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Currently, there is limited data on the comparative effectiveness of radiation therapy (RT) vs. chemoradiation (CHT) for high-grade T1 (HGT1) non-muscle invasive bladder cancer (non-MIBC). Patients diagnosed with HGT1 non-MIBC, and treated with transurethral resection of bladder tumor followed by either treatment with RT alone or CRT, were identified in the National Cancer Database. A total of 259 patients with HGT1 UC were treated with: (i) RT alone (n = 123) or (ii) CRT (n = 136). Propensity-weighted MVA showed that combined modality treatment with CRT was associated with improved OS relative to radiation alone (Hazard Ratio (HR): 0.62, 95% Confidence Interval (95% CI): 0.44-0.88, P = .007). Background: Non-muscle invasive bladder cancer (non-MIBC) that is high-grade and confined to the lamina propria (HGT1) often has an aggressive clinical course. Currently, there is limited data on the comparative effectiveness of RT vs. CRT for HGT1 non-MIBC. We hypothesized that CRT would be associated with improved overall survival (OS) vs. RT in HGT1 bladder cancer. Methods: Patients diagnosed with HGT1 non-MIBC, and treated with transurethral resection of bladder tumor followed by either treatment with RT alone or CRT, were identified in the National Cancer Database. Inverse probability of treatment weighting (IPTW) was employed and weight-adjusted multivariable analysis (MVA) using Cox regression modeling was used to compare overall survival (OS) hazard ratios. OS was the primary endpoint, and was estimated using the Kaplan-Meier method and log-rank tests. Results: A total of 259 patients with HGT1 UC were treated with: (i) RT alone (n = 123) or (ii) CRT (n = 136). Propensity-weighted MVA showed that combined modality treatment with CRT was associated with improved OS relative to radiation alone (Hazard Ratio [HR]: 0.62, 95% Confidence Interval (95% CI): 0.44-0.88, P = .007). Four-year OS for the CRT vs. RT alone was 36% and 19%, respectively (log-rank P < .008). Conclusion: For patients with HGT1 bladder cancer, concurrent CRT was associated with improved OS compared with radiation alone in a retrospective cohort. These results are hypothesisgenerating. The NRG is currently developing a phase II randomized clinical trial comparing CRT to other novel, bladder preservation strategies. [ABSTRACT FROM AUTHOR]

The benefit of adding neoadjuvant chemotherapy to bladder-sparing chemoradiation for muscle-invasive bladder cancer remains unclear. This retrospective, large database study of 2566 patients found no survival benefit with the addition of neoadjuvant chemotherapy to definitive chemoradiation. These results do not support the routine addition of neoadjuvant chemotherapy to definitive chemoradiation for bladder cancer, which should be investigated under prospective clinical trials. Background: Bladder-sparing chemoradiation therapy is a definitive first-line treatment option for muscle-invasive bladder cancer. Randomized trials have demonstrated that the addition of neoadjuvant chemotherapy to radical cystectomy or radiation monotherapy results in a survival benefit. Whether neoadjuvant chemotherapy improves outcomes when used with definitive chemoradiation is unknown. Patients and Methods: We identified 2566 patients in the National Cancer Data Base with cT2-4N0M0 urothelial cell carcinoma of the bladder treated with definitive intent concurrent chemoradiation from 2004 to 2015. The exposure of interest was receipt of neoadjuvant chemotherapy versus those without neoadjuvant chemotherapy. The primary outcome was overall survival defined from the time of diagnosis. Kaplan-Meier and multivariable Cox proportional hazard analyses were used to compare survival between groups. Sensitivity analyses tested (1) an interaction term for clinical T stage and (2) defining survival from start of radiation (as opposed to time of diagnosis) to address potential leading time bias. Results: We identified 462 patients treated with neoadjuvant chemotherapy followed by chemoradiation and 2104 patients treated with chemoradiation alone. With a median follow-up of 6.2 years, we found no difference in survival between groups: 5-year or 10-year overall survival of 30.6% (95% confidence interval [CI], 28.4%-32.9%) in the neoadjuvant group versus 31.8% (95% CI, 27.0%-36.8%) in the standard chemoradiation therapy group and 13.3% (95% CI, 11.2%-15.5%) in the neoadjuvant group versus 13.0% (95% CI, 8.4%-18.7%) in the standard chemoradiation therapy group, respectively (log-rank P = .19). On multivariable analysis we found no association between receipt of neoadjuvant chemotherapy and overall survival (hazard ratio, 1.01; 95% CI, 0.88-1.15; P = .921). The sensitivity analyses did not identify any differential effect by clinical T stage nor by defining survival from start of radiation. Conclusion: These results do not support the routine addition of neoadjuvant chemotherapy to definitive chemoradiation for bladder cancer, and optimizing the chemotherapy sequencing and regimens for bladder-preserving approaches to muscle invasive bladder cancer should continue to be studied under prospective clinical trials. [ABSTRACT FROM AUTHOR]

Radiation therapy plays a crucial role for the management of genitourinary malignancies, with technological advancements that have led to improvements in outcomes and decrease in treatment toxicities. However, better risk-stratification and identification of patients for appropriate treatments is necessary. Recent advancements in imaging and novel genomic techniques can provide additional individualized tumor and patient information to further inform and guide treatment decisions for genitourinary cancer patients. In addition, the development and use of targeted molecular therapies based on tumor biology can result in individualized treatment recommendations. In this review, we discuss the advances in precision oncology techniques along with current applications for personalized genitourinary cancer management. We also highlight the opportunities and challenges when applying precision medicine principles to the field of radiation oncology. The identification, development and validation of biomarkers has the potential to personalize radiation therapy for genitourinary malignancies so that we may improve treatment outcomes, decrease radiation-specific toxicities, and lead to better long-term quality of life for GU cancer survivors. [ABSTRACT FROM AUTHOR]

There is an underutilization of potentially curative treatments for patients with muscle-invasive bladder cancer. Contemporary trimodality bladder-preservation therapy - which includes a maximally safe transurethral resection of the bladder tumor followed by concurrent chemoradiation and close cystoscopic surveillance with salvage cystectomy reserved for invasive tumor recurrence - can help fulfill this unmet need. Over the past few decades, cumulative published data from prospective clinical trials and large institutional series have established trimodality therapy (TMT) for select patients as a safe and effective alternative to upfront cystectomy. Indeed, TMT is now supported as an accepted option for muscle-invasive bladder cancer patients by numerous clinical guidelines. Following TMT, the vast majority of long-term survivors maintain their native bladders, which tend to function well with relatively low rates of long-term toxicity and good long-term quality of life. There is the potential to further improve outcomes by optimizing systemic therapy integration and by validating predictive biomarkers for improved patient and treatment selection. TMT offers a unique opportunity for urologic surgeons, radiation oncologists and medical oncologists to work hand-in-hand in a multidisciplinary effort to deliver such therapy optimally, to support its research, to promote informed decision-making and ultimately to preserve the autonomy of patients with bladder cancer. The third annual meeting of the Johns Hopkins Greenberg Bladder Cancer Institute/American Urological Association Translational Research Collaboration allowed bladder cancer experts to meet and advance this mission. [ABSTRACT FROM AUTHOR]

Limited data are available on the effect of treatment delays for initiating chemoradiotherapy (CRT) for muscleinvasive bladder cancer. We used the National Cancer Database and found that 1387 patients had started CRT < 90 days after transurethral resection of bladder tumor (TURBT) compared with 197 with delayed CRT (≥ 90 days after TURBT). On multivariable analysis, delayed CRT was not associated with differences in overall survival. These results suggest that short, strategic treatment delays during a pandemic can be considered based on clinician judgment. Introduction: During the coronavirus disease 2019 (COVID-19) pandemic, providers and patients must engage in shared decision making to ensure that the benefit of early intervention for muscle-invasive bladder cancer exceeds the risk of contracting COVID-19 in the clinical setting. It is unknown whether treatment delays for patients eligible for curative chemoradiation (CRT) compromise long-term outcomes. Patients and Methods: We used the National Cancer Data Base to investigate whether there is an association between a ≥ 90-day delay from transurethral resection of bladder tumor (TURBT) in initiating CRT and overall survival. We included patients with cT2-4N0M0 muscle-invasive bladder cancer from 2004 to 2015 who underwent TURBT and curative-intent concurrent CRT. Patients were grouped on the basis of timing of CRT: ≤ 89 days after TURBT (earlier) vs. ≥ 90 and < 180 days after TURBT (delayed). Results: A total of 1387 (87.5%) received earlier CRT (median, 45 days after TURBT; interquartile range, 34-59 days), and 197 (12.5%) received delayed CRT (median, 111 days after TURBT; interquartile range, 98-130 days). Median overall survival was 29.0 months (95% CI, 26.0-32.0) versus 27.0 months (95%CI, 19.75-34.24) for earlier. [ABSTRACT FROM AUTHOR]

Bladder-sparing trimodality therapy (TMT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), and biomarkers to inform therapy selection are needed. To evaluate the prognostic value of immune and stromal signatures in MIBC treated with TMT. We used a clinical-grade platform to perform transcriptome-wide gene expression profiling of primary tumors from 136 MIBC patients treated with TMT at a single institution. We observed 60 overall survival events at 5 yr, and median follow-up time for patients without an event was 5.0 yr (interquartile range 3.1, 5.0). Expression data from another cohort of 223 MIBC patients treated with neoadjuvant chemotherapy (NAC) and RC were also analyzed. Molecular subtype, immune, and stromal signatures were evaluated for associations with disease-specific survival (DSS) and overall survival (OS) in TMT patients, and in patients treated with NAC and RC. Gene expression profiling of TMT cases identified luminal (N = 40), luminal-infiltrated (N = 26), basal (N = 54), and claudin-low (N = 16) subtypes. Signatures of T-cell activation and interferon gamma signaling were associated with improved DSS in the TMT cohort (hazard ratio 0.30 [0.14–0.65], p = 0.002 for T cells), but not in the NAC and RC cohort. Conversely, a stromal signature was associated with worse DSS in the NAC and RC cohort (p = 0.006), but not in the TMT cohort. This study is limited by its retrospective nature. Higher immune infiltration in MIBC is associated with improved DSS after TMT, whereas higher stromal infiltration is associated with shorter DSS after NAC and RC. Additional studies should be conducted to determine whether gene expression profiling can predict treatment response. We used gene expression profiling to study the association between tumor microenvironment and outcomes following bladder preservation therapy for invasive bladder cancer. We found that outcomes varied with immune and stromal signatures within the tumor. We conclude that gene expression profiling has potential to guide treatment decisions in bladder cancer. Gene expression profiling of muscle-invasive bladder cancer reveals that immune infiltration is associated with improved disease-specific survival after bladder-sparing trimodality therapy, but not after radical cystectomy. Conversely, stromal infiltration is associated with worse outcomes after cystectomy, but not after trimodality therapy. [ABSTRACT FROM AUTHOR]

Purpose: Trimodality therapy with maximal transurethral resection of bladder tumor and definitive chemoradiation reserving cystectomy for salvage of local recurrence is an accepted treatment alternative to upfront cystectomy for selected patients with muscle-invasive bladder cancer. There is a need for molecular biomarkers to predict which patients will respond to bladder preservation therapy.Methods and Materials: We sought to identify biomarkers with the ability to predict response to chemoradiation and survival after selective bladder preservation therapy in a cohort of 40 patients using a microRNA profiling approach. In vitro experiments were performed using transitional cell carcinoma lines CRL1749, HTB5, and HTB4.Results: We identified a panel of microRNAs associated with overall survival in our bladder preservation cohort and in the TCGA cohort. We also identified several microRNAs, including miR-23a and miR-27a, microRNAs of the miR-23a cluster, to be suggestively associated with complete response to chemoradiation therapy. The microRNAs were significantly associated with overall survival in The Cancer Genome Atlas cohort. In vitro studies suggest that the functional roles of miR-23a and miR-27a involve targeting the SFRP1 protein, a negative regulator of the Wnt signaling pathway. The upregulation of β-catenin in the Wnt signaling pathway mediated proliferation, migration, invasion, and sensitivity to radiation and cisplatin treatment in bladder cancer cells.Conclusions: Our results indicate that miR-23a and miR-27a act as oncomirs, and once independently validated, they may help appropriately triage selected bladder cancer patients to individualize treatment. [ABSTRACT FROM AUTHOR]

Purpose: To provide a comprehensive overview and update of the Joint Société Internationale d'Urologie-International Consultation on Urological Diseases (SIU-ICUD) Consultation on Bladder Cancer for muscle-invasive presumably node-negative bladder cancer (MIBC).Methods: Contemporary literature was analyzed for the latest evidence in treatment options, outcomes, including radical surgery, neoadjuvant and adjuvant treatment modalities, and bladder-sparing approaches. An international multi-disciplinary expert panel evaluated and graded the data according to guidelines from the Oxford Centre for Evidence-Based Medicine.Results: Radical cystectomy (RC) is the standard of care for MIBC patients considered to be surgical candidates. While associated with substantial morbidity and mortality, this has been mitigated with improved technique, minimally invasive technology, and better perioperative care pathways (e.g., enhanced recovery after surgery). Neoadjuvant (NA) cisplatin-based combination chemotherapy improves overall survival and should be offered to eligible ≥ cT2N0 patients. Adjuvant (Adj) cisplatin-based combination chemotherapy may be considered, particularly for pT3-4 and/or pN+ disease without prior NA chemotherapy. Trimodal bladder-preserving treatment via maximum transurethral resection of bladder tumor followed by concurrent chemoradiation is safe and, when combined with early salvage RC for recurrence, offers long-term survival rates in selected patients comparable to RC. Immunotherapy is still experimental and is given either alone or in combination with chemotherapy and/or radiation.Conclusion: A multi-disciplinary approach is paramount to achieving optimal outcomes for MIBC patients, irrespective of their age, performance and nutritional status, fitness/frailty, renal and other organ function, or disease severity. [ABSTRACT FROM AUTHOR]

Intravenous anti–PD-L1 durvalumab therapy can safely be combined with intravesical bacillus Calmette-Guerin (BCG) treatments or a short-course of bladder-focused external beam radiation therapy (6 Gy × 3) in BCG-unresponsive non–muscle-invasive bladder cancer patients. Encouraging preliminary efficacy requires validation. Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) patients. To evaluate the safety and preliminary efficacy of anti–PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT). A multicenter phase 1 trial was conducted at community and academic sites. Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only). Post-treatment cystoscopy and urine cytology were performed at 3 and 6 –mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates. Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients. D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches. Durvalumab combination therapy can be safely administered to non–muscle-invasive bladder cancer patients with the goal of increasing durable response rates. [ABSTRACT FROM AUTHOR]

The 10th Annual Bladder Cancer Think Tank was hosted by the Bladder Cancer Advocacy Network and brought together a multidisciplinary group of clinicians, researchers, representatives and Industry to advance bladder cancer research efforts. Think Tank expert panels, group discussions, and networking opportunities helped generate ideas and strengthen collaborations between researchers and physicians across disciplines and between institutions. Interactive panel discussions addressed a variety of timely issues: 1) data sharing, privacy and social media; 2) improving patient navigation through therapy; 3) promising developments in immunotherapy; 4) and moving bladder cancer research from bench to bedside. Lastly, early career researchers presented their bladder cancer studies and had opportunities to network with leading experts.

Abstract: Context: New guidelines of the International Consultation on Urological Diseases for the treatment of muscle-invasive bladder cancer (MIBC) have recently been published. Objective: To provide a comprehensive overview of the current role of radical cystectomy (RC) in MIBC. Evidence acquisition: A detailed Medline analysis was performed for original articles addressing the role of RC with regard to indication, timing, surgical extent, perioperative morbidity, oncologic outcome, and follow-up. The analysis also included radiation-based bladder-preserving strategies. Evidence synthesis: The major findings are presented in an evidence-based fashion and are based on large retrospective unicenter and multicenter series with some prospective data. Conclusions: Open RC is the standard treatment for locoregional control of MIBC. Delay of RC is associated with reduced cancer-specific survival. In males, standard RC includes the removal of the bladder, prostate, seminal vesicles, and distal ureters; in females, RC includes an anterior pelvic exenteration including the bladder, entire urethra and adjacent vagina, uterus, and distal ureters. A procedure sparing the urethra and the urethra-supplying autonomous nerves can be performed in case of a planned orthotopic neobladder. Further technical variations (ie, seminal-sparing or vaginal-sparing techniques) aimed at improving functional outcomes must be weighed against the risk of a positive margin. Laparoscopic surgery is promising, but long-term data are required prior to accepting it as an option equivalent to the open procedure. Lymphadenectomy should remove all lymphatic tissue around the common iliac, external iliac, internal iliac, and obturator region bilaterally. Complications after RC should be reported according to the modified Clavien grading system. In selected patients with MIBC, bladder-preserving therapy with cystectomy reserved for tumor recurrence represents a safe and effective alternative to immediate RC. [Copyright &y& Elsevier]

Abstract: Background: Whether organ-conserving treatment by combined-modality therapy (CMT) achieves comparable long-term survival to radical cystectomy (RC) for muscle-invasive bladder cancer (BCa) is largely unknown. Objective: Report long-term outcomes of patients with muscle-invasive BCa treated by CMT. Design, setting, and participants: We conducted an analysis of successive prospective protocols at the Massachusetts General Hospital (MGH) treating 348 patients with cT2–4a disease between 1986 and 2006. Median follow-up for surviving patients was 7.7 yr. Interventions: Patients underwent concurrent cisplatin-based chemotherapy and radiation therapy (RT) after maximal transurethral resection of bladder tumor (TURBT) plus neoadjuvant or adjuvant chemotherapy. Repeat biopsy was performed after 40Gy, with initial tumor response guiding subsequent therapy. Those patients showing complete response (CR) received boost chemotherapy and RT. One hundred two patients (29%) underwent RC—60 for less than CR and 42 for recurrent invasive tumors. Measurements: Disease-specific survival (DSS) and overall survival (OS) were evaluated using the Kaplan-Meier method. Results and limitations: Seventy-two percent of patients (78% with stage T2) had CR to induction therapy. Five-, 10-, and 15-yr DSS rates were 64%, 59%, and 57% (T2=74%, 67%, and 63%; T3–4=53%, 49%, and 49%), respectively. Five-, 10-, and 15-yr OS rates were 52%, 35%, and 22% (T2: 61%, 43%, and 28%; T3–4=41%, 27%, and 16%), respectively. Among patients showing CR, 10-yr rates of noninvasive, invasive, pelvic, and distant recurrences were 29%, 16%, 11%, and 32%, respectively. Among patients undergoing visibly complete TURBT, only 22% required cystectomy (vs 42% with incomplete TURBT; log-rank p <0.001). In multivariate analyses, clinical T-stage and CR were significantly associated with improved DSS and OS. Use of neoadjuvant chemotherapy did not improve outcomes. No patient required cystectomy for treatment-related toxicity. Conclusions: CMT achieves a CR and preserves the native bladder in >70% of patients while offering long-term survival rates comparable to contemporary cystectomy series. These results support modern bladder-sparing therapy as a proven alternative for selected patients. [Copyright &y& Elsevier]

The objective of the European Association of Urology guidelines is to provide practical evidence-based recommendations and consensus statements on the clinical management of urological conditions, with a focus on diagnosis and treatment. In this context the summary of the 2023 guideline on muscle-invasive and metastatic bladder cancer provides updated information on the diagnosis and treatment of this disease for incorporation in clinical practice. We present an overview of the updated 2023 European Association of Urology (EAU) guidelines for muscle-invasive and metastatic bladder cancer (MMIBC). To provide practical evidence-based recommendations and consensus statements on the clinical management of MMIBC with a focus on diagnosis and treatment. A broad and comprehensive scoping exercise covering all areas of the MMIBC guidelines has been performed annually since 2017. Searches cover the Medline, EMBASE, and Cochrane Libraries databases for yearly guideline updates. A level of evidence and strength of recommendation are assigned. The evidence cutoff date for the 2023 MIBC guidelines was May 4, 2022. Patients should be counselled regarding risk factors for bladder cancer. Pathologists should describe tumour and lymph nodes in detail, including the presence of histological subtypes. The importance of the presence or absence of urothelial carcinoma (UC) in the prostatic urethra is emphasised. Magnetic resonance imaging (MRI) of the bladder is superior to computed tomography (CT) for disease staging, specifically in differentiating T1 from T2 disease, and may lead to a change in treatment approach in patients at high risk of an invasive tumour. Imaging of the upper urinary tract, lymph nodes, and distant metastasis is performed with CT or MRI; the additional value of flurodeoxyglucose positron emission tomography/CT still needs to be determined. Frail and comorbid patients should be evaluated by a multidisciplinary team. Postoperative histology remains the most important prognostic variable, while circulating tumour DNA appears to be an interesting predictive marker. Neoadjuvant systemic therapy remains cisplatin-based. In motivated and selected women and men, sexual organ–preserving cystectomy results in better functional outcomes without compromising oncological outcomes. Robotic and open cystectomy have comparable outcomes and should be combined with (extended) lymph node dissection. The diversion type is an individual choice after taking patient and tumour characteristics into account. Radical cystectomy remains a highly complex procedure with considerable morbidity and risk of mortality, although lower rates are observed for higher hospital volumes (>20 cases/yr). With proper patient selection, trimodal therapy (chemoradiation) has comparable outcomes to radical cystectomy. Adjuvant chemotherapy after surgery improves disease-specific survival and overall survival (OS) in patients with high-risk disease who did not receive neoadjuvant treatment, and is strongly recommended. There is a weak recommendation for adjuvant nivolumab, as OS data are not yet available. Health-related quality of life should be assessed using validated questionnaires at baseline and after treatment. Surveillance is needed to monitor for recurrent cancer and functional outcomes. Recurrences detected on follow-up seem to have better prognosis than symptomatic recurrences. This summary of the 2023 EAU guidelines provides updated information on the diagnosis and treatment of MMIBC for incorporation into clinical practice. The European Association of Urology guidelines panel on muscle-invasive and metastatic bladder cancer has released an updated version of the guideline containing information on diagnosis and treatment of this disease. Recommendations are based on studies published up to May 4, 2022. Surgical removal of the bladder and bladder preservation are discussed, as well as updates on the use of chemotherapy and immunotherapy in localised and metastatic disease. [ABSTRACT FROM AUTHOR]

There is a lack of accepted consensus on what should constitute appropriate quality-of-care indicators for bladder cancer. To evaluate the optimal management of bladder cancer and propose quality indicators (QIs). A systematic review was performed to identify literature on current optimal management and potential quality indicators for both non–muscle-invasive (NMIBC) and muscle-invasive (MIBC) bladder cancer. A panel of experts was convened to select a recommended list of QIs. For NMIBC, preoperative QIs include tobacco cessation counselling and appropriate imaging before initial transurethral resection of bladder tumour (TURBT). Intraoperative QIs include administration of antibiotics, proper safe conduct of TURBT using a checklist, and performing restaging TURBT with biopsy of the prostatic urethra in appropriate cases. Postoperative QIs include appropriate receipt of perioperative adjuvant therapy, risk-stratified surveillance, and appropriate decision to change therapy when indicated (eg, bacillus Calmette-Guerin [BCG] unresponsive). For MIBC, preoperative QIs include multidisciplinary care, selection for candidates for continent urinary diversion, receipt of neoadjuvant cisplatin-based chemotherapy, time to commencing radical treatment, consideration of trimodal therapy as a bladder-sparing alternative in select patients, preoperative counselling with stoma marking, surgical volume of radical cystectomy, and enhanced recovery after surgery protocols. Intraoperative QIs include adequacy of lymphadenectomy, blood loss, and operative time. Postoperative QIs include prospective standardised monitoring of morbidity and mortality, negative surgical margins for pT2 disease, appropriate surveillance after primary treatment, and adjuvant cisplatin-based chemotherapy in appropriate cases. Participation in clinical trials was highlighted as an important component indicating high quality of care. We propose a set of QIs for both NMIBC and MIBC based on established clinical guidelines and the available literature. Although there is currently a lack of level 1 evidence for the benefit of implementing these QIs, we believe that the measurement of these QIs could aid in the improvement and benchmarking of optimal care for bladder cancer. After a systematic review of existing guidelines and literature, a panel of experts has recommended a set of quality indicators that can help providers and patients measure and strive towards optimal outcomes for bladder cancer care. The measurement of quality indicators in bladder cancer services based on established clinical guidelines and available literature can help improve and benchmark optimal care for bladder cancer patients. [ABSTRACT FROM AUTHOR]

Ataxia-telangiectasia mutated (ATM) plays a central role in the cellular response to DNA damage and ATM alterations are common in several tumor types including bladder cancer. However, the specific impact of ATM alterations on therapy response in bladder cancer is uncertain. Here, we combine preclinical modeling and clinical analyses to comprehensively define the impact of ATM alterations on bladder cancer. We show that ATM loss is sufficient to increase sensitivity to DNA-damaging agents including cisplatin and radiation. Furthermore, ATM loss drives sensitivity to DNA repair-targeted agents including poly(ADP-ribose) polymerase (PARP) and Ataxia telangiectasia and Rad3 related (ATR) inhibitors. ATM loss alters the immune microenvironment and improves anti-PD1 response in preclinical bladder models but is not associated with improved anti-PD1/PD-L1 response in clinical cohorts. Last, we show that ATM expression by immunohistochemistry is strongly correlated with response to chemoradiotherapy. Together, these data define a potential role for ATM as a predictive biomarker in bladder cancer. [ABSTRACT FROM AUTHOR]

Patients with treatment-naïve metastatic urothelial carcinoma are grouped according to platinum eligibility based on clear definitions. In general, first-line treatment consists of platinum-based chemotherapy in which cisplatin is to be preferred to carboplatin. Patients who are cisplatin ineligible but carboplatin eligible should receive carboplatin-gemcitabine combination chemotherapy. In case of positive programmed death ligand 1 (PD-L1) status, treatment with checkpoint inhibitors (atezolizumab or pembrolizumab) could be an alternative option. Patients unfit for both cisplatin and carboplatin (platinum unfit) can be considered for immunotherapy (U.S. Food and Drug Administration approved irrespective of PD-L1 status and European Medicines Agency approved only for PD-L1 positive) or can receive best supportive care. Treatment of metastatic urothelial carcinoma is currently undergoing a rapid evolution. This overview presents the updated European Association of Urology (EAU) guidelines for metastatic urothelial carcinoma. A comprehensive scoping exercise covering the topic of metastatic urothelial carcinoma is performed annually by the Guidelines Panel. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries, resulting in yearly guideline updates. Platinum-based chemotherapy is the recommended first-line standard therapy for all patients fit to receive either cisplatin or carboplatin. Patients positive for programmed death ligand 1 (PD-L1) and ineligible for cisplatin may receive immunotherapy (atezolizumab or pembrolizumab). In case of nonprogressive disease on platinum-based chemotherapy, subsequent maintenance immunotherapy (avelumab) is recommended. For patients without maintenance therapy, the recommended second-line regimen is immunotherapy (pembrolizumab). Later-line treatment has undergone recent advances: the antibody-drug conjugate enfortumab vedotin demonstrated improved overall survival and the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib appears active in case of FGFR3 alterations. This 2021 update of the EAU guideline provides detailed and contemporary information on the treatment of metastatic urothelial carcinoma for incorporation into clinical practice. In recent years, several new treatment options have been introduced for patients with metastatic urothelial cancer (including bladder cancer and cancer of the upper urinary tract and urethra). These include immunotherapy and targeted treatments. This updated guideline informs clinicians and patients about optimal tailoring of treatment of affected patients. [ABSTRACT FROM AUTHOR]

• Chemoradiation is a first-line treatment option for muscle-invasive bladder cancer. • Radiation may be administered to the bladder-only or whole pelvis. • The optimal treatment volume remains unknown. • This analysis found no difference in survival between these 2 approaches. Bladder-sparing chemoradiation therapy (CRT) is a definitive first-line treatment for muscle-invasive bladder cancer. The optimal radiotherapy target volume, either bladder-only (BO) or bladder plus pelvic lymph nodes (BPN), remains unclear. We identified 2,104 patients in the National Cancer Database with cT2-4N0M0 urothelial cell carcinoma of the bladder treated with CRT following maximal transurethral resection of bladder tumor from 2004 to 2016. The exposure of interest was BO vs. BPN treatment volume. The primary outcome was overall survival (OS), compared between groups using Kaplan-Meier and multivariable Cox proportional hazards. Sensitivity analysis tested an interaction term for clinical T stage (T2 vs. T3–4) and radiation modality (3-dimensional conformal radiotherapy vs. intensity modulated radiotherapy or proton therapy). Annual use of BO vs. BPN from 2004 to 2016 was compared using Cochran-Armitage test. A total of 578 patients were treated with BO and 1,526 patients treated with BPN CRT. There was a significant increase in BPN use from 2004 to 2016 (66.9%–76.8%, P < 0.0001). With a median follow-up of 6.2 years, there was no survival difference between groups: 5- and 10-year OS 27.4% (95% CI 23.4%–31.4%) in the BO group vs. 31.9% (95% CI 29.3%–34.6%) in the BPN group, and 13.1% (95% CI 9.7%–17.1%) in the BO group vs. 13.2% (95% CI 10.6%–16.0%) in the BPN group, respectively (log-rank P = 0.10). On multivariable analysis, there was no significant association between BPN and OS (adjusted HR 0.90, 95% CI 0.81–1.02, P = 0.09). On sensitivity analysis, we found no differential effect by T stage or radiation modality. Use of pelvic lymph node radiation has risen in the US but may not impact long-term survival outcomes for patients with node-negative muscle-invasive bladder cancer (MIBC). Optimizing radiation treatment volumes for CRT for MIBC will be important to study under prospective trials, such as the SWOG/NRG 1806. [ABSTRACT FROM AUTHOR]

Context Management of bladder cancer (BC) is primarily driven by stage, grade, and biological potential. Knowledge of each is derived using clinical, histopathological, and radiological investigations. This multimodal approach reduces the risk of error from one particular test, but may present a staging dilemma when results conflict. Multiparametric magnetic resonance imaging (mpMRI) may improve patient care through imaging of the bladder with better resolution of the tissue planes than computed tomography and without radiation exposure. Objective To define a standardized approach to imaging and reporting mpMRI for BC, by developing a VI-RADS score. Evidence acquisition We created VI-RADS (Vesical Imaging-Reporting And Data System) through consensus using existing literature. Evidence synthesis We describe standard imaging protocols and reporting criteria (including size, location, multiplicity, and morphology) for bladder mpMRI. We propose a five-point VI-RADS score, derived using T2-weighted MRI, diffusion-weighted imaging, and dynamic contrast enhancement, which suggests the risks of muscle invasion. We include sample images used to understand VI-RADS. Conclusions We hope that VI-RADS will standardize reporting, facilitate comparisons between patients, and in future years, will be tested and refined if necessary. While we do not advocate mpMRI for all patients with BC, this imaging may compliment pathology or reduce radiation-based imaging. Bladder mpMRI may be most useful in patients with non–muscle-invasive cancers, in expediting radical treatment or for determining response to bladder-sparing approaches. Patient summary Magnetic resonance imaging (MRI) scans for bladder cancer are becoming more common and may provide accurate information that helps improve patient care. Here, we describe a standardized reporting criterion for bladder MRI. This should improve communication between doctors and allow better comparisons between patients. [ABSTRACT FROM AUTHOR]

Background Trimodality bladder-sparing therapy (TMT) is an acceptable treatment for selected patients with muscle-invasive urothelial cancer. Outcomes of TMT in histologic variants remains largely unknown. Objective To compare outcomes of pure urothelial carcinoma (PUC) to variant urothelial carcinoma (VUC) after TMT. Design, setting, and participants Retrospective study of patients treated with TMT at a single cancer center from 1993 until 2013. Outcome measurements and statistical analysis Kaplan-Meier survival probabilities, and univariate and multivariable Cox regression analysis. Results and limitations Of 303 patients treated with TMT, 66 (22%) had VUC. Fifty (76%) had VUC with squamous and/or glandular differentiation and 16 (24%) had other forms. Complete response rate after induction TMT was 83% in PUC and 82% in VUC ( p = 0.9). The 5-yr and 10-yr disease-specific survival (DSS) was 75% and 67% in PUC versus 64% and 64% in VUC. The 5-yr and 10-yr overall survival (OS) was 61% and 42% in PUC versus 52% and 42% in VUC. On multivariable analysis VUC was not associated with DSS (hazard ratio: 1.3, 95% confidence interval: 0.8–2.2, p = 0.3) or OS (hazard ratio: 1.2, 95% confidence interval: 0.8–1.7, p = 0.4). Salvage cystectomy rates were similar (log-rank p = 0.3). Limitations include retrospective design and restriction to variants of urothelial cancer. Conclusions VUC responded to TMT, and there was no significant difference in complete response, OS, DSS, or salvage cystectomy rates compared with PUC. The presence of VUC should not exclude patients from TMT. Patient summary The response of histologic variants of bladder cancer to bladder-sparing chemoradiation is largely unknown. We compared the outcomes of histologic variants of urothelial cancer to pure urothelial cancer in a large series of patients from a single institution. We found that variant histology does not significantly influence outcomes. [ABSTRACT FROM AUTHOR]

Background Tri-modality therapy (TMT) is a recognized treatment strategy for selected patients with muscle-invasive bladder cancer (MIBC). Objective Report long-term outcomes of patients with MIBC treated by TMT. Design, setting, and participants Four hundred and seventy-five patients with cT2–T4a MIBC were enrolled on protocols or treated as per protocol at the Massachusetts General Hospital between 1986 and 2013. Intervention Patients underwent transurethral resection of bladder tumor followed by concurrent radiation and chemotherapy. Patients with less than a complete response (CR) to chemoradiation or with an invasive recurrence were recommended to undergo salvage radical cystectomy. Outcome measurements and statistical analysis Disease-specific survival (DSS) and overall survival (OS) were calculated using the Kaplan-Meier method. Results and limitations Median follow-up for surviving patients was 7.21 yr. Five- and 10-yr DSS rates were 66% and 59%, respectively. Five- and 10-yr OS rates were 57% and 39%, respectively. The risk of salvage cystectomy at 5 yr was 29%. In multivariate analyses, T2 disease (OS hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.44–0.75, DSS HR: 0.51, 95% CI: 0.36–0.73), CR to chemoradiation (OS HR: 0.61, 95% CI: 0.46–0.81, DSS HR: 0.49, 95% CI: 0.34–0.71), and presence of tumor-associated carcinoma in situ (OS HR: 1.56, 95% CI: 1.17–2.08, DSS HR: 1.50, 95% CI: 1.03–2.17) were significant predictors for OS and DSS. When evaluating our cohort over treatment eras, rates of CR improved from 66% to 88% and 5-yr DSS improved from 60% to 84% during the eras of 1986–1995 to 2005–2013, while the 5-yr risk of salvage radical cystectomy rate decreased from 42% to 16%. Conclusions These data demonstrate high rates of CR and bladder preservation in patients receiving TMT, and confirm DSS rates similar to modern cystectomy series. Contemporary results are particularly encouraging, and therefore TMT should be discussed and offered as a treatment option for selected patients. Patient summary Tri-modality therapy is an alternative to radical cystectomy for patients with muscle-invasive bladder cancer, and is associated with comparable long-term survival and high rates of bladder preservation. [ABSTRACT FROM AUTHOR]

Objectives The 8th Annual Bladder Cancer Think Tank (BCAN-TT) brought together a multidisciplinary group of clinicians, researchers, and patient advocates in an effort to advance bladder cancer research. Methods and Materials With the theme of “Collaborating to Move Research Forward,” the meeting included three panel presentations and seven small working groups. Results The panel presentations and interactive discussions focused on three main areas: gender disparities, sexual dysfunction, and targeting novel pathways in bladder cancer. Small working groups also met to identify projects for the upcoming year, including: (1) improving enrollment and quality of clinical trials; (2) collecting data from multiple institutions for future research; (3) evaluating patterns of care for non-muscle-invasive bladder cancer; (4) improving delivery of care for muscle-invasive disease; (5) improving quality of life for survivors; (6) addressing upper tract disease; and (7) examining the impact of health policy changes on research and treatment of bladder cancer. Conclusions The goal of the BCAN-TT is to advance the care of patients with bladder cancer and to promote collaborative research throughout the year. The meeting provided ample opportunities for collaboration among clinicians from multiple disciplines, patients and patient advocates, and industry representatives. [ABSTRACT FROM AUTHOR]

Background: The comparative effectiveness of radical cystectomy (RC) and trimodality therapy (TMT) for muscle-invasive bladder cancer remains uncertain, as no randomized data exist. A phase 3 trial (SPARE) was attempted in the UK, however, was deemed infeasible and closed.Objective: To emulate the SPARE trial using observational data.Design, Setting, and Participants: We identified patients aged 40 to 79 with cT2-3cN0cM0 urothelial carcinoma of the bladder diagnosed from 2006 to 2015 who were treated with multiagent neoadjuvant chemotherapy + RC with lymphadenectomy (RC arm) or multiagent chemotherapy + 3D conformal radiotherapy to the bladder (TMT arm) in the National Cancer Database.Outcome Measurements and Statistical Analysis: The primary outcome was overall survival (OS). We fit a flexible logistic regression model for treatment to estimate the propensity score, and then used inverse probability of treatment weights to evaluate the associations of treatment group with OS.Results and Limitations: A total of 2,048 patients were included, of whom 1,812 underwent RC and 236 underwent TMT. Median follow-up was 29.0 months. After propensity score adjustment, compared to TMT, RC was not associated with a statistically significant difference in OS (HR 0.87; 95% CI 0.64-1.19; P = 0.40). When examining heterogeneity of treatment effects, RC appeared to be associated with improved OS only for patients with cT3 disease. Similar results were observed in sensitivity analyses. Our study is limited by the retrospective design and the lack of cancer-specific survival data.Conclusions: In observational analyses designed to emulate the SPARE trial, there was no statistically significant difference in OS between RC and TMT. Heterogeneity of treatment effects suggested improved survival with RC only for cT3 disease. [ABSTRACT FROM AUTHOR]

Purpose: Selective bladder preservation by use of trimodality therapy is an established management strategy for muscle-invasive bladder cancer. Individual disease features have been associated with response to therapy, likelihood of bladder preservation, and disease-free survival. We developed prognostic nomograms to predict the complete response rate, disease-specific survival, and likelihood of remaining free of recurrent bladder cancer or cystectomy. Methods and Materials: From 1986 to 2009, 325 patients were managed with selective bladder preservation at Massachusetts General Hospital (MGH) and had complete data adequate for nomogram development. Treatment consisted of a transurethral resection of bladder tumor followed by split-course chemoradiation. Patients with a complete response at midtreatment cystoscopic assessment completed radiation, whereas those with a lesser response underwent a prompt cystectomy. Prognostic nomograms were constructed predicting complete response (CR), disease-specific survival (DSS), and bladder-intact disease-free survival (BI-DFS). BI-DFS was defined as the absence of local invasive or regional recurrence, distant metastasis, bladder cancer-related death, or radical cystectomy. Results: The final nomograms included information on clinical T stage, presence of hydronephrosis, whether a visibly complete transurethral resection of bladder tumor was performed, age, sex, and tumor grade. The predictive accuracy of these nomograms was assessed. For complete response, the area under the receiving operating characteristic curve was 0.69. The Harrell concordance index was 0.61 for both DSS and BI-DFS. Conclusions: Our nomograms allow individualized estimates of complete response, DSS, and BI-DFS. They may assist patients and clinicians making important treatment decisions. [ABSTRACT FROM AUTHOR]

Abstract: Background: Despite its lethal potential, many patients with muscle-invasive bladder cancer (MIBC) do not receive aggressive, potentially curative therapy consistent with established practice standards. Objective: To characterize the treatments received by patients with MIBC and analyze their use according to sociodemographic, clinical, pathologic, and facility measures. Design, setting, and participants: Using the National Cancer Data Base, we analyzed 28 691 patients with MIBC (stages II–IV) treated between 2004 and 2008, excluding those with cT4b tumors or distant metastases. Treatments included radical or partial cystectomy with or without chemotherapy (CT), chemoradiotherapy (CRT), radiation therapy (RT), or CT alone and observation following biopsy. Aggressive therapy (AT) was defined as radical or partial cystectomy or definitive RT/CRT (total dose ≥50Gy). Outcome measurements and statistical analysis: AT use and correlating variables were assessed by multivariable, generalized estimating equation models adjusted for facility clustering. Results and limitations: According to the database, 52.5% of patients received AT; 44.9% were treated surgically, 7.6% received definitive CRT or RT, and 25.9% of patients received observation only. AT use decreased with advancing age (odds ratio [OR]: 0.34 for age 81–90 yr vs ≤50 yr; p <0.001). AT use was also lower in racial minorities (OR: 0.74 for black race; p < 0.001), the uninsured (OR: 0.73; p < 0.001), Medicaid-insured patients (OR: 0.81; p = 0.01), and at low-volume centers (OR: 0.64 vs high-volume centers; p < 0.001). Use of AT was higher with increasing tumor stage (OR: 2.23 for T3/T4a vs T2; p < 0.001) and nonurothelial histology (OR: 1.25 and 1.43 for squamous and adenocarcinoma, respectively; p < 0.001). Study limitations include retrospective design and lack of information about patient and provider motivations regarding therapy selection. Conclusions: AT for MIBC appears underused, especially in the elderly and in groups with poor socioeconomic status. These data point to a significant unmet need to inform policy makers, payers, and physicians regarding appropriate therapies for MIBC. [Copyright &y& Elsevier]

Objectives: To determine the clinical characteristics, treatment patterns, and outcomes of patients with nonurothelial cell bladder cancer (NUBC) in the United States.Methods: A total of 163,683 patients with bladder cancer from 1998 to 2014 in the National Cancer Data Base were identified. Of all, 153,262 had urothelial cell (UC) carcinoma (93.6%) and 10,421 had NUBC (6.4%) further classified as: squamous cell carcinoma (SC, 2.4%), adenocarcinoma (AC, 1.7%), neuroendocrine (NE, 1.3%), micropapillary (MP, a UC variant histology, 0.3%), lymphoid/haematopoietic (LH, 0.3%), and sarcoma/mesenchymal (SM, 0.3%). Analyses were run on the entire cohort, those with non-muscle-invasive disease (T0-1, N0, M0), muscle-invasive disease (MIBC, T2-4A, N0, M0), and metastatic disease (T4B or N+ or M+). Clinical characteristics and treatment received (surgery, chemotherapy, and radiation) were reported by histologic subtype. Survival analysis was performed via Kaplan-Meier estimates and Cox proportional hazards models.Results: Patients with NE, SC, MP, and AC were more likely to be diagnosed with metastatic disease (11.5% for UC vs. 40%, 31.3%, 17.8%, and 30.6%, respectively, P<0.001). Patients with NUBC were also more likely to have MIBC compared to UC (43% vs. 32.5%, respectively). For all patients, those with UC may be less likely to undergo cystectomy, chemotherapy, and radiation therapy (P<0.001). For all patients, NUBC, with the exception of LH, SM, and MP, was associated with inferior survival compared to UC (P<0.001).Conclusions: This encompassing clinical characterization and prognosis of NUBC patients in the United States shows NUBC patients have significantly different disease characteristics compared to those with UC, and present with more advanced disease, receive more treatment, and overall have inferior outcomes. Further work is needed to help improve outcomes for these patients. [ABSTRACT FROM AUTHOR]

Purpose: To assess characteristics and outcome of patients treated with radiotherapy for muscle-invasive bladder cancer at 44 community-based radiotherapy centers and compare these to those on clinical trials.Materials and Methods: We reviewed 155 patients who had been treated from 2010 to 2014. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Results were compared to a pooled analysis of 6 Radiation Therapy Oncology Group (RTOG) protocols.Results: What stood out was that our patients' characteristics were significantly inferior than those on RTOG studies: lower rate of complete transurethral resection of bladder tumor: 36.8% vs. 70% (P<0.0001), higher median age: 79 years vs. 66 (P<0.0001), more medically inoperable: (51.0%) vs. 0% in RTOG (P<0.001), and 46.9% had refused surgery. Fewer patients underwent concurrent chemotherapy: 56.1% vs. 100% (P<0.0001). It was also striking that at median follow-up 12.6 months (range: 3.1-49.2), the 36-month overall survival was 51.3% for those who refused surgery vs. 24.5% for medically inoperable (P = 0.009); 58.1% with complete transurethral resection of bladder tumor vs. 29.8% if incomplete (P = 0.07); 54.3% with chemoradiotherapy (CRT) vs. 17.2% without (P = 0.03); 66.3% for those who refused surgery and had CRT vs. 38.9% for medically inoperable who had CRT (P = 0.04).Conclusions: The cohort at community-based centers was older, more medically inoperable, and less likely to receive CRT than clinical trial patients. This suggests that we may not be able to apply trial-derived regimens for many patients in this setting. There is a pressing need to find treatment options for such patients, especially given the aging population. Survival of medically operable CRT patients was comparable to results of RTOG protocols notwithstanding this study's smaller sample size, retrospective nature and suboptimal documentation of patient characteristics. [ABSTRACT FROM AUTHOR]