Perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin in muscle-invasive bladder cancer (VESPER): survival endpoints at 5 years in an open-label, randomised, phase 3 study.

BACKGROUND: The optimal perioperative chemotherapy for patients with muscle-invasive bladder cancer is not defined. The VESPER (French Genito-Urinary Tumor Group and French Association of Urology V05) trial reported improved 3-year progression-free survival with dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (dd-MVAC) versus gemcitabine and cisplatin (GC) in patients who received neoadjuvant therapy, but not in the overall perioperative setting. In this Article, we report on the secondary endpoints of overall survival and time to death due to bladder cancer at 5-year follow-up. METHODS: VESPER was an open-label, randomised, phase 3 trial done at 28 university hospitals or comprehensive cancer centres in France, in which adults (age ≤18 years and ≤80 years) with primary bladder cancer and histologically confirmed muscle-invasive urothelial carcinoma were randomly allocated (1:1; block size four) to treatment with dd-MVAC (every 2 weeks for a total of six cycles) or GC (every 3 weeks for a total of four cycles). Overall survival and time to death due to bladder cancer (presented as 5-year cumulative incidence of death due to bladder cancer) was analysed by intention to treat (ITT) in all randomly assigned patients. Overall survival was assessed by the Kaplan-Meier method with the treatment groups compared with log-rank test stratified for mode of administration of chemotherapy (neoadjuvant or adjuvant) and lymph node involvement. Time to death due to bladder cancer was analysed with an Aalen model for competing risks and a Fine and Gray regression model stratified for the same two covariates. Results were presented for the total perioperative population and for the neoadjuvant and adjuvant subgroups. The trial is registered with ClinicalTrials.gov, NCT01812369, and is complete. FINDINGS: From Feb 25, 2013, to March 1, 2018, 500 patients were randomly assigned, of whom 493 were included in the final ITT population (245 [50%] in the GC group and 248 [50%] in the dd-MVAC group; 408 [83%] male and 85 [17%] female). 437 (89%) patients received neoadjuvant chemotherapy. Median follow-up was 5·3 years (IQR 5·1-5·4); 190 deaths at the 5-year cutoff were reported. In the perioperative setting (total ITT population), we found no evidence of association of overall survival at 5 years with dd-MVAC treatment versus GC treatment (64% [95% CI 58-70] vs 56% [50-63], stratified hazard ratio [HRstrat] 0·79 [95% CI 0·59-1·05]). Time to death due to bladder cancer was increased in the dd-MVAC group compared with in the GC group (5-year cumulative incidence of death: 27% [95% CI 21-32] vs 40% [34-46], HRstrat 0·61 [95% CI 0·45-0·84]). In the neoadjuvant subgroup, overall survival at 5 years was improved in the dd-MVAC group versus the GC group (66% [95% CI 60-73] vs 57% [50-64], HR 0·71 [95% CI 0·52-0·97]), as was time to death due to bladder cancer (5-year cumulative incidence: 24% [18-30] vs 38% [32-45], HR 0·55 [0·39-0·78]). In the adjuvant subgroup, the results were not conclusive due to the small sample size. Bladder cancer progression was the cause of death for 157 (83%) of the 190 deaths; other causes of death included cardiovascular events (eight [4%] deaths), deaths related to chemotherapy toxicity (four [2%]), and secondary cancers (four [2%]). INTERPRETATION: Our results on overall survival at 5 years were in accordance with the primary endpoint analysis (3-year progression-free survival). We found no evidence of improved overall survival with dd-MVAC over GC in the perioperative setting, but the data support the use of six cycles of dd-MVAC over four cycles of GC in the neoadjuvant setting. These results should impact practice and future trials of immunotherapy in bladder cancer. FUNDING: French National Cancer Institute.

Avelumab First-Line Maintenance Therapy: Managing Patients With Advanced Urothelial Carcinoma.

BACKGROUND: The phase 3 of JAVELIN Bladder 100 trial demonstrated that avelumab first-line (1L) maintenance in addition to best supportive care significantly prolonged overall survival compared to best supportive care alone. It is now the standard of care for platinum-eligible patients with locally advanced or metastatic urothelial carcinoma that has not progressed with 1L platinum-containing chemotherapy. OBJECTIVES: This article provides considerations for oncology nurses to effectively implement avelumab 1L maintenance treatment in the clinical setting. METHODS: This article reviews clinical evidence and implications for oncology nurses caring for patients receiving avelumab 1L maintenance treatment. FINDINGS: Oncology nurses can provide comprehensive care for patients with advanced urothelial carcinoma and ensure the safe and appropriate use of avelumab 1L maintenance treatment by educating patients and caregivers, ensuring correct administration, and promptly recognizing and managing immune-related adverse events.

Avelumab as First-Line Maintenance Treatment in Locally Advanced or Metastatic Urothelial Carcinoma.

This work provides a summary of guideline recommendations and an expert position on the use of maintenance avelumab therapy based on a review of current international clinical practice guidelines for locally advanced or metastatic urothelial carcinoma (UC). A PubMed literature search was conducted in March 2022 (updated in July 2023) to identify guidelines for locally advanced or metastatic UC. An expert panel (four oncologists and one urologist) reviewed the guidelines and clinical evidence, and discussed practical questions regarding the use of avelumab maintenance therapy in this clinical setting. The National Comprehensive Cancer Network, European Association of Urology and European Society for Medical Oncology guidelines recommend first-line cisplatin-containing chemotherapy for cisplatin-eligible patients, carboplatin-gemcitabine for cisplatin-ineligible patients who are fit for carboplatin, or immunotherapy with programmed death ligand-1 (PD-L1) inhibitors (e.g. atezolizumab) in platinum-ineligible patients. Maintenance avelumab is recommended in patients with response/stable disease following chemotherapy (regardless of PD-L1 status). In patients who relapse after/during chemotherapy, options include immunotherapy, erdafitinib [in those with fibroblast growth factor receptor (FGFR) mutations], enfortumab vedotin or further chemotherapy. The expert panel provided the following practical guidance: (1) consider maintenance avelumab in all eligible patients; (2) continue avelumab until disease progression/unacceptable toxicity; (3) ideally, administer six cycles of platinum-based chemotherapy prior to maintenance avelumab; (4) perform radiological evaluation after four chemotherapy cycles and prior to maintenance avelumab; (5) carboplatin-gemcitabine followed by maintenance avelumab is preferred in cisplatin-ineligible patients (regardless of PD-L1 expression), but consider first-line immunotherapy in PD-L1-positive patients and platinum-ineligible patients (regardless of PD-L1 status); and (6) for patients who relapse on avelumab, second-line options include enfortumab vedotin, FGFR inhibitors (in those with FGFR mutations) or clinical trial inclusion. In conclusion, avelumab maintenance therapy is recommended following platinum-based chemotherapy in all eligible patients with locally advanced or metastatic UC, continued until disease progression or unacceptable toxicity.

Artesunate Exhibits Synergy With Cisplatin and Cytotoxicity for Upper Tract and Bladder Urothelial Carcinoma Cells.

BACKGROUND/AIM: Urothelial carcinoma (UC) may arise from the urothelium of the upper tract and the bladder. Cisplatin-based therapy remains the gold standard for UC treatment. The poor 5-year survival rate of UC patients creates an urgent need to develop new drugs for advanced UC therapy. Artesunate (ART), a traditional Chinese medicine for treating malaria, is a potential anticancer agent, but its antigrowth effects on upper tract and bladder UC have not been investigated. MATERIALS AND METHODS: The antigrowth effect of ART in HT 1376 (bladder UC cells) and BFTC 909 [upper tract urothelial carcinoma (UTUC) cells] was determined by the CCK-8 assay. Flow cytometric analysis was used to evaluate the cell cycle distribution and apoptosis. The cell cycle, apoptosis, and autophagy-related protein expression were analyzed by western blotting. The efficacy of combination treatment with cisplatin was determined by the Calcusyn software. RESULTS: ART induced HT 1376 and BFTC 909 cell death in a concentration- and time-dependent manner, inducing G2/M cell-cycle arrest. ART induced apoptosis and redox imbalance in HT 1376 and BFTC 909 cells. Application of the reactive oxygen species (ROS) scavenger, N-acetyl-L-cysteine (NAC), attenuated cell death in ART-treated UC cells. BFTC 909 cells show a better response after ART treatment. CONCLUSION: ART may be a candidate drug for treating UTUC and bladder UC while increasing the therapeutic effect of cisplatin.

Patient-reported Outcomes from JAVELIN Bladder 100: Avelumab First-line Maintenance Plus Best Supportive Care Versus Best Supportive Care Alone for Advanced Urothelial Carcinoma.

BACKGROUND: In JAVELIN Bladder 100, avelumab first-line maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS; primary endpoint) versus BSC alone in patients with advanced urothelial carcinoma (aUC) without disease progression with first-line platinum-containing chemotherapy. OBJECTIVE: To evaluate patient-reported outcomes (PROs) with avelumab plus BSC versus BSC alone. DESIGN, SETTING, AND PARTICIPANTS: A randomized phase 3 trial (NCT02603432) was conducted in 700 patients with locally advanced or metastatic urothelial carcinoma that had not progressed with first-line gemcitabine plus cisplatin or carboplatin. PROs were a secondary endpoint. INTERVENTION: Avelumab plus BSC (n = 350) or BSC alone (n = 350). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Bladder Symptom Index-18 (FBlSI-18) and EuroQol five-level EQ-5D (EQ-5D-5L) assessments were analyzed using descriptive statistics and mixed-effect models. Time to deterioration (TTD; prespecified definition: a ≥3-point decrease from baseline in the FBlSI-18 disease-related symptoms-physical subscale for two consecutive assessments) was evaluated via Kaplan-Meier analyses. RESULTS AND LIMITATIONS: Completion rates for scheduled on-treatment PRO assessments were >90% (overall and average per assessment). Results from descriptive analyses and mixed-effect or repeated-measures models of FBlSI-18 and EQ-5D-5L were similar between arms. TTD was also similar, both in the prespecified analysis (hazard ratio 1.26 [95% confidence interval: 0.90, 1.77]) and in the post hoc analyses including off-treatment assessments and different event definitions. Limitations included the open-label design and limited numbers of evaluable patients at later time points. CONCLUSIONS: Addition of avelumab first-line maintenance to BSC in patients with aUC that had not progressed with first-line platinum-containing chemotherapy prolonged OS, with a relatively minimal effect on quality of life. PATIENT SUMMARY: In this trial of people with advanced urothelial carcinoma who had benefited from first-line chemotherapy (ie, had stable disease or reduced tumor size), treatment with avelumab maintenance plus best supportive care (BSC) versus BSC alone improved survival significantly, without compromising quality of life, as reported by the patients themselves.

Immunogenic Cell Death Role in Urothelial Cancer Therapy.

PURPOSE: Bladder cancer is the 13th most common cause of cancer death with the highest lifetime cost for treatment of all cancers. This scoping review clarifies the available evidence on the role of a novel therapeutic approach called immunogenic cell death (ICD) in urothelial cancer of the bladder. METHODS: In accordance with the recommendations of the Joanna Briggs Institute, we searched MEDLINE (Ovid), EMBASE, CENTRAL databases, and supplemented with manual searches through the conferences, Google scholar, and clinicaltrials.gov for published studies up to April 2022. We included literature that studied molecular mechanisms of ICD and the role of certain danger-associated molecular patterns (DAMPs) in generating ICD, safety and efficacy of different ICD inducers, and their contributions in combination with other urothelial cancer treatments. RESULTS: Oncolytic viruses, radiotherapy, certain chemo/chemo radiation therapy combinations, photodynamic therapy, and novel agents were studied as ICD-inducing treatment modalities in the included studies. ICD was observed in vitro (murine or human urothelial carcinoma) in ten studies, eight studies were performed on mouse models (orthotopic or subcutaneous), and five clinical trials assessed patient response to ICD inducing agents. The most common studied DAMPs were Calreticulin, HMGB1, ATP, and Heat Shock Proteins (HSP) 70 and 90, which were either expressed on the cancer cells or released. CONCLUSION: ICD inducers were able to generate lasting antitumor immune responses with memory formation in animal studies (vaccination effect). In clinical trials these agents generally had low side effects, except for one trial, and could be used alone or in combination with other cancer treatment strategies in urothelial cancer patients.

[A Case of Reactive Arthritis after BCG Intravesical Infusion Therapy Successfully Treated with Salazosulfapyridine].

The patient was a 70-year-old woman who underwent transurethral resection of bladder tumor in May 2020. She was diagnosed with urothelial carcinoma (high grade, pT1 by pathology). We started bacillus Calmette-Guerin (BCG) intravesical infusion (80 mg Tokyo strain) in August of the same year after a second transurethral resection. Pain during urination persisted during the administration of BCG, and it worsened after the completion of six doses. The patient was hospitalized with back and neck pain and difficulty in physical movement. At the time of admission, bilateral conjunctivitis was observed. The patient was diagnosed with reactive arthritis associated with BCG intravesical injection therapy, as three typical symptoms were observed (bilateral conjunctivitis, urethritis, polyarthritis). The patient was treated with prednisolone and non-steroidal anti-inflammatory drugs for arthritis, but the symptoms did not improve. We administered salazosulfapyridine and her reactive arthritis improved.

Avelumab First-Line Maintenance Treatment in Advanced Bladder Cancer: Practical Implementation Steps for Infusion Nurses.

Immune checkpoint inhibitors, such as programmed cell death ligand 1 inhibitors pembrolizumab, nivolumab, atezolizumab, and avelumab, are used to treat patients with advanced urothelial carcinoma (UC). Based on data from the phase 3 JAVELIN Bladder 100 trial, avelumab first-line (1L) maintenance is now considered the standard-of-care treatment for patients with locally advanced or metastatic UC who responded or experienced disease stabilization after 1L platinum-containing chemotherapy, and it is the only category 1 preferred checkpoint inhibitor maintenance option in the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for patients with cisplatin-eligible and cisplatin-ineligible locally advanced or metastatic UC. This article reviews key considerations related to avelumab 1L maintenance therapy that infusion nurses should be familiar with, including dosing, administration, and immune-related adverse event recognition and management, to ensure safe and appropriate use of this important and impactful therapy.

Recent therapeutic advances in urothelial carcinoma: A paradigm shift in disease management.

Management of first-line advanced urothelial carcinoma (UC) has consisted during the past three decades in the administration of platinum-based chemotherapy followed by observation. Despite moderate to high response rates to first-line treatment, most patients will relapse shortly after and the outcomes with subsequent therapies are poor with 5-year overall survival rates of 5% in the pre-immunotherapy era. Nonetheless, recent therapeutic developments including the paradigm shift of first-line maintenance therapy with avelumab after response or stabilization on platinum-based chemotherapy, along with the incorporation of new drug classes in further lines of treatment such as antibody drug-conjugates and fibroblast growth factor receptor inhibitors have reshaped the field leading to better outcomes in this patient population. This article reviews the current state of the art with an overview on UC management, recent advances, and the upcoming strategies currently in development in advanced UC with an insight into the biology of this disease.

Omega-3 polyunsaturated fatty acids: a modified approach for chemo-prevention of bladder cancer in a rat model and molecular studies of antineoplastic mechanisms.

OBJECTIVES: To test the chemo-preventative effects of omega-3 against bladder cancer (BC) induction in a rat model and its potential antineoplastic mechanisms. MATERIAL AND METHODS: Ninety male Fisher rats were divided into three groups during a 22-week protocol: group 1 (control), group 2 (Placebo + N-butyl-N-4- hydroxybutyl nitrosamine (BBN) for induction of BC and group 3 received omega-3 (1200 mg/kg/day) + BBN. At the end, blood samples and bladder tissues were collected and checked for the presence of malignancy, markers of angiogenesis (VEGF relative gene expression), inflammation (IL-6), proliferation (KI-67 expressions), oxidative stress (serum MDA and serum SOD) and epigenetic control (miRNA-145 level). RESULTS: At the end of the study, 60% and 86.6% rats survived in group 2 and 3 with significant weight loss among rats in group 2 when compared with other groups. In group 2, all rats developed visible bladder lesions of which five and 13 developed squamous cell carcinoma (SCC) and transitional cell carcinoma (TCC). In omega3-treated group, only one developed low grade SCC and one developed high grade non- invasive TCC. Bladders from omega-3-treated rats showed lower expression ofKI-67 (p < 0.05), VEGF (p < 0.001) and IL-6 (p < 0.001) and significant higher expression of mi-RNA (p < 0.001). Also, omega-3-treated group showed statistically significant lower MDA level (p < 0.001). CONCLUSION: Omega-3 inhibits bladder tumor growth in the BBN-induced BC rat model, due to anti-inflammatory, antioxidant, anti-proliferative, and anti-angiogenic properties together with epigenetic control.

Carboplatin-based adjuvant chemotherapy versus observation after radical cystectomy in patients with pN1-3 urothelial bladder cancer.

PURPOSE: To test the impact of carboplatin-based ACT on overall survival (OS) in patients with pN1-3 cM0 BCa. METHODS: A retrospective analysis was conducted on 1057 patients with pTany pN1-3 cM0 urothelial BCa treated with or without carboplatin-based ACT after radical cystectomy and bilateral lymph-node dissection between 2002 and 2018 at 12 European and North-American hospitals. No patient received neoadjuvant chemotherapy or radiation therapy. Only patients with negative surgical margins at surgery were included. A 3:1 propensity score matching (PSM) was performed using logistic regression to adjust for baseline characteristics. Univariable and multivariable Cox regression analyses were used to predict the effect of carboplatin-based ACT on OS. The Kaplan-Meier method was used to display OS in the matched cohort. RESULTS: Of the 1057 patients included in the study, 69 (6.5%) received carboplatin-based ACT. After PSM, 244 total patients were identified in two cohorts that did not differ for baseline characteristics. Death was recorded in 114 (46.7%) patients over a median follow-up of 19 months. In the multivariable Cox regression analyses, increasing age at surgery (hazard ratio [HR] 1.02, 95% confidence interval [CI] 1.01-1.06, p < 0.001) and increasing number of positive lymph nodes (HR 1.06, 95% CI 1.01-1.07, p = 0.02) were independent predictors of worse OS. The delivery of carboplatin-based ACT was not predictive of improved OS (HR 0.67, 95% CI 0.43-1.04, p = 0.08). The main limitations of this study are its retrospective design and the relatively low number of patients involved. CONCLUSIONS: Carboplatin-based might not improve OS in patients with pN1-3 cM0 BCa. Our results underline the need for alternative therapies for cisplatin-ineligible patients.

Platinum-based adjuvant chemotherapy for upper tract urothelial carcinoma: a change of paradigm? A meta-analysis of aggregate data.

We performed a systematic review and meta-analysis to evaluate the role of platinum-based adjuvant chemotherapy (AC) in upper tract urothelial carcinoma. Eligible studies were identified using Pubmed/Medline, Cochrane library, Embase and meeting abstracts. Outcomes of interest included: overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS). Platinum-based AC was associated with improved DFS, while the benefit in OS and CSS was not statistically significant compared to observation. Conversely, platinum-based AC showed a modest OS benefit in an analysis combing multivariable HRs with estimated HRs from Kaplan-Meier curves. Our results suggest that platinum-based AC is associated with improved DFS and a modest OS benefit in patients with locally advanced urothelial carcinomas.

Novel colchicine derivative CR42-24 demonstrates potent anti-tumor activity in urothelial carcinoma.

Bladder cancers, and specifically urothelial carcinoma, have few effective treatment options, and tumors typically develop resistance against standard of care chemotherapies leading to significant mortality. The development of alternative therapies with increased selectivity and improved tolerability would significantly impact this patient population. Here, we investigate a novel colchicine derivative, CR42-24, with increased selectivity for the ßIII tubulin subtype as a treatment for urothelial carcinoma. ßIII tubulin is a promising target due to its low expression in healthy tissues and its clinical association with poor prognosis. This study demonstrated that CR42-24 is selectively cytotoxic to several cancer cell lines at low nanomolar IC50, with high activity in bladder cancer cell lines both in vitro and in vivo. CR42-24 monotherapy in an aggressive urothelial carcinoma xenograft model results in effective control when treated early. We observed significant ablation of large tumors and patient-derived xenografts at low doses with excellent tolerability. CR42-24 was highly synergistic in combination with the standard of care chemotherapies gemcitabine and cisplatin, further increasing its therapeutic potential as a novel treatment for urothelial carcinoma.

Establishment of Canine Transitional Cell Carcinoma Cell Lines Harboring BRAF V595E Mutation as a Therapeutic Target.

Transitional cell carcinoma (TCC) is the most common malignant tumor of the canine urinary tract and tends to have a poor prognosis due to its invasive potential. Recent studies have reported that up to 80% of canine urothelial carcinoma has the BRAF V595E mutation, which is homologous to the human V600E mutation. Activating the BRAF mutation is an actionable target for developing effective therapeutic agents inhibiting the BRAF/mitogen-activated protein kinase (MAPK) pathway in canine cancer as well as human cancer. We established novel canine TCC cell lines from two tumor tissues and one metastatic lymph node of canine TCC patients harboring the BRAF V595E mutation. Tumor tissues highly expressed the BRAF mutant and phosphorylated extracellular signal-related kinases (ERK)1/2 proteins. The derived cell lines demonstrated activated MAPK pathways. We also evaluated the cell lines for sensitivity to BRAF inhibitors. Sorafenib, a multiple kinase inhibitor targeting RAF/vascular endothelial growth factor receptor (VEGFR), successfully inhibited the BRAF/MAPK pathway and induced apoptosis. The established canine TCC cell lines responded with greater sensitivity to sorafenib than to vemurafenib, which is known as a specific BRAF inhibitor in human cancer. Our results demonstrated that canine TCC cells showed different responses compared to human cancer with the BRAF V600E mutation. These cell lines would be valuable research materials to develop therapeutic strategies for canine TCC patients.

Longitudinal assessment of B-RAF V595E levels in the peripheral cell-free tumor DNA of a 10-year-old spayed female Korean Jindo dog with unresectable metastatic urethral transitional cell carcinoma for monitoring the treatment response to a RAF inhibitor (sorafenib).

Transitional cell carcinoma (TCC) is the most common malignant tumor of the canine urinary tract. In this case study, a dog with metastatic urethral TCC was treated with sorafenib. The tumor expression levels of receptor tyrosine kinase genes, including VEGFR-1, VEGFR-2, PDGFR-α, PDGFR-ß, ALK, EGFR, ErbB2, and B-RAF, were analyzed. VEGFR was overexpressed in tumor tissues compared to the normal tissues. Considering the high frequency of B-RAF mutation in canine urological tumors, the B-RAF gene was examined, and the B-RAF V595E mutation was detected in the tumor tissue. Therefore, the antitumor effect of sorafenib, a multi-tyrosine kinase inhibitor, on unresectable metastatic urethral TCC characterized by B-RAF V595E was evaluated and circulating cell-free tumor DNA (ctDNA) was assessed for monitoring the treatment response. After the initiation of oral sorafenib therapy (4 mg/kg/day escalated to 10 mg/kg/day), the dysuria was alleviated gradually, and the patient remained stable for 3 months. During that treatment period, the patient showed various levels of changes associated with B-RAF V595E mutation in ctDNA as evident from longitudinal plasma samples after initiation of sorafenib therapy. The findings of this study suggest that ctDNA may serve as a useful non-invasive tool for monitoring the treatment response to anticancer drugs.

Predictive Impact of Prognostic Nutritional Index on Pembrolizumab for Metastatic Urothelial Carcinoma Resistant to Platinum-based Chemotherapy.

BACKGROUND/AIM: We investigated the prognostic nutritional index (PNI), comprised of lymphocytes and albumin, as a potential prognosticator of metastatic urothelial carcinoma (mUC) patients receiving pembrolizumab. PATIENTS AND METHODS: Sixty-five patients were retrospectively enrolled and classified as low (<40) and high (≥40) based on pretreatment PNI. Progression-free survival (PFS), overall survival (OS) and response rates were evaluated. RESULTS: In the low PNI group, significantly shorter PFS and OS were observed. PNI was shown to be an independent predictor of PFS and OS in the multivariate analysis. C-index for both PFS and OS improved with the addition of PNI to the model described in the KEYNOTE-045 study. Significantly more patients experienced initial disease progression in the low PNI group. CONCLUSION: PNI is a useful predictor of prognosis and disease progression in mUC patients receiving pembrolizumab.

An evaluation of UGN-101, a sustained-release hydrogel polymer-based formulation containing mitomycin-C, for the treatment of upper urothelial carcinomas.

INTRODUCTION: The treatment of low-grade upper tract urothelial carcinomas (UTUCs) after either surgery, or nephron-sparing techniques remains an unmet need in Genitourinary (GU) Oncology. UGN-101 is a novel drug in development for the treatment of UTUCs; it is composed of a sustained-release hydrogel polymer-based formulation containing the antitumor antibiotic mitomycin-C (MM-C); cold UGN-101 is liquid, but at body temperature, it becomes a gel, and thus, when administered through a ureteral catheter, it sticks to the upper tract urothelium, slowly releasing MM-C. AREAS COVERED: Here, the authors review the preclinical rationale for the development of UGN-101, as well as presently available clinical results for the treatment of low-grade UTUCs. EXPERT OPINION: The positive results of the recently completed OLYMPUS trial suggest the feasibility, activity (59% of complete responses, with just 6 of these complete responders on follow-up who recurred), and safety (68% of patients experiencing mild to moderate urinary adverse events) of UGN-101 instillations into the upper urinary tract. Our expectations are that UGN-101 will soon become a standard of treatment for low-grade UTUC at risk of relapse after either surgery, or nephron-sparing techniques.

Increased Bacillus Calmette-Guérin Treatment Intensity Associated With Improved Outcomes in Elderly Patients With Non-Muscle-invasive Bladder Cancer in United States Clinical Practice.

OBJECTIVE: To characterize Bacillus Calmette-Guérin (BCG) treatment patterns and associated outcomes in a large cohort of patients with non-muscle-invasive bladder cancer (NMIBC). METHODS: Our retrospective analysis of patients aged ≥66 years with stage 0-1 urothelial bladder carcinoma diagnosed between 2000 and 2012 in the United States Surveillance, Epidemiology, and End Results-Medicare database estimated proxies for recurrence and secondary events and both all-cause and bladder cancer-specific mortality. Proportional hazards models were used in conditional landmark analyses to compare adequate (≥5 induction instillations and ≥2 maintenance instillations) and inadequate BCG, stratified by National Comprehensive Cancer Network risk group. RESULTS: Of 39,532 patients who met the selection criteria, 16,225 (41.0%) received BCG; of them, 4602 (28.4%; 11.6% overall) received adequate treatment. Adequately treated patients were slightly younger and healthier than inadequately treated patients. Half of patients with intermediate- and high-risk NMIBC did not receive BCG; few received adequate treatment. At the 12-month landmark, adequate BCG treatment was associated with decreased risks of recurrence and of cancer-specific and all-cause mortality in patients with intermediate- and high-risk disease. CONCLUSION: We observed lower than expected use of adequate BCG treatment in patients with intermediate- to high-risk NMIBC despite evidence of improved outcomes, which suggested that practice patterns may not be in line with management recommendations in this population.

Systematic Literature Review and Meta-Analysis of Response to First-Line Therapies for Advanced/Metastatic Urothelial Cancer Patients Who Are Cisplatin Ineligible.

OBJECTIVE: The purpose of this systematic literature review (SLR) and meta-analysis was to compile the response of historic treatment options in first-line settings for patient populations who are cisplatin ineligible. MATERIALS AND METHODS: SLR was conducted to compile objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) of historic therapies for this population based on stringent criteria. Clinical trials published in English from January 1991 to June 2016 were identified by searching the PubMed (Medline), Cochrane, and Embase databases. RESULTS: Eighteen studies (21 arms; N=810) were identified and used for this meta-analysis. For all treatments included in these studies, the pooled ORR was 0.36 (95% confidence interval [CI], 0.30-0.42). The ORR for the carboplatin+gemcitabine arms (6 arms; N=259), which is the National Comprehensive Cancer Network's recommended first-line treatment (before approval of atezolizumab and pembrolizumab) for this population was 0.36 (95% CI, 0.30-0.42), the median DOR (4 arms) was 7.00 months (95% CI, 4.34-11.29), and the median OS was 8.39 months (95% CI, 7.05-9.98). CONCLUSIONS: The results of this SLR clearly demonstrate the paucity of clinical studies that assess therapeutic intervention in truly cisplatin-ineligible advanced/metastatic urothelial carcinoma subjects and highlight the development of novel therapies that can create real improvement in long-term outcomes. The recent approval of 2 checkpoint inhibitors, atezolizumab and pembrolizumab, were added in the National Comprehensive Cancer Network guidance as recommended first-line treatment for cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma and has provided alternatives for this patient population.