Icaritin inhibits the progression of urothelial cancer by suppressing PADI2-mediated neutrophil infiltration and neutrophil extracellular trap formation.

Tumor relapse and metastasis are the major causes of mortality associated with urothelial cancer. In the tumor microenvironment, negative regulatory molecules and various immune cell subtypes suppress antitumor immunity. The inflammatory microenvironment, associated with neutrophils and neutrophil extracellular traps (NETs), promotes tumor metastasis. However, no drugs are currently available to specifically inhibit neutrophils and NETs. In this study, we first demonstrated that icaritin (ICT), a Chinese herbal remedy that is a first-line treatment for advanced and incurable hepatocellular carcinoma, reduces NETs caused by suicidal NETosis and prevents neutrophil infiltration in the tumor microenvironment. Mechanistically, ICT binds to and inhibits the expression of PADI2 in neutrophils, thereby suppressing PADI2-mediated histone citrullination. Moreover, ICT inhibits ROS generation, suppresses the MAPK signaling pathway, and inhibits NET-induced tumor metastasis. Simultaneously, ICT inhibits tumoral PADI2-mediated histone citrullination, which consequently suppresses the transcription of neutrophil-recruiting genes such as GM-CSF and IL-6. The downregulation of IL-6 expression, in turn, forms a regulatory feedback loop through the JAK2/STAT3/IL-6 axis. Through a retrospective study of clinical samples, we found a correlation between neutrophils, NETs, UCa prognosis, and immune evasion. Combining ICT with immune checkpoint inhibitors may have synergistic effects. In summary, our study demonstrated that ICT could be a novel inhibitor of NETs and a novel UCa treatment.

Oligometastatic Urothelial Cancer and Stereotactic Body Radiotherapy: A Systematic Review and an Updated Insight of Current Evidence and Future Directions.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is the most commonly used metastasis-directed therapy (MDT) for oligometastatic urothelial carcinoma (omUC). Despite efforts in defining this disease entity, open questions remain concerning the role of MDT and the use of biomarkers, imaging, and its combination with systemic therapies. The aim of the present systematic review is to provide an updated overview of the current clinical evidence on SBRT for omUC in terms of survival and local control benefits. We also aim to provide updates on controversial areas and future directions in this emerging field. METHODS: With a systematic approach, following PRISMA recommendations, we searched two databases to identify and select articles published up until March 2024 reporting the use of SBRT for omUC with or without concomitant systemic therapies. Prospective randomized or non-randomized studies as well as retrospective studies were included. RESULTS: Eight studies were selected for data extraction and 293 omUC patients treated with SBRT were collectively analyzed. In metachronous omUC patients, SBRT delivered with ablative doses (BED10 ≥ 78 Gy) was associated with a 2-year overall survival (OS) rate of 50.7% (95% CI 35.1-64.4%). The use of sub-ablative SBRT doses (BED10 = 43.2 Gy) in combination with immunotherapy did not demonstrate significant clinical outcome improvement in two prospective studies. The overall tolerance was good, with only one study reporting toxicity of grade 3 in up to 18% of the patients treated with SBRT in combination with immunotherapy. CONCLUSIONS: SBRT is an effective and widely available MDT option in omUC, although this is based on a limited number of studies. Despite the attempt to use SBRT as an immune response trigger in combination with immunotherapy, no significant improvement in survival outcomes has been observed. The integration of new systemic agents with MDT will likely define a new scenario for the treatment of omUC. The review protocol was registered in PROSPERO, ID: CRD42024522381.

Urothelial cancer: state of art in Ukraine and improvement pathways.

Aim: This study aims to assess the effectiveness of urothelial cancer treatment in Ukraine, utilizing population-based data from the National Cancer Registry. The primary goal is to evaluate trends and approaches to therapy, with a focus on overall survival rates in patients with urothelial tumors. Materials and methods: A retrospective cross-sectional analysis was conducted based on the National Cancer Registry, involving 12 698 patients (2008-2020) with urothelial tumors of the upper urinary tract (UTUC) and bladder cancer (BC) who underwent surgical treatment. Demographic indicators, surgical interventions, complications, and survival rates were analyzed. Results: The average age for all patients was 70 years. The number of patients undergoing radical treatment was 1820 (15%) among BC and 573 (59%) among UTUC. The 30-day readmission rate was low for both, with a slightly higher preference for UTUC (2.3 vs. 4.6%). Whereas grade III or higher Cl-Dindo complications were seen in only 0.2% of cases. Notable findings include low frequency of neoadjuvant (7%) and adjuvant chemotherapy (28%) among patients with invasive urothelial carcinomas. Median eGFR for invasive UTUC before and after surgery was 63.2 and 51.4 ml/min, respectively (P=0.00054). The directly opposite trend was seen in BC-61.2 and 68.7 ml/min, respectively (P=0.0026).For BC, the overall survival rates by stages were: I-73%, II-49%, III-18%, and IV-11% (χ2=1807.207; P=0.000001). As for UTUC, the 5-year overall survival rates corresponded to the literature data, but there was a pronounced negative trend towards a decrease in this indicator after a 10-year period for all stages (χ2=146.298; P=0.000003). Conclusion: The study emphasizes the importance of effective systemic treatments, adherence to treatment guidelines, and the need for multidisciplinary consultations among Ukrainian patients with urothelial cancer.

MicroRNAs in Genitourinary Malignancies: An Exciting Frontier of Cancer Diagnostics and Therapeutics.

Genitourinary (GU) malignancies, including prostate, urothelial, kidney, testicular, penile, and adrenocortical cancers, comprise a significant burden of cancers worldwide. While many practice-changing advances have been made in the management of GU malignancies in the last decade, there is still significant room for improvement. MicroRNAs (miRNAs) are noncoding RNAs that regulate post-transcription gene expression and which have been implicated in multiple mechanisms of carcinogenesis. Therefore, they have the potential to revolutionize personalized cancer therapy, with several ongoing preclinical and clinical studies underway to investigate their efficacy. In this review, we describe the current landscape of miRNAs as diagnostics, therapeutics, and biomarkers of response for GU malignancies, reflecting a novel frontier in cancer treatment.

New Advances in Metastatic Urothelial Cancer: A Narrative Review on Recent Developments and Future Perspectives.

The standard of care for advanced or metastatic urothelial carcinoma (mUC) was historically identified with platinum-based chemotherapy. Thanks to the advances in biological and genetic knowledge and technologies, new therapeutic agents have emerged in this setting recently: the immune checkpoint inhibitors and the fibroblast growth factor receptor inhibitors as the target therapy for patients harboring alterations in the fibroblast growth factor receptor (FGFR) pathway. However, chasing a tumor's tendency to recur and progress, a new class of agents has more recently entered the scene, with promising results. Antibody-drug conjugates (ADCs) are in fact the latest addition, with enfortumab vedotin being the first to receive accelerated approval by the U.S. Food and Drug Administration in December 2019, followed by sacituzumab govitecan. Many other ADCs are still under investigation. ADCs undoubtedly represent the new frontier, with the potential of transforming the management of mUC treatment in the future. Therefore, we reviewed the landscape of mUC treatment options, giving an insight into the molecular basis and mechanisms, and evaluating new therapeutic strategies in the perspective of more and more personalized treatments.

Risk of Progression of High-grade Primary T1 Non-muscle-invasive Bladder cancer in a Contemporary Cohort.

Patients with high-risk non-muscle-invasive bladder cancer (NMIBC) receive bacillus Calmette-Guérin (BCG) instillations to reduce the risk of progression. For patients with very high-risk NMIBC, immediate radical cystectomy may be considered, as patients who experience disease progression despite BCG treatment have a worse prognosis. However, guideline-recommended stratification for the risk of progression is based on data from patients who were not exposed to BCG. We evaluated the risk of progression in a contemporary cohort of patients with primary high-grade/grade 3 (HG/G3) T1 NMIBC (n = 1268) who received at least one BCG instillation and underwent at least one cystoscopic evaluation. The primary endpoint was the 1-yr risk of progression for all patients and for the subgroup that received adequate BCG, defined as at least five induction instillations and at least two instillations provided as a second BCG course within 6 mo. Progression was defined as detrusor muscle invasion or lymph node or distant metastasis. The 1-yr risk of progression was 6.5% (95% confidence interval [CI] 5.2-8.0) for patients with primary HG/G3 T1 NMIBC who started BCG treatment, and 4.6% (95% CI 3.3-6.4) 1 yr after the first instillation of the second BCG course for patients who received adequate BCG (n = 746). In conclusion, the contemporary risk of progression for patients with HG/G3 T1 NMIBC who receive BCG appears to be low, especially for patients who receive adequate BCG treatment. PATIENT SUMMARY: Our study shows that for patients with a high-grade bladder tumor who received in-bladder BCG (bacillus Calmette-Guérin), the risk of disease progression was 6.5% at 1 yr after their first BCG instillation. For patients who continued with BCG maintenance treatments, the risk of progression was 4.6% after the first BCG maintenance instillation.

Narrative review of value frameworks in urothelial carcinoma and positioning of enfortumab vedotin.

AIMS: Evaluate existing oncology value frameworks in terms of their methodology, structure, characteristics, and functionality using the example of enfortumab vedotin, an approved therapy for urothelial carcinoma. METHODS: A search of PubMed, grey literature, and official websites of relevant international organizations was performed from January 2022 to March 2023. RESULTS: Six frameworks were identified and analyzed, including the American Society of Clinical Oncology's assessment framework, European Society for Medical Oncology's Magnitude of Clinical Benefit Scale, the National Comprehensive Cancer Network's Evidence Blocks, Memorial Sloan Kettering Cancer Center's DrugAbacus, Institute for Clinical and Economic Review's assessment framework, and the Drug Assessment Framework. Comparisons across frameworks were challenging, owing to differing approaches, objectives, perspectives, methodology, and criteria. Based on the results of the EV-301 study (NCT03474107), the European Society for Medical Oncology's Magnitude of Clinical Benefit Scale assigned a score of 4 out of 5 to enfortumab vedotin administered after chemotherapy and immunotherapy. The National Comprehensive Cancer Network's Evidence Blocks enabled assessment of enfortumab vedotin compared with other treatments for locally advanced or metastatic urothelial carcinoma, resulting in the positioning of enfortumab vedotin as a preferred regimen after chemotherapy and immunotherapy. CONCLUSIONS: Application of value frameworks in oncology can contribute to informed value-based decision-making. However, comparisons across frameworks should be made with caution and limited to the same lines of treatment. Enfortumab vedotin may contribute to optimizing outcomes in patients previously treated with chemotherapy and immunotherapy for locally advanced or metastatic urothelial carcinoma.

A single-center retrospective comparison of pT1 substaging methods in bladder cancer.

Substaging of T1 urothelial cancer is associated with tumor progression and its reporting is recommended by international guidelines. However, it has not been integrated in risk stratification tools and there is no agreement on the best method to use for its reporting. We aimed to investigate the applicability, interobserver variability, and prognostic value of histological landmark based and micrometric (aggregate linear length of invasive carcinoma (ALLICA), microscopic vs. extensive system, Rete Oncologica Lombarda (ROL) system) substaging methods. A total of 79 patients with the primary diagnosis of T1 urothelial cancer treated with conventional transurethral resection and adjuvant BCG therapy between 2000 and 2020 at the Medical University of Vienna were included. The anatomical and metrical substaging systems were evaluated using agreement rate, Cohen's kappa, Kendall's tau, and Spearman rank correlation. Prognostic value for high-grade recurrence or T2 progression was evaluated in uni- and multivariable analysis. Applicability and reproducibility were good to moderate and varied between substaging methods. Obstacles are mainly due to fragmentation of samples. Anatomical substaging was associated with progression in univariable and multivariable analysis. In our cohort, we could only identify anatomical landmark-based substaging to be prognostic for T2 progression. A major obstacle for proper pathological assessment is fragmentation of samples due to operational procedure. Avoiding such fragmentation might improve reproducibility and significance of pathological T1 substaging of urothelial cancer.

Split-Dose Cisplatin in Patients With Locally Advanced or Metastatic Urothelial Carcinoma: A Systematic Literature Review and Network Meta-Analysis.

BACKGROUND: Gemcitabine plus cisplatin (GC) is a highly active and commonly used regimen in locally advanced/metastatic urothelial carcinoma (la/mUC). With GC, cisplatin is dosed at 70 mg/m2 on day 1 of a 3-week cycle; however, for many patients, impaired renal or cardiac function, neuropathy, or poor performance status (PS) can preclude the use of cisplatin. A promising alternative is split-dose GC, in which the cisplatin dose is divided over 2 days. METHODS: We conducted a systematic literature review (SLR) and network meta-analysis (NMA) to better understand treatment patterns and comparative effectiveness and safety of split-dose GC vs gemcitabine plus carboplatin (GCa), GC, and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). RESULTS: Among 120 identified studies, 16 studies representing 1,767 patients included split-dose GC. Common reasons for choosing split-dose GC were impaired renal function, age > 70 years, comorbidities, and physician preference. Split-dose GC had objective response rates (ORRs) of 39%-80%, median progression-free survival (PFS) of 3.5-9.9 months, and median overall survival (OS) of 8.5-18.1 months. Discontinuation rates due to adverse events were 5%-38%. In the NMA, ORR with split-dose GC was significantly higher than with GCa. PFS and OS for split-dose GC were similar to that observed with the other regimens (GCa, GC, and MVAC). CONCLUSIONS: This is the first SLR and NMA of split-dose GC in la/mUC. Despite heterogeneity in the limited studies included, split-dose GC demonstrated comparable effectiveness and safety profile to those seen with other regimens. Split-dose GC thus has the potential to extend the la/mUC population eligible to receive cisplatin-based regimens and warrants further prospective study.

Robot-assisted nephroureterectomy: surgical and mid-term oncological outcomes in over 1100 patients (ROBUUST 2.0 collaborative group).

OBJECTIVE: To analyse surgical, functional, and mid-term oncological outcomes of robot-assisted nephroureterectomy (RANU) in a contemporary large multi-institutional setting. PATIENTS AND METHODS: Data were retrieved from the ROBotic surgery for Upper tract Urothelial cancer STtudy (ROBUUST) 2.0 database, an international, multicentre registry encompassing data of patients with upper urinary tract urothelial carcinoma undergoing curative surgery between 2015 and 2022. The analysis included all consecutive patients undergoing RANU except those with missing data in predictors. Detailed surgical, pathological, and postoperative functional data were recorded and analysed. Oncological time-to-event outcomes were: recurrence-free survival (RFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). Survival analysis was performed using the Kaplan-Meier method, with a 3-year cut-off. A multivariable Cox proportional hazard model was built to evaluate predictors of each oncological outcome. RESULTS: A total of 1118 patients underwent RANU during the study period. The postoperative complications rate was 14.1%; the positive surgical margin rate was 4.7%. A postoperative median (interquartile range) estimated glomerular filtration rate decrease of -13.1 (-27.5 to 0) mL/min/1.73 m2 from baseline was observed. The 3-year RFS was 59% and the 3-year MFS was 76%, with a 3-year OS and CSS of 76% and 88%, respectively. Significant predictors of worse oncological outcomes were bladder-cuff excision, high-grade tumour, pathological T stage ≥3, and nodal involvement. CONCLUSIONS: The present study contributes to the growing body of evidence supporting the increasing adoption of RANU. The procedure consistently offers low surgical morbidity and can provide favourable mid-term oncological outcomes, mirroring those of open NU, even in non-organ-confined disease.

Bilateral nephrolithiasis and upper tract transitional cell carcinoma in horseshoe kidney.

Nephroureterectomy is currently the criterion-standard treatment for high-grade upper tract urothelial carcinoma (UTUC). Current guidelines and expert opinions propose some exceptions to this approach based on patient characteristics, disease status, and function of the contralateral kidney. We present a rare case of a patient with horseshoe kidney, bilateral large nephrolithiasis, high-grade UTUC in one moiety, and relative parenchymal thinning of the contralateral side. The patient was treated with a percutaneous, minimally invasive, nephron sparing approach. The patient also had intracollecting system instillations of gemcitabine and docetaxel. Minimally invasive percutaneous resection of high-grade UTUC is a safe procedure in select cases. Current guidelines may not apply to all patients; unique scenarios with UTUC may require personalized decision-making and treatment at specialized centers.

The prognostic value of preoperative plasma fibrinogen in Asian patients with urothelial cancer: a systematic review and meta-analysis.

Objective: We conducted this meta-analysis to comprehensively explore the prognostic value of the preoperative plasma fibrinogen in Asian patients diagnosed with urothelial cancer (UC). Methods: After a systematic search of Web of Science, PubMed, and Embase before May 2024, we included 10 studies in our meta-analysis. The hazard ratios (HRs) with 95% confidence interval (CI) for overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and progression free survival (PFS) were estimated using fixed effect model. Results: This meta-analysis included a total of 2875 patients. UC patients with an elevated preoperative plasma fibrinogen had worse OS (pooled HR: 2.13, 95% CI: 1.81-2.51; P<0.001), CSS (pooled HR: 2.22, 95% CI: 1.83-2.70; P<0.001), RFS (pooled HR: 1.90, 95% CI: 1.59-2.27; P<0.001), and PFS (pooled HR: 2.12, 95% CI: 1.36-3.29, P=0.001). No significant heterogeneity or publication bias was found. Additionally, statistically significant pooled HRs were also calculated in subgroup analysis when stratified by cancer type, country, and cut-off value. Conclusions: The presence of elevated preoperative plasma fibrinogen levels is significantly correlated with unfavorable tumor outcomes in UCs.

Uncommon presentation of transitional cell carcinoma: A case report of hand involvement.

It is uncommon to see bladder cancer metastases in the hand. A 65-year-old man had bladder cancer surgery 3 years ago. His axilla and wrist swelled after surgery. Final amputation was necessary as the cancer had spread to hand. Transitional cell carcinoma was detected by immunohistochemistry with GATA-3, CK7, CK20, and p63 positivity.

An Extremely Rare Case of a 24-Year-Old Female Diagnosed With High-Grade Muscle-Invasive Urothelial Carcinoma in the Bladder.

Bladder cancer most commonly affects older adults. Although extremely rare, it can still be detected in the younger population. Bladder cancer often exhibits distinct behavior in these cases, typically manifesting as a low-grade, non-muscle-invasive disease. We documented a remarkable case involving a 24-year-old female diagnosed with high-grade muscle-invasive bladder cancer. Our report emphasizes the distinctive challenges encountered by clinicians in the journey of diagnosis, treatment, and follow-up of bladder cancer in young patients.

Central pathology review and its prognostic value in upper tract urothelial carcinoma patients: a nationwide multi-institutional study.

The prognostic value of central pathology review in upper urinary tract cancer (UTUC) remains inadequately addressed in existing literature. In this study, we conducted an extensive central pathology review and presented its influence on multi-center UTUC studies. We conducted a retrospective review of patients who underwent radical nephroureterectomy or segmental resection for UTUC to determine eligibility for central pathology review. In the Taiwan UTUC Collaboration cohort, 377 cases met the criteria for pathology review. We assessed agreement between pathologists using both the total percentage of agreement and simple kappa statistics. The prognostic implications of original and review pathology for various parameters were examined using the Cox regression model. This study included 209 female and 168 male participants. Pathology review revealed substantial interobserver variability in pT staging, with a particularly high rate of pT2 cases being upgraded to pT3 upon central review (17/70 pT2 stage made by local pathologists were finally confirmed as pT3 disease by the review pathologist). The local pathologist cohort identified fewer significant histological predictors in survival models compared to the review pathology cohort. Advanced pT stage, perineural invasion (PNI), and positive surgical margin were independent predictors of poorer overall survival and cancer-specific survival. PNI, lymphatic vascular invasion, and positive surgical margin were independent predictors of disease recurrence. Substantial interobserver variability in histological assessment underscores the importance of centralized pathology review for both multi-center studies and accurate post-operative management of UTUC patients. Advanced stage, perineural invasion, and margin status were significant histological predictors of oncological outcomes.

Potential role of transmembrane 9 superfamily member 1 as a biomarker in urothelial cancer.

Bladder cancer is a urological tumor with high rates of recurrence despite recent advances in novel therapies. Many proteins involved in the molecular mechanisms are currently an enigma, especially the transmembrane 9 superfamily member 1 which has an unclear function. Wei et al published the function and mechanism of this protein, and showed that it could participate in the proliferation, migration and invasion of tumor cells in bladder cancer, therefore treatments directed against this protein may be beneficial in avoiding this condition.

Prolonged Response to Osimertinib in EGFR-Mutated Metastatic Urothelial Carcinoma, a Case Report.

A 48-year-old woman without obvious environmental risk factors was diagnosed with metastatic urothelial carcinoma harboring a mutation in EGFR typical of driver mutations for non-small cell lung cancer. Within a year, her cancer progressed on four standard therapies for urothelial cancer, including cancer in lungs, liver, bone, and brain. As fifth-line therapy, she received osimertinib, leading to a complete response in the brain and improvement elsewhere, and the cancer remained controlled for six months. Targeted therapy for rare driver mutations can be effective in urothelial cancer and should be considered prior to exhausting standard therapies.

A Curious Case of Diabetic Ketoacidosis Secondary to Avelumab.

Immune checkpoint inhibitors (ICIs) have completely changed cancer treatment in the last decade and are now widely used in several cancers. In the era of immunotherapy, oncologists have changed not only the way they evaluate treatment efficacy but also the management of treatment-related adverse events. This new profile of immune adverse events has resulted in an urgent need for a more holistic view of cancer patients and for more collaborations with other organ specialists to optimize patient treatment and support. The anti-programmed death-ligand 1 antibody, avelumab, has been widely used as a maintenance treatment in stage IV urothelial carcinoma since the results from the Javelin 100 bladder trial were published. We report a case of a 75-year-old man with stage IV urothelial carcinoma submitted to first-line platinum-based chemotherapy followed by maintenance avelumab. He achieved a complete bone and pulmonary response 10 months after stopping avelumab, which was suspended due to a serious immune adverse event, an ICI-induced type 1 diabetes mellitus. At present, the patient has an overall survival of 24 months and shows no evidence of disease with a good quality of life 16 months after avelumab suspension. We hypothesized that a late response to avelumab could explain this unexpected outcome.

A Head-to-Head Comparison of the First-Line Treatments for Locally Advanced or Metastatic Urothelial Cancer: Is There Still a Role for Chemotherapy?

BACKGROUND: Patients with locally advanced/metastatic urothelial cancer have been conventionally treated with platinum-based chemotherapy. Recently, numerous new treatments have been proposed to improve overall survival (OS) and reduce adverse effects, but no direct head-to-head comparisons among these agents are available. METHODS: The treatments evaluated in our analyses included (a) monotherapy with immune checkpoint inhibitors (ICI); (b) combinations of an ICI with chemotherapy; and (c) combinations of an ICI with other drugs. Using OS as the endpoint, a series of indirect comparisons were performed to rank the most effective regimens against both chemotherapy and each other. Our analysis was based on the application of an artificial intelligence software program (IPDfromKM method) that reconstructs individual patient data from the information reported in the graphs of Kaplan-Meier curves. RESULTS: A total of five studies published in six articles were included. In our main analysis, nivolumab plus chemotherapy showed better OS compared to chemotherapy (HR = 0.70, 95% CI: 0.59-0.82), while durvalumab plus tremelimumab showed no OS benefit (HR = 0.95, 95% CI 0.82-1.11). More interestingly, enfortumab vedotin plus pembrolizumab significantly prolonged OS compared to both chemotherapy alone (HR = 0.53, 95% CI 0.45-0.63) and nivolumab plus chemotherapy (HR = 0.76, 95% CI 0.60-0.97). DISCUSSION AND CONCLUSION: Among new treatments for locally advanced and metastatic urothelial cancer, enfortumab vedotin plus pembrolizumab showed the best efficacy in terms of OS. Our results support the use of this combination as a first-line treatment in this setting.

Factors associated with receipt of systemic anticancer treatment for locally advanced or metastatic urothelial carcinoma in England: a population-based study.

INTRODUCTION: Systemic anticancer therapy for locally advanced or metastatic urothelial carcinoma (la/mUC) is associated with efficacy benefits, including longer overall survival (OS), but many patients remain untreated. This observational, real-world, national study aimed to investigate factors associated with receiving systemic anticancer therapy for la/mUC in England. PATIENTS AND METHODS: Adults diagnosed with la/mUC between 2013 and 2019 were identified in the National Cancer Registration Dataset and followed until March 2021. Healthcare and comorbidity data were obtained from Hospital Episode Statistics Admitted Patient Care and Outpatient datasets. Treatment data were obtained from the Systemic Anti-Cancer Therapy dataset. Factors associated with treatment were identified using multivariable logistic regression. OS from la/mUC diagnosis was estimated using Kaplan-Meier methodology. RESULTS: Of 16,610 patients diagnosed with la/mUC, 5,191 (31%) received systemic anticancer therapy; 4,700 (91%) received platinum-based chemotherapy. Only 18% of patients were cisplatin ineligible. Patients were significantly less likely to receive treatment if they were female, cisplatin ineligible, older, or diagnosed before 2018; had laUC, an Eastern Cooperative Oncology Group performance status >1, or greater comorbidity; or resided outside London or in income-deprived areas. Median OS (95% CI) from diagnosis in treated vs. untreated patients was 19.9 (19.4-20.6) vs. 5.8 (5.6-6.0) months, respectively. Limitations include retrospective analysis of data not initially collected for research purposes. CONCLUSION: From 2013 to 2019, ≈70% of patients with la/mUC in England were untreated, which is high given the availability of effective treatments. Reasons for undertreatment should be addressed. Given the evolving treatment landscape, analysis of more recent data would be informative. MICROABSTRACT: This study investigated systemic anticancer treatment for patients diagnosed with advanced urothelial carcinoma in England between 2013 and 2019. Of 16,610 patients, 31% received treatment. Various factors were associated with not receiving treatment, including female sex, older age, worse performance status, greater comorbidity, and resident in income-deprived areas. Median overall survival in treated vs. untreated patients was 19.9 vs. 5.8 months.