Bladder Cancer Journal Vol. 6, Issue 4

FGFR3 – a Central Player in Bladder Cancer Pathogenesis?

ABSTRACT:

The identification of mutations in FGFR3 in bladder tumors in 1999 led to major interest in this receptor and during the subsequent 20 years much has been learned about the mutational profiles found in bladder cancer, the phenotypes associated with these and the potential of this mutated protein as a target for therapy. Based on mutational and expression data, it is estimated that >80% of non-muscle-invasive bladder cancers (NMIBC) and ∼40% of muscle-invasive bladder cancers (MIBC) have upregulated FGFR3 signaling, and these frequencies are likely to be even higher if alternative splicing of the receptor, expression of ligands and changes in regulatory mechanisms are taken into account. Major efforts by the pharmaceutical industry have led to the development of a range of agents targeting FGFR3 and other FGF receptors. Several of these have entered clinical trials, and some have presented very encouraging early results in advanced bladder cancer. Recent reviews have summarised the drugs and related clinical trials in this area. This review will summarise what is known about the effects of FGFR3 and its mutant forms in normal urothelium and bladder tumors will suggest when and how this protein contributes to urothelial cancer pathogenesis, and will highlight areas that may benefit from further study. 

ABSTRACT:

From 2016 through the present day, we have witnessed extraordinarily rapid advances and regulatory approvals of immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway, which has significantly improved survival among patients with advanced and metastatic urothelial carcinoma (mUC). Although these agents usually are well tolerated, their unique mechanism of action may enhance cytotoxic T-cell mediated immunity, evoking unique side effects that differ from conventional chemotherapy or molecularly targeted agents. The most common immune-related adverse events (irAEs) are dermatitis, colitis, pneumonitis, thyroid dysfunction, and transaminitis, but any organ system permeated by the lymphatic vasculature can be affected; also, neuropathies and arthralgias may occur. Immune-mediated events of any grade require prompt recognition and appropriate management to mitigate the risk of irAE exacerbation. Most patients with mild (grade 1) irAEs may continue checkpoint inhibitor treatment with careful monitoring. For grade 2 irAEs, it is appropriate to suspend treatment, initiate corticosteroid therapy, and only resume treatment if the irAE resolves to < grade 1. Events classified as > grade 3 may require permanent treatment cessation and high-dose corticosteroid therapy. In clinical trials of PD-1/PD-L1 inhibitors across multiple cancer types, approximately 15% of patients with mUC developed irAEs requiring corticosteroid therapy. Training physicians and nurse providers and counseling patients regarding the early recognition of irAEs are mandatory to ensure timely irAE detection and optimized patient management. Hence, operationalizing an advanced bladder cancer clinic requires collaboration and coordination amongst urologists, medical and radiation oncologists, and other medical specialists who participate in the increasingly multimodal and multidisciplinary care of patients with bladder cancer.

Etiology of Treatment Delays in Patients Receiving Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer

ABSTRACT: 

BACKGROUND: Neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) improves overall survival in muscle-invasive bladder cancer (MIBC), but successful completion rates of NAC are low. A retrospective analysis was undertaken to determine the etiology of deviations of NAC administration for MIBC. METHODS: We performed a retrospective review of MIBC patients in an institutional database who received NAC followed by RC from 2008 to 2016. Patients were characterized as having completed NAC without deviation (“No Deviation”) or with deviation (“Deviation”). Factors associated with “Deviation” were assessed with logistic regression models.

RESULTS: 172 MIBC patients received NAC followed by RC; 49 were excluded due to incomplete NAC data. Of the remaining 123 patients, 80 (65%) received Gemcitabine and Cisplatin (GC) and 25 (20%) received dose-dense MVAC (ddMVAC). In all, 85 (69%) patients had “Deviation” in planned NAC administration, while the remaining 38 (31%) patients had “No Deviation.” Twenty-six (33%) of GC patients experienced delays (mean = 21.5±17.0 days) and 6 (24%) ddMVAC patients experienced delays (mean = 10.5±9.5 days). Receipt of GC was associated with a higher likelihood of “Deviation” in comparison to ddMVAC (OR = 15.4; 95% CI 4.43–53.72, p  < 0.01), and administration of NAC at our institution was associated with a lower likelihood of “Deviation” in comparison to receipt in the community (OR = 0.25; 95% CI 0.25–0.72, p  = 0.01).

CONCLUSIONS: Deviations in the administration of NAC were common in our cohort (69%) and were associated with receipt of GC and administration of NAC at an outside institution.

25-Year Trends in Stage-Specific Incidence Rates for Bladder Cancer in a Large Statewide Registry

ABSTRACT

BACKGROUND: Bladder cancer (BC) is a common genitourinary malignancy with over 80,000 new cases diagnosed annually and over 17,000 associated deaths. OBJECTIVE: We review 25 years of BC incidence (1993-2017) within the state of Pennsylvania to better define the incidence, geographic distribution, and trends over time. METHODS: The Pennsylvania Cancer Registry was reviewed for statewide and component county age-adjusted BC incidence rates and stage distribution. Chloropleth maps plotting statewide and county-specific incidence rates across time were created using the GeoDa statistical package.

RESULTS: 93,476 cases of BC were recorded in Pennsylvania from 1993 to 2017. Age-adjusted annual rates of BC over the study interval were stable at 24.5 patients per 100,000 (range, 22.7–25.6). However, annual rates of distant disease increased from 0.5 to 1.1 patients per 100,000 (p  < 0.001) with an average percent change increase of 6.6% over the study interval. The annual percent distribution of distant disease doubled from 2.3% to 5.1% (p  < 0.001) with a greater increase in women compared to men. Chloropleth maps highlighted growing “hot spots” of bladder cancer incidence in the northwestern, northeastern, and southeastern portions of the state.

CONCLUSIONS: While BC incidence in the state of Pennsylvania has remained relatively stable over the past 25 years, a concerning increase in distant disease was observed. Geospatial investigation implicates higher risk regions. Further studies are necessary to delineate the underlying etiologies for these observations.

Outcomes of Trimodal Therapy for cT2-3 Urothelial Carcinoma in a Racially Diverse Population: A Single Institution Experience in the Bronx

ABSTRACT: 

BACKGROUND: Radical cystectomy (RC) is the historical “gold standard” treatment for cT2-3 urothelial carcinoma (UC). However, recent evidence supports comparable outcomes of bladder preserving trimodal therapy (TMT) to RC in select patients.

OBJECTIVE: To assess the oncologic outcomes of our institutional TMT experience. METHODS: We retrospectively identified all patients that received radiation therapy (RT) for cT2-3 UC from 2012 to 2018. Clinicopathologic data were then extracted from the patients’ medical records. We included patients who underwent RT with or without concurrent chemotherapy for curative intent after diagnostic TURBT, with or without re-staging TURBT. Patient clinical (age, sex, race) and pathologic/disease characteristics of bladder cancer (stage, presence of hydronephrosis, concurrent carcinoma in-situ ) were collected. Primary outcomes were: response to TMT (complete response [CR], partial response [PR], progression), recurrence-free, and overall survival. We also analyzed rates of salvage cystectomy and associated disease-specific outcomes. The response was based on the first surveillance imaging, cystoscopy, or TURBT after completion of TMT. RESULTS: 24 patients underwent TMT during the study period. 29.2% of patients were black/non-Hispanic, 37.5% were Latino/Hispanic, and 20.8% were white/non-Hispanic. 58.3% of patients were female. 19 (79.2%), 3 (12.5%), and 2 (8.3%) patients experienced CR, PR and progression after TMT, respectively. At a median follow-up of 22.4 months, 19 (79.2%) patients were recurrence-free, 3 were alive with disease (12.5%), and 2 expired from other causes (8.3%; 1 with and 1 without disease present). Overall, 22 (92.7%) patients were still alive at the last follow-up. No clinical variables were significant predictors of CR to TMT.

CONCLUSIONS: In concordance with prior reports, TMT offers excellent tumor response rates for patients seeking definitive therapy for cT2-3 UC. Extended follow-up is needed to assess the durability of response and long-term survival after TMT.

Hyperthermia Improves Solubility of Intravesical Chemotherapeutic Agents

ABSTRACT:

BACKGROUND: Nearly 70% of all new cases of bladder cancer are non-muscle invasive disease, the treatment for which includes transurethral resection followed by intravesical therapy. Unfortunately, recurrence rates approach 50% in part due to poor intravesical drug delivery. Hyperthermia is frequently used as an adjunct to intravesical chemotherapy to improve drug delivery and response to treatment.

OBJECTIVE: To assess the solubility profile of intravesical chemotherapies under varying conditions of pH and temperature.

METHODS: Using microplate laser nephelometry we measured the solubility of three intravesical chemotherapy agents (mitomycin C, gemcitabine, and cisplatin) at varying physical conditions. Drugs were assessed at room temperature (23°C), body temperature (37°C), and 43°C, the temperature used for hyperthermic intravesical treatments. To account for variations in urine pH, solubility was also investigated at pH 4.00, 6.00, and 8.00.

RESULTS: Heat incrementally increased the solubility of all three drugs studied. Conversely, pH largely did not impact solubility aside for gemcitabine which showed slightly reduced solubility at pH 8.00 versus 6.00 or 4.00. Mitomycin C at the commonly used 2.0 mg/mL was insoluble at room temperature but soluble at both 37 and 43°C.

CONCLUSIONS: Hyperthermia as an adjunct to intravesical treatment would improve drug solubility, and likely drug delivery as some current regimens are insoluble without heat. Improvements in solubility also allow for testing of alternative administration regimens to improve drug delivery or tolerability. Further studies are needed to confirm that improvements in solubility result in increased drug delivery.

Synthesis, Characterization, and Biological Activity of Anthraquinone-Substituted Imidazolium Salts for the Treatment of Bladder Cancer

ABSTRACT: 

BACKGROUND: Bladder cancer is one of the most common types of cancer diagnosed each year, and more than half of patients have non-muscle invasive bladder cancer (NMIBC). The standard of care for patients with high-grade NMIBC is Bacillus Calmette-Guerin (BCG). Unfortunately, multiple BCG shortages have limited access to this treatment. Available alternatives using intravesical administration of chemotherapy have some efficacy, but lack prospective validation and long-term outcomes. Development of novel intravesical therapies may provide more active alternatives to BCG for patients with high-grade NMIBC.

OBJECTIVE: To develop an optimal imidazolium salt for the intravesical treatment of NMIBC and determine preliminary in vitro activity of anthraquinone-substituted imidazolium salts.

METHODS: The development of the anthraquinone-substituted imidazolium salts was undertaken in an attempt to increase the potency of this class of compounds by incorporating the quinone functional group observed in the chemotherapeutics doxorubicin, valrubicin, and mitomycin. All compounds were characterized by 1 H and 13 C NMR spectroscopy and infrared spectroscopy. Furthermore, these imidazolium salts were tested for in vitro cytotoxicity by the Developmental Therapeutics Program (DTP) on the NCI-60 human tumor cell line screening. Additional in vitro testing was performed against diverse bladder cancer cell lines (RT112, TCCSUP, J82, and UMUC13) using CellTiter-Glo® assays and colony-forming assays.

RESULTS: The NCI-60 cell line screening indicated that compound 7 had the highest activity and was concluded to be the optimal compound for further study. Using CellTiter-Glo® assays on bladder cancer cell lines, 50% growth inhibitory concentration (IC50 ) values were determined to range from 32–50μ M after an exposure of 1 h, for compound 7 . Further evaluation of the compound by colony-forming assays showed the complete inhibition of growth at 10 days post a 100μ M dose of compound 7 for 1 h.

CONCLUSIONS: The most active lipophilic anthraquinone imidazolium salt, compound 7 , could be a viable treatment for non-muscle invasive bladder cancer as it exhibits a cell-killing effect at a 1 h time period and completely inhibits cancer regrowth in colony-forming assays

5α-Reductase Inhibitors Do Not Prevent the Development and Progression of Urothelial Cancer: In Vitro Evidence

ABSTRACT: 

BACKGROUND: Androgen receptor (AR) activation has been implicated in the pathogenesis of urothelial cancer. However, it remains controversial whether 5α-reductase inhibitors (5α-RIs), which are known for blocking the conversion of testosterone to the more potent androgen dihydrotestosterone and often prescribed for the treatment of, for instance, benign prostatic hyperplasia, contribute to preventing the development of bladder cancer.

OBJECTIVE: To determine the role of 5α-RI therapy in urothelial tumorigenesis and tumor progression, using cell line models. METHODS: In a human non-neoplastic urothelial SVHUC subline stably expressing a full-length wild-type human AR (SVHUC-AR) with carcinogen/MCA challenge and human bladder cancer lines, we assessed the effects of three 5α-RIs, dutasteride (up to 100 nM), finasteride (up to 500 nM), and epristeride (up to 5μ M), on neoplastic/malignant transformation and cell growth, respectively.

RESULTS: In AR-positive bladder cancer UMUC3 and 5637-AR cells, an AR antagonist bicalutamide significantly inhibited their proliferation, whereas three 5α-RIs failed to do. Similarly, these 5α-RIs did not significantly inhibit the migration of bladder cancer cells induced by the treatment of testosterone which could be metabolized into dihydrotestosterone in culture medium. In MCA-SVHUC-AR cells, induction of their neoplastic transformation by testosterone, which was prevented by bicalutamide, was confirmed. However, no significant inhibitory effects of 5α-RIs on the neoplastic transformation of AR-positive urothelial cells treated with or without testosterone were observed.

CONCLUSIONS: Using in vitro models for urothelial cancer, 5α-RI treatment even at supra-pharmacological doses was thus found to have no significant impact on the prevention of both tumorigenesis and tumor progression.

Deciding When to Omit Repeat Transurethral Resection of Superficial Bladder Cancer: Do Photodynamic Diagnostics help?

ABSTRACT:

BACKGROUND: Repeat transurethral resection of bladder tumor is recommended when certain risk constellations are present on initial resection. Current evidence is conflicting, leading to dissenting recommendations in multinational guidelines around the world. Photodynamic diagnostics (PDD) is a tool which has been shown to increase diagnostic accuracy, but evidence is still lacking if this may permit omission of repeat resections in certain cases.

OBJECTIVE: To evaluate whether the use of photodynamic diagnostics has an impact on resection quality and residual tumor rate, and to explore which parameters may have an impact on the necessity of repeat transurethral resections. 

METHODS: We retrospectively evaluated 373 patients in the timeframe of ten years, in whom a repeat transurethral resection of bladder tumor has been performed following initial resection at our department. About half of those resections were performed using photodynamic diagnostics.

RESULTS: When PDD was used, more tumor mass was revealed and resected, but the shown trend toward a lower residual tumor rate was non-significant. Muscularis was shown more often on PDD resections. While being a rare occurrence, upstaging on repeat resection happened significantly less often after initial PDD use. Furthermore, tumor size and multifocality significantly influenced residual tumor rate in Ta high-grade stage.

CONCLUSIONS: PDD use may lead to a more accurate initial staging but this may not have an impact on short-term residual tumor rate. Tumor size and multifocality should be granted more weight in the decision-making process as when to perform a repeat resection.

Bladder Cancer Incidence and Survival in the United States and Texas Non-Latino Whites and Latinos

ABSTRACT

BACKGROUND: Bladder cancer (BC) poses an enormous burden on health care systems. Latinos in Texas (TX) were underrepresented in previous studies on racial/ethnic disparity of BC in the US.

OBJECTIVE: To examine whether BC incidence and survival rates differ among Latinos compared to non-Latino whites (NLW) in South TX, TX, and the US SEER.

METHODS: Data was collected from the US SEER Program and the Texas Cancer Registry. Annual age-specific and age-adjusted BC incidence rates and annual 5-year relative survival were calculated.

RESULTS: South TX and TX had significantly lower BC incidence rates than SEER for both Latinos and NLW regardless of gender (P s < 0.05). South TX women had worse BC survival rates than SEER women for both Latinos and NLW (P s < 0.05). TX NLW had worse BC survival rates than SEER NLW for both genders together and men only (P s < 0.05). All Latino groups had lower incidence but worse survival rates than NLW groups for both men and women in each geographic area (all P s < 0.05). Women had significantly lower BC incidence but worse survival rates than men regardless of race/ethnicity in each geographic area (all P s < 0.05).

CONCLUSIONS: South TX women had lower BC incidence but worse survival rates than US SEER women for both Latinos and NLW. Latinos had worse survival but lower incidence rates than NLW. Women had lower BC incidence but worse survival rates than men. The study identifies the BC distribution and high-risk population, racial/ethnic disparities, and geographic differences. It facilitates health care services planning. 

Identification of Sex Differences in Tumor-Specific T Cell Infiltration in Bladder Tumor-Bearing Mice Treated with BCG Immunotherapy

ABSTRACT:

BACKGROUND: Bladder cancer is the fourth most common cancer for men. However, women are often diagnosed with later stage disease and have poorer outcomes. Whether immune-based sex differences contribute to this discrepancy is unclear. In addition, models to investigate tumor-specific immunity in bladder cancer, in the context of tumor development or response to therapy, are lacking.

OBJECTIVE: To address this specific unmet need, we incorporated a commonly used model antigen, ovalbumin, into two well-established models of bladder cancer; the orthotopic MB49 cell line model and the carcinogenic BBN bladder cancer model.

METHOD: We tested the utility of these models to investigate tumor-specific immunity in the context of immunotherapy in both sexes.

RESULTS: We found that BCG vaccination, prior to weekly BCG instillation does not impart an immune-specific benefit to tumor-bearing mice in the context of multiple BCG instillations. Furthermore, tumors developed in the testes in male mice, precluding the use of the MB49 model to directly investigate sex-based immune differences. In the BBN model, we observed that more tumor antigen-specific CD8+ T cells infiltrated male bladders compared to female bladders in the context of BCG immunotherapy whereas regulatory T cells had higher levels of the exhaustion marker PD-1 in female mice.

CONCLUSIONS: We propose our modified BBN model will contribute to our understanding of how tumor-specific immunity arises in bladder cancer. Additionally, the BBN bladder cancer model may help to uncover sex differences in tumor-specific immunity, which would provide valuable information for the development of new treatments or combination therapies for bladder cancer in women and men.

Adjuvant Treatment of Residual Disease Following Neoadjuvant Chemotherapy and Radical Cystectomy for Muscle Invasive Bladder Cancer

ABSTRACT: 

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) has shown overall survival benefit for patients with muscle invasive bladder cancer (MIBC). In contrast, there is limited data for adjuvant treatment options in patients with residual muscle invasive disease after NAC followed by radical cystectomy (RC).

OBJECTIVE: This systematic review aims to give an overview of studies examining adjuvant treatment options for patients with residual MIBC at RC despite NAC.

METHODS: We systematically searched the PubMed database and Clinicaltrials.gov (end point August 2019) for publications and registered trials combining NAC, RC, and adjuvant treatment options.

RESULTS: After removal of duplicates, 659 articles and registered trials were further analyzed. Finally, 10 studies and 7 registered clinical trials met inclusion criteria. While 5 publications did not further characterize NAC and adjuvant regimens, the remaining 5 studies reported mainly platinum-based regimens. Altogether, the selected studies showed conflicting results regarding the potential role of adjuvant treatment strategies in the setting of residual disease after NAC and RC.

CONCLUSION: Although there is an urgent need for adjuvant treatment options for patients with MIBC after NAC and residual muscle invasive disease at RC, there has been very limited evidence available. Inclusion of such patients into ongoing adjuvant clinical trials is urgently needed; active surveillance is strongly recommended in the absence of trials.