Bladder Cancer Death Research Articles

Disparities in trends in bladder cancer mortality between urban and rural patients: A 2000-2020 analysis.

4583 Background: Patients in rural areas in the US often have worse healthcare outcomes due to socioeconomic deprivation, higher rates of smoking, and limited access to medical care. Despite a general decline in bladder cancer mortality over the past two decades, comprehensive studies comparing these trends between urban and rural mortality are scarce. Methods: Utilizing the CDC WONDER database, we extracted mortality data for bladder cancer from 2000 to 2020. Age-adjusted mortality rates per 100,000 persons were standardized to the Year 2000 US standard population. Data segmentation by urbanity utilized the 2013 National Center for Health Statistics Urban-Rural Classification Scheme. The National Cancer Institute's Joinpoint Regression Program was employed to calculate average annual percent changes (AAPCs) and annual percent changes (APCs). Results: In our analysis, we identified a total of 306,750 bladder cancer death cases from 2000 to 2020. Significant improvements in bladder cancer mortality were observed in urban areas, with large central metros experiencing the most pronounced decrease (AAPC -1.0%, p<0.001). This decline was moderate between 2000 and 2016 (APC -0.3, p< 0.001) but accelerated between 2016 and 2020 (APC -3.8%, p<0.001). Large fringe and medium metros also saw comparatively smaller but significant declines (AAPC -0.6%, P<0.05) and also accelerated between 2016-2020. In contrast, small metro and rural areas (micropolitan and noncore) showed no significant improvement, with mortality rates remaining stable between 2000 and 2020 (AAPC 0.2%, P=0.099). Conclusions: This analysis, the largest to date comparing urban and rural mortality trends in bladder cancer, highlights significant disparities in outcomes between large urban and rural areas. The marked improvement in urban areas, especially noted around the time novel agents such as immunotherapy were introduced, underscores the potential impact of advanced treatments. However, the stable mortality rates in rural areas suggest that access to advanced care, environmental influences, socioeconomic status, and slower adaptation of new guidelines in rural settings may play critical roles. These findings underline the urgent need for strategies to close the urban-rural gap. [Table: see text]

Longitudinal Analysis of Bladder Cancer-Specific Mortality Trends in the United States.

Bladder cancer is the tenth leading cause of cancer death in the United States (US). Advances in diagnosis, imaging, and treatments have led to improvements in bladder cancer management. To evaluate longitudinal bladder cancer mortality trends from 1999-2020 in the US by gender, race, ethnicity, age, geographic region, and urbanization category. Age-adjusted bladder cancer death and incidence rates of individuals in the US of all ages between 1999-2020 were obtained using the CDC WONDER and NAACCR databases. Trends and average annual percent changes (AAPC) in age-adjusted Bladder Cancer-Specific Mortality (BCSM) and incidence rates were estimated. Data were analyzed from May 2023 to October 2023. From 1999-2020, overall BCSM decreased by 0.4% annually, with a dramatic decrease in deaths between 2015-2020 (AAPC: -2.0% [95% CI: -2.6,-1.3]). However, BCSM rates and metastatic malignant bladder cancer incidence rates from 1999-2020 increased for individuals≥85 years old (AAPC for BCSM: 0.8% [95% CI:0.5,1.1]; AAPC for metastatic malignant incidence: 2.5% [95% CI: 2.0,2.9]). Increases in BCSM were found for certain years in the South, in rural areas, and for Non-Hispanic White and Asian or Pacific Islander individuals. Overall mortality from bladder cancer has been decreasing in the US over two decades. Upon disaggregation, increasing trends were found for BCSM and for metastatic malignant bladder cancer incidence for individuals≥85 years old from 1999-2020. Further evaluation of these trends is essential to understand how to target specific populations to improve patient outcomes.

Second TURB, restaging TURB or repeat TURB in primary T1 non-muscle invasive bladder cancer: impact on prognosis?

A re-transurethral resection of the bladder (re-TURB) is a well-established approach in managing non-muscle invasive bladder cancer (NMIBC) for various reasons: repeat-TURB is recommended for a macroscopically incomplete initial resection, restaging-TURB is required if the first resection was macroscopically complete but contained no detrusor muscle (DM) and second-TURB is advised for all completely resected T1-tumors with DM in the resection specimen. This study assessed the long-term outcomes after repeat-, second-, and restaging-TURB in T1-NMIBC patients. Individual patient data with tumor characteristics of 1660 primary T1-patients (muscle-invasion at re-TURB omitted) diagnosed from 1990 to 2018 in 17 hospitals were analyzed. Time to recurrence, progression, death due to bladder cancer (BC), and all causes (OS) were visualized with cumulative incidence functions and analyzed by log-rank tests and multivariable Cox-regression models stratified by institution. Median follow-up was 45.3 (IQR 22.7-81.1) months. There were no differences in time to recurrence, progression, or OS between patients undergoing restaging (135 patients), second (644 patients), or repeat-TURB (84 patients), nor between patients who did or who did not undergo second or restaging-TURB. However, patients who underwent repeat-TURB had a shorter time to BC death compared to those who had second- or restaging-TURB (multivariable HR 3.58, P = 0.004). Prognosis did not significantly differ between patients who underwent restaging- or second-TURB. However, a worse prognosis in terms of death due to bladder cancer was found in patients who underwent repeat-TURB compared to second-TURB and restaging-TURB, highlighting the importance of separately evaluating different indications for re-TURB.

Secondary Bladder Cancer After Prostate Cancer Treatment: An Age-matched Comparison Between Radiation and Surgery

BackgroundSecondary malignancy is a long-term risk of radiation. External beam radiation therapy (EBRT) for prostate cancer treatment has been associated with later development of bladder cancer and worse bladder cancer features. ObjectiveWe sought to provide an updated comparison of the long-term risk of bladder cancer after different localized prostate cancer treatments. Design, setting, and participantsUsing the Surveillance, Epidemiology, and End Results (SEER) cancer registry, we compared an age-matched subset of patients who underwent radical prostatectomy (RP) with those who underwent EBRT, brachytherapy (BT), EBRT + BT, and RP followed by EBRT (RPtoEBRT) between 2000 and 2018. Our final cohort included 261 609 patients with a median follow-up of 11.6 yr. Outcome measurements and statistical analysisOur primary outcomes were time to bladder cancer diagnosis, muscle-invasive bladder cancer diagnosis, and bladder cancer death. We used cause-specific hazard models considering death as a competing event. A similar analysis was performed on lung cancer, as a surrogate marker for smoking. We also compared proportions of variant histology, high-grade, and invasive disease among bladder cancers that occurred after radiation versus RP using chi-square testing. Results and limitationsAll radiation groups were associated with bladder cancer diagnosis; hazard ratios (HRs) were 1.72, 1.85, 1.80, and 1.53 for EBRT, BT, EBRT + BT, and RPtoEBRT, respectively, using RP as a referent (all p < 0.001). HRs for bladder cancer death were even higher: 2.39, 2.57, and 3.02 for EBRT, BT, and EBRT + BT, respectively (all p < 0.001), except for RPtoEBRT (HR 1.43, p = 0.28). Lung cancer diagnosis was also associated with radiation but at lower HRs—1.63, 1.32, 1.42, and 1.30 for EBRT, BT, EBRT + BT, and RPtoEBRT, respectively (all p < 0.001). There were a higher proportion of ≥T2, ≥T3, and sarcomatoid variant bladder cancers after radiation (all p < 0.01) ConclusionsThe risk of developing and dying from bladder cancer is increased in patients treated with radiation compared with those treated with RP. The risk was similar for BT and EBRT. Bladder cancers after radiation are more likely to be sarcomatoid variant and present as muscle invasive. Patient summaryWe observed the rates of bladder cancer after patients had undergone surgery or radiation for prostate cancer, and found higher rates of bladder cancer after radiation. We also observed that bladder cancers that occur after radiation tend to be more aggressive.

PD29-07 BOTH EBRT AND BRACHYTHERAPY INCREASE PROBABILITY OF SUBSEQUENT BLADDER CANCER COMPARED TO PROSTATECTOMY

You have accessJournal of UrologyCME1 Apr 2023PD29-07 BOTH EBRT AND BRACHYTHERAPY INCREASE PROBABILITY OF SUBSEQUENT BLADDER CANCER COMPARED TO PROSTATECTOMY Steven Monda, Hans Lui, Manolis Pratsinis, Onika Noel, Christopher Evans, and Marc Dall'Era Steven MondaSteven Monda More articles by this author , Hans LuiHans Lui More articles by this author , Manolis PratsinisManolis Pratsinis More articles by this author , Onika NoelOnika Noel More articles by this author , Christopher EvansChristopher Evans More articles by this author , and Marc Dall'EraMarc Dall'Era More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003315.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The comparative risk of bladder cancer among patients treated for prostate cancer with prostatectomy (RP), external beam radiation therapy (EBRT), and brachytherapy (BT) in long-term follow up is not well known. We aimed to characterize this risk with an age-matched time-to-event comparison between radiation and surgical treatments arms. METHODS: Using the 2000 to 2019 SEER database, we identified 261,609 age-matched patients treated for prostate cancer with RP, BT, EBRT, EBRT&BT, and RP followed by EBRT (RPtoEBRT). Our primary analyses were cause-specific Cox proportional hazards models using time to bladder cancer diagnosis and bladder cancer death as the events of interest. A parallel analysis was run on lung cancer as a control cancer outside of the field of pelvic radiation but also highly associated with smoking status. RESULTS: The adjusted cause-specific hazard ratio of bladder cancer diagnosis after prostate cancer treatment, compared to RP as reference, was 1.86 for BT, 1.76 for EBRT, 1.85 for EBRT&BT, and 1.49 for RPtoEBRT (p<0.001). See Table 1. Except for in RPtoEBRT, the hazard ratios for bladder cancer death among the radiation arms were even greater, 2.64 for BT, 2.76 for EBRT, and 2.99 for EBRT&BT. Lung cancer was associated with all radiation arms (p<0.001) but at lower hazard ratios. CONCLUSIONS: Radiation, in all forms, is associated with bladder cancer diagnosis and death, when matching and controlling for age. Although a major limitation is that smoking status is not available within SEER, our lung cancer analysis was intended to address this. The hazard ratios of radiation were much higher for bladder cancer diagnosis and death, compared to lung cancer diagnosis and death. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e826 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Steven Monda More articles by this author Hans Lui More articles by this author Manolis Pratsinis More articles by this author Onika Noel More articles by this author Christopher Evans More articles by this author Marc Dall'Era More articles by this author Expand All Advertisement PDF downloadLoading ...

Oncological outcome of intraarterial chemotherapy combined with radiotherapy compared to radical cystectomy for patients with muscle invasive bladder cancer.

515 Background: Although radical cystectomy (RC) has been a standard treatment for muscle invasive bladder cancer (MIBC), some patients are unfit or refuse RC. Intraarterial chemotherapy combined with radiotherapy (IAC-RT) is one of the bladder preservation techniques, but there are a few data in patients who performed IAC-RT without salvage RC. The aim of this study was to evaluate the efficacy and tolerability of IAC-RT without RC compared to RC in patients with MIBC. Methods: We retrospectively reviewed patients with MIBC (T2-4N0M0) who had received either IAC-RT or RC in our hospital between January 1999 and December 2019. Intraarterial chemotherapy consisted of cisplatin (30mg/m2) and adriamycin (20mg/m2) on day 1 of each 1st, 2nd, 5th, 6th week. Concomitant radiotherapy (2 Gy/session, total 60 Gy) to whole pelvis was performed during chemotherapy. Salvage RC was not performed in all patients. Overall survival (OS), disease-specific survival (DSS), and metastasis-free survival (MFS) were compared between patients who received IAC-RT and RC. The prognostic factors of IAC-RT associated with OS were also investigated. Results: Forty-two and 143 patients received IAC-RT and RC, respectively. Of 42 patients who received IAC-RT, 28 (67%) and 14 (33%) were elective (refused RC) and imperative (comorbidity:7 poor PS:6 unresectable:1) cases, respectively. The patients who underwent IAC-RT were older (median; 77 vs 69 years old) and had poorer PS (≥2; 43% vs 4.9%) and shorter follow-up time (median; 21.9 vs 40.0 months) than those of RC. During follow up periods, metastasis, bladder cancer death, death of any cause was observed in 20, 19, and 27 patients with IAC-RT, 59, 55, and 49 patients with RC. In survival analyses, median OS was 38.7 months (95%CI, 16.9-74.7) with IAC-RT versus 154.0 months (95%CI, 70.6- not estimable (NE)) with RC, these OS curves were significantly different (P=0.001). There were not significant differences between two groups in DSS (median 46.5 vs not reached, P=0.06) and MFS (median 38.7 vs not reached, P=0.21). In multivariate analysis, clinical stage (≥T3; HR, 1.89; 95% CI, 1.04-3.46; P=0.04) and PS (≥2; HR, 2.24; 95% CI, 1.16-4.33; P=0.02) were suggested as risk factors associated with poor OS, however, treatment procedure (IAC-RT or RC) did not associate with OS. Forty of 42 (95%) patients with IAC-RT had any adverse events (AEs). Although grade3 AEs were observed in 21 (50%) patients, most of them were hematological AEs and Grade 4/5 AEs was not observed. Conclusions: IAC-RT was a useful and tolerable treatment option for patients with MIBC who were unfit or refused RC.

Abstract 3239: OXCT1: Role of ketone bodies in acquired gemcitabine resistance in bladder cancer

Abstract Urinary bladder cancer accounts for 81,000 new cases per year and 4.7% of the new cancer diagnosis in the US. Even though most of the patients suffer from non-invasive lesions, around 70% will recur following surgical intervention. Chemotherapy with gemcitabine in combination with cisplatin is a common treatment option for recurrent disease, however 60% of the patients will relapse due to resistance. Gemcitabine (2’,2’-difluoro 2’-deoxycytidine) is classified as an antimetabolite, is commonly administered to BCa patients. This DNA synthesis inhibitor, is also used to treat pancreatic, breast, ovarian, and non-small cell lung cancer patients. Having lower relative toxicity, BCa patients are given gemcitabine as a single agent for intravesical therapy. Resistance mechanisms for gemcitabine have been reported to involve Hedgehog, Wnt, and Notch, signaling as potential means of cancer stem cell programming dependent on the tumor type. In examining mechanisms of resistance, we identified ketone body metabolism to be important. OXCT1, a rate-limiting enzyme in ketone metabolism, was found to be highly associated with bladder cancer death - Hoglund et al. P = 2.3x10-3 and TCGA, P = 6.5x10-4. We measured the expression of OXCT1 in RT4, UMUC3, T24 and 5637 bladder cancer cell lines and observed that expression correlated with gemcitabine resistance. The generation of gemcitabine resistance of otherwise sensitive 5637 cells (5637GR) resulted in elevation of OXCT1. Conversely, the CRISPR/Cas9 knockout of OXCT1 was able to sensitize inherently resistant UMUC3 and generated 5637GR lines. Given that OXCT1 is a rate limiting enzyme in ketone metabolism, we evaluated oxygen consumption rate finding increase metabolic activity. Furthermore we evaluated stemness through sphere forming assays (hanging drop and forced floating methods) to reveal that the OXCT1-KO lines had reduced spheres compared to their parental lines. Keeping in mind that several developmental processes were altered in 5637GR and restored to parental levels in the 5637GR-OXCT1-KO, we evaluated the transcriptomic differences in the cell types to determine the mechanism that led to the metabolic changes induced by gemcitabine resistance. master regulator analysis that revealed three key transcription factors (TFs), TBX2, SOX15 and OVOL1. Analysis of the downstream targets of the three master regulators in the TCGA BCa data (n = 408), the Peter C. Black neoadjuvant chemotherapy data (n = 134) and the Hoglund muscle invasive data (n = 308) demonstrated that OVOL1 is highly associated with recurrence. Moreover, downstream targets of OVOL1 are involved in fatty acid metabolism, survival and differentiation. These data links ketone metabolism and stemness. Additionally, it opens the door for targets in gemcitabine treatment Citation Format: Krizia Rohena Rivera, Sungyoung You, Minhyung Kim, Sandrine Billet, Johanna Hoeve-Scott, Gabrielle Gonzales, Chengqun Huang, Ashley Heard, Neil A. Bhowmick. OXCT1: Role of ketone bodies in acquired gemcitabine resistance in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3239.

Determination of four trihalomethanes in ship ballast water by gas chromatography-negative chemical ionization-mass spectrometry

我国每年的船舶压载水排放量巨大,压载水中含有浮游生物、病原体及其幼虫或孢子等,若处理不当,会对排放水域的生态环境造成严重影响。排放压载水前常使用电解法对其进行处理,电解产生的次氯酸钠溶液,能有效杀灭残余的微生物。但电解后会产生副产物三卤甲烷(THMs),其对人体有一定的健康风险,建立船舶压载水中三卤甲烷的测定方法具有重要意义。该研究建立了采用气相色谱-负化学源质谱(GC-NCI-MS)测定船舶压载水中4种三卤甲烷(包括三氯甲烷、二氯一溴甲烷、一氯二溴甲烷、三溴甲烷)的分析方法。船舶压载水样品经过顶空进样技术处理后,通过DB-5MS UI毛细管色谱柱(30 m×0.25 mm×1.0 μm)分离,气相色谱-负化学源质谱仪测定,在选择离子扫描(SIM)模式下分析,采用外标法进行定量。4种三卤甲烷在0.2~50 μg/L范围内线性关系良好,相关系数(r)≥0.995,定量限(S/N=10)为0.1~0.2 μg/L,在0.2、0.5、2.0 μg/L 3个加标水平下,4种THMs的平均回收率为90.3%~106.8%,相对标准偏差(RSD)为1.4%~6.2%。该方法准确、稳定、可靠,可用于测定船舶压载水中4种THMs的含量。使用建立的测定方法对36个船舶压载水进行测定,三溴甲烷、二溴一氯甲烷、一溴二氯甲烷与三氯甲烷的检出率分别为83.3%、69.4%、22.2%和19.4%,检出值分别为34.25~221.5 μg/L、3.52~41.87 μg/L、1.52~8.56 μg/L和0.02~5.46 μg/L。

Primary versus secondary muscle-invasive bladder cancer: survival after curative treatment

Purpose To assess if cancer-specific survival (CSS) following curative intent treatment (CIT) for muscle-invasive bladder cancer (MIBC) differs between patients presenting with MIBC (primary) and patients presenting with non-muscle-invasive bladder cancer who progress to MIBC (secondary). Methods This study uses data from the Cancer Registry of Norway on patients initially diagnosed with bladder cancer in 2008–2012 and treated with radical cystectomy (RC) or radiotherapy (RT). To ensure a clinically relevant population, we selected patients with a pre-treatment histology confirming muscle-invasion. Survival models were applied to evaluate differences in observed and adjusted CSS by type of MIBC and stratified by type of CIT. Adjustment was made for age group, sex, previous cancer, diagnostic hospital’s academic status and geographical region, and type of CIT. Results We identified 650 eligible patients: 589 (91%) primary MIBC and 61 (9%) secondary MIBC. A total of 556 (86%) patients underwent RC and 94 (14%) RT. The 5-year CSS for primary MIBC was 56% and 59% for secondary MIBC (p = 0.68). The type of MIBC did not impact the risk of bladder cancer death (HR = 0.85, CI = 0.55–1.33, p = 0.48), nor when stratified for CIT (RC: HR = 0.93, CI = 0.57–1.53, p = 0.78); RT: HR = 0.71, CI = 0.24–2.16, p = 0.55). Conclusion This first nation-wide population-based study comparing CSS between primary and secondary MIBC showed no significant difference in survival regardless of type of CIT. Continued surveillance of patients with non-muscle-invasive bladder cancer is necessary to detect early progression to MIBC. Future studies should include molecular and genetic characteristics in addition to detailed clinicopathologic information.

Risk of bladder cancer death in patients younger than 50 with non-muscle-invasive and muscle-invasive bladder cancer

Introduction and objectives Bladder cancer is primarily a disease of older age and little is known about the differences between patients diagnosed with bladder cancer at a younger versus older age. Our objectives were to compare bladder cancer specific survival in patients aged <50 versus those aged 50–70 at time of diagnosis. Materials and methods The Swedish bladder cancer database provided data on patient demographics, clinical characteristics and treatments for this observational study. Cox proportional hazard regression models were adjusted for appropriate variables. All analyses were stratified by disease stage (non-muscle-invasive bladder cancer and muscle-invasive bladder cancer. Furthermore, we compared the frequency of lower urinary tract infections within 24 months prior to bladder cancer diagnosis by sex and age groups. Results The study included 15,452 newly-diagnosed BC patients (1997–2014); 1,207 (8%) patients were <50 whilst 14,245 (92%) were aged 50–70. Patients aged <50 at diagnosis were at a decreased risk of bladder cancer death (HR = 0.82, 95%CI: 0.68–0.99) compared to those aged 50–70. When stratified by non-muscle-invasive and muscle-invasive bladder cancer, this association remained in non-muscle-invasive patients only (<50, HR = 0.43, 95% CI: 0.28–0.64). The frequency of lower urinary tract infection diagnoses did not differ between younger and older patients in either men or women. Conclusions Patients diagnosed with non-muscle-invasive bladder cancer when aged <50 are at decreased risk of bladder cancer-specific death when compared to their older (50-70) counterparts. These observations raise relevant research questions about age-related differences in diagnostic procedures, clinical decision-making and, not least, potential differences in tumour biology.

Survival Impact of Current-Smoking-Related COPD or COPD with Acute Exacerbation on Bladder Preservation through Concurrent Chemoradiotherapy for Muscle-Invasive Bladder Urothelial Carcinoma.

PURPOSE: The survival effect of smoking-related chronic obstructive pulmonary disease (COPD) and COPD with acute exacerbation (COPDAE) on patients with muscle-invasive bladder urothelial carcinoma (MIBUC) receiving concurrent chemoradiotherapy (CCRT) for bladder preservation is unclear. METHODS: We recruited patients with MIBUC, clinical stages IIA–IVB, who had received maximal transurethral resection of bladder tumor (TURBT) followed by CCRT from the Taiwan Cancer Registry Database. The Cox proportional hazards model was used to analyze all-cause mortality. We categorized the patients into two groups by using propensity score matching based on the preexisting COPD status (within 1 year before CCRT) to compare overall survival outcomes: Group 1 (never smokers without COPD) and Group 2 (current smokers with COPD). RESULTS: In multivariate Cox regression analyses, the adjusted hazard ratio (aHR; 95% confidence interval (CI)) of all-cause mortality in Group 2 compared with Group 1 was 1.89 (1.12–3.18), p = 0.017. The aHRs (95% CIs) of all-cause mortality for ≥1 and ≥2 hospitalizations for COPDAE within 1 year before CCRT for bladder preservation were 3.26 (1.95–5.46) and 6.33 (3.55–11.281) compared with non-COPDAE patients with MIBUC undergoing CCRT for bladder preservation. CONCLUSIONS: Among patients with MIBUC undergoing TURBT followed by CCRT for bladder preservation, current smokers with smoking-related COPD had worse survival outcomes than did nonsmokers without COPD. CONDENSED ABSTRACT: This was the first study to estimate the survival impact of smoking-related chronic obstructive pulmonary disease (COPD) on patients with muscle-invasive bladder urothelial carcinoma (MIBUC) receiving maximal transurethral resection of bladder tumor (TURBT) followed by concurrent chemoradiotherapy (CCRT) for bladder preservation. Smoking-related COPD was a significant independent risk factor for all-cause mortality in patients with clinical stages IIA–IVB receiving TURBT followed by CCRT. Hospitalization frequency for COPD with at least one acute exacerbation within 1 year before CCRT was highly associated with high mortality for patients with MIBUC receiving CCRT for bladder preservation. Not only all-cause death but also bladder cancer death and COPD death were significantly higher in the current-smoking COPD group than in the never-smoking non-COPD group.

P0738 - Risk of bladder cancer death in patients younger than 50 with non-muscle-invasive and muscle-invasive bladder cancer

P0738 - Risk of bladder cancer death in patients younger than 50 with non-muscle-invasive and muscle-invasive bladder cancer

Partial Versus Complete Bacillus Calmette-Guérin Intravesical Therapy and Bladder Cancer Outcomes in High-risk Non–muscle-invasive Bladder Cancer: Is NIMBUS the Full Story?

BackgroundIt is important to understand the implications of reduced bacillus Calmette-Guérin (BCG) treatment intensity, given global shortages and early termination of the NIMBUS trial. ObjectiveTo assess the association of partial versus complete BCG induction with outcomes. Design, setting, and participantsThis is a retrospective cohort study of veterans diagnosed with high-risk non–muscle-invasive bladder cancer (NMIBC; high grade [HG] Ta, T1, or carcinoma in situ) between 2005 and 2011 with follow-up through 2014. InterventionPatients were categorized into partial versus complete BCG induction (one to five vs five or more instillations). Partial BCG induction subgroups were defined for comparison with the NIMBUS trial. Outcome measurements and statistical analysisPropensity score–adjusted regression models were used to assess the association of partial BCG induction with risk of recurrence and bladder cancer death. Results and limitationsAmong 540 patients, 114 (21.1%) underwent partial BCG induction. Partial versus complete BCG induction was not significantly associated with the risk of recurrence in HG Ta (cumulative incidence [CIn] 46.6% vs 53.9% at 5 yr, p = 0.38) or T1 (CIn 47.1% vs 56.7 at 5 yr, p = 0.19) disease. Similarly, we found no increased risk of bladder cancer death (HG Ta: CIn 4.7%7vs 5.4% at 5 yr, p = 0.87; T1: CIn 10.0% vs 11.4% at 5 yr, p = 0.77). NIMBUS-like induction was associated with an increased risk of recurrence in patients with HG Ta disease, although not statistically significant. Unmeasured confounding is a limitation. ConclusionsCancer outcomes were similar among high-risk NMIBC patients who underwent partial versus complete BCG induction, suggesting that future research is needed to determine how to optimize BCG delivery for the greatest number of patients, especially during global shortages. Patient summaryOutcomes were similar between patients receiving partial and complete courses of bacillus Calmette-Guérin (BCG) therapy. Future research is needed to determine how to best deliver BCG to the greatest number of patients, particularly during medication shortages.

Geographic Distribution of Racial Differences in Bladder Cancer Mortality in the United States: A Nationwide Population-Based Study

African-Americans (AAs) have up to two times increased risk of bladder cancer death than Caucasians. Bladder cancer mortality increases exponentially once it invades the muscle. Geographic heterogeneity in bladder cancer mortality according to race remains to be determined. The purpose of this study was to determine the geographic distribution of muscle-invasive bladder cancer (MIBC) mortality according to race. Analysis of Surveillance, Epidemiology, and End Results (SEER)-Medicare data for 6,044 patients aged 66-85 diagnosed with clinical stage T2-T4 N0M0 bladder cancer from January 1, 2002 to December 31, 2011. Fine and Gray competing risks regression models, including an unadjusted model and an adjusted model with an interaction term between race and registry, were used to assess the association of race with bladder cancer-specific mortality (BCSM) according to tumor registry. Out of 6,044 patients, 5,408 (89.5%) were Caucasian, 352 (5.82%) were non-Hispanic AA, 85 (1.4%) were Hispanic, and 199 (3.29%) were other. Of the 18 registries, AAs with bladder cancer were largely concentrated in Louisiana (19%), New Jersey (17.9%) and Georgia (17.6%). New Jersey was the only registry where AAs had increased risk of BCSM than Caucasians and only for stage T2 disease: (AHR, 1.74; 95% CI 1.22-2.47, P=0.002). AAs in New Jersey had worse BCSM than Caucasians regardless of management: no curative treatment (AHR, 1.61; 95% CI 1.09-2.37, P=0.0168), radical cystectomy (AHR, 2.05; 95% CI 1.26-3.35, P=0.0039), and trimodal therapy (AHR, 1.55; 95% CI 1.03-2.35, P=0.0367). We observed geographic variation in death from bladder cancer which impacted one registry which had one of the largest population of AAs. These findings support further investigation into the social determinants of race (i.e. socioeconomic status and distance to health care facility) which may drive these results.

5\u03b1-reductase inhibitors impact prognosis of urothelial carcinoma

Background5α-reductase inhibitors (5-ARIs) inhibit the pathway of converting the testosterone to dihydrotestosterone and are widely used in benign prostatic hyperplasia patients. Since androgen receptor activation may play a role in urothelial tumorigenesis, we conducted this retrospective cohort study to determine whether 5α-reductase inhibitors (5-ARIs) administration is associated with bladder cancer mortality, bladder cancer recurrence and upper tract urothelial carcinoma mortality, using the Taiwan National Health Insurance database.MethodsThe data of this retrospective cohort study were sourced from the Longitudinal Health Insurance Database of Taiwan, compiled by the Taiwan National Health Insurance database from 1996 to 2010. It consists of 18,530 men with bladder cancer, of whom 474 were 5-ARIs recipients and 4384 men with upper tract urothelial carcinoma, of whom 109 were 5-ARIs recipients. Propensity Score Matching on the age and geographic data was done at the ratio of 1:10. We analyzed the odds ratios (OR) and 95% confidence interval (CI) of the risk of bladder cancer death, bladder cancer recurrence rate and upper tract urothelial carcinoma related death by the 5-ARIs administration.ResultsThose who received 5-ARIs showed a lower risk of bladder cancer related death compared to nonusers in multivariable adjusted analysis (OR 0.835, 95% CI 0.71–0.98). However, there was no significant difference in the bladder cancer recurrence rate (OR 0.956, 95% CI 0.82–1.11) and upper tract urothelial carcinoma related mortality in multivariable adjusted analysis (OR 0.814, 95% CI 0.6–1.1).ConclusionsPatients who receive 5-ARIs have lower bladder cancer related mortality compared to those who don’t. 5-ARIs may prove to be a viable strategy to improve bladder cancer outcomes.

Abstract PR01: Novel role of ketone body metabolism in acquired gemcitabine resistance

Abstract Urinary bladder cancer accounts for 81,000 new cases per year and 4.7% of the new cancer diagnosis in the US. Even though most of the patients suffer from noninvasive lesions, around 70% will recur following surgical intervention. Chemotherapy with gemcitabine in combination with cisplatin is a common treatment option for recurrent disease; however, 60% of the patients will relapse due to resistance. Gemcitabine is a synthetic pyrimidine nucleoside prodrug, without a known mechanism for resistance. In examining mechanisms of resistance, we identified ketone body metabolism to be important. OXCT1, a rate-limiting enzyme in ketone metabolism, was found to be highly associated with bladder cancer death—Hoglund et al, P = 2.3 × 10-3 and TCGA, P = 6.5 × 10-4. We measured the expression of OXCT1 in RT4, UMUC3, T24, and 5637 bladder cancer cell lines and observed that expression correlated with gemcitabine resistance. The generation of gemcitabine resistance of otherwise sensitive 5637 cells (5637GR) resulted in elevation of OXCT1 expression, as well as PGC1a and SIRT1 involved in mitochondrial biogenesis. Conversely, the CRISPR/Cas9 knockout of OXCT1 was able to sensitize inherently resistant UMUC3 and generated 5637GR lines. Given that OXCT1 is a rate-limiting enzyme in ketone metabolism, we evaluated oxygen consumption rate among parental and resistant cells with Seahorse. Surprisingly, resistant cells were found to be metabolically quiescent. We evaluated the role OXCT1 has on cancer stemness through sphere-forming assays (hanging drop and forced floating methods) to reveal that the OXCT1-KO lines had reduced spheres compared to their parental lines. We identified bone morphogenic protein (BMP) signaling to be induced in promoting SOX9 expression, in OXTC1-dependent manner. Gene expression analysis further corroborated the novel role of ketone metabolism in stemness and therapeutic resistance. This abstract is also being presented as Poster B28. Citation Format: Krizia Rohena-Rivera, Neil Bhowmick. Novel role of ketone body metabolism in acquired gemcitabine resistance [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr PR01.

Intravesical therapy and risk of cystectomy and bladder cancer death after BCG fails.

e17026 Background: Management of non-muscle-invasive bladder cancer (NMIBC) when BCG fails engages complex decision-making that incorporates consideration of radical cystectomy (RC) and several intravesical options. We sought to characterize trends in practice variation and health outcomes for patients receiving intravesical therapy and radical cystectomy for presumption of recurrent or progressive high-risk NMIBC that has failed BCG. Methods: We identified patients with high-risk NMIBC from SEER-Medicare diagnosed from 2004-2015 who completed a full dose of BCG treatment. We evaluated receipt of intravesical therapy after BCG fails based on a code for a transurethral resection of bladder tumor (TURBT) within 6 months of BCG treatment followed by a switch to a different intravesical agent, systemic therapy, or radical cystectomy. We constructed risk estimates for disease-specific survival and subsequent need for radical cystectomy and using the Kaplan-Meier method and multivariate Cox proportional-hazards models adjusted for competing risks of death and patient clinical/demographic factors. Results: Among high-risk NMIBC patients who received BCG in their first year of diagnosis (n = 14,369), 9.7% (n = 1,273) went on to receive intravesical therapy, 4.2% (n = 607) proceeded directly to cystectomy, 15.8% (n = 2,272) underwent re-induction with BCG, 7.0% (n = 1,009) initiated systemic chemotherapy and 4.4% died without receiving treatment after BCG. Median follow-up after the post-BCG recurrence was 29 months (IQR 42, 14-56). Those receiving intravesical therapy after BCG fails were older, had more comorbidities, resided in rural areas, and had higher proportion of clinical Ta cancers (p &lt; 0.05 for all) compared with immediate RC patients. Intravesical agents after BCG fails are listed in the Figure. Among those undergoing intravesical therapy, 12.9% (n = 478) eventually underwent RC a median 13 months (IQR 20, 7-27) after treatment post-BCG (2-year cystectomy free survival 89.4% [95% CI 88.3-90.5%]). Actuarial 2-year and 5-year bladder cancer-specific survival was 84.0% (95% CI 82.3-85.7%) and 71.0% (95% CI 68.3-73.7%), respectively, after intravesical treatment post-BCG. Conclusions: The heterogeneity in treatments used for NMIBC that fails BCG indicates potential provider uncertainty in the management of this challenging clinical situation. The paucity of effective bladder-sparing therapies, which is reflected in a high 2-year risk of RC and bladder cancer-specific death, highlights the urgent need for new therapies in this patient population.

Late Recurrences Following Radical Cystectomy Have Distinct Prognostic and Management Considerations.

Disease recurrence after radical cystectomy generally occurs within 2 years and has a poor prognosis. Less well defined are the outcomes in patients who experience a late recurrence (more than 3 years after radical cystectomy). We report our institutional experience with late recurrences and describe the relationships between time to recurrence, management strategies and survival. The study cohort comprised 2,315 patients who underwent radical cystectomy for urothelial carcinoma at our center between 2000 and 2014, of whom 617 had a recurrence. Median followup for survivors was 2.6 years after recurrence (IQR 0.95-4.5). For the study we considered disease recurrence as recurrences outside the urinary tract. We compared baseline characteristics and post-recurrence management between those with recurrence 3 or less and more than 3 years after radical cystectomy. A total of 58 patients with late recurrence had significantly lower consensus T stage and lower frequency of nodal involvement. The average 1-year bladder cancer death rate from the time of recurrence declined from 66% to 50% to 33% for patients with recurrence times of 6 months, 2 years, and 5 years after radical cystectomy, respectively. For patients who survived at least 1 year after recurrence, the estimated survival at 5 years after recurrence was 45% for those with late recurrence and 21% for patients who had an early recurrence. Local consolidative therapy (metastasectomy or radiation) was more common in patients with late recurrence (19% vs 3.6%, p <0.0001). Cancer specific survival in early recurring cases was significantly worse than in late recurring cases in the subset receiving local consolidation (p=0.02). The prolonged lifespan of patients experiencing a late recurrence after radical cystectomy can be leveraged to individualize management. There is strong rationale for investigating the role of metastasectomy in the management of late recurrences.

PD50-08 THE IMPACT OF LOW- VERSUS HIGH-INTENSITY SURVEILLANCE CYSTOSCOPY ON SURGICAL CARE AND CANCER OUTCOMES IN PATIENTS WITH HIGH-RISK NON-MUSCLE-INVASIVE BLADDER CANCER (NMIBC)

INTRODUCTION AND OBJECTIVE: Surveillance guidelines for NMIBC are based on expert opinion and informed by limited evidence. To assess the association of low- vs. guideline-recommended high-intensity cystoscopic surveillance with outcomes among patients with high-risk non-muscle invasive bladder cancer (NMIBC). METHODS: A retrospective cohort study of Veterans Affairs patients diagnosed with high-risk NMIBC between 2005 and 2011 with follow-up through 2014. Patients were categorized by number of surveillance cystoscopies over two years following diagnosis: low- (1-5) vs. high-intensity (6 or more) surveillance. Propensity score adjusted regression models were used to assess the association of low-intensity cystoscopic surveillance with frequency of transurethral resections, and risk of progression to invasive disease and bladder cancer death. RESULTS: Among 1,542 patients, 520 (33.7%) underwent low-intensity cystoscopic surveillance. Patients undergoing low-intensity surveillance had fewer transurethral resections (37 vs. 99 per 100 person-years; p<0.001). Low vs. high-intensity surveillance was not associated with risk of bladder cancer death among patients with non-invasive (cumulative incidence [CIn] 5.7% vs. 8.2% at 5 years, p=0.25) or with invasive disease at diagnosis (CIn 10.1% vs. 9.7% at 5 years, p=0.81). Among a subset of patients with non-invasive disease, low-intensity surveillance was associated with decreased risk of progression to invasive disease or bladder cancer death (CIn 19.3% vs. 31.4% at 5 years, p=0.002). CONCLUSIONS: Patients with high-risk NMIBC undergoing low- vs. high-intensity cystoscopic surveillance underwent fewer transurethral resections, but did not experience an increased risk of progression or bladder cancer death. These findings provide a strong rationale for a clinical trial to determine whether low-intensity surveillance is comparable to high-intensity surveillance for cancer control in high-risk NMIBC.Source of Funding: None

The impact of low- versus high-intensity surveillance cystoscopy on surgical care and cancer outcomes in patients with high-risk non-muscle-invasive bladder cancer (NMIBC).

To assess the association of low- vs. guideline-recommended high-intensity cystoscopic surveillance with outcomes among patients with high-risk non-muscle invasive bladder cancer (NMIBC). A retrospective cohort study of Veterans Affairs patients diagnosed with high-risk NMIBC between 2005 and 2011 with follow-up through 2014. Patients were categorized by number of surveillance cystoscopies over two years following diagnosis: low- (1-5) vs. high-intensity (6 or more) surveillance. Propensity score adjusted regression models were used to assess the association of low-intensity cystoscopic surveillance with frequency of transurethral resections, and risk of progression to invasive disease and bladder cancer death. Among 1,542 patients, 520 (33.7%) underwent low-intensity cystoscopic surveillance. Patients undergoing low-intensity surveillance had fewer transurethral resections (37 vs. 99 per 100 person-years; p<0.001). Risk of death from bladder cancer did not differ significantly by low (cumulative incidence [CIn] 8.4% [95% CI 6.5-10.9) at 5 years) vs. high-intensity surveillance (CIn 9.1% [95% CI 7.4-11.2) at 5 years, p = 0.61). Low vs. high-intensity surveillance was not associated with increased risk of bladder cancer death among patients with Ta (CIn 5.7% vs. 8.2% at 5 years p = 0.24) or T1 disease at diagnosis (CIn 10.2% vs. 9.1% at 5 years, p = 0.58). Among patients with Ta disease, low-intensity surveillance was associated with decreased risk of progression to invasive disease (T1 or T2) or bladder cancer death (CIn 19.3% vs. 31.3% at 5 years, p = 0.002). Patients with high-risk NMIBC undergoing low- vs. high-intensity cystoscopic surveillance underwent fewer transurethral resections, but did not experience an increased risk of progression or bladder cancer death. These findings provide a strong rationale for a clinical trial to determine whether low-intensity surveillance is comparable to high-intensity surveillance for cancer control in high-risk NMIBC.