Faculty Bibliography

Background: Bacillus Calmette-Guerin (BCG) therapy is the standard of care for high-risk non-muscle invasive bladder cancer after transurethral bladder tumor resection, but disease recurrence or progression is common and subsequent treatment options (eg, cystectomy) are limited. In a phase 1 study, administration of PF-06801591, a monoclonal antibody to programmed cell death protein 1 (PD-1), administered subcutaneously (SC) at 300 mg every 4 wk (Q4W) had an acceptable safety profile and showed clinical activity in patients (pts) with advanced solid tumors, including a dose-expansion cohort of pts with urothelial carcinoma. BCG therapy is associated with increased PD-L1 expression; preclinical and clinical data suggest combining BCG with an inhibitor of PD-1 or its ligand (PD-L1) yields greater antitumor activity vs either agent alone. Trial design: This randomized, open-label phase 3 study will enroll ~999 BCG-naive pts with histologically confirmed high-risk, non-muscle invasive transitional cell carcinoma of the bladder urothelium (T1 tumor, high-grade Ta tumor, or carcinoma in situ [CIS]); no prior PD-1/L1/L2 inhibitors; and no intravesical BCG within 2 y. Pts are randomized 1:1:1 to PF-06801591 + BCG induction and maintenance, PF-06801591 + BCG induction only, or BCG induction and maintenance; stratification factors include presence of CIS and geographic region. Efficacy is assessed by cystoscopy and urine cytology every 12 wk for 2 y and every 24 wk thereafter and by biopsy and imaging as clinically indicated. Primary endpoint is event-free survival; overall survival is a key secondary endpoint. Other secondary endpoints are disease-specific survival, time to cystectomy, time to low-grade disease recurrence, complete response rate and duration of complete response in pts with CIS, safety, and health-related quality of life. This study is currently enrolling in the US, with planned sites in North America, Europe, Asia, and Australia. Clinical trial identification: NCT04165317. Editorial acknowledgement: Medical writing support was provided by Joanna Bloom, PhD, of Engage Scientific Solutions, and funded by Pfizer. Legal entity responsible for the study: Pfizer.
Funding(s): Pfizer. Disclosure: G.D. Steinberg: Shareholder/Stockholder/Stock options, Stock or other ownership : Epivax Oncology, Urogen; Advisory/Consultancy, Consulting or advisory role: Heat Biologics, Cold Genesys, PhotoCure, Merck, Roche/Genentech, Ciclomed, Taris Biomedical, MDxHealth, Fidia Farmaceuticals, Urogen, Ferring, Aduro, Boston Scientific, BMS, AstraZeneca, Pfizer, Janssen, Epivax Oncology, Natera, FKD, Ferring, EnGene Bi; Advisory/Consultancy, Clinical Trial Protocol Committee member: Merck, BMS, Janssen, Cold Genesys, Pfizer, PhotoCure, Fidia. N. Shore: Advisory/Consultancy: AstraZeneca, BMS, Ferring, Janssen, Merck, Pfizer, Sanofi-Genzyme, SesenBio; Research grant/Funding (institution): AstraZeneca, BMS, Ferring, Janssen, Merck, Pfizer, Sanofi-Genzyme, SesenBio. R. Cesari: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. J. Vermette: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. K. Pierce: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. J.A. Blake-Haskins: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. S. Hariharan: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. J. Bedke: Advisory/Consultancy: AstraZeneca, Astellas, BMS, Eisai, Ipsen, MSD, Novartis, Roche, EUSA Pharma, Pfizer; Speaker Bureau/Expert testimony: BMS, Eisai, Ipsen, MSD, Novartis, Roche, EUSA Pharma, Pfizer. T. Powles: Research grant/Funding (institution): AstraZeneca, Roche, MSD, Bristol-Myers Squibb; Advisory/Consultancy: Novartis, Bristol-Myers Squibb, Ipsen, Roche, Pfizer, Astellas Pharma, Seattle Geneticis, Merck, MSD, AstraZeneca, Exelixis, and Peloton Therapeutics. All other authors have declared no conflicts of interest.
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BACKGROUND, CONTEXT AND PURPOSE/UNASSIGNED:In spite of the mixed evidence for their impact, survivorship Care Plans (SCPs) are recommended to enhance quality of care for cancer survivors. Data on the feasibility of SCPs in bladder cancer (BC) is sparse. Using a mixed-methods approach, this study describes the iterative development, acceptability and feasibility of BC specific SCP (BC-SCP) in clinical settings. METHODS:In Phase I, we developed the BC-SCP. In Phase II, we conducted four focus groups with 19 patients and 15 providers to examine its acceptability and usability challenges. Data analyses using the Atlas.ti program, informed refinement of the BC-SCP. In Phase III, we conducted feasibility testing of the refined BC-SCP with 18 providers from 12 health-centers. An encounter survey was completed after each assessment to examine the feasibility of the BC-SCP. Chi-square and Fisher Exact tests were used for comparative analyses. RESULTS:During phase I, we observed high patient and provider acceptability of the BC-SCP and substantial engagement in improving its content, design, and structure. In Phase II, providers completed 59 BC-SCPs. Mean time for BC-SCP completion was 12.3 min. Providers reported that BC-SCP content was clear, did not hamper clinic flow and was readily completed with easy-to-access information. Comparative analyses to examine differences in SCP completion time by patient clinico-demographic characteristics and provider type revealed no significant differences. CONCLUSIONS:Our BC-SCP has clinical relevance, and can be used in an active practice setting. However, considerable progress will be necessary to achieve implementation of and sharing the BC-SCP with patients and care providers, particularly within the electronic medical record. In summary, BC-SCPs are essential to improve the follow up care of BC survivors. Clinical resources are required to ensure appropriate implementation of BC-SCPs. TRIAL REGISTRATION/BACKGROUND:Study HUM00056082.

Transurethral resection of bladder tumour is the initial, most critical step in the management of bladder cancer; as such, this is a call to arms for the urological community to it the due diligence it deserves regarding technology and training.

Background: Nonmuscle-invasive bladder cancer (NMIBC) is the most common form of bladder cancer, with high rates of disease recurrence and progression. Current treatment for high-risk NMIBC involves Bacillus Calmette-Guérin (BCG) therapy, but treatment options are limited for patients with recurrent or BCG-unresponsive disease. Aberrant programmed death 1 signaling has been implicated in BCG resistance and bladder cancer recurrence and progression, and pembrolizumab has shown efficacy in patients with BCG-unresponsive high-risk NMIBC. Aim: To describe the rationale and design for the randomized, comparator-controlled Phase III KEYNOTE-676 study, which will evaluate the efficacy and safety of pembrolizumab in combination with BCG in patients with persistent/recurrent high-risk NMIBC after BCG induction therapy. Trial registration number: NCT03711032.

BACKGROUND:Lymphovascular invasion (LVI) in muscle-invasive bladder cancer is associated with a poor prognosis when identified from radical cystectomy (RC) specimens. However, LVI is not clearly emphasized in any risk models to guide clinical decision-making. The impact of LVI on the risk of lymph node (LN) metastasis after a transurethral resection of bladder tumor (TURBT) specimen is less understood. OBJECTIVE:The goal was to describe the impact of LVI and the risk of LN metastasis at each clinical stage of urothelial carcinoma of the bladder (UC). DESIGN, SETTING, AND PARTICIPANTS/METHODS:The National Cancer Database was queried for patients with bladder cancer who underwent RC with LN dissection from 2004 to 2014. Patients with non-bladder primary, non-UC histology, clinical metastatic disease, and having received chemotherapy/radiation were excluded. Pathologic LN positive rates at RC were determined. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS/UNASSIGNED:The primary outcome was pathologic upstaging at RC and pathologic node positivity. Secondary outcomes included determining overall survival (OS). All hypotheses testing were two-sided and a p value of <0.05 was considered statistically significant. All statistical analyses were performed using Stata version 13.1. RESULTS AND LIMITATIONS/CONCLUSIONS:A total of 3007 patients with UC underwent RC with pelvic LN dissection. In patients with LVI, the risk of LN metastasis was significantly higher at each clinical stage as was the rate of pathologic upstaging. Patients with LVI on TURBT had worse OS stage for stage in pure UC (p<0.001). Limitations include that there was no central pathologic review and the number of TURBTs per patient was not known. CONCLUSIONS:Patients with UC with LVI had worse OS and are at higher risk for LN-positive disease and pathologic upstaging at surgery than patients without LVI. PATIENT SUMMARY/UNASSIGNED:In this report we examined the impact of lymphovascular invasion (LVI) at transurethral resection of bladder tumor on pathologic upstaging and lymph node metastasis at radical cystectomy using the National Cancer Database. We identified LVI as being prognostic at each stage of urothelial carcinoma.

Non-muscle invasive bladder cancer (NMIBC) is the most common form of bladder cancer with frequent recurrences and risk for progression. Risk stratified treatment and surveillance protocols are often utilized to guide management. In 2017, this journal reviewed guidelines on NMIBC from four major organizations: the American Urological Association (AUA)/ Society of Urologic Oncology (SUO), the European Association of Urology (EAU), the National Comprehensive Cancer Network (NCCN), and the National Institute for Health and Care Excellence (NICE). This update will review major changes in the guidelines and broadly summarize new recommendations for treatment of NMIBC in an era of BCG shortage and immense novel therapy development.

Immune checkpoint inhibitors have revolutionized the treatment of patients with metastatic urothelial carcinoma. In cisplatin-eligible muscle-invasive bladder cancer (MIBC), cisplatin-based neoadjuvant chemotherapy (NAC) before radical cystectomy improves overall survival. Tumor PD-L1 expression increases in MIBC after NAC, suggesting potential synergy in combining PD1/PD-L1 inhibitors with NAC. IDO1 is overexpressed in bladder cancer and is associated with poor outcomes. Linrodostat mesylate (BMS-986205) - a selective, potent, oral IDO1 inhibitor - combined with nivolumab has demonstrated safety and preliminary evidence of clinical activity in metastatic urothelial carcinoma. Here, we discuss the rationale and trial design of the ENERGIZE, a Phase III trial investigating the efficacy of NAC in combination with nivolumab with or without linrodostat followed by postsurgery nivolumab or nivolumab with linrodostat in cisplatin-eligible patients with MIBC. Clinical trial registration number: NCT03661320.

Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous subclassification of urothelial carcinoma with significant variation in individual risk of recurrence and progression to muscle-invasive disease. Risk stratification by American Urological Association (AUA) and European Association of Urology (EAU) guidelines or by using nomograms/risk calculators developed from clinical trial data can help inform patient treatment decisions but may not accurately classify all patients. Risk-adapted adjuvant (post-transurethral resection of bladder tumor [TURBT]) treatment strategies using intravesical therapies are an important means of balancing disease control with potential adverse effects. Adjuvant intravesical instillation with various chemotherapy agents and bacillus Calmette-Guérin (BCG) is well studied and associated with excellent outcomes for most patients. However, upwards of 40% of patients recur within 2 years and roughly 10% progress to muscle-invasive bladder cancer. Novel approaches and agents that aim to reduce the treatment burden associated with NMIBC are increasingly needed. We review the current landscape of NMIBC as it pertains to the use of and rationale for emerging neoadjuvant chemoablative therapies.

PURPOSE OF REVIEW/OBJECTIVE:BCG is the gold standard agent used in high-risk non-muscle-invasive bladder cancer (NMIBC) that is amenable to bladder sparing management. However, recent BCG shortages appear to be a chronic problem. There are limited effective intravesical options in lieu of BCG or in patients in whom BCG is not effective. This review aims to highlight emerging bladder sparing therapies and trials for NMIBC. RECENT FINDINGS/RESULTS:Patients with high-risk NMIBC who do not respond to BCG are at increased risk for progression and death from bladder cancer. There are a variety of clinical trials exploring different therapeutic approaches including checkpoint inhibition, novel chemotherapy and drug delivery, viral and gene therapy, vaccines, and targeted therapy. In the era of limited supply of BCG, there is a need for both effective first-line alternatives as and options for patients who do not respond to BCG. Fortunately, there are a variety of active trials and mechanisms exploring these areas aggressively.

Objective/UNASSIGNED:To harmonize eligibility criteria and radiographic disease assessments in clinical trials of adjuvant therapy for muscle-invasive bladder cancer (MIBC). Methods/UNASSIGNED:National experts in bladder cancer clinical trial research, including medical and urologic oncologists, radiologists, biostatisticians, and patient advocates, convened at a public workshop on November 28, 2017, to discuss eligibility, radiographic entry criteria, and assessment of disease recurrence in adjuvant clinical trials in patients with MIBC. Results/UNASSIGNED:The key workshop conclusions for adjuvant MIBC clinical trials included the following points: (1) patients with urothelial carcinoma with divergent histologic differentiation should be allowed to enroll; (2) neoadjuvant chemotherapy is defined as at least 3 cycles of neoadjuvant cisplatin-based combination chemotherapy; (3) patients with muscle-invasive, upper-tract urothelial carcinoma should be included in adjuvant trials of MIBC; (4) patients with severe renal insufficiency can enroll into trials using agents that are not renally excreted; (5) patients with microscopic surgical margins can be included; (6) patients should undergo a standard bilateral lymph node dissection prior to enrollment; (7) computed tomographic (CT) imaging should be performed within 4 weeks prior to enrollment. For patients with renal insufficiency who cannot undergo CT imaging with contrast, noncontrast chest CT and magnetic resonance imaging of the abdomen and pelvis with gadolinium should be done; (8) biopsy of indeterminate lesions to evaluate for malignant disease should be done when feasible; (9) a uniform approach to evaluate indeterminate radiographic lesions when biopsy is not feasible should be included in any trial design; (10) a uniform approach to determining the date of recurrence is important in interpreting adjuvant trial results; and (11) new high-grade, upper-tract primary tumors and new MIBC tumors should be considered recurrence events. Conclusions and Relevance/UNASSIGNED:A uniform approach to eligibility criteria, definitions of no evidence of disease, and definitions of disease recurrence may lead to more consistent interpretations of adjuvant trial results in MIBC.