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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.

Recently, immunotherapy with checkpoint inhibitors has been showing promise in clinical trials for stage IV bladder cancer. Herein, we review the literature regarding the role for radiation therapy, the role for immunotherapy, and the potential synergy of these treatments combined in bladder cancer. There is ample pre-clinical data in a number of different tumor models, coupled with a growing body of clinical evidence in melanoma and other malignancies to suggest combining radiation and immunotherapy could lead to substantial advances in treatment outcomes for bladder cancer. Yet, these data for bladder cancer remain at the pre-clinical stage, and further study is needed.

Sex-specific differences exist in muscle invasive bladder cancer (MIBC): men have a higher incidence; women present with more advanced disease; and surgical options differ between men and women. Health related quality of life (HRQoL) for male versus female patients with MIBC is not well understood and limited data exists in patients who undergo bladder preservation with trimodality therapy (TMT). The purpose of this study was to compare long-term HRQoL between men and women who have undergone TMT. This was a secondary analysis of a prior study that reported long-term HRQoL differences for patients who underwent TMT. We analyzed patient reported HRQoL data to assess differences in HRQoL between men and women. Of the 64/74 (86%) TMT patients that completed questionnaires, 14 (22%) were women. Median age at diagnosis was 60 years for women and 66 years for men (p = 0.007). From six HRQoL instruments, there were two responses with a statistically significant difference between women and men –incidence of diarrhea and degree of sexual activity. Fifty percent of women compared to 86%of men reported no diarrhea (p = 0.02). A greater percentage of women reported some degree of sexual activity in the 4 weeks prior to questionnaire completion (p = 0.04), and sexual interest following TMT declined significantly with age in men, but not in women. In general, men and women report very good long-term HRQoL following TMT. There were, however, some differences between the sexes. Understanding this difference, especially related to sexual function, will allow more informed decision making by patients when choosing between treatment modalities.

IMPORTANCE: Decipher (Decipher Biosciences Inc) is a genomic classifier (GC) developed to estimate the risk of distant metastasis (DM) after radical prostatectomy (RP) in patients with prostate cancer. OBJECTIVE: To validate the GC in the context of a randomized phase 3 trial. DESIGN, SETTING, AND PARTICIPANTS: This ancillary study used RP specimens from the phase 3 placebo-controlled NRG/RTOG 9601 randomized clinical trial conducted from March 1998 to March 2003. The specimens were centrally reviewed, and RNA was extracted from the highest-grade tumor available in 2019 with a median follow-up of 13 years. Clinical-grade whole transcriptomes from samples passing quality control were assigned GC scores (scale, 0-1). A National Clinical Trials Network–approved prespecified statistical plan included the primary objective of validating the independent prognostic ability of GC for DM, with secondary end points of prostate cancer–specific mortality (PCSM) and overall survival (OS). Data were analyzed from September 2019 to December 2019. INTERVENTION: Salvage radiotherapy (sRT) with or without 2 years of bicalutamide. MAIN OUTCOMES AND MEASURES: The preplanned primary end point of this study was the independent association of the GC with the development of DM. RESULTS: In this ancillary study of specimens from a phase 3 randomized clinical trial, GC scores were generated from 486 of 760 randomized patients with a median follow-up of 13 years; samples from a total of 352 men (median [interquartile range] age, 64.5 (60-70) years; 314 White [89.2%] participants) passed microarray quality control and comprised the final cohort for analysis. On multivariable analysis, the GC (continuous variable, per 0.1 unit) was independently associated with DM (hazard ratio [HR], 1.17; 95% CI, 1.05-1.32; P = .006), PCSM (HR, 1.39; 95% CI, 1.20-1.63; P < .001), and OS (HR, 1.17; 95% CI, 1.06-1.29; P = .002) after adjusting for age, race/ethnicity, Gleason score, T stage, margin status, entry prostate-specific antigen, and treatment arm. Although the original planned analysis was not powered to detect a treatment effect interaction by GC score, the estimated absolute effect of bicalutamide on 12-year OS was less when comparing patients with lower vs higher GC scores (2.4% vs 8.9%), which was further demonstrated in men receiving early sRT at a prostate-specific antigen level lower than 0.7 ng/mL (−7.8% vs 4.6%). CONCLUSIONS AND RELEVANCE: This ancillary validation study of the Decipher GC in a randomized trial cohort demonstrated association of the GC with DM, PCSM, and OS independent of standard clinicopathologic variables. These results suggest that not all men with biochemically recurrent prostate cancer after surgery benefit equally from the addition of hormone therapy to sRT. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00002874

A novel transcriptional profiling platform revealed that gene expression consistent with high immune-cell infiltration and of specific genes associated with T-cell infiltration or IFNγ signaling was correlated with better survival following chemoradiation for muscle-invasive bladder cancer.

Background: A systematic literature review of the performance of 18Fluorine-fluciclovine PET/CT for imaging of men with recurrent prostate cancer was performed. Methods: Scientific literature databases (MEDLINE, ScienceDirect and Cochrane Libraries) were searched systematically during Oct 2020 using PRISMA criteria. No limit was put on the date of publication. Prospective studies reporting a patient-level 18F-fluciclovine detection rate (DR) from ≥25 patients with recurrent prostate cancer were sought. Proceedings of relevant meetings held from 2018 through Oct 2020 were searched for abstracts meeting criteria. Results: Searches identified 321 unique articles. In total, nine articles (six papers and three conference abstracts), comprising a total of 850 patients met inclusion criteria. Most studies (n= 6) relied on ASTRO-Phoenix Criteria, EAU-ESTRO-SIOG, and/or ASTRO-AUA guidelines to identify patients with biochemical recurrence. Patients’ PSA levels ranged from 0.02–301.7 ng/mL (median level per study, 0.34–4.10 ng/mL [n= 8]). Approximately 64% of patients had undergone prostatectomy, but three studies focused solely on post-prostatectomy patients. Adherence to imaging protocol guidelines was heterogeneous, with variance seen in administered activity, uptake and scan times. Overall patient-level DR varied between studies from 26% to 83%, with 78% of studies reporting a DR > 50%. DR was proportional to PSA, but even at PSA < 0.5 ng/mL DR of up to 53% were reported. Prostate/bed DR (n= 7) ranged from 18% to 78% and extra-prostatic rates (n= 6) from 8% to 72%. Pelvic node and bone lesion DR ranged from 8% to 47% and 0% to 26%, respectively (n= 5). 18F-Fluciclovine PET/CT was shown to impact patient management and outcomes. Two studies reported 59–63% of patients to have a management change post-scan. A further study showed significant increase in failure-free survival following 18F-fluciclovine-guided compared with conventional imaging-guided radiotherapy planning. Conclusions: 18F-Fluciclovine PET/CT shows good performance in patients with recurrent prostate cancer leading to measurable clinical benefits. Careful adherence to recommended imaging protocols may help optimize DR.

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.

IMPORTANCE: In men with recurrent prostate cancer, addition of long-term antiandrogen therapy to salvage radiotherapy (SRT) was associated with overall survival (OS) in the NRG/RTOG 9601 study. However, hormone therapy has associated morbidity, and there are no validated predictive biomarkers to identify which patients derive most benefit from treatment. OBJECTIVE: To examine the role of pre-SRT prostate-specific antigen (PSA) levels to personalize hormone therapy use with SRT. INTERVENTIONS: Men were randomized to SRT plus high-dose nonsteroidal antiandrogen (bicalutamide, 150 mg/d) or placebo for 2 years. DESIGN, SETTING, AND PARTICIPANTS: In this secondary analysis of the multicenter RTOG 9601 double-blind, placebo-controlled randomized clinical trial conducted from 1998 to 2003 by a multinational cooperative group, men with a positive surgical margin or pathologic T3 disease after radical prostatectomy with pre-SRT PSA of 0.2 to 4.0 ng/mL were included. Analysis was performed between March 4, 2019, and December 20, 2019. MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival (OS). Secondary end points included distant metastasis (DM), other-cause mortality (OCM), and grades 3 to 5 cardiac and neurologic toxic effects. Subgroup analyses were performed using the protocol-specified PSA stratification variable (1.5 ng/mL) and additional PSA cut points, including test for interaction. Competing risk analyses were performed for DM and other-cause mortality (OCM). RESULTS: Overall, 760 men with PSA elevation after radical prostatectomy for prostate cancer were included. The median (range) age of particpants was 65 (40-83) years. Antiandrogen assignment was associated with an OS benefit in the PSA stratum greater than 1.5 ng/mL (n = 118) with a 25% 12-year absolute benefit (hazard ratio [HR], 0.45; 95% CI, 0.25-0.81), but not in the PSA of 1.5 ng/mL or less stratum (n = 642) (1% 12-year absolute difference; HR, 0.87; 95% CI, 0.66-1.16). In a subanalysis of men with PSA of 0.61 to 1.5 (n = 253), there was an OS benefit associated with antiandrogen assignment (HR, 0.61; 95% CI, 0.39-0.94). In those receiving early SRT (PSA ≤0.6 ng/mL, n = 389), there was no improvement in OS (HR, 1.16; 95% CI, 0.79-1.70), an increased OCM hazard (subdistribution HR, 1.94; 95% CI, 1.17-3.20; P = .01), and an increased odds of late grades 3 to 5 cardiac and neurologic toxic effects (odds ratio, 3.57; 95% CI, 1.09-15.97; P = .05). CONCLUSIONS AND RELEVANCE: These results suggest that pre-SRT PSA level may be a prognostic biomarker for outcomes of antiandrogen treatment with SRT. In patients receiving late SRT (PSA >0.6 ng/mL, hormone therapy was associated with improved outcomes. In men receiving early SRT (PSA ≤0.6 ng/mL), long-term antiandrogen treatment was not associated with improved OS. Future randomized clinical trials are needed to determine hormonal therapy benefit in this population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00002874

Background: Advances in radiation technology have transformed treatment options for patients with localized prostate cancer. The evolution of three-dimensional conformal radiation therapy and intensity-modulated radiation therapy (IMRT) have allowed physicians to spare surrounding normal organs and reduce adverse effects. The introduction of proton beam technology and its physical advantage of depositing its energy in tissue at the end-of-range maximum may potentially spare critical organs such as the bladder and rectum in prostate cancer patients. Data thus far are limited to large, observational studies that have not yet demonstrated a definite benefit of protons over conventional treatment with IMRT. The cost of proton beam treatment adds to the controversy within the field. Methods: We performed an extensive literature review for all proton treatment-related prostate cancer studies. We discuss the history of proton beam technology, as well as its role in the treatment of prostate cancer, associated controversies, novel technology trends, a discussion of cost-effectiveness, and an overview of the ongoing modern large prospective studies that aim to resolve the debate between protons and photons for prostate cancer. Results: Present data have demonstrated that proton beam therapy is safe and effective compared with the standard treatment options for prostate cancer. While dosimetric studies suggest lower whole-body radiation dose and a theoretically higher relative biological effectiveness in prostate cancer compared with photons, no studies have demonstrated a clear benefit with protons. Conclusions: Evolving trends in proton treatment delivery and proton center business models are helping to reduce costs. Introduction of existing technology into proton delivery allows further control of organ motion and addressing organs-at-risk. Finally, the much-awaited contemporary studies comparing photon with proton-based treatments, with primary endpoints of patient-reported quality-of-life, will help us understand the differences between proton and photon-based treatments for prostate cancer in the modern era.

Multidisciplinary care is crucial for the optimal treatment of patients with muscle-invasive bladder cancer. We surveyed practitioners regarding the multidisciplinary care models currently used in their practices. Most providers used some form of multidisciplinary care, with sequential clinic visits on different days the most common approach. However, most providers preferred an integrated multidisciplinary care protocol involving same-day concurrent or sequential clinic visits.

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 TP53in 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 TP53and ATMgenes, commonly mutated in MIBC and other cancers, are candidate biomarkers of PARPi-mediated radiosensitization.

Local-regional recurrence for patients with ≥pT3 disease after radical cystectomy is a significant problem. Chemotherapy has not been shown to reduce the risk of local-regional recurrences in randomized prospective trials, and salvage therapies for local-regional failure are rarely successful. There is promising evidence, particularly from a recent Egyptian NCI trial, that radiation therapy plus chemotherapy can significantly reduce local recurrences compared to chemotherapy alone, and that this improvement in local-regional control may translate to meaningful improvements in disease-free and overall survival with acceptable toxicity. In light of the high rates of local failure following cystectomy for locally advanced disease and the progress that has been made in identifying patients at high risk of failure and the patterns of failure in the pelvis, the NCCN guidelines were revised in 2016 to include post-operative radiotherapy as an option to consider for patients with ≥pT3 disease. Despite advances in our understanding of the problem of local-regional failure after cystectomy and the potential role of adjuvant radiotherapy, the question of whether adjuvant radiotherapy should have a defined role for patients with locally advanced urothelial carcinoma has not yet been determined. The results of the NRG, European, Indian, and Egyptian trials on adjuvant radiotherapy are eagerly awaited. While none of these trials on their own may provide definitive conclusions, their aggregate outcomes will help clarify whether this treatment should have a role in the management of patients with locally advanced bladder cancer.

We studied a modified chemoradiotherapy regimen to treat a group of patients with invasive bladder cancer who were unfit for conventional radical cystectomy or chemotherapy. One group had tumors that overexpressed her2/neu. We found that patients could reasonably tolerate the treatment despite their frail medical conditions with moderate control of their cancer. Trastuzumab therapy in the her2/neu tumors did not improve treatment response.

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.

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.

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

The NCI Bladder Cancer Task Force convened a Clinical Trials Planning Meeting (CTPM) Workshop focused on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer (NMIBC). Meeting attendees included a broad and multi-disciplinary group of clinical and research stakeholders and included leaders from NCI, FDA, National Clinical Trials Network (NCTN), advocacy and the pharmaceutical and biotech industry. The meeting goals and objectives were to: 1) create a collaborative environment in which the greater bladder research community can pursue future optimally designed novel clinical trials focused on the theme of molecular targeted and immune-based therapies in NMIBC; 2) frame the clinical and translational questions that are of highest priority; and 3) develop two clinical trial designs focusing on immunotherapy and molecular targeted therapy. Despite successful development and implementation of large Phase II and Phase III trials in bladder and upper urinary tract cancers, there are no active and accruing trials in the NMIBC space within the NCTN. Disappointingly, there has been only one new FDA approved drug (Valrubicin) in any bladder cancer disease state since 1998. Although genomic-based data for bladder cancer are increasingly available, translating these discoveries into practice changing treatment is still to come. Recently, major efforts in defining the genomic characteristics of NMIBC have been achieved. Aligned with these data is the growing number of targeted therapy agents approved and/or in development in other organ site cancers and the multiple similarities of bladder cancer with molecular subtypes in these other cancers. Additionally, although bladder cancer is one of the more immunogenic tumors, some tumors have the ability to attenuate or eliminate host immune responses. Two trial concepts emerged from the meeting including a window of opportunity trial (Phase 0) testing an FGFR3 inhibitor and a second multi-arm multi-stage trial testing combinations of BCG or radiotherapy and immunomodulatory agents in patients who recur after induction BCG (BCG failure).

We used the Surveillance, Epidemiology, and End Results database to determine whether any changes in postprostatectomy radiotherapy (PPRT) recommendations occurred after the publication of the Southwestern Oncology Group 87-94 update in 2009 and what factors were associated with PPRT recommendations. To our knowledge, our study is the first to use a large national contemporary cohort to demonstrate an increase in PPRT uptake after the dissemination of survival benefit data. Still, absolute PPRT utilization rates remain low, suggesting that the oncologic community remains unconvinced that PPRT is needed for most patients with adverse features after prostatectomy.