Prognostic Factor Risk Groups for Clinical Stage I Seminoma: An Individual Patient Data Analysis by the European Association of Urology Testicular Cancer Guidelines Panel and Guidelines Office.

BACKGROUND: The relapse rate in patients with clinical stage I (CSI) seminomatous germ cell tumor of the testis (SGCTT) who were undergoing surveillance after radical orchidectomy is 4-30%, depending on tumor size and rete testis invasion (RTI). However, the level of evidence supporting the use of both risk factors in clinical decision-making is low. OBJECTIVE: We aimed to identify the most important prognostic factors for relapse in CSI SGCTT patients. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data for 1016 CSI SGCTT patients diagnosed between 1994 and 2019 with normal postorchidectomy serum tumor marker levels and undergoing surveillance were collected from nine institutions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable Cox proportional hazard regression models were fit to identify the most important prognostic factors. The primary endpoint was the time to first relapse by imaging and/or markers. Relapse probabilities were estimated by the Kaplan-Meier method. RESULTS AND LIMITATIONS: After a median follow-up of 7.7 yr, 149 (14.7%) patients had relapsed. Categorical tumor size (≤2, >2-5, and >5 cm), presence of RTI, and lymphovascular invasion were used to form three risk groups: low (56.4%), intermediate (41.3%), and high (2.3%) risks with 5-yr cumulative relapse probabilities of 8%, 20%, and 44%, respectively. The model outperformed the currently used model with tumor size ≤4 versus >4 cm and presence of RTI (Harrell's C index 0.65 vs 0.61). The low- and intermediate-risk groups were validated successfully in an independent cohort of 285 patients. CONCLUSIONS: The risk of relapse after radical orchidectomy in CSI SGCTT patients under surveillance is low. We propose a new risk stratification model that outperformed the current model and identified a small subgroup with a high risk of relapse. PATIENT SUMMARY: The risk of relapse after radical orchidectomy in patients with clinical stage I seminomatous germ cell tumor of the testis is low. We propose a new risk stratification model that outperformed the current model and identified a small subgroup with a high risk of relapse.

Repeat Transurethral Resection (TUR) + Bacillus Calmette-Guérin (BCG) Versus Upfront Induction BCG After TUR in High-risk Non-muscle-invasive Bladder Cancer: Feasibility Phase of a Randomized Controlled Study.

BACKGROUND: High-level evidence supporting the role of repeat transurethral resection (reTUR) in non-muscle-invasive bladder cancer (NMIBC) is lacking. A randomized controlled trial (RCT) assessing whether immediate reTUR has an impact on patient prognosis is essential. However, since such a RCT will require enrollment of a high number of patients, a preliminary feasibility study is appropriate. OBJECTIVE: To assess the feasibility of an RCT investigating the impact of immediate reTUR + adjuvant bacillus Calmette-Guérin (BCG) versus upfront induction BCG after initial TUR in NMIBC. DESIGN, SETTING, AND PARTICIPANTS: Eligible patients were randomly assigned to receive either reTUR + adjuvant BCG or upfront induction BCG after TUR. Patients with macroscopically completely resected high-grade T1 NMIBC, with or without concomitant carcinoma in situ, and with detrusor muscle (DM) present in the initial TUR specimen were considered eligible for inclusion. Exclusion criteria included lymphovascular invasion (LVI), histological subtypes, hydronephrosis, concomitant upper tract urothelial carcinoma (UTUC), or urothelial carcinoma within the prostatic urethra. The aim was to enroll 30 patients in this feasibility study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The patient recruitment rate was the primary outcome. Oncological outcomes (recurrence-free and progression-free survival) were secondary endpoints. RESULTS AND LIMITATIONS: Overall, 30 patients (15 per arm) were randomized over a period of 14 mo (August 2020-October 2021). Two eligible patients refused the randomization, resulting in a patient compliance rate of 93.3% for the study protocol. We excluded 49 ineligible patients before randomization because of histological subtypes (n = 16, 33%), LVI (n = 9, 18%), DM absence in the TUR specimen (n = 12, 24%), metastatic disease (n = 5, 10%), concomitant UTUC (n = 3, 6%), or hydronephrosis (n = 4, 8%). At reTUR, persistent disease was found in four patients (29%) and upstaging to muscle-invasive disease in one (7%). Over median follow-up of 17 mo, disease recurrence was detected in three patients (23%) in the reTUR arm and six patients (40%) in the upfront BCG arm. Progression to muscle-invasive disease was observed in one patient treated with upfront BCG. CONCLUSIONS: The feasibility of conducting an RCT comparing upfront BCG versus reTUR + BCG in high-grade T1 NMIBC has been demonstrated. Our results underline the need to screen a large number of patients owing to characteristics meeting the exclusion criteria in a high percentage of cases. PATIENT SUMMARY: We found that a clinical trial of the role of a repeat surgical procedure to remove bladder tumors through the urethra would be feasible among patients with high-grade non-muscle-invasive bladder cancer. These preliminary results may help in refining the role of this repeat procedure for patients in this category.

Definitions, End Points, and Clinical Trial Designs for Bladder Cancer: Recommendations From the Society for Immunotherapy of Cancer and the International Bladder Cancer Group.

PURPOSE: There is a significant unmet need for new and efficacious therapies in urothelial cancer (UC). To provide recommendations on appropriate clinical trial designs across disease settings in UC, the Society for Immunotherapy of Cancer (SITC) and the International Bladder Cancer Group (IBCG) convened a multidisciplinary, international consensus panel. METHODS: Through open communication and scientific debate in small- and whole-group settings, surveying, and responses to clinical questionnaires, the consensus panel developed recommendations on optimal definitions of the disease state, end points, trial design, evaluations, sample size calculations, and pathology considerations for definitive studies in low- and intermediate-risk nonmuscle-invasive bladder cancer (NMIBC), high-risk NMIBC, muscle-invasive bladder cancer in the neoadjuvant and adjuvant settings, and metastatic UC. The expert panel also solicited input on the recommendations through presentations and public discussion during an open session at the 2021 Bladder Cancer Advocacy Network (BCAN) Think Tank (held virtually). RESULTS: The consensus panel developed a set of stage-specific bladder cancer clinical trial design recommendations, which are summarized in the table that accompanies this text. CONCLUSION: These recommendations developed by the SITC-IBCG Bladder Cancer Clinical Trial Design consensus panel will encourage uniformity among studies and facilitate drug development in this disease.

International Opinions on Grading of Urothelial Carcinoma: A Survey Among European Association of Urology and International Society of Urological Pathology Members.

Background: Grade of non-muscle-invasive bladder cancer (NMIBC) is an important prognostic factor for progression. Currently, two World Health Organization (WHO) classification systems (WHO1973, categories: grade 1-3, and WHO2004 categories: papillary urothelial neoplasm of low malignant potential [PUNLMP], low-grade [LG], high-grade [HG] carcinoma) are used. Objective: To ask the European Association of Urology (EAU) and International Society of Urological Pathology (ISUP) members regarding their current practice and preferences of grading systems. Design setting and participants: A web-based, anonymous questionnaire with ten questions on grading of NMIBC was created. The members of EAU and ISUP were invited to complete an online survey by the end of 2021. Thirteen experts had previously answered the same questions. Outcome measurements and statistical analysis: The submitted answers from 214 ISUP members, 191 EAU members, and 13 experts were analyzed. Results and limitations: Currently, 53% use only the WHO2004 system and 40% use both systems. According to most respondents, PUNLMP is a rare diagnosis with management similar to Ta-LG carcinoma. The majority (72%) would consider reverting back to WHO1973 if grading criteria were more detailed. Separate reporting of WHO1973-G3 within WHO2004-HG would influence clinical decisions for Ta and/or T1 tumors according the majority (55%). Most respondents preferred a two-tier (41%) or a three-tier (41%) grading system. The current WHO2004 grading system is supported by a minority (20%), whereas nearly half (48%) supported a hybrid three- or four-tier grading system composed of both WHO1973 and WHO2004. The survey results of the experts were comparable with ISUP and EAU respondents. Conclusions: Both the WHO1973 and the WHO2004 grading system are still widely used. Even though opinions on the future of bladder cancer grading were strongly divided, there was limited support for WHO1973 and WHO2004 in their current formats, while the hybrid (three-tier) grading system with LG, HG-G2, and HG-G3 as categories could be considered the most promising alternative. Patient summary: Grading of non-muscle-invasive bladder cancer (NMIBC) is a matter of ongoing debate and lacks international consensus. We surveyed urologists and pathologists of European Association of Urology and International Society of Urological Pathology on their preferences regarding NMIBC grading to generate a multidisciplinary dialogue. Both the "old" World Health Organization (WHO) 1973 and the "new" WHO2004 grading schemes are still used widely. However, continuation of both the WHO1973 and the WHO2004 system showed limited support, while a hybrid grading system composed of both the WHO1973 and the WHO2004 classification system may be considered a promising alternative.

Reducing the Frequency of Follow-up Cystoscopy in Low-grade pTa Non-muscle-invasive Bladder Cancer Using the ADXBLADDER Biomarker.

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) is one of the most expensive cancers owing to frequent follow-up cystoscopies for detection of recurrence. OBJECTIVE: To assess if the noninvasive ADXBLADDER urine test could permit a less intensive surveillance schedule for patients with low-grade (LG) pTa tumor without carcinoma in situ (CIS) at the previous diagnosis. DESIGN, SETTING, AND PARTICIPANTS: In a prospective, double-blind, multicenter study, 629 patients underwent follow-up cystoscopy, transurethral resection of bladder tumor/biopsy of suspect lesions, and ADXBLADDER testing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Diagnostic test accuracy and decision curve analysis were used to evaluate the impact of ADXBLADDER on decision-making on whether to perform follow-up cystoscopy. The primary endpoint was the negative predictive value (NPV) of ADXBLADDER for detection of high-grade and/or CIS (HG/CIS) recurrence and its impact on reducing unnecessary cystoscopies. RESULTS AND LIMITATIONS: ADXBLADDER had sensitivity of 66.7% (95% confidence interval [CI] 34.9-90.1%) and an NPV of 99.15% (95% CI 97.8-99.8%) for detection of HG/CIS recurrence. The probability of HG/CIS recurrence was 5.0% for ADXBLADDER-positive patients and 0.85% for ADXBLADDER-negative patients. For HG/CIS recurrence threshold probabilities between 0.85% and 5.0%, ADXBLADDER yields a net benefit with omission of cystoscopy for ADXBLADDER-negative patients. The corresponding net reduction in unnecessary cystoscopies ranges from 11 to 62 per 100 patients. CONCLUSIONS: Patients with LG pTa tumor at the previous diagnosis, for which the risk of HG/CIS recurrence is low and the ADXBLADDER NPV for ruling out HG/CIS recurrence is 99.15%, are ideally suited for a less intensive, personalized follow-up surveillance strategy using ADXBLADDER, with omission of cystoscopy for ADXBLADDER-negative patients. PATIENT SUMMARY: ADXBLADDER is a urine test that can predict the probability of recurrence of bladder cancer. Patients diagnosed with low-grade cancer confined to the bladder mucosa are ideally suited for less intensive follow-up using this test, which could reduce unnecessary cystoscopy procedures for those with a negative result, potentially improve quality of life, and reduce overall health care costs.

International Bladder Cancer Group Consensus Statement on Clinical Trial Design for Patients with Bacillus Calmette-Guérin-exposed High-risk Non-muscle-invasive Bladder Cancer.

CONTEXT: A large proportion of patients with non-muscle-invasive bladder cancer (NMIBC) fall in the gap between bacillus Calmette-Guérin (BCG)-naïve 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-Guérin (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.

European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (Ta, T1, and Carcinoma in Situ).

CONTEXT: The European Association of Urology (EAU) has released an updated version of the guidelines on non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE: To present the 2021 EAU guidelines on NMIBC. EVIDENCE ACQUISITION: A broad and comprehensive scoping exercise covering all areas of the NMIBC guidelines since the 2020 version was performed. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries. Previous guidelines were updated, and the level of evidence and grade of recommendation were assigned. EVIDENCE SYNTHESIS: Tumours staged as Ta, T1 and carcinoma in situ (CIS) are grouped under the heading of NMIBC. Diagnosis depends on cystoscopy and histological evaluation of tissue obtained via transurethral resection of the bladder (TURB) for papillary tumours or via multiple bladder biopsies for CIS. For papillary lesions, a complete TURB is essential for the patient's prognosis and correct diagnosis. In cases for which the initial resection is incomplete, there is no muscle in the specimen, or a T1 tumour is detected, a second TURB should be performed within 2-6 wk. The risk of progression may be estimated for individual patients using the 2021 EAU scoring model. On the basis of their individual risk of progression, patients are stratified as having low, intermediate, high, or very high risk, which is pivotal to recommending adjuvant treatment. For patients with tumours presumed to be at low risk and for small papillary recurrences detected more than 1 yr after a previous TURB, one immediate chemotherapy instillation is recommended. Patients with an intermediate-risk tumour should receive 1 yr of full-dose intravesical bacillus Calmette-Guérin (BCG) immunotherapy or instillations of chemotherapy for a maximum of 1 yr. For patients with high-risk tumours, full-dose intravesical BCG for 1-3 yr is indicated. For patients at very high risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is also recommended for BCG-unresponsive tumours. The extended version of the guidelines is available on the EAU website at https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/. 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 the classification, risk factors, diagnosis, prognostic factors, and treatment of non-muscle-invasive bladder cancer. The recommendations are based on the literature up to 2020, with emphasis on the highest level of evidence. Classification of patients as having low, intermediate, or and high risk is essential in deciding on suitable treatment. Surgical removal of the bladder should be considered for tumours that do not respond to bacillus Calmette-Guérin (BCG) treatment and tumours with the highest risk of progression.

Updated European Association of Urology (EAU) Prognostic Factor Risk Groups Overestimate the Risk of Progression in Patients with Non-muscle-invasive Bladder Cancer Treated with Bacillus Calmette-Guérin.

BACKGROUND: The 2021 European Association of Urology (EAU) guidelines contain updated prognostic factor risk groups for non-muscle-invasive bladder cancer (NMIBC). These groups are based on the following predictors of progression: tumour stage, grade, number, and size; concomitant carcinoma in situ; and age. However, the groups were derived from datasets excluding patients treated with bacillus Calmette-Guérin (BCG). OBJECTIVE: To determine the validity of the updated EAU prognostic factor risk groups in patients with NMIBC treated with BCG. DESIGN, SETTING, AND PARTICIPANTS: We reviewed patients treated with BCG at our institution between 2000 and 2018. Patients were analysed according to the receipt of "at least induction" and "adequate" BCG (as defined by the US Food and Drug Administration). Risk groups were assigned according to the 2021 EAU NMIBC risk calculator (https://nmibc.net/). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The Kaplan-Meier method was used to estimate the risks of progression at 1 and 5 yr. Probabilities of progression obtained with the updated prognostic factor risk groups in our series were compared with those reported by the EAU. Discrimination was assessed using the concordance index (c-index). RESULTS AND LIMITATIONS: A total of 529 patients received at least induction BCG with a median follow-up of 47.3 mo (interquartile range 25.3-86.9). Of these patients, 494 received adequate BCG. We found lower progression rates at 1 yr in the very-high-risk group patients receiving at least induction (6.9%) and adequate BCG (4.0%) versus 16.0% for the EAU predicted rates. Additionally, progression rates were also lower at 5 yr in the high-risk group-7.4% for at least induction and 5.3% for adequate BCG versus 9.6% for EAU predicted rates; the rates in the very-high-risk group were as follows: 16.7% for at least induction and 14.9% for adequate BCG versus 40.0% for EAU predicted rates. The c-index in our series was lower than that reported by the EAU (0.63 vs 0.80). Of interest, our multivariable analysis identified grade, stage, and age (p < 0.02) to be the predictors of progression after BCG therapy. CONCLUSIONS: While the 2021 EAU prognostic factor risk groups successfully stratified progression risks in our cohort, treatment with BCG reduced their discriminative ability. Furthermore, the groups overestimate progression risks in BCG-treated patients. These findings should be used in conjunction with the updated risk groups to counsel patients with higher-risk NMIBC about their risk of progression with and without BCG. PATIENT SUMMARY: Although the updated European Association of Urology prognostic factor risk groups are able to stratify patients with non-muscle-invasive bladder cancer according to their risk of progression to muscle-invasive bladder cancer, this risk is overestimated in patients treated with bacillus Calmette-Guérin (BCG).

Association of patients' sex with treatment outcomes after intravesical bacillus Calmette-Guérin immunotherapy for T1G3/HG bladder cancer.

PURPOSE: To investigate the association of patients' sex with recurrence and disease progression in patients treated with intravesical bacillus Calmette-Guérin (BCG) for T1G3/HG urinary bladder cancer (UBC). MATERIALS AND METHODS: We analyzed the data of 2635 patients treated with adjuvant intravesical BCG for T1 UBC between 1984 and 2019. We accounted for missing data using multiple imputations and adjusted for covariate imbalance between males and females using inverse probability weighting (IPW). Crude and IPW-adjusted Cox regression analyses were used to estimate the hazard ratios (HR) with their 95% confidence intervals (CI) for the association of patients' sex with HG-recurrence and disease progression. RESULTS: A total of 2170 (82%) males and 465 (18%) females were available for analysis. Overall, 1090 (50%) males and 244 (52%) females experienced recurrence, and 391 (18%) males and 104 (22%) females experienced disease progression. On IPW-adjusted Cox regression analyses, female sex was associated with disease progression (HR 1.25, 95%CI 1.01-1.56, p = 0.04) but not with recurrence (HR 1.06, 95%CI 0.92-1.22, p = 0.41). A total of 1056 patients were treated with adequate BCG. In these patients, on IPW-adjusted Cox regression analyses, patients' sex was not associated with recurrence (HR 0.99, 95%CI 0.80-1.24, p = 0.96), HG-recurrence (HR 1.00, 95%CI 0.78-1.29, p = 0.99) or disease progression (HR 1.12, 95%CI 0.78-1.60, p = 0.55). CONCLUSION: Our analysis generates the hypothesis of a differential response to BCG between males and females if not adequately treated. Further studies should focus on sex-based differences in innate and adaptive immune system and their association with BCG response.

Prognostic Value of the WHO1973 and WHO2004/2016 Classification Systems for Grade in Primary Ta/T1 Non-muscle-invasive Bladder Cancer: A Multicenter European Association of Urology Non-muscle-invasive Bladder Cancer Guidelines Panel Study.

BACKGROUND: In the current European Association of Urology (EAU) non-muscle-invasive bladder cancer (NMIBC) guideline, two classification systems for grade are advocated: WHO1973 and WHO2004/2016. OBJECTIVE: To compare the prognostic value of these WHO systems. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data for 5145 primary Ta/T1 NMIBC patients from 17 centers were collected between 1990 and 2019. The median follow-up was 3.9 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariate and multivariable analyses of WHO1973 and WHO2004/2016 stratified by center were performed for time to recurrence, progression (primary endpoint), cystectomy, and duration of survival, taking into account age, concomitant carcinoma in situ, gender, multiplicity, tumor size, initial treatment, and tumor stage. Harrell's concordance (C-index) was used for prognostic accuracy of classification systems. RESULTS AND LIMITATIONS: The median age was 68 yr; 3292 (64%) patients had Ta tumors. Neither classification system was prognostic for recurrence. For a four-tier combination of both WHO systems, progression at 5-yr follow-up was 1.4% in low-grade (LG)/G1, 3.8% in LG/G2, 7.7% in high grade (HG)/G2, and 18.8% in HG/G3 (log-rank, p < 0.001). In multivariable analyses with WHO1973 and WHO2004/2016 as independent variables, WHO1973 was a significant prognosticator of progression (p < 0.001), whereas WHO2004/2016 was not anymore (p = 0.067). C-indices for WHO1973, WHO2004, and the WHO systems combined for progression were 0.71, 0.67, and 0.73, respectively. Prognostic analyses for cystectomy and survival showed results similar to those for progression. CONCLUSIONS: In this large prognostic factor study, both classification systems were prognostic for progression but not for recurrence. For progression, the prognostic value of WHO1973 was higher than that of WHO 2004/2016. The four-tier combination (LG/G1, LG/G2, HG/G2, and HG/G3) of both WHO systems proved to be superior, as it divides G2 patients into two subgroups (LG and HG) with different prognoses. Hence, the current EAU-NMIBC guideline recommendation to use both WHO classification systems remains correct. PATIENT SUMMARY: At present, two classification systems are used in parallel to grade non-muscle-invasive bladder tumors. Our data on a large number of patients showed that the older classification system (WHO1973) performed better in terms of assessing progression than the more recent (WHO2004/2016) one. Nevertheless, we conclude that the current guideline recommendation for the use of both classification systems remains correct, since this has the advantage of dividing the large group of WHO1973 G2 patients into two subgroups (low and high grade) with different prognoses.

European Association of Urology (EAU) Prognostic Factor Risk Groups for Non-muscle-invasive Bladder Cancer (NMIBC) Incorporating the WHO 2004/2016 and WHO 1973 Classification Systems for Grade: An Update from the EAU NMIBC Guidelines Panel.

BACKGROUND: The European Association of Urology (EAU) prognostic factor risk groups for non-muscle-invasive bladder cancer (NMIBC) are used to provide recommendations for patient treatment after transurethral resection of bladder tumor (TURBT). They do not, however, take into account the widely used World Health Organization (WHO) 2004/2016 grading classification and are based on patients treated in the 1980s. OBJECTIVE: To update EAU prognostic factor risk groups using the WHO 1973 and 2004/2016 grading classifications and identify patients with the lowest and highest probabilities of progression. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data for primary NMIBC patients were collected from the institutions of the members of the EAU NMIBC guidelines panel. INTERVENTION: Patients underwent TURBT followed by intravesical instillations at the physician's discretion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable Cox proportional-hazards regression models were fitted to the primary endpoint, the time to progression to muscle-invasive disease or distant metastases. Patients were divided into four risk groups: low-, intermediate-, high-, and a new, very high-risk group. The probabilities of progression were estimated using Kaplan-Meier curves. RESULTS AND LIMITATIONS: A total of 3401 patients treated with TURBT ± intravesical chemotherapy were included. From the multivariable analyses, tumor stage, WHO 1973/2004-2016 grade, concomitant carcinoma in situ, number of tumors, tumor size, and age were used to form four risk groups for which the probability of progression at 5 yr varied from <1% to >40%. Limitations include the retrospective collection of data and the lack of central pathology review. CONCLUSIONS: This study provides updated EAU prognostic factor risk groups that can be used to inform patient treatment and follow-up. Incorporating the WHO 2004/2016 and 1973 grading classifications, a new, very high-risk group has been identified for which urologists should be prompt to assess and adapt their therapeutic strategy when necessary. PATIENT SUMMARY: The newly updated European Association of Urology prognostic factor risk groups for non-muscle-invasive bladder cancer provide an improved basis for recommending a patient's treatment and follow-up schedule.

European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2020 Update.

CONTEXT: The European Association of Urology (EAU) Guidelines Panel on Upper Urinary Tract Urothelial 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 an 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 the following keywords: urinary tract cancer, urothelial carcinomas, upper urinary tract carcinoma, renal pelvis, ureter, bladder cancer, chemotherapy, ureteroscopy, nephroureterectomy, neoplasm, adjuvant treatment, instillation, recurrence, risk factors, and survival. References were weighted by a panel of experts. EVIDENCE SYNTHESIS: Owing to the rarity of UTUC, there are insufficient data to provide strong recommendations. The 2017 tumour, node, metastasis (TNM) classification is recommended. Recommendations are given for diagnosis and risk stratification as well as for 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. Kidney-sparing management should be offered as a primary treatment option to patients with low-risk tumour and two functional kidneys. After radical nephroureterectomy, cisplatin-based chemotherapy is indicated in locally advanced UTUC. 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.

Comparison of the performances of the ADXBLADDER test and urinary cytology in the follow-up of non-muscle-invasive bladder cancer: a blinded prospective multicentric study.

OBJECTIVE: To compare directly the performance of the ADXBLADDER test with that of cytology in the detection of non-muscle-invasive bladder cancer (NMIBC) recurrences. BACKGROUND: ADXBLADDER is a urine test based on the detection of MCM5, a DNA licensing factor expressed in all cells capable of dividing. Expression is usually restricted to the basal stem cell compartment; however, in malignancy, MCM5-expressing cells can be found throughout the epithelium. Detection of MCM5 in urine sediment can be indicative of the presence of a bladder tumour. PATIENTS AND METHODS: A multicentre prospective, blinded study was carried out from August 2017 and July 2019 at 21 European Union centres, 14 of which collected matching cytology data. Urine was collected from patients prior to cystoscopy. Urine cytology and ADXBLADDER were performed and compared to the diagnosis obtained by cystoscopy. The performance of cytology and ADXBLADDER were then compared. RESULTS: The overall performance of ADXBLADDER demonstrated a sensitivity of 51.9%, a specificity of 66.4%, and a negative predictive value (NPV) of 92%. The sensitivity of ADXBLADDER for low- and high-grade recurrences was 44.1% and 58.8%, respectively. By contrast, cytology sensitivity was 16.7%, specificity was 98% and NPV was 90.7%. Cytology sensitivity for both low- and high-grade disease was 17.6%. CONCLUSIONS: ADXBLADDER detection of both low- and high-grade NMIBC recurrence is superior to that of cytology, with ADXBLADDER able to exclude the presence of high-grade recurrence in 97.8% of cases compared to 97.1% with cytology. These results show that ADXBLADDER has promise as a more reliable alternative to urine cytology in the follow-up of NMIBC.

A Systematic Review of Outcome Reporting, Definition and Measurement Heterogeneity in Non-Muscle Invasive Bladder Cancer Effectiveness Trials of Adjuvant, Prophylactic Treatment After Transurethral Resection.

BACKGROUND: Heterogenous outcome reporting in non-muscle-invasive bladder cancer (NMIBC) effectiveness trials of adjuvant treatment after transurethral resection (TURBT) has been noted in systematic reviews (SRs). This hinders comparing results across trials, combining them in meta-analyses, and evidence-based decision-making for patients and clinicians. OBJECTIVE: We aimed to systematically review the extent of reporting and definition heterogeneity. METHODS: We included randomized controlled trials (RCTs) identified from SRs comparing adjuvant treatments after TURBT or TURBT alone in patients with NMIBC (with or without carcinoma in situ) published between 2000-2020. Abstracts and full texts were screened independently by two reviewers. Data were extracted by one reviewer and checked by another. RESULTS: We screened 807 abstracts; from 15 SRs, 57 RCTs were included. Verbatim outcome names were coded to standard outcome names and organised using the Williamson and Clarke taxonomy. Recurrence (98%), progression (74%), treatment response (in CIS studies) (40%), and adverse events (77%) were frequently reported across studies. However, overall (33%) and cancer-specific (33%) survival, treatment completion (17%) and treatment change (37%) were less often reported. Quality of Life (3%) and economic outcomes (2%) were rarely reported. Heterogeneity was evident throughout, particularly in the definitions of progression and recurrence, and how CIS patients were handled in the analysis of studies with predominantly papillary patients, highlighting further issues with the definition of recurrence and progression vs treatment response for CIS patients. Data reporting was also inconsistent, with some trials reporting event rates at various time-points and others reporting time-to-event with or without Hazard Ratios. Adverse events were inconsistently reported. QoL data was absent in most trials. CONCLUSIONS: Heterogenous outcome reporting is evident in NMIBC effectiveness trials. This has profound implications for meta-analyses, SRs and evidence-based treatment decisions. A core outcome set is required to reduce heterogeneity. PATIENT SUMMARY: This systematic review found inconsistencies in outcome definitions and reporting, pointing out the urgent need for a core outcome set to help improve evidence-based treatment decisions.

Diagnostic Accuracy of MCM5 for the Detection of Recurrence in Nonmuscle Invasive Bladder Cancer Followup: A Blinded, Prospective Cohort, Multicenter European Study.

PURPOSE: Detection of MCM5 containing cells in urine has been shown to be indicative of the presence of a bladder tumor on primary diagnosis. In this study we evaluate diagnostic performance of ADXBLADDER in patients undergoing cystoscopic surveillance in nonmuscle invasive bladder cancer followup. MATERIALS AND METHODS: A multicenter prospective blinded study was performed at 21 European centers with patients undergoing cystoscopy for nonmuscle invasive bladder cancer surveillance, diagnosed in the preceding 2 years. Urine was collected from all eligible patients and ADXBLADDER-MCM5 testing was performed. Performance characteristics were calculated by comparing MCM5 results to the outcome of cystoscopy plus pathological assessment. RESULTS: Of 1,431 eligible patients enrolled 127 were diagnosed with a bladder cancer recurrence. The overall sensitivity for the ADXBLADDER-MCM5 test in detecting bladder cancer recurrence was 44.9% (95% CI 36.1-54) with a 75.6% sensitivity for nonpTaLG tumors (95% CI 59.7-87.6). Specificity was 71.1% (95% CI 68.5-73.5). The overall negative predictive value was 93% (95% CI 91.2-94.5). However, ADXBLADDER was able to rule out the presence of a nonpTaLG recurrent tumor with a negative predictive value of 99.0% (95% CI 98.2-99.5). No statistically significant differences in the performance of ADXBLADDER were observed as a result of age or sex. CONCLUSIONS: This large blinded prospective study demonstrates that in the followup of patients with nonmuscle invasive bladder cancer ADXBLADDER is able to exclude the presence of the most aggressive tumors with a negative predictive value of 99%. These results indicate that ADXBLADDER could be incorporated in the followup strategy of nonmuscle invasive bladder cancer.

Systematic Review of the Therapeutic Efficacy of Bladder-preserving Treatments for Non-muscle-invasive Bladder Cancer Following Intravesical Bacillus Calmette-Guérin.

CONTEXT: There is a critical need for effective bladder-sparing therapies for bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). Owing to the current lack of effective agents that can be used as a control, the US Food and Drug Administration began to accept single-arm trials for patients with carcinoma in situ (CIS), using complete response rate (CRR) and duration of response as the primary endpoints to support marketing applications. Despite the ensuing growth of clinical trials in this space, no consensus exists on a clinically relevant benchmark for CRR. OBJECTIVE: To elucidate the CRR and recurrence-free rate (RFR) using bladder-sparing agents after BCG failure in order to provide a frame of reference for future clinical trial results. EVIDENCE ACQUISITION: We performed a systematic review of clinical trials utilizing bladder-sparing therapeutics for NMIBC recurring after intravesical BCG (PROSPERO CRD42019130553). The search was performed in MEDLINE, EMBASE, and Cochrane Library. Relevant studies identified from bibliography search and conference abstracts were searched to complement the systematic review. A total of 42 studies utilizing 24 treatment options and consisting of 2254 patients were included for final analysis. EVIDENCE SYNTHESIS: Median CRRs in the treatment of CIS-containing tumors were 26% at 6 mo, 17% at 12 mo, and 8% at 24 mo after treatment. In comparison, median RFRs in the papillary-only studies were 67% at 6 mo, 44% at 12 mo, and 10% at 24 mo. Specifically in the BCG-unresponsive population, 6- and 12-mo CRRs in CIS-containing patients treated with Mycobacterium phlei cell wall-nucleic acid complex were 45% and 27%, respectively, and the median 6-, 12-, and 24-mo disease-free rates in the other studies were 43%, 35%, and 18%, respectively. The median progression-free rate was 91%: 95% in the CIS-containing studies and 89% in studies restricted to papillary-only recurrences. Toxicities of intravesical agents were generally mild, with very few dose limiting toxicities. CONCLUSIONS: We demonstrate that, to date, bladder-sparing therapies achieved modest efficacy in patients with NMIBC after BCG. Results from the current study will serve as a frame of reference for emerging trial results in the BCG-unresponsive space. PATIENT SUMMARY: In this study, we found that bladder-sparing therapies achieved modest efficacy in patients with non-muscle-invasive bladder cancer after bacillus Calmette-Guérin (BCG). These results will serve to inform future clinical trial results for salvage agents used to treat BCG-unresponsive bladder cancer.

Transurethral Resection of Bladder Tumour: The Neglected Procedure in the Technology Race in Bladder Cancer.

Transurethral resection of bladder tumour is the initial, most critical step in the management of bladder cancer; as such, this is a call to arms for the urological community to it the due diligence it deserves regarding technology and training.

Diagnostic accuracy of photodynamic diagnosis with 5-aminolevulinic acid, hexaminolevulinate and narrow band imaging for non-muscle invasive bladder cancer.

Objective: To assess the diagnostic test accuracy (DTA) of photodynamic diagnosis with 5-aminolaevulinic acid (5-ALA), hexylaminolevulinate (HAL) and narrow band imaging (NBI) for non-muscle-invasive bladder cancer (NMIBC), with white light-guided cystoscopy (WLC) as reference standard. Materials and Methods: A systematic review and narrative synthesis was performed in accordance with PRISMA. Major electronic databases were searched until 20th May 2019. All studies assessing the DTA of 5-ALA, HAL and NBI compared with WLC at patient and lesion-level were included. Relevant sensitivity analyses and risk of bias (RoB) assessment were undertaken. Results: 26 studies recruiting 3979 patients were eligible for inclusion. For patient-level analysis, NBI appeared to be the best (median sensitivity (SSY) 100%, median specificity (SPY) 68.45%, median positive predictive value (PPV) 90.75%, median negative predictive value (NPV) 100% and median false positive rate (FPR) 31.55%), showing better DTA outcomes than either HAL or 5-ALA. For lesion-level analysis, median SSY across NBI, HAL and 5-ALA were 93.08% (IQR 87.04-98.81%), 93.16% (IQR 91.48-97.04%) and 94.42% (IQR 82.37-95.73%) respectively. As for FPR, median values for NBI, HAL and 5-ALA were 20.40% (IQR 13.68-27.36%), 17.43% (IQR 12.79-22.40%) and 28.12% (IQR 22.08-42.39%), respectively. Sensitivity analyses based on studies with low to moderate RoB and studies with n>100 patients show similar findings. Conclusions: NBI appears to outperform 5-ALA and HAL in terms of diagnostic accuracy. All three modalities present high FPR, hence indicating the ability to detect additional cases and lesions beyond WLC.

Sample size computation in phase II designs combining the A'Hern design and the Sargent and Goldberg design.

This work focuses on the modification of two classical phase II trials designs, the A'Hern design, a single-arm single-stage design, and the Sargent and Goldberg design introduced in the context of flexible screening designs. In the first part of the paper, we have proposed a drift-adjusted A'Hern design, a hybrid design combining the A'Hern design and the Sargent and Goldberg design. Indeed, classical single-arm phase II designs such as the A'Hern design are still widely used in oncology. Conducting randomized comparative phase II trials may be challenging in many settings due to the increased sample size and this despite larger type 1 errors. Randomized non-comparative phase II designs first introduced by Herson and Carter include a simultaneous randomized standard-treatment reference arm to detect any drift in the reference arm assumption, but the trial is analyzed against historical controls as if it were a single-arm study. However, not incorporating at all an internal control arm in the trial design has been criticized in the literature. Our new design takes into account the observed response rate in a non-comparative reference arm to reduce the trial's risk of a false-positive conclusion. In the second part, we have proposed an alternative strategy to determining the sample size of the screened selection design. The latter, introduced in recent years by Yap et al. and Wu et al., extended the Sargent and Goldberg design to include a comparison to a historical control. However, their sample size computations may have potential weaknesses, which motivated us to revisit the existing approaches. A detailed simulation study has been carried out to evaluate the operating characteristics of the drift-adjusted A'Hern design and the different sample size strategies of the screened selection designs.