All High-Grade Ta Tumors Should Be Classified as High Risk: Bacillus Calmette-Guérin Response in High-Grade Ta Tumors.

PURPOSE: There is variation amongst guidelines with respect to risk stratification of Ta tumors, specifically high-grade (HG) Ta tumors. We sought to investigate the response of all Ta tumors to bacillus Calmette-Guérin (BCG) and compare response rates based on European Association of Urology (EAU) classification as intermediate- (IR) or high-risk (HR). MATERIALS AND METHODS: An institutional review of all patients who received adequate BCG from 2000-2018 was conducted. EAU 2021 prognostic risk groups were used to stratify patients including by the newly proposed adverse risk factors. RESULTS: When patient with Ta tumors were stratified into IR and HR, 37 (16%) had IR low-grade (LG) Ta, 92 (40%) had IR HG Ta and 101 (44%) had HR HG Ta tumors. BCG unresponsiveness developed in 13% of HR HG Ta tumors and 14% of IR HG Ta tumors compared to 0.0% of IR LG Ta tumors (p=0.003). While no patients with IR LG Ta tumors progressed, progression rates were similar in HR HG Ta and IR HG Ta tumors (≥T2: 5.9% and 6.5%; [Formula: see text]T1: 13% and 13%, respectively). Rates of recurrence, BCG unresponsiveness and progression were similar, irrespective of number of EAU risk factors present (p=0.9, p=0.8 and p=0.9, respectively). CONCLUSIONS: All HG Ta tumors, regardless of EAU risk stratification, have inferior response to BCG and increased rates of progression compared to IR LG Ta tumors. EAU clinical risk factors did not improve prediction of oncologic outcomes among HG Ta patients who received adequate BCG. These data support consideration of all HG tumors as high risk.

Implications of Guideline-based, Risk-stratified Restaging Transurethral Resection of High-grade Ta Urothelial Carcinoma on Bacillus Calmette-Guérin Therapy Outcomes.

BACKGROUND: Guideline indications for restaging transurethral resection (reTUR) for high-grade (HG) Ta bladder tumors vary due to a paucity of data. OBJECTIVE: To investigate guideline-based, risk-adapted approaches to reTUR for HG Ta lesions. DESIGN, SETTING, AND PARTICIPANTS: An institutional review of HG Ta patients who received adequate bacillus Calmette-Guérin (BCG) from 2000 to 2019 was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Guideline criteria for reTUR were used to stratify patients. Kaplan-Meier product limits estimated survival. Cox regression and log-rank tests identified association of variables with survival. RESULTS AND LIMITATIONS: Of the 209 patients with HG Ta bladder cancer, 104 (50%) underwent reTUR, which identified residual disease in 39 patients (38%). Only one patient (1%) was upstaged to pT1 on reTUR. In all unstratified HG Ta patients, reTUR was associated with improved progression-free survival (p = 0.050) and recurrence-free survival (RFS; p = 0.003). The 5-yr RFS for patients who underwent versus those who did not undergo reTUR based on AUA guidelines was 73% (95% confidence interval 63-81%) versus 52% (40-62%), and for those who underwent versus those who did not undergo reTUR based on EAU guidelines was 76% (61-86%) versus 22% (4-49%). In 45 patients meeting both AUA high-risk criteria (large, multifocal tumors) and EAU criteria (lack of detrusor muscle) for reTUR, lack of restaging was associated with over a two-fold increase in recurrence (67% vs 15%, p = 0.002) and progression (25% vs 6%, p = 0.109). Data were limited by selection bias unaccounted for in selecting candidates for reTUR. CONCLUSIONS: Restaging TUR in all HG Ta patients, regardless of risk stratification, was associated with improved outcomes. The benefit of reTUR was most notable in high-risk patients without muscle in the index specimen, consistent with components of both AUA and EAU guidelines. These data support a non-risk-adapted approach to reTUR for all HG Ta lesions. PATIENT SUMMARY: Restaging bladder tumor resection improves outcomes in patients with high-grade Ta tumors treated with bacillus Calmette-Guérin (BCG).

Contemporary Outcomes of Patients with Nonmuscle-Invasive Bladder Cancer Treated with bacillus Calmette-Guérin: Implications for Clinical Trial Design.

PURPOSE: Recurrent disease after bacillus Calmette-Guérin treatment presents a therapeutic challenge. To aid trial development, the U.S. Food and Drug Administration defined "adequate bacillus Calmette-Guérin" therapy and adopted the "bacillus Calmette-Guérin unresponsive" disease state. Available data for efficacy benchmark comparison are outdated, leading to concerns about appropriate control arms and sample size calculations. We describe a contemporary cohort of patients with nonmuscle-invasive bladder cancer treated with intravesical bacillus Calmette-Guérin, and provide benchmark outcomes data. MATERIALS AND METHODS: We retrospectively reviewed patients receiving adequate bacillus Calmette-Guérin therapy at a tertiary cancer center between January 2004 and August 2018. Unadjusted univariable analysis was conducted using the Pearson chi-square test. Kaplan-Meier estimates for recurrence-free survival-high grade, progression-free survival-muscle-invasive bladder cancer and overall survival were used to create survival curves and compared using the log-rank test. RESULTS: Of the 542 patients who received adequate bacillus Calmette-Guérin, 518 (90%) had European Association Urology high risk disease, with carcinoma in situ present in 175 (32%). With a median followup of 47.8 months, freedom from high grade recurrence at 1, 3 and 5 years was 81%, 76% and 74%, respectively, and progression-free survival was 97%, 93% and 92%. Progression to muscle invasion at 5 years was exclusively seen in patients with high risk disease (progression-free survival 91%; log-rank test, p=0.024). CONCLUSIONS: A contemporary cohort of patients with nonmuscle-invasive bladder cancer treated with adequate bacillus Calmette-Guérin demonstrated markedly better outcomes than seen in prior studies. These data could be used in the design of clinical trials, to guide power calculations, as well as serve as benchmarks for comparison to evaluate nonrandomized studies.

The obesity paradox: defining the impact of body mass index and diabetes mellitus for patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin.

OBJECTIVES: To evaluate if the obesity paradox, wherein obesity portends worse overall prognosis for a disease but improved outcomes for patients receiving immunotherapy, exists for patients receiving bacillus Calmette-Guérin (BCG) in a contemporary cohort. PATIENTS AND METHODS: We performed an Institutional Review Board-approved database review to identify patients with non-muscle-invasive bladder cancer (NMIBC) completing at least an induction course of BCG. Clinicopathological variables collected included: body mass index (BMI), medications, and diabetes mellitus (DM). Outcomes of interest included: recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS), and overall survival (OS). Univariate and multivariate modelling were used to evaluate the association between outcomes and clinical factors. RESULTS: A total of 579 patients (median follow-up 4.6 years) received BCG induction for NMIBC; 90% had high-grade disease (47.2% clinical stage T1). In all, 75.7% of patients were overweight or obese and 18% had DM. Aspirin, statins, metformin and ß-blockers were used in 34%, 42%, 11%, and 29% of patients, respectively. Overweight and obese patients had improved PFS, CSS and OS. DM was associated with worse RFS. Medications of interest had no association with outcomes. CONCLUSION: Elevated BMI is associated with improved outcomes in patients with NMIBC treated with BCG immunotherapy. Patients with DM are at increased risk of recurrence. These findings support a potential obesity paradox in bladder cancer. Evaluation of the underlying mechanism and the role of global patient assessment, counselling, and risk factor modification are warranted.

Can Biomarkers Guide the Use of Neoadjuvant Chemotherapy in T2 Bladder Cancer?

Current guidelines recommend cisplatin-based neoadjuvant chemotherapy prior to radical cystectomy as the preferred treatment of muscle-invasive bladder cancer. Nevertheless, for multiple reasons compliance with this guideline recommendation is low. This is particularly evident in clinical T2 bladder cancer, where controversy exists regarding the role of proceeding with radical cystectomy alone. Novel biomarkers such as molecular phenotype and DNA damage repair and response gene alterations may be able to predict who will respond to cisplatin-based neoadjuvant chemotherapy. This clinical problem is discussed, and a recommendation is made given the current state of the art. PATIENT SUMMARY: Neoadjuvant chemotherapy improves survival for patients with muscle-invasive bladder cancer. In the future, perhaps validated biomarkers may predict who should and should not receive this treatment.

Using Grade of Recurrent Tumor to Guide Further Therapy While on Bacillus Calmette-Guerin: Low-grade Recurrences Are not Benign.

BACKGROUND: Tumors that recur after bacillus Calmette-Guerin (BCG) therapy are considered to be of very high risk, and patients are often recommended to undergo radical cystectomy (RC). However, the nuances associated with the grade of tumor recurrence after BCG treatment are not well understood. OBJECTIVE: To characterize the pattern of bladder cancer progression and cancer-specific survival (CSS) in patients with recurrences dichotomized by low grade (LG) versus high grade (HG) after intravesical BCG treatment, and to assess the safety of continued bladder-sparing therapy in these patients. DESIGN, SETTING, AND PARTICIPANTS: We performed an Institutional Review Board-approved review of our bladder cancer database. Overall, 146 non-muscle-invasive bladder cancer (NMIBC) patients were found to have NMIBC recurrence while on BCG therapy; this recurrence was LG in 38 and HG in 108. Baseline clinicopathologic characteristics including age, gender, primary tumor grade, stage, size, multiplicity, and concurrent carcinoma in situ were also evaluated. The primary endpoint was progression-free survival (PFS), with progression defined as the development of muscle-invasive bladder cancer (MIBC)/distant metastasis. In addition, recurrence-free survival (RFS), HG RFS, cystectomy-free survival (CFS), and CSS were also compared. Multivariable analysis was performed using the Cox regression model. All tests were two sided, and p<0.05 was considered statistically significant. INTERVENTION: Further intravesical therapy versus salvage RC. RESULTS AND LIMITATIONS: Overall, estimated 5-yr PFS was 72.4% (95% confidence interval [CI] 60.4-81.3%). As dichotomized by grade of recurrent tumor, PFS was greater for patients with LG recurrences (85.6%, 95% CI 60.8-95.2%) than for those with HG recurrence (67.9%, 95% CI 54.1-78.4%; p=0.010). Furthermore, patients whose initial recurrence on BCG therapy was LG had improved subsequent RFS (median 62 vs 34mo, p=0.007), HG RFS (median 112 vs 36mo, p<0.001), and CFS (estimated 5-yr CFS 80.8% vs 49.8%, p<0.001) compared with those who had HG initial recurrence. On univariate and multivariate analyses, grade of tumor recurrence after BCG was an independent predictor of time to progression to MIBC/distant metastasis (hazard ratio 3.60, 95% CI 1.18-10.94, p=0.024). CONCLUSIONS: Grade of tumor recurrence after intravesical BCG is an important predictor of bladder cancer progression to MIBC/metastatic urothelial carcinoma. While, patients with LG recurrences have less than half the progression events compared with those with HG recurrences, their estimated 5-yr progression rate is still 14.4%. Hence all patients should be carefully counseled on bladder-sparing therapy. This also has implications for clinical trial design. PATIENT SUMMARY: If bladder cancer recurs after bacillus Calmette-Guerin treatment, there are many factors that determine the further clinical outcome. Although low-grade recurrent tumors confer a less aggressive course, disease progression can still occur, and hence continued vigilance is important.

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer.

Sarcomatoid urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs show a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses reveal that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.

Whole-Organ Genomic Characterization of Mucosal Field Effects Initiating Bladder Carcinogenesis.

We used whole-organ mapping to study the locoregional molecular changes in a human bladder containing multifocal cancer. Widespread DNA methylation changes were identified in the entire mucosa, representing the initial field effect. The field effect was associated with subclonal low-allele frequency mutations and a small number of DNA copy alterations. A founder mutation in the RNA splicing gene, ACIN1, was identified in normal mucosa and expanded clonally with an additional 21 mutations in progression to carcinoma. The patterns of mutations and copy number changes in carcinoma in situ and foci of carcinoma were almost identical, confirming their clonal origins. The pathways affected by the DNA copy alterations and mutations, including the Kras pathway, were preceded by the field changes in DNA methylation, suggesting that they reinforced mechanisms that had already been initiated by methylation. The results demonstrate that DNA methylation can serve as the initiator of bladder carcinogenesis.

Epidemiology, prevention, screening, diagnosis, and evaluation: update of the ICUD-SIU joint consultation on bladder cancer.

PURPOSE: To update current recommendations on prevention, screening, diagnosis, and evaluation of bladder cancer (BC) based on a thorough assessment of the most recent literature on these topics. METHODS: A non-systematic review was performed, including articles until June 2017. A variety of original articles, reviews, and editorials were selected according to their epidemiologic, demographic, and clinical relevance. Assessment of the level of evidence and grade of recommendations was performed according to the International Consultation on Urological Diseases grading system. RESULTS: BC is the ninth most common cancer worldwide with 430,000 new cases in 2012. Currently, approximately 165,000 people die from the disease annually. Absolute incidence and prevalence of BC are expected to rise significantly during the next decades because of population ageing. Tobacco smoking is still the main risk factor, accounting for about 50% of cases. Smoking cessation is, therefore, the most relevant recommendation in terms of prevention, as the risk of developing BC drops almost 40% within 5 years of cessation. BC screening is not recommended for the general population. BC diagnosis remains mainly based on cystoscopy, but development of new endoscopic and imaging technologies may rapidly change the diagnosis algorithm. The same applies for local, regional, and distant staging modalities. CONCLUSIONS: A thorough understanding of epidemiology, risk factors, early detection strategies, diagnosis, and evaluation is essential for correct, evidence-based management of BC patients. Recent developments in endoscopic techniques and imaging raise the hope for providing better risk-adopted approaches and thereby improving clinical outcomes.

Prognostic Implication of the United States Food and Drug Administration-defined BCG-unresponsive Disease.

The category "BCG-unresponsive disease", formulated by experts at the request of the United States Food and Drug Administration, denotes a group of patients with recurrent non-muscle-invasive bladder cancer for whom continued BCG treatment is unlikely to provide benefit. Although quickly adopted for trial design, many of the nuances within the definition lack validation. In this study, we evaluated the prognostic value of BCG unresponsive designation (i.e. recurrence after induction plus at least 1 maintenance course of BCG) by comparing the oncologic outcomes of these patients with those recurring after induction BCG alone. We confirm that appropriately defined, BCG-unresponsive patients are more likely to require salvage radical cystectomy (54.5% vs 17.9%, p=0.002). Moreover, those opting for second-line bladder-sparing therapies are less likely to remain free of tumor recurrence (23% vs 69.2%, p=0.003). On multivariate analysis, BCG-unresponsive disease independently predicts inferior high-grade recurrence-free survival (hazard ratio [HR]: 6.25, 95% confidence interval [CI]: 2.27-16.67; p<0.001) and cystectomy-free survival (HR: 3.85, 95% CI: 1.49-10.0; p=0.006). Our data confirm the prognostic implication of the BCG unresponsive definition i.e. recurrence of high grade disease after induction and one course of maintenance BCG, and support its use in counseling and risk stratification of patients with tumor recurrence after BCG. Patient summary: Patients who have BCG-unresponsive disease, that is, high-grade non-muscle-invasive bladder cancer recurring after BCG induction and maintenance, have a low likelihood to respond to further BCG treatment and should consider radical cystectomy or clinical trial enrollment.

Is folic acid safe for non-muscle-invasive bladder cancer patients? An evidence-based cohort study.

Background: Patients with cancer are highly concerned about food choices and dietary supplements that may affect their treatment outcomes. Excess folic acid (synthetic folate) from supplements or fortification can lead to accumulation of unmetabolized folic acid in the systemic circulation and urine and may promote cancer growth, especially among those with neoplastic alterations. Objective: We investigated the prospective association between synthetic compared with natural folate intake and clinical outcomes in non-muscle-invasive bladder cancer (NMIBC), which is a highly recurrent disease. Design: In a cohort of 619 NMIBC patients, folate intake at diagnosis was assessed with a previously validated food-frequency questionnaire and categorized according to tertiles. After a median follow-up of 5.2 y, 303 tumor recurrence and 108 progression events were documented from medical record review. Multivariable Cox proportional hazards and logistic models were used to estimate adjusted HRs and ORs with 95% CIs. Results: Synthetic folic acid intake was positively associated with a risk of recurrence among NMIBC patients (medium compared with low intake-HR: 1.72; 95% CI: 1.20, 2.48; P = 0.003; high compared with low intake-HR: 1.80; 95% CI: 1.14, 2.84; P = 0.01). Patients with a higher folic acid intake were more likely to have multifocal tumors at diagnosis (medium or high compared with low-OR: 2.08; 95% CI: 1.08, 4.02; P = 0.03). In contrast, natural folate intake tended to be inversely associated with the risk of progression (medium or high compared with low-HR: 0.68; 95% CI: 0.44, 1.04; P = 0.08). Conclusions: A high intake of synthetic folic acid, in contrast to the natural forms, is associated with an increased risk of recurrence in NMIBC and multifocal tumors at diagnosis, which suggests that folic acid may be unsafe for NMIBC patients. These findings provide some evidence for nutritional consultation with regard to folate intake among NMIBC patients.

Clinical risk stratification in patients with surgically resectable micropapillary bladder cancer.

OBJECTIVE: To analyse survival in patients with clinically localised, surgically resectable micropapillary bladder cancer (MPBC) undergoing radical cystectomy (RC) with and without neoadjuvant chemotherapy (NAC) and develop risk strata based on outcome data. PATIENTS AND METHODS: A review of our database identified 103 patients with surgically resectable (≤cT4acN0 cM0) MPBC who underwent RC. Survival estimates were calculated using Kaplan-Meier method and compared using log-rank tests. Classification and regression tree (CART) analysis was performed to identify risk groups for survival. RESULTS: For the entire cohort, estimated 5-year overall survival and disease-specific survival (DSS) rates were 52% and 58%, respectively. CART analysis identified three risk subgroups: low-risk: cT1, no hydronephrosis; high-risk: ≥cT2, no hydronephrosis; and highest-risk: cTany with tumour-associated hydronephrosis. The 5-year DSS for the low-, high-, and highest-risk groups were 92%, 51%, and 17%, respectively (P < 0.001). Patients down-staged at RC

Microhematuria assessment an IBCN consensus-Based upon a critical review of current guidelines.

RATIONALE: Assessment of patients with asymptomatic microhematuria (aMh) has been a challenge to urologists for decades. The aMh is a condition with a high prevalence in the general population and also an established diagnostic indicator of bladder cancer. Acknowledging aMh needs to be assessed within a complex context, multiple guidelines have been developed to identify individuals at high risk of being diagnosed with bladder cancer. MATERIAL & METHODS: This structured review and consensus of the International Bladder Cancer Network (IBCN) identified and examined 9 major guidelines. These recommendations are partly based on findings from a long-term study on the effects of home dipstick testing, but also on the assumption that early detection of malignancy might be beneficial. RESULTS: Despite similar designs, these guidelines differ in a variety of parameters including definition of aMh, rating of risks, use of imaging modalities, and the role of urine cytology. In addition, recommendations for further follow-up after negative initial assessment are controversial. In this review, different aspects for aMh assessment are analyzed based upon the evidence currently available. DISCUSSION: We question whether adherence to the complicated algorithms as recommended by most guidelines is practical for routine use. Based upon a consensus, the authors postulate a need for better tools. New concepts for risk assessment permitting improved risk stratification and prepone cystoscopy before refined imaging procedures (computed tomography scan and magnetic resonance imaging) are suggested.

Innovation in Bladder Cancer Immunotherapy.

Bladder cancer is understudied despite its high prevalence and its remarkable response to immunotherapy. Indeed, funding for studies to explore mechanisms of tumor immunity and novel new therapeutics is disproportionately lower for bladder cancer in comparison with malignancies of the breast, prostate, or lung. However, the recent successes of checkpoint blockade therapy suggest that new therapeutic strategies are on the horizon for bladder cancer. Here, we give a perspective into the evolution of bladder cancer therapy, focusing on strategies to treat high-risk nonmuscle invasive disease, followed by a discussion of recent advances in the treatment of muscle invasive bladder cancer and their potential applicability to lower stage disease. Finally, we explore immunotherapeutic strategies, which have been demonstrated to be successful in the treatment of other malignancies, for their potential to treat and cure patients with nonmuscle and muscle invasive bladder cancer.

Phase 1b Trial to Evaluate Tissue Response to a Second Dose of Intravesical Recombinant Adenoviral Interferon α2b Formulated in Syn3 for Failures of Bacillus Calmette-Guerin (BCG) Therapy in Nonmuscle Invasive Bladder Cancer.

BACKGROUND: A phase 1b trial was conducted to evaluate the duration of interferon-alpha (IFNα) production after intravesical administration of recombinant adenovirus-mediated interferon α2b (Ad-IFN) formulated with the excipient Syn3. The primary aim was to determine whether a second instillation 3 days after initial treatment produced prolonged urinary IFN production. METHODS: The study enrolled seven patients who experienced recurrent non-muscle invasive bladder cancer after bacillus Calmette-Guerin therapy. Each treatment consisted of intravesical instillation of SCH721015 (Syn3) and Ad-IFN at a concentration of 3 × 1011 particles/mL to a total volume of 75 mL given on days 1 and 4. The patients were followed for 12 weeks, during which the magnitude and duration of gene transfer were determined by urine INFα levels. Drug efficacy was determined by cystoscopy and biopsy, and patients who had no recurrence at 12 weeks were eligible for a second course of treatment. RESULTS: Seven patients were treated with an initial course (instillation on days 1 and 4). Two of the patients had a complete response at 12 weeks and received a second course of treatment. One patient remained without evidence of recurrence after a second course (total 24 weeks). One patient experienced a non-treatment-associated adverse event. Despite a transient rise in IFNα levels, sustained production was not demonstrated. CONCLUSION: Previously, Ad-IFNα intravesical therapy has shown promising drug efficacy. A prior phase 1 trial with a single instillation compared similarly with the current study, suggesting that a second instillation is not necessary to achieve sufficient urinary IFNα levels.

The Impact of Blue Light Cystoscopy with Hexaminolevulinate (HAL) on Progression of Bladder Cancer - A New Analysis.

Background: The International Bladder Cancer Group (IBCG) recently proposed a new definition of disease progression in non-muscle invasive bladder cancer (NMIBC), including change in T-stage, change to T2 or higher or change from low to high grade. Objective: To establish whether blue light cystoscopy with hexaminolevulinate (HAL) impacts the rate of progression and time to progression using the revised definition. Methods: An earlier long-term follow-up of a controlled Phase III study reported outcomes following blue light cystoscopy with HAL (255 patients) or white light (WL) cystoscopy (261 patients) in NMIBC patients. The data was re-analysed according to the new definition. Results: In the original analysis, after 4.5 years (median), eight HAL and 16 WL patients were deemed to have progressed (transition from NMIBC to muscle invasive bladder cancer, (T2-4)). According to the new definition, additional patients in both groups were found to have progressed: 31 (12.2%) HAL vs 46 (17.6%) WL (p = 0.085) with four (1.6%) HAL and 11 (4.2%) WL patients progressing from Ta to CIS. Time to progression was longer in the HAL group (p = 0.05). Conclusions: Applying the new IBCG definition there was a trend towards a lower rate of progression in HAL patients, particularly in those progressing from Ta to CIS. Time to progression was significantly prolonged. This suggests that patients should receive blue light cystoscopy with HAL rather than WL at resection. Adoption of the new definition could allow more patients at risk of progression to be treated appropriately earlier.