Faculty Bibliography

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/CONCLUSIONS: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.

PURPOSE/OBJECTIVE:The American Urological Association (AUA) introduced evidence-based guidelines for the management of nonmuscle invasive bladder cancer (NMIBC) in 2016. We sought to assess the implementation of these guidelines among members of the Society of Urologic Oncology (SUO) with an aim to identifying addressable gaps. METHODS AND MATERIALS/METHODS:An SUO approved survey was distributed to 747 members from December 28, 2018 to February 2, 2019. This 14-question online survey (Qualtrics, SAP SE, Germany) consisted of 38 individual items addressing specific statements from the AUA NMIBC guidelines within 3 broad categories - initial diagnosis, surveillance, and imaging/biomarkers. Adherence to guidelines was assessed by dichotomizing responses to each item that was related to recommended action statement within the guidelines. Statistical analysis was applied using Pearson's chi-squared test, where a P-value of <0.05 was considered statistically significant. RESULTS:A total of 121 (16.2%) members completed the survey. Members reported a mean of 71% guidelines adherence; adherence was higher for the intermediate- and high-risk subgroups (82% and 76%, respectively) compared to low-risk (58%). Specifically, adherence to guideline recommended cystoscopic surveillance intervals for low-risk disease differed based on clinical experience (60.9% [<10 years] vs. 36.8% [≥10 years], P = 0.01) and type of fellowship training (55.2% [urologic oncology] vs. 28.0% [none/other], P = 0.02). CONCLUSION/CONCLUSIONS:Adherence to guidelines across risk-categories was higher for intermediate- and high-risk patients. Decreased adherence observed for low-risk patients resulted in higher than recommended use of cytology, imaging, and surveillance cystoscopy. These results identify addressable gaps and provide impetus for targeted interventions to support high-value care, especially for low-risk patients.

Several molecular subtypes of bladder cancer were identified with differing clinical behavior and responses to platinum-based chemotherapy. But so far, their urothelial histomorphologic features, besides association to some variant histologies, remained fully undefined. We sought to characterize the histological features of genomically-classified bladder cancers more extensively to tumor in radical cystectomy (RC) specimens. Forty-eight bladder cancers submitted to TCGA were classified by BASE47 genomic classifier into luminal (LS) (14), basal (BS) (18) and claudin-low (CLS) (16) subtypes and the TCGA samples and corresponding RC specimens were histologically assessed. Marked pleomorphism was more extensive in CLS (87.5% had >15% extent) than LS (21.4%) (p=0.0006), while extent in BS was in between LS and CLS. Pleomorphism in distant carcinoma in situ appeared to correlate with that in the main tumor. Ki-67 proliferation was higher in CLS (mean 61%) than in LS (mean 29%) or BS (mean 30%) (p<0.001). Squamous differentiation was more extensive in BS and CLS (38.2% BS and CLS versus 7.1% LS had >30% squamous, p=0.040). Sarcomatoid change was present in BS and CLS only. Micropapillary variant was identified in LS (3/14) and BS (4/18) only. Histologic features associated with aggressiveness (e.g. marked pleomorphism, high proliferation, and sarcomatoid) are enriched in CLS correlating with its known poorer outcome that may provide hints in their microscopic distinction. Features more associated with BS than LS (e.g. squamous, marked pleomorphism, and sarcomatoid) are also identified or enhanced in CLS, supporting the genomic findings suggesting CLS as a "hyperbasal" form of BS.

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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CONTEXT/BACKGROUND:There is a critical need for effective bladder-sparing therapies for bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). Owing to the current lack of effective agents that can be used as a control, the US Food and Drug Administration began to accept single-arm trials for patients with carcinoma in situ (CIS), using complete response rate (CRR) and duration of response as the primary endpoints to support marketing applications. Despite the ensuing growth of clinical trials in this space, no consensus exists on a clinically relevant benchmark for CRR. OBJECTIVE:To elucidate the CRR and recurrence-free rate (RFR) using bladder-sparing agents after BCG failure in order to provide a frame of reference for future clinical trial results. EVIDENCE ACQUISITION/METHODS:We performed a systematic review of clinical trials utilizing bladder-sparing therapeutics for NMIBC recurring after intravesical BCG (PROSPERO CRD42019130553). The search was performed in MEDLINE, EMBASE, and Cochrane Library. Relevant studies identified from bibliography search and conference abstracts were searched to complement the systematic review. A total of 42 studies utilizing 24 treatment options and consisting of 2254 patients were included for final analysis. EVIDENCE SYNTHESIS/RESULTS:Median CRRs in the treatment of CIS-containing tumors were 26% at 6 mo, 17% at 12 mo, and 8% at 24 mo after treatment. In comparison, median RFRs in the papillary-only studies were 67% at 6 mo, 44% at 12 mo, and 10% at 24 mo. Specifically in the BCG-unresponsive population, 6- and 12-mo CRRs in CIS-containing patients treated with Mycobacterium phlei cell wall-nucleic acid complex were 45% and 27%, respectively, and the median 6-, 12-, and 24-mo disease-free rates in the other studies were 43%, 35%, and 18%, respectively. The median progression-free rate was 91%: 95% in the CIS-containing studies and 89% in studies restricted to papillary-only recurrences. Toxicities of intravesical agents were generally mild, with very few dose limiting toxicities. CONCLUSIONS:We demonstrate that, to date, bladder-sparing therapies achieved modest efficacy in patients with NMIBC after BCG. Results from the current study will serve as a frame of reference for emerging trial results in the BCG-unresponsive space. PATIENT SUMMARY/UNASSIGNED:In this study, we found that bladder-sparing therapies achieved modest efficacy in patients with non-muscle-invasive bladder cancer after bacillus Calmette-Guérin (BCG). These results will serve to inform future clinical trial results for salvage agents used to treat BCG-unresponsive bladder cancer.

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.