Search

Background: Chemo-radiation is a well-established alternative to radical cystectomy in patients with muscle-invasive bladder cancer. Many patients due to age or medical comorbidity are unfit for either radical cystectomy, or standard cisplatin- or 5-fluorouracil-based chemoradiation, and do not receive appropriate treatment with curative intent. We treated patients with a less aggressive protocol employing seven weekly doses of paclitaxel and daily irradiation. In those whose tumors showed overexpression of her2/neu, seven weekly doses of trastuzumab were also administered., Objective: To report the long-term survival outcomes and toxicity results of the of NRG Oncology RTOG 0524 study., Design, Setting, and Participants: Seventy patients were enrolled and 65 (median age: 76 yr) were deemed eligible. Patients were assigned to daily radiation and weekly paclitaxel + trastuzumab (group 1, 20 patients) or to daily radiation plus weekly paclitaxel (group 2, 45 patients) based on tumor her2/neu overexpression. Radiation was delivered in 1.8 Gy fractions to a total dose of 64.8 Gy., Outcome Measurements and Statistical Analysis: The primary endpoint was unresolved treatment-related toxicity. The secondary endpoints were complete response rate, protocol completion rate, and disease-free and overall survival., Results and Limitations: Protocol therapy was completed by 60% (group 1) and 76% (group 2); complete response rates at 12 wk were 62% in each group. Acute treatment-related adverse events (AEs) of grade ≥3 were observed in 80% in group 1 and 58% in group 2. There was one treatment-related grade 5 AE in group 1. Unresolved acute treatment-related toxicity was 35% in group 1 and 31% in group 2. The median follow-up was 2.3 yr in all patients and 7.2 yr in surviving patients. Overall survival at 5 yr was 25.0% in group 1 and 37.8% in group 2 (33.8% overall). At 5 yr, disease-free survival was 15.0% in group 1 and 31.1% in group 2., Conclusions: In a cohort of patients with muscle-invasive bladder cancer who are not candidates for cystectomy or cisplatin chemotherapy, chemoradiation therapy offers a treatment with a significant response rate and 34% 5-yr overall survival. While there were many AEs in this medically fragile group, there were few grade 4 events and one grade 5 event attributable to therapy., Patient Summary: Patients with invasive bladder cancer who cannot tolerate surgery were treated with radiation and systemic therapy without surgically removing their bladders. Most patients tolerated the treatment, were able to keep their bladders, and showed a significant treatment response rate., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: We present an overview of the updated 2023 European Association of Urology (EAU) guidelines for muscle-invasive and metastatic bladder cancer (MMIBC)., Objective: To provide practical evidence-based recommendations and consensus statements on the clinical management of MMIBC with a focus on diagnosis and treatment., Evidence Acquisition: 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., Evidence Synthesis: 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., Conclusions: This summary of the 2023 EAU guidelines provides updated information on the diagnosis and treatment of MMIBC for incorporation into clinical practice., Patient Summary: 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., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: There is an urgent need for biomarkers of radiation response in organ-sparing therapies. Bladder preservation with trimodality therapy (TMT), consisting of transurethral tumor resection followed by chemoradiation, is an alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), but molecular determinants of response are poorly understood., Experimental Design: We characterized genomic and transcriptomic features correlated with long-term response in a single institution cohort of patients with MIBC homogeneously treated with TMT. Pretreatment tumors from 76 patients with MIBC underwent whole-exome sequencing; 67 underwent matched transcriptomic profiling. Molecular features were correlated with clinical outcomes including modified bladder-intact event-free survival (mBI-EFS), a composite endpoint that reflects long-term cancer control with bladder preservation., Results: With a median follow-up of 74.6 months in alive patients, 37 patients had favorable long-term response to TMT while 39 had unfavorable long-term response. Tumor mutational burden was not associated with outcomes after TMT. DNA damage response gene alterations were associated with improved locoregional control and mBI-EFS. Of these alterations, somatic ERCC2 mutations stood out as significantly associated with favorable long-term outcomes; patients with ERCC2 mutations had significantly improved mBI-EFS [HR, 0.15; 95% confidence interval (CI), 0.06-0.37; P = 0.030] and improved BI-EFS, an endpoint that includes all-cause mortality (HR, 0.33; 95% CI, 0.15-0.68; P = 0.044). ERCC2 mutant bladder cancer cell lines were significantly more sensitive to concurrent cisplatin and radiation treatment in vitro than isogenic ERCC2 wild-type cells., Conclusions: Our data identify ERCC2 mutation as a candidate biomarker associated with sensitivity and long-term response to chemoradiation in MIBC. These findings warrant validation in independent cohorts., (©2023 The Authors; Published by the American Association for Cancer Research.)

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.

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 hypothesis-generating. The NRG is currently developing a phase II randomized clinical trial comparing CRT to other novel, bladder preservation strategies., Competing Interests: Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BCB declares consulting work for Varian Medical Systems and Boston Scientific, outside of the scope of thesubmitted work. The others have no conflicts of interest that are relevant to the submitted work., (Copyright © 2023. Published by Elsevier Inc.)

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.

Bladder cancer is a global health issue with sex differences in incidence and prognosis. Bladder cancer has distinct molecular subtypes with multiple pathogenic pathways depending on whether the disease is non-muscle invasive or muscle invasive. The mutational burden is higher in muscle-invasive than in non-muscle-invasive disease. Commonly mutated genes include TERT, FGFR3, TP53, PIK3CA, STAG2 and genes involved in chromatin modification. Subtyping of both forms of bladder cancer is likely to change considerably with the advent of single-cell analysis methods. Early detection signifies a better disease prognosis; thus, minimally invasive diagnostic options are needed to improve patient outcomes. Urine-based tests are available for disease diagnosis and surveillance, and analysis of blood-based cell-free DNA is a promising tool for the detection of minimal residual disease and metastatic relapse. Transurethral resection is the cornerstone treatment for non-muscle-invasive bladder cancer and intravesical therapy can further improve oncological outcomes. For muscle-invasive bladder cancer, radical cystectomy with neoadjuvant chemotherapy is the standard of care with evidence supporting trimodality therapy. Immune-checkpoint inhibitors have demonstrated benefit in non-muscle-invasive, muscle-invasive and metastatic bladder cancer. Effective management requires a multidisciplinary approach that considers patient characteristics and molecular disease characteristics., (© 2023. Springer Nature Limited.)

Background: 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., Methods: 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., Results: 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., Conclusion: 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., Competing Interests: Conflict of interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Previous randomised controlled trials comparing bladder preservation with radical cystectomy for muscle-invasive bladder cancer closed due to insufficient accrual. Given that no further trials are foreseen, we aimed to use propensity scores to compare trimodality therapy (maximal transurethral resection of bladder tumour followed by concurrent chemoradiation) with radical cystectomy., Methods: This retrospective analysis included 722 patients with clinical stage T2-T4N0M0 muscle-invasive urothelial carcinoma of the bladder (440 underwent radical cystectomy, 282 received trimodality therapy) who would have been eligible for both approaches, treated at three university centres in the USA and Canada between Jan 1, 2005, and Dec 31, 2017. All patients had solitary tumours less than 7 cm, no or unilateral hydronephrosis, and no extensive or multifocal carcinoma in situ. The 440 cases of radical cystectomy represent 29% of all radical cystectomies performed during the study period at the contributing institutions. The primary endpoint was metastasis-free survival. Secondary endpoints included overall survival, cancer-specific survival, and disease-free survival. Differences in survival outcomes by treatment were analysed using propensity scores incorporated in propensity score matching (PSM) using logistic regression and 3:1 matching with replacement and inverse probability treatment weighting (IPTW)., Findings: In the PSM analysis, the 3:1 matched cohort comprised 1119 patients (837 radical cystectomy, 282 trimodality therapy). After matching, age (71·4 years [IQR 66·0-77·1] for radical cystectomy vs 71·6 years [64·0-78·9] for trimodality therapy), sex (213 [25%] vs 68 [24%] female; 624 [75%] vs 214 [76%] male), cT2 stage (755 [90%] vs 255 [90%]), presence of hydronephrosis (97 [12%] vs 27 [10%]), and receipt of neoadjuvant or adjuvant chemotherapy (492 [59%] vs 159 [56%]) were similar between groups. Median follow-up was 4·38 years (IQR 1·6-6·7) versus 4·88 years (2·8-7·7), respectively. 5-year metastasis-free survival was 74% (95% CI 70-78) for radical cystectomy and 75% (70-80) for trimodality therapy with IPTW and 74% (70-77) and 74% (68-79) with PSM. There was no difference in metastasis-free survival either with IPTW (subdistribution hazard ratio [SHR] 0·89 [95% CI 0·67-1·20]; p=0·40) or PSM (SHR 0·93 [0·71-1·24]; p=0·64). 5-year cancer-specific survival for radical cystectomy versus trimodality therapy was 81% (95% CI 77-85) versus 84% (79-89) with IPTW and 83% (80-86) versus 85% (80-89) with PSM. 5-year disease-free survival was 73% (95% CI 69-77) versus 74% (69-79) with IPTW and 76% (72-80) versus 76% (71-81) with PSM. There were no differences in cancer-specific survival (IPTW: SHR 0·72 [95% CI 0·50-1·04]; p=0·071; PSM: SHR 0·73 [0·52-1·02]; p=0·057) and disease-free survival (IPTW: SHR 0·87 [0·65-1·16]; p=0·35; PSM: SHR 0·88 [0·67-1·16]; p=0·37) between radical cystectomy and trimodality therapy. Overall survival favoured trimodality therapy (IPTW: 66% [95% CI 61-71] vs 73% [68-78]; hazard ratio [HR] 0·70 [95% CI 0·53-0·92]; p=0·010; PSM: 72% [69-75] vs 77% [72-81]; HR 0·75 [0·58-0·97]; p=0·0078). Outcomes for radical cystectomy and trimodality therapy were not statistically different among centres for cancer-specific survival and metastasis-free survival (p=0·22-0·90). Salvage cystectomy was done in 38 (13%) trimodality therapy patients. Pathological stage in the 440 radical cystectomy patients was pT2 in 124 (28%), pT3-4 in 194 (44%), and 114 (26%) node positive. The median number of nodes removed was 39, the soft tissue positive margin rate was 1% (n=5), and the perioperative mortality rate was 2·5% (n=11)., Interpretation: This multi-institutional study provides the best evidence to date showing similar oncological outcomes between radical cystectomy and trimodality therapy for select patients with muscle-invasive bladder cancer. These results support that trimodality therapy, in the setting of multidisciplinary shared decision making, should be offered to all suitable candidates with muscle-invasive bladder cancer and not only to patients with significant comorbidities for whom surgery is not an option., Funding: Sinai Health Foundation, Princess Margaret Cancer Foundation, Massachusetts General Hospital., Competing Interests: Declaration of interests ARZ reports participation on a data safety monitoring board or advisory board for Janssen, Verity Pharmaceuticals, Ferring, mIR Scientific, Tolmar, and Theralase; and consulting fees from Janssen, Verity Pharmaceuticals, Ferring, mIR Scientific, Tolmar, and Theralase. NEF reports grants or contracts from Janssen, Sanofi, Astellas, Nucleix, Bayer, and Progenix; consulting fees from Amgen, Sanofi, Janssen, AbbVie, Astellas, Ferring, and Bayer; stock or stock options in Verity Pharmaceuticals and POINT Biopharma; and is Chief Medical Officer for Verity Pharmaceuticals and Chief Medical Officer for POINT Biopharma. GSK reports grants or contracts from Janssen; and participation on a data safety monitoring board or advisory board for BMS, Pfizer, EMD Serono, Theralase, Verity Pharmaceuticals, Merck, Janssen, AstraZeneca, and Ferring. MASJ reports an honorarium from Pfizer; support for attending meetings or travel from the European Association of Urology; and is the Chair of the Board of Directors of the International Kidney Cancer Coalition. SSS reports grants or contracts from Bayer, Janssen, and Seagen; consulting fees from Astellas, AstraZeneca, Bayer, BMS, Eisai, EMD Serona, Hoffmann-LaRoche, Immunomedics, Ipsen, Janssen, Merck, Pfizer, and Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, EMD Serono, Seagen, and Bayer; and support for attending meetings or travel from EMD Serono. MDM reports participation on a data safety monitoring board or advisory board for Merck, Janssen, Eisai, and Exelixis. JAE reports consulting fees from Blue Earth Diagnostics, Boston Scientific, AstraZeneca, and Genentech; and participation on a data safety monitoring board or advisory board for Merck, Roviant Pharma, Myovant Sciences, Janssen, Bayer Healthcare, Progenics Pharmaceuticals, Pfizer, Gilead, and Lantheus. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients., Objective: 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)., Design, Setting, and Participants: A multicenter phase 1 trial was conducted at community and academic sites., Intervention: 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)., Outcome Measurements and Statistical Analysis: 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., Results and Limitations: 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., Conclusions: 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., Patient Summary: Durvalumab combination therapy can be safely administered to non-muscle-invasive bladder cancer patients with the goal of increasing durable response rates., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

For muscle-invasive bladder cancer, the historical, gold standard treatment was radical cystectomy. However, the notion of organ preservation using trimodality therapy (TMT, consisting of maximal transurethral resection of bladder tumor followed by chemoradiation) has been established as a viable treatment alternative to complete removal of the bladder. Despite the lack of direct head-to-head randomized comparisons of TMT to radical cystectomy, the Radiation Therapy Oncology Group (RTOG)/NRG has spearheaded the use of radiation therapy as part of bladder preservation for years, with prospective data demonstrating similar long-term clinical outcomes to cystectomy series, particularly with contemporary treatment. We summarize these trials and discuss the evolution of bladder preservation throughout the decades, culminating in our current TMT protocols. We further discuss the future of organ-preservation therapy in MIBC, with continued improvement in radiation techniques, incorporation of novel therapies, and personalization of treatment to optimize benefit for bladder cancer patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

There are limited data regarding the optimal management of patients with pelvic node-positive, but non-metastatic, bladder cancer. Increasing data demonstrate that this is a distinct clinical entity with outcomes bridging between bladder-confined muscle-invasive bladder cancer and metastatic advanced bladder cancer. Guidelines and staging systems have formalized the need to incorporate the unique considerations of management of pelvic node-positive bladder cancer. However, there remains an absence of a definite standard of care. Treatment options include systemic therapy alone, neoadjuvant chemotherapy followed by radical cystectomy, or bladder-preserving trimodality therapy. Furthermore, ongoing studies aim to determine the benefit of incorporating immunotherapy into these treatment paradigms. In this review article, we will discuss the key considerations for management of patients with pelvic node-positive bladder cancer., (Published by Elsevier Inc.)

Importance: Bladder-preserving trimodality therapy can be an effective alternative to radical cystectomy for treatment of muscle-invasive bladder cancer (MIBC), but biomarkers are needed to guide optimal patient selection. The DNA repair protein MRE11 is a candidate response biomarker that has not been validated in prospective cohorts using standardized measurement approaches., Objective: To evaluate MRE11 expression as a prognostic biomarker in MIBC patients receiving trimodality therapy using automated quantitative image analysis., Design, Setting, and Participants: This prognostic study analyzed patients with MIBC pooled from 6 prospective phase I/II, II, or III trials of trimodality therapy (Radiation Therapy Oncology Group [RTOG] 8802, 8903, 9506, 9706, 9906, and 0233) across 37 participating institutions in North America from 1988 to 2007. Eligible patients had nonmetastatic MIBC and were enrolled in 1 of the 6 trimodality therapy clinical trials. Analyses were completed August 2020., Exposures: Trimodality therapy with transurethral bladder tumor resection and cisplatin-based chemoradiation therapy., Main Outcomes and Measures: MRE11 expression and association with disease-specific (bladder cancer) mortality (DSM), defined as death from bladder cancer. Pretreatment tumor tissues were processed for immunofluorescence with anti-MRE11 antibody and analyzed using automated quantitative image analysis to calculate a normalized score for MRE11 based on nuclear-to-cytoplasmic (NC) signal ratio., Results: Of 465 patients from 6 trials, 168 patients had available tissue, of which 135 were analyzable for MRE11 expression (median age of 65 years [minimum-maximum, 34-90 years]; 111 [82.2%] men). Median (minimum-maximum) follow-up for alive patients was 5.0 (0.6-11.7) years. Median (Q1-Q3) MRE11 NC signal ratio was 2.41 (1.49-3.34). Patients with an MRE11 NC ratio above 1.49 (ie, above first quartile) had a significantly lower DSM (HR, 0.50; 95% CI, 0.26-0.93; P = .03). The 4-year DSM was 41.0% (95% CI, 23.2%-58.0%) for patients with an MRE11 NC signal ratio of 1.49 or lower vs 21.0% (95% CI, 13.4%-29.8%) for a ratio above 1.49. MRE11 NC signal ratio was not significantly associated with overall survival (HR, 0.84; 95% CI, 0.49-1.44)., Conclusions and Relevance: Higher MRE11 NC signal ratios were associated with better DSM after trimodality therapy. Lower MRE11 NC signal ratios identified a poor prognosis subgroup that may benefit from intensification of therapy.

Context: Treatment of metastatic urothelial carcinoma is currently undergoing a rapid evolution., Objective: This overview presents the updated European Association of Urology (EAU) guidelines for metastatic urothelial carcinoma., Evidence Acquisition: 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., Evidence Synthesis: 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., Conclusions: This 2021 update of the EAU guideline provides detailed and contemporary information on the treatment of metastatic urothelial carcinoma for incorporation into clinical practice., Patient Summary: 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., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The success of the use of novel therapies in the treatment of advanced urothelial carcinoma has contributed to growing interest in evaluating these therapies at earlier stages of the disease. However, trials evaluating these therapies in the neoadjuvant setting must have clearly defined study elements and appropriately selected end points to ensure the applicability of the trial and enable interpretation of the study results. To advance the development of rational trial design, a public workshop jointly sponsored by the US Food and Drug Administration and the Bladder Cancer Advocacy Network convened in August 2019. Clinicians, clinical trialists, radiologists, biostatisticians, patients, advocates and other stakeholders discussed key elements and end points when designing trials of neoadjuvant therapy for muscle-invasive bladder cancer (MIBC), identifying opportunities to refine eligibility, design and end points for neoadjuvant trials in MIBC. Although pathological complete response (pCR) is already being used as a co-primary end point, both individual-level and trial-level surrogacy for time-to-event end points, such as event-free survival or overall survival, remain incompletely characterized in MIBC. Additionally, use of pCR is limited by heterogeneity in pathological evaluation and the fact that the magnitude of pCR improvement that might translate into a meaningful clinical benefit remains unclear. Given existing knowledge gaps, capture of highly granular patient-related, tumour-related and treatment-related characteristics in the current generation of neoadjuvant MIBC trials will be critical to informing the design of future trials., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Salvage cystectomy is required for some patients with intravesical recurrence after trimodality therapy. We compared postoperative outcomes between salvage cystectomy post-trimodality therapy, primary cystectomy and primary cystectomy with prior history of nontrimodality therapy abdominal or pelvic radiotherapy., Materials and Methods: We included 265 patients who underwent radical cystectomy at Massachusetts General Hospital for cT1-T4 bladder cancer between 2003 and 2013. Patients were grouped as salvage cystectomy post-trimodality therapy, primary cystectomy or primary cystectomy with prior history of nontrimodality therapy abdominal or pelvic radiotherapy. Early (≤90 days) and late (>90 days) complications were compared. Disease-specific survival and overall survival were calculated using a Cox regression model, and adjusted survival curves were generated., Results: The median followup from the time of cystectomy was 65.5 months. There was no difference in intraoperative and early complications between the groups. The detection of late complications was higher in salvage cystectomy post-trimodality therapy compared to primary cystectomy and primary cystectomy with prior history of nontrimodality therapy abdominal or pelvic radiotherapy (p=0.03). In multivariable Cox regression analysis, salvage cystectomy post-trimodality therapy was associated with a higher incidence of any late (HR 2.3, p=0.02) and major late complications (HR 2.1, p <0.05). There was no difference in disease-specific survival (p=0.8) or overall survival (p=0.9) between the groups., Conclusions: Salvage cystectomy post-trimodality therapy for intravesical recurrence post-trimodality therapy has an intraoperative and early complication rate comparable to primary cystectomy and primary cystectomy with prior history of nontrimodality therapy abdominal or pelvic radiotherapy. Salvage cystectomy post-trimodality therapy is associated with a higher risk of overall and major late complications than primary cystectomy. The disease-specific survival and overall survival of patients who require salvage cystectomy post-trimodality therapy are comparable to both groups.

Bladder-preserving trimodality therapy (TMT), consisting of trans-urethral bladder tumor resection followed by concurrent chemoradiotherapy, is an established standard of care for patients with muscle-invasive bladder cancer. For appropriately selected patients, TMT offers oncologic outcomes comparable to radical cystectomy while preserving the patient's native bladder. Optimal TMT outcomes require careful patient selection, which is currently based on clinical and pathologic factors. The role of immune checkpoint blockade (ICB) in TMT is currently being investigated in several on-going clinical trials. In the future, molecular features associated with response to TMT or ICB may further improve patient selection and guide post-treatment surveillance., Competing Interests: Disclosure D.J. Konieczkowski: none. J.A. Efstathiou: consulting (Blue Earth Diagnostics, Boston Scientific, AstraZeneca), Advisory Board (Roivant); honoraria (UpToDate). K.W. Mouw: research funding (Pfizer); consulting (EMD Serono/Pfizer); honoraria (UpToDate, OncLive)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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 and delayed CRT (P = .94). On multivariable analysis, delayed CRT was not associated with an overall survival difference (hazard ratio, 1.05; 95% CI, 0.87-1.27; P = .60)., Conclusion: Although these results are limited and require validation, short, strategic treatment delays during a pandemic can be considered on the basis of clinician judgment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Muscle-invasive bladder cancer (MIBC) is a sex-biased cancer with a higher incidence in men but worse outcomes in women. The root cause behind these observations remains unclear. To investigate whether sex-specific tumor biology could explain the differences in clinical behavior of MIBC, we analyzed the transcriptome profiles from transurethral resected bladder tumors of 1000 patients. Female tumors expressed higher levels of basal- and immune-associated genes, while male tumors expressed higher levels of luminal markers. Using molecular subtyping, we found that the rates of the basal/squamous subtype were higher in females than in males. Males were enriched with tumors of the luminal papillary (LumP) and neuroendocrine-like subtypes. Male MIBC tumors had higher androgen response activity across all luminal subtypes and male patients with LumP tumors were younger. Taken together, these data confirm differences in molecular subtypes based on sex. The role of the androgen response pathway in explaining subtype differences between men and women should be studied further. PATIENT SUMMARY: We explored the sex-specific biology of bladder cancer in 1000 patients and found that women had more aggressive cancer with higher immune activity. Men tended toward less aggressive tumors that showed male hormone signaling, suggesting that male hormones may influence the type of bladder cancer that a patient develops., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: There is a lack of accepted consensus on what should constitute appropriate quality-of-care indicators for bladder cancer., Objective: To evaluate the optimal management of bladder cancer and propose quality indicators (QIs)., Evidence Acquisition: 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., Evidence Synthesis: 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., Conclusions: 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., Patient Summary: 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., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on the clinical presentation and workup of suspected bladder cancer, treatment of non-muscle-invasive urothelial bladder cancer, and treatment of metastatic urothelial bladder cancer because important updates have recently been made to these sections. Some important updates include recommendations for optimal treatment of non-muscle-invasive bladder cancer in the event of a bacillus Calmette-Guérin (BCG) shortage and details about biomarker testing for advanced or metastatic disease. The systemic therapy recommendations for second-line or subsequent therapies have also been revised. Treatment and management of muscle-invasive, nonmetastatic disease is covered in the complete version of the NCCN Guidelines for Bladder Cancer available at NCCN.org. Additional topics covered in the complete version include treatment of nonurothelial histologies and recommendations for nonbladder urinary tract cancers such as upper tract urothelial carcinoma, urothelial carcinoma of the prostate, and primary carcinoma of the urethra.

Purpose: Neuroendocrine (NE) bladder carcinoma is a rare and aggressive variant. Molecular subtyping studies have found that 5% to 15% of muscle-invasive bladder cancer (MIBC) have transcriptomic patterns consistent with NE bladder cancer in the absence of NE histology. The clinical implications of this NE-like subtype have not been explored in depth., Experimental Design: Transcriptome-wide expression profiles were generated for MIBC collected from 7 institutions and clinical-use of Decipher Bladder. Using unsupervised clustering, we generated a clustering solution on a prospective training cohort (PTC; n = 175), developed single-sample classifiers to predict NE tumors, and evaluated the resultant models on a testing radical cystectomy (RC) cohort ( n = 225). A random forest model was finalized and applied to 5 validation cohorts ( n = 1302). Uni- and multivariable survival analyses were used to characterize clinical outcomes., Results: In the training cohort (PTC), hierarchical clustering using an 84-gene panel showed a cluster of 8 patients (4.6%) with highly heterogeneous expression of NE markers in the absence of basal or luminal marker expression. NE-like tumors were identified in 1% to 6.6% of cases in validation cohorts. Patients with NE-like tumors had significantly worse 1-year progression-free survival (65% NE-like vs. 82% overall; P = 0.046) and, after adjusting for clinical and pathologic factors, had a 6.4-fold increased risk of all-cause mortality ( P = 0.001). IHC confirmed the neuronal character of these tumors., Conclusions: A single-patient classifier was developed that identifies patients with histologic urothelial cancer harboring a NE transcriptomic profile. These tumors represent a high-risk subgroup of MIBC, which may require different treatment., (©2019 American Association for Cancer Research.)

Background: 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., Objective: To evaluate the prognostic value of immune and stromal signatures in MIBC treated with TMT., Design, Setting, and Participants: 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 5yr, and median follow-up time for patients without an event was 5.0yr (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., Outcome Measurements and Statistical Analysis: 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., Results and Limitations: 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., Conclusions: 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., Patient Summary: 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., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: There are limited randomized data comparing radical cystectomy (RC) with bladder-sparing tri-modality therapy (TMT) in the treatment of muscle-invasive bladder cancer (MIBC). Both strategies are thought to have similar survival outcomes with different morbidity profiles. We compare the effectiveness of TMT and RC using decision-analytic modeling and the endpoint of quality-adjusted life years (QALYs)., Patients and Methods: Using a Markov model, we simulated the lifetime outcomes after TMT versus RC ± neoadjuvant chemotherapy for 67-year-old patients with clinical stage T2-T4aN0M0 MIBC. Model probabilities and utilities were extracted from the literature. The incremental effectiveness was reported in QALYs and sensitivity analyses were performed., Results: For all patients with MIBC, although the model showed identical survival, TMT was the most effective strategy with an incremental gain of 0.59 QALYs over RC (7.83 vs. 7.24 QALYs, respectively). When limiting the model to favorable, contemporary cohorts in both the TMT and RC strategies, TMT remained more effective with an incremental gain of 1.61 QALYs (9.37 vs. 7.76 QALYs, respectively). One-way sensitivity analyses demonstrated the model was sensitive to the quality of life parameters (ie, the utilities) for RC and TMT. When testing the 95% confidence interval of the RC utility parameter the model demonstrated an incremental gain with TMT from -0.54 to 4.23 QALYs. Probabilistic sensitivity analysis demonstrated that TMT was more effective than RC for 63% of model iterations., Conclusions: This modeling study found that treatment of MIBC with organ-sparing TMT in appropriately-selected patients may result in a gain of QALYs relative to RC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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.

Purpose: Fluorouracil plus cisplatin and radiation twice a day (FCT) is an established chemoradiation (CRT) regimen for selective bladder-sparing treatment of muscle-invasive bladder cancer. Gemcitabine and once daily radiation (GD) is a well-supported alternative. The current trial evaluates these regimens., Methods: Patients with cT2-4a muscle-invasive bladder cancer were randomly assigned to FCT or GD. Patients underwent transurethral resection and induction CRT to 40 Gy. Patients who achieved a complete response (CR) received consolidation CRT to 64 Gy and others underwent cystectomy. We administered adjuvant gemcitabine/cisplatin chemotherapy. The primary end point was the rate of freedom from distant metastasis at 3 years (DMF3). The trial was not statistically powered to compare regimens, but to assess whether either regimen exceeded a DMF3 benchmark of 75%. Toxicity and efficacy end points, including CR and bladder-intact distant metastasis free survival at 3 years (BI-DMFS3), were assessed., Results: From December 2008 to April 2014, 70 patients were enrolled, of which 66 were eligible for analysis, 33 per arm. Median follow-up was 5.1 years (range, 0.4 to 7.8 years) for eligible living patients. DMF3 was 78% and 84% for FCT and GD, respectively. BI-DMFS3 was 67% and 72%, respectively. Postinduction CR rates were 88% and 78%, respectively. Of 33 patients in the FCT arm, 21 (64%) experienced treatment-related grade 3 and 4 toxicities during protocol treatment, with 18 (55%), two (6%), and two patients (6%) experiencing grade 3 and 4 hematologic, GI, and genitourinary toxicity, respectively. For the 33 patients in the GD arm, these figures were 18 (55%) overall and 14 (42%), three (9%) and two patients (6%), respectively., Conclusion: Both regimens demonstrated DMF3 greater than 75%. There were fewer toxicities observed in the GD arm. Either gemcitabine and once daily radiation or a cisplatin-based regimen could serve as a base for future trials of systemic therapy.

Although muscle-invasive bladder cancer is commonly treated with radical cystectomy, a standard alternative is bladder preservation therapy, consisting of maximum transurethral bladder tumour resection followed by radiotherapy with concurrent chemotherapy. Although no successfully completed randomised comparisons are available, the two treatment paradigms seem to have similar long-term outcomes; however, clinicopathologic parameters can be insufficient to provide clear guidance in the selection of one treatment over the other. Recent advances in the molecular understanding of bladder cancer have led to the identification of new predictive biomarkers that ultimately might help guide the tailored selection of therapy on the basis of the intrinsic biology of the tumour. In this Review, we discuss the existing evidence for molecular alterations and genomic signatures as prognostic or predictive biomarkers for bladder preservation therapy. If validated in prospective clinical trials, such biomarkers could enable the identification of subgroups of patients who are more likely to benefit from one treatment over another, and guide the use of combination therapies that include other modalities, such as immunotherapy, which might act synergistically with radiotherapy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2018 European Association of Urology. All rights reserved.)

The NCCN Clinical Practice Guidelines in Oncology for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer. These NCCN Guidelines Insights discuss important updates to the 2018 version of the guidelines, including implications of the 8th edition of the AJCC Cancer Staging Manual on treatment of muscle-invasive bladder cancer and incorporating newly approved immune checkpoint inhibitor therapies into treatment options for patients with locally advanced or metastatic disease., (Copyright © 2018 by the National Comprehensive Cancer Network.)

Background: Multidisciplinary clinics integrate the expertise of several specialties to provide effective treatment to patients. This exposure is especially relevant in the management of muscle-invasive bladder cancer (MIBC), which requires critical input from urology, radiation oncology, and medical oncology, among other supportive specialties., Materials and Methods: In the present study, we sought to catalog the different styles of multidisciplinary care models used in the management of MIBC and to identify barriers to their implementation. We surveyed providers from academic and community practices regarding their currently implemented multidisciplinary care models, available resources, and perceived barriers using the Bladder Cancer Advocacy Network and the Genitourinary Medical Oncologists of Canada e-mail databases., Results: Of the 101 responding providers, most practiced at academic institutions in the United States (61%) or Canada (29%), and only 7% were from community practices. The most frequently used model was sequential visits on different days (57%), followed by sequential same-day (39%) and concurrent (1 visit with all providers; 22%) models. However, most practitioners preferred a multidisciplinary clinic involving sequential same-day (41%) or concurrent (26%) visits. The lack of clinic space (58%), funding (41%), staff (40%), and time (32%) were the most common barriers to implementing a multidisciplinary clinic., Conclusion: Most surveyed practitioners at academic centers use some form of a multidisciplinary care model for patients with MIBC. The major barriers to more integrated multidisciplinary clinics were limited time and resources rather than a lack of provider enthusiasm. Future studies should incorporate patient preferences, further evaluate practice patterns in community settings, and assess their effects on patient outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Biomarkers and mechanisms of poly (ADP-ribose) polymerase (PARP) inhibitor-mediated cytotoxicity in tumor cells lacking a BRCA-mutant or BRCA-like phenotype are poorly defined. We sought to explore the utility of PARP-1 inhibitor (PARPi) treatment with/without ionizing radiation in muscle-invasive bladder cancer (MIBC), which has poor therapeutic outcomes. We assessed the DNA damaging and cytotoxic effects of the PARPi olaparib in nine bladder cancer cell lines. Olaparib radiosensitized all cell lines with dose enhancement factors from 1.22 to 2.27. Radiosensitization was correlated with the induction of potentially lethal DNA double-strand breaks (DSB) but not with RAD51 foci formation. The ability of olaparib to radiosensitize MIBC cells was linked to the extent of cell kill achieved with the drug alone. Unexpectedly, increased levels of reactive oxygen species (ROS) resulting from PARPi treatment were the cause of DSB throughout the cell cycle in vitro and in vivo. ROS originated from mitochondria and were required for the radiosensitizing effects of olaparib. Consistent with the role of TP53 in ROS regulation, loss of p53 function enhanced radiosensitization by olaparib in non-isogenic and isogenic cell line models and was associated with increased PARP-1 expression in bladder cancer cell lines and tumors. Impairment of ATM in addition to p53 loss resulted in an even more pronounced radiosensitization. In conclusion, ROS suppression by PARP-1 in MIBC is a potential therapeutic target either for PARPi combined with radiation or drug alone treatment. The TP53 and ATM genes, commonly mutated in MIBC and other cancers, are candidate biomarkers of PARPi-mediated radiosensitization.

Purpose: We describe the incidence, clinicopathological risk factors, management and outcomes of recurrent nonmuscle invasive bladder cancer after a complete response to trimodality therapy of muscle invasive bladder cancer., Materials and Methods: We retrospectively reviewed the records of 342 patients with cT2-4aN0M0 muscle invasive bladder cancer and a complete response after trimodality therapy from 1986 to 2013. Using competing risks analyses we examined the association between baseline clinicopathological variables and nonmuscle invasive bladder cancer outcomes. Kaplan-Meier and the generalized Fleming-Harrington test were used to compare disease specific and overall survival., Results: At a median followup of 9 years nonmuscle invasive bladder cancer recurred in 85 patients (25%) who had had a complete response. On Kaplan-Meier analysis baseline carcinoma in situ was associated with recurrent nonmuscle invasive bladder cancer (p = 0.02). However, on multivariate analysis carcinoma in situ and other baseline clinicopathological characteristics did not predict such recurrence. Patients with recurrent nonmuscle invasive bladder cancer had worse 10-year disease specific survival than those without recurrence (72.1% vs 78.4%, p = 0.002), although overall survival was similar (p = 0.66). Of the 39 patients (46%) who received adjuvant intravesical bacillus Calmette-Guérin 29 (74%) completed induction therapy and 19 (49%) reported bacillus Calmette-Guérin toxicity. Three-year recurrence-free and progression-free survival after induction bacillus Calmette-Guérin was 59% and 63%, respectively., Conclusions: After a complete response to trimodality therapy nonmuscle invasive bladder cancer recurred in 25% of patients, developing in some of them more than a decade after trimodality therapy. No baseline clinicopathological characteristics were associated with such recurrence after a complete response. Patients with nonmuscle invasive bladder cancer recurrence had worse disease specific survival than those without such recurrence but similar overall survival. Adjuvant intravesical bacillus Calmette-Guérin had a reasonable toxicity profile and efficacy in this population. Properly selected patients with recurrent nonmuscle invasive bladder cancer after a complete response may avoid immediate salvage cystectomy., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on systemic therapy for muscle-invasive urothelial bladder cancer, as substantial revisions were made in the 2017 updates, such as new recommendations for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. The complete version of the NCCN Guidelines for Bladder Cancer addresses additional aspects of the management of bladder cancer, including non-muscle-invasive urothelial bladder cancer and nonurothelial histologies, as well as staging, evaluation, and follow-up., (Copyright © 2017 by the National Comprehensive Cancer Network.)

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., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Bladder cancer is a complex disease associated with high morbidity and mortality rates if not treated optimally. Awareness of haematuria as the major presenting symptom is paramount, and early diagnosis with individualised treatment and follow-up is the key to a successful outcome. For non-muscle-invasive bladder cancer, the mainstay of treatment is complete resection of the tumour followed by induction and maintenance immunotherapy with intravesical BCG vaccine or intravesical chemotherapy. For muscle-invasive bladder cancer, multimodal treatment involving radical cystectomy with neoadjuvant chemotherapy offers the best chance for cure. Selected patients with muscle-invasive tumours can be offered bladder-sparing trimodality treatment consisting of transurethral resection with chemoradiation. Advanced disease is best treated with systemic cisplatin-based chemotherapy; immunotherapy is emerging as a viable salvage treatment for patients in whom first-line chemotherapy cannot control the disease. Developments in the past 2 years have shed light on genetic subtypes of bladder cancer that might differ from one another in response to various treatments., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: Health-related quality of life (QOL) has not been well-studied in survivors of muscle-invasive bladder cancer (MIBC). The present study compared long-term QOL in MIBC patients treated with radical cystectomy (RC) versus bladder-sparing trimodality therapy (TMT)., Methods and Materials: This cross-sectional bi-institutional study identified 226 patients with nonmetastatic cT2-cT4 MIBC, diagnosed in 1990 to 2011, who were eligible for RC and were disease free for ≥2 years. Six validated QOL instruments were administered: EuroQOL EQ-5D, European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire and EORTC MIBC module, Expanded Prostate Cancer Index Composite bowel scale, Cancer Treatment and Perception Scale, and Impact of Cancer, version 2. Multivariable analyses of the mean QOL scores were conducted using propensity score matching., Results: The response rate was 77% (n=173). The median follow-up period was 5.6 years. Of the 173 patients, 64 received TMT and 109, RC. The median interval from diagnosis to questionnaire completion was 9 years after TMT and 7 years after RC (P=.009). No significant differences were found in age, gender, comorbidities, tobacco history, performance status, or tumor stage. On multivariable analysis, patients who received TMT had better general QOL by 9.7 points of 100 compared with those who had received RC (P=.001) and higher physical, role, social, emotional, and cognitive functioning by 6.6 to 9.9 points (P≤.04). TMT was associated with better bowel function by 4.5 points (P=.02) and fewer bowel symptoms by 2.7 to 7.1 points (P≤.05). The urinary symptom scores were similar. TMT was associated with better sexual function by 8.7 to 32.1 points (P≤.02) and body image by 14.8 points (P<.001). The patients who underwent TMT reported greater informed decision-making scores by 13.6 points (P=.01) and less concern about the negative effect of cancer by 6.8 points (P=.006). The study limitations included missing baseline QOL data and different follow-up times., Conclusions: Both TMT and RC result in good long-term QOL outcomes in MIBC survivors, supporting TMT as a good alternative to RC for selected patients. Whether TMT leads to superior QOL requires prospective validation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

These NCCN Guidelines Insights discuss the major recent updates to the NCCN Guidelines for Bladder Cancer based on the review of the evidence in conjunction with the expert opinion of the panel. Recent updates include (1) refining the recommendation of intravesical bacillus Calmette-Guérin, (2) strengthening the recommendations for perioperative systemic chemotherapy, and (3) incorporating immunotherapy into second-line therapy for locally advanced or metastatic disease. These NCCN Guidelines Insights further discuss factors that affect integration of these recommendations into clinical practice., (Copyright © 2016 by the National Comprehensive Cancer Network.)

Purpose: To develop multi-institutional consensus clinical target volumes (CTVs) and organs at risk (OARs) for male and female bladder cancer patients undergoing adjuvant radiation therapy (RT) in clinical trials., Methods and Materials: We convened a multidisciplinary group of bladder cancer specialists from 15 centers and 5 countries. Six radiation oncologists and 7 urologists participated in the development of the initial contours. The group proposed initial language for the CTVs and OARs, and each radiation oncologist contoured them on computed tomography scans of a male and female cystectomy patient with input from ≥1 urologist. On the basis of the initial contouring, the group updated its CTV and OAR descriptions. The cystectomy bed, the area of greatest controversy, was contoured by another 6 radiation oncologists, and the cystectomy bed contouring language was again updated. To determine whether the revised language produced consistent contours, CTVs and OARs were redrawn by 6 additional radiation oncologists. We evaluated their contours for level of agreement using the Landis-Koch interpretation of the κ statistic., Results: The group proposed that patients at elevated risk for local-regional failure with negative margins should be treated to the pelvic nodes alone (internal/external iliac, distal common iliac, obturator, and presacral), whereas patients with positive margins should be treated to the pelvic nodes and cystectomy bed. Proposed OARs included the rectum, bowel space, bone marrow, and urinary diversion. Consensus language describing the CTVs and OARs was developed and externally validated. The revised instructions were found to produce consistent contours., Conclusions: Consensus descriptions of CTVs and OARs were successfully developed and can be used in clinical trials of adjuvant radiation therapy for bladder cancer., Competing Interests: J.C. discloses employment at Elekta AB. The authors have nothing else to disclose., (Copyright © 2016 Elsevier Inc. All rights reserved.)