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Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference.Setting: Online Delphi survey and consensus conference.Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.Outcome measurements and statistical analysis: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), and 7-9 (agree). A priori (level 1) consensus was defined as >= 70% agreement and

Context: A large proportion of patients with non-muscle-invasive bladder cancer (NMIBC) fall in the gap between bacillus Calmette-Guerin (BCG)-naive and BCG-unresponsive disease. As multiple therapeutic agents move into this gray area, there is a critical need to define the disease state and establish recommendations for optimal trial design. Objective: To develop a consensus on optimal trial design for patients with BCG-exposed NMIBC, defined as high-grade recurrence after BCG treatment that does not meet the criteria for BCG-unresponsive disease. Evidence acquisition: We conducted a literature review using the Cochrane Library, Medline, and Embase and a review of clinical trials in ClinicalTrials.gov as a basis to generate consensus recommendations for clinical trial design in BCG-exposed NMIBC. Evidence synthesis: BCG-exposed NMIBC encompasses BCG resistance (presence of high-grade Ta or carcinoma in situ [CIS] at 3-mo evaluation after induction BCG) and delayed relapse. Randomized controlled trials are required to compare experimental therapies to a control arm receiving additional BCG, although ongoing BCG shortages may impact our ability to follow an optimal trial design. A placebo should be used in combination with BCG if the treatment arm includes BCG plus a study drug. Trials will either need to separate patients with and without CIS into two cohorts, or stratify by the presence of CIS at the time of randomization. If two cohorts are used, the primary endpoint for CIS patients should be complete response within a predetermined time. The primary endpoint in a cohort with Ta/T1 only, or if a single combined cohort is used, should be the duration of event-free survival. Suggested efficacy thresholds and corresponding sample sizes are provided. Conclusions: The International Bladder Cancer Group has developed recommendations regarding definitions, endpoints, and clinical trial design for BCG-exposed NMIBC to encourage uniformity among studies in this disease state. Patient summary: Our consensus provides a precise definition of the disease state for bladder cancer not invading the bladder muscle and exposed to bacillus Calmette-Guerin (BCG) treatment. Clear guidance for conducting optimal clinical trials in this disease setting was established and we believe that this will promote further progress in this field. (C) 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Context: Transurethral resection of bladder tumour (TURBT) for bladder cancer (BC) is an underappreciated common urological procedure. TURBT outcomes are highly variable, and results are dependent on judgement and surgical skill. Objective: To perform a narrative review and identify optimal best practice in TURBT including preparation, choice of equipment, procedural steps, surgical technique, and management of difficult scenarios and complications. Evidence acquisition: Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched. Important studies were identified and reviewed by an international panel of urologists representing major urological societies and guideline panels with a record of academic publication in this field. In areas where the group identified a lack of evidence or agreement, discussions took place until a consensus was reached. Evidence synthesis: A total of 814 studies were identified and 43 were included. The majority were retrospective (level of evidence 3), with only two prospective randomised trials. Four broad themes were identified, which formed the basis for the review: (1) the role of TURBT within the overall management of BC, (2) TURBT techniques, (3) measurement of outcomes including quality control and checklists, and (4) postoperative management. Familiarity with all aspects of the procedure is necessary to minimise morbidity and improve oncological outcomes. Development of new instruments and techniques, and prospective audit of TURBT outcomes are important future goals. Conclusions: TURBT is a common and challenging operation with known variable outcomes. To reduce these variations and optimise outcomes, best practice based on evidence and expert opinion is recommended. Patient summary: Transurethral resection of bladder tumour (TURBT) is a common but deceptively difficult urological operation. Optimal outcomes depend on experience and surgical skill. An international group of experienced TURBT surgeons review critical aspects of the procedure and share best practice to stimulate further discussion. (C) 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Objective To provide a contemporary update and recommendations for the diagnosis and management of low-grade non-muscle-invasive bladder cancer (BCa) based on current literature and expert consensus of the International Bladder Cancer Group. Methods We reviewed published trials, guidelines, meta-analyses and reviews (up to March 2019) and provide recommendations on baseline evaluations, treatment, endpoints, study design and surveillance protocols. Results Low-grade Ta BCa poses minimal risk to patients in terms of progression and disease-specific survival. Thus, to minimize patient morbidity, this entity should be managed appropriately. After initial diagnosis of low-grade Ta tumour, subsequent stable, low-grade-appearing recurrences can be managed conservatively with office cystoscopy and fulguration or even followed using an active surveillance protocol. Intravesical therapy other than single-dose peri-operative chemotherapy instillation should be used judiciously, and only after assigning appropriate risk points. Routine use of urinary cytology - other than at initial risk stratification, or for patients on active surveillance without therapy - is not recommended; and surveillance cystoscopy may be discontinued after 5 years. Clinical studies in this group of patients should focus on recurrence rates, and time to recurrence, rather than progression events. Conclusions The International Bladder Cancer Group has developed formal recommendations regarding the diagnosis, treatment and surveillance of low-grade non-muscle-invasive BCa to minimize morbidity and encourage uniformity among studies in this disease.

Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference. Setting: Online Delphi survey and consensus conference. Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. Outcome measurements and statistical analysis: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), and 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). Results and limitations: Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease. Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach. Patient summary: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.

Intravesical immunotherapy with live attenuated BCG remains the standard of care for patients with high-risk and intermediate-risk non-muscle-invasive bladder cancer (NMIBC). Most patients initially respond, but recurrence is frequent and progression to invasive cancer is a concern. No established and effective intravesical therapies are available for patients whose tumours recur after BCG, representing a clinically important unmet need. Development and discovery of treatment options for BCG-unresponsive NMIBC is a high priority in order to decrease the morbidity, burden of health-care expenditures, and mortality related to bladder cancer. This Review of treatment options after BCG failure focuses on principles of optimal management emerging therapies, thus enabling a synthesis of recommendations for management for such patients.

Objective: Non-muscle-invasive bladder cancer (NMIBC) comprises a wide spectrum of tumors with different behaviors and prognoses. It follows that the surveillance for these tumors should be adapted according to the risks of recurrence and progression and should be dynamic in design. Methods and materials: Medline search was conducted from 1980 to 2016 using a combination of MeSH and keyword terms. The highest available evidence was reviewed to define different risk groups in NMIBC. The performance of different follow-up tools such as urine cytology, cystoscopy, and upper tract imaging in detecting bladder carcinoma was assessed. Different commercially available urinary markers were investigated to determine whether such markers would contribute to the surveillance of patients with NMIBC. A follow-up scheme based on the early evidence is proposed. Results: A risk-based approach is paramount. Cystoscopy and cytology are recommended to be done at 3 months following transurethral resection of bladder tumor. For low-risk tumors, annual cystoscopy alone is sufficient; no upper tract evaluations or cytology is needed except at diagnosis. High-risk tumors should be followed up with a more intense schedule: cystoscopy every 3 months for 2 years, 6 months for 2 years, and then annually, with cytology at frequent intervals, and imaging for upper tract evaluation at 1 year and then every 2 years. Intermediate-risk tumors should be subclassified as per the International Bladder Cancer Group recommendations and when associated with 3 or more of the following findings (multiple tumors, size >= 3cm, early recurrence 1 per year) then a surveillance strategy similar to that of high risk should be followed. Several urine markers were more sensitive than cytology in the detection of NMIBC; however, these tests are still costly, require specialized laboratories, and do not replace cystoscopy. Until better and cheaper markers are available, their routine use has not been integrated in the follow-up recommendation of current guidelines. Conclusions: Surveillance of NMIBC should follow a risk-adapted approach, with a combination of cystoscopy, cytology, and upper tract imaging. The aim of this approach is to minimize the therapeutic burden of a disease with high recurrence rates without missing progressing tumors. When designing a diagnostic pathway, first-line diagnostic imaging tests should have high sensitivity to ensure disease positives are included in the test population for further investigation. Second-line investigations should be highly specific, to ensure false-positives are minimized. (C) 2016 Elsevier Inc. All rights reserved

Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 x 10(-5) was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 x 10(-9)) and rs907611 on 11p15.5 (P = 4.11 x 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 x 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 x 10(-7)); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.

Purpose: Low, intermediate and high risk categories have been defined to help guide the treatment of patients with nonmuscle invasive bladder cancer (Ta, T1, CIS). However, while low and high risk disease has been well classified, the intermediate risk category has traditionally comprised a heterogeneous group that does not fit into either of these categories. As a result, many urologists remain uncertain about the categorization of patients as intermediate risk as well as the selection of the most appropriate therapeutic option for this patient population. We review the current literature and clinical practice guidelines on intermediate risk nonmuscle invasive bladder cancer and, based on our findings, provide urologists with a better understanding of this heterogeneous risk group as well as practical recommendations for the treatment of intermediate risk patients. Materials and Methods: The IBCG analyzed published clinical trials, meta-analyses and current clinical practice guidelines on intermediate risk nonmuscle invasive bladder cancer available as of September 2013. The definitions of intermediate risk, patient outcomes and guideline recommendations were considered, as were the limitations of the available literature and additional parameters that may be useful in guiding treatment decisions in intermediate risk patients. Results: Current definitions and management recommendations for intermediate risk nonmuscle invasive bladder cancer vary. The most simple and practical definition is that proposed by the IBCG and the AUA of multiple and/or recurrent low grade Ta tumors. The IBCG suggests that several factors should be considered in clinical decisions in intermediate risk disease, including number (greater than 1) and size (greater than 3 cm) of tumors, timing (recurrence within 1 year) and frequency (more than 1 per year) of recurrence, and previous treatment. In patients without these risk factors a single, immediate instillation of chemotherapy is advised. In those with 1 to 2 risk factors adjuvant intravesical therapy (intravesical chemotherapy or maintenance bacillus Calmette-Guerin) is recommended, and previous intravesical therapy should be considered when choosing between these adjuvant therapies. For those patients with 3 to 4 risk factors, maintenance bacillus Calmette-Guerin is recommended. It is also important that all intermediate risk patients are accurately risk stratified at initial diagnosis and during subsequent followup. This requires appropriate transurethral resection of the bladder tumor, vigilance to rule out carcinoma in situ or other potential high risk tumors, and review of histological material directly with the pathologist. Conclusions: Intermediate risk disease is a heterogeneous category, and there is a paucity of independent studies comparing therapies and outcomes in subgroups of intermediate risk patients. The IBCG has proposed a management algorithm that considers tumor characteristics, timing and frequency of recurrence, and previous treatment. Subgroup analyses of intermediate risk subjects in pivotal EORTC trials and meta-analyses will be important to validate the proposed algorithm and support clear evidence-based recommendations for subgroups of intermediate risk patients.

Purpose: Despite being one of the most important clinical outcomes in nonmuscle invasive bladder cancer, there is currently no standard definition of disease progression. Major clinical trials and meta-analyses have used varying definitions or have failed to define this end point altogether. A standard definition of nonmuscle invasive bladder cancer progression as determined by reproducible and reliable procedures is needed. We examine current definitions of nonmuscle invasive bladder cancer progression, and propose a new definition that will be more clinically useful in determining patient prognosis and comparing treatment options. Materials and Methods: The IBCG (International Bladder Cancer Group) analyzed published clinical trials and meta-analyses that examined nonmuscle invasive bladder cancer progression as of December 2012. The limitations of the definitions of progression used in these trials were considered, as were additional parameters associated with the advancement of nonmuscle invasive bladder cancer. Results: The most commonly used definition of nonmuscle invasive bladder cancer progression is an increase in stage from nonmuscle invasive to muscle invasive disease. Although this definition is clinically important, it fails to include other important parameters of advancing disease such as progression to lamina propria invasion and increase in grade. Conclusions: The IBCG proposes the definition of nonmuscle invasive bladder cancer progression as an increase in T stage from CIS or Ta to T1 (lamina propria invasion), development of T2 or greater or lymph node (N+) disease or distant metastasis (M1), or an increase in grade from low to high. Investigators should consider the use of this new definition to help standardize protocols and improve the reporting of progression.

Objective: Diagnosis and surveillance of high risk non muscle-invasive bladder cancer (NMIBC) represent specific challenges to urologists. In contrast to low/intermediate risk tumors, these tumors recur more frequently. A significant number will eventually progress to muscle-invasive bladder cancer, a life threatening disease requiring extensive therapeutic efforts. Although clinical risk factors have been identified that may predict tumor recurrence and progression, additional biomarkers are desperately needed to improve tumor diagnosis and guide clinical management of these patients. In this article, the role of molecular urine markers in the management of high risk NMIBC is analyzed. Methods: In this context, several potential indications (diagnostic, prognostic, predictive) were identified and the requirements for molecular markers were defined. In addition, current knowledge within the different indications was summarized. Results: Significant progress has been made in the last decade studying the impact of molecular urine markers in patients with high risk NMIBC. Conclusions: Although we may not be ready for the inclusion of molecular markers in clinical decision-making, and many questions remain unanswered, recent studies have identified situations in which the use of molecular markers in particular in high grade tumors may prove beneficial for patient diagnosis and surveillance. (C) 2014 Elsevier Inc. All rights reserved.

To externally validate the prognostic value of lymphovascular invasion (LVI) in a large international cohort of patients treated with radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB).We collected data from 4257 patients treated with RC and pelvic lymphadenectomy for UCB, without neoadjuvant chemotherapy, at 12 centres. LVI was defined as presence of nests of tumour cells within an endothelium-lined space.LVI was detected in 1407 patients (33.1%); the proportion of LVI increased with advancing stage, higher grade, soft-tissue surgical margin involvement, and lymph node metastasis (P0.001 for all). In standard multivariate models, LVI was associated with both disease recurrence (hazard ratio 1.43, P0.001) and cancer-specific mortality (1.45, P0.001). In the entire cohort, adding LVI to a base model that included standard features improved only minimally its predictive accuracy for both recurrence and cancer-specific mortality (by 1.1% and 1.2%, respectively). In 3122 patients with negative lymph nodes, LVI remained independently associated with and improved the predictive accuracy of the standard predictors for recurrence (hazard ratio 1.68, P0.001; +2.3%) and cancer-specific mortality (1.70, P0.001; +2.4%). By contrast, in 1071 node-positive patients, LVI only marginally improved the prediction of cancer-specific recurrence (hazard ratio 1.20, P0.001; +0.2%) and survival (1.23, P0.001; +0.5%).LVI is strongly associated with clinical outcome in node-negative patients treated with RC. The assessment of LVI might help to identify patients who could benefit from adjuvant therapy after RC. After confirmation in different populations, LVI should be included in the staging of UCB.

Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. Setting: Online Delphi survey and consensus conference. Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. Outcome measurements and statistical analysis: Statements were ranked by experts according to their level of agreement: 1–3 (disagree), 4–6 (equivocal), 7–9 (agree). A priori (level 1) consensus was defined as 70% agreement and 15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). Results and limitations: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach, The authors would like to thank Peter E. Clark from Atrium Health, Levine Cancer Institute, Charlotte, NC, USA, for his contribution to the Delphi survey. Angela Corstorphine of Kstorfin Medical Communications Ltd provided medical writing support with the preparation of this manuscript; this support was funded jointly by EAU and ESMO.

Rationale: Several guidelines exist that address treatment of patients with nonmetastatic muscle-invasive bladder cancer (MIBC). However, most only briefly mention follow-up strategies for patients and hence the treating physician is often left to infer on what the preferred follow-up schema would be for an individual patient. Herein, we aim to synthesize recommendations for follow-up of patients with MIBC for easy reference. Methods: A multidisciplinary MIBC expert panel from the International Bladder Cancer Network was assembled to critically assess currently available major guidelines on surveillance of MIBC patients. Recommendations for follow-up were extracted and critically evaluated. Important considerations for guideline assessment included both aspects of oncological and functional follow-up-frequency of visits, the use of different imaging modalities, the role of cytology and molecular markers, and the duration of follow-up. Outcome: An International Bladder Cancer Network expert consensus recommendation was constructed for the follow-up of patients with MIBC based on the currently available evidence-based data.

Context Checkpoint inhibitors (CPIs) are established as a standard therapy option for metastatic bladder cancer; however, their role in earlier-stage disease remains undefined. Objective To summarize the preclinical and clinical evidence forming the rationale for multiple ongoing investigations of CPIs in patients with localized bladder cancer defined by non–muscle-invasive or muscle-invasive stages. Evidence acquisition A systematic review of the literature in the MEDLINE database was performed. The central search strategy used the terms bladder cancer, urothelial carcinoma, transitional cell, localized, muscle-invasive, non–muscle-invasive, superficial, PD-1, PD-L1, CTLA-4, and checkpoint inhibitor, both alone and in combination. The search was limited to publications between January 2000 and December 2017. Publicly available relevant abstracts from recent meetings were also included. Evidence synthesis Preclinical immunocompetent murine, rodent, and canine models have each demonstrated proof-of-concept support for CPI therapy approaches in localized urothelial carcinoma (UC). Retrospective analysis of localized UC tumor samples confirms the presence of PD-1, PD-L1, or CTLA-4 in a proportion of patients. Prospective pilot trials of CPI therapy in localized UC demonstrated enhanced adaptive immune response measures. Improved whole-transcriptome platforms may further refine patient selection for CPI therapy. Multiple clinical trials of CPI therapy in localized UC are under way with significant practice-changing potential. Conclusions Evidence from preclinical models and retrospective data for patients with localized UC and metastatic UC sufficiently justifies the investigation of CPI approaches in the context of prospective clinical trials. Patient summary Checkpoint inhibitor (CPI) therapy has provided durable tumor control in a small portion of patients with metastatic urothelial carcinoma (UC). Investigating the potential for similar sustained tumor control in localized UC is logical. Ongoing prospective clinical trials will define whether or not CPI therapy should be extended to patients with curable localized UC in whom standards for successful clinical outcomes are higher and acceptance rates of severe treatment-related toxicity are lower.

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 x 10(-39); Region 3: rs2853677, P = 3.30 x 10(-36) and PConditional = 2.36 x 10(-8); Region 4: rs2736098, P = 3.87 x 10(-12) and PConditional = 5.19 x 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 x 10(-6); and Region 6: rs10069690, P = 7.49 x 10(-15) and PConditional = 5.35 x 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 x 10(-18) and PConditional = 7.06 x 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.