chemotherapy. Adjuvant chemotherapy was more commonly administered in the context of increased tumor grade and stage (p <0.001). Median survival in the entire cohort was 24 months (range 0 to 231). There was no significant difference in overall or cancer specific survival between patients who did and did not receive adjuvant chemotherapy. However, age, performance status, and tumor grade and stage were significant predictors of overall and cancer specific survival. CONCLUSIONS Adjuvant chemotherapy is infrequently used to treat high risk upper tract urothelial carcinoma after nephroureterectomy. Despite this finding it appears that adjuvant chemotherapy confers minimal impact on overall or cancer specific survival in this group.

Prognostic Factors and Predictive Models in Renal Cell Carcinoma: A Contemporary Review

CONTEXT The natural history of renal cell carcinoma (RCC) is highly unpredictable. Small renal masses may be accompanied by metastatic disease. Conversely, patients with locally advanced disease may enjoy long-term disease-free survival. OBJECTIVE To review the status of prognostic factors in RCC. EVIDENCE ACQUISITION A literature review was performed using the PubMed, MEDLINE, and Cochrane databases for articles published as of February 15, 2010. Electronic articles published ahead of print were also considered. Search was limited to the English language. Search was conducted using the following keywords: renal cell carcinoma, molecular, tissue, markers, blood, urine, progression, prognosis, risk factor, and survival. Studies were selected according to the relevance of the study, the number of patients included, originality, actuality, and clinical applicability of the results. EVIDENCE SYNTHESIS Four areas of prediction were examined: (1) new RCC diagnostics, (2) RCC grade and stage at diagnosis, (3) disease progression, and (4) disease-specific mortality. All identified reports represented either case series or controlled studies. Although a large number of markers were identified, only a few were validated. Several prognostic factors were integrated in predictive or prognostic models. CONCLUSIONS Several prognostic factors can help discriminate between favourable and unfavourable RCC phenotypes. Of those, several clinical, pathologic, and biologic markers have been tested and validated, and they are used in predictive and prognostic models. Nonetheless, the search continues, especially for informative markers predicting the response to targeted therapies.