Faculty Bibliography

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.

PURPOSE/OBJECTIVE:BCG is the gold standard in management of high-risk non-muscle invasive bladder cancer (HRNMIBC). However, in patients who fail BCG, there are few effective intrasvesical options. This review aims to explore standard and emerging therapies in HRNMIBC. METHODS:A non-systematic literature review was performed using Medline and PubMed. Literature focused on HRNMIBC and BCG failure studies, with particular attention to Phase II and III clinical trials. RESULTS:The only FDA approved therapy for BCG failure patients in Valrubicin. Patients with HRNMIBC and BCG failure patients are at increased risk for progression and death from bladder cancer. There are a variety of clinical trials exploring different therapeutic approaches such as immunotherapy, vaccines, radiotherapy, and gene therapy. These trials are showing some promise in the early reporting phase. CONCLUSION/CONCLUSIONS:Despite limited intravesical treatment options in BCG failure patients, there are several promising therapies currently being developed and several with promising early results.

Blue light cystoscopy (BLC) with hexaminolevulinate (HAL) during transurethral resection of bladder cancer improves detection of non-muscle-invasive bladder cancer (NMIBC) and reduces recurrence rates. Flexible BLC was approved by the FDA in 2018 for use in the surveillance setting and was demonstrated to improve detection. Results of a phase III prospective multicentre study of blue light flexible cystoscopy (BLFC) in surveillance of intermediate-risk and high-risk NMIBC showed that 20.6% of malignancies were identified only by BLFC. Improved detection rates in the surveillance setting are anticipated to lead to improved clinical outcomes by reducing future recurrences and earlier identification of tumours that are unresponsive to therapy. Thus, BLFC has a role in surveillance cystoscopy, and determining which patients will benefit from BLFC and optimal and cost-effective ways of incorporating this technology into surveillance cystoscopy must be developed.

BACKGROUND:To evaluate efficacy and morbidity prospectively in a contemporary multi-institutional salvage radical prostatectomy (SRP) series. METHODS:disease. Surgical morbidity, quality of life, biochemical progression-free survival (BPFS) and overall survival (OS) were evaluated. RESULTS:Twenty-four men had undergone external beam radiotherapy, 11 brachytherapy, and six both. Median time between radiation and SRP was 64 months. Median age at SRP was 64 years. Pathologic staging revealed 44% pT2, 54% pT3, and 3% pT4. Surgical margins were positive in 17 and 88% were pN0. Twenty-two percent required intraoperative blood transfusion. Three rectal and one obturator nerve injuries occurred. Seventeen of 38 evaluable patients (45%) had urinary incontinence ( ≥ 3 pads/day) prior to SRP; 88% reported urinary incontinence at 6 months, 85% at 12 months, 63% at 24 months after SRP. Furthermore, 37% of men reported impotence prior to SRP; 78% reported impotence at 6 months, 82% at 12 months, and 44% at 24 months after SRP. The 2-, 5- and 10-year BPFS rates were 51, 39, and 33% respectively; the 2-, 5- and 10-year OS rates were 100, 89, and 52%, respectively, at median follow-up 91 months. CONCLUSIONS:Modern surgical techniques continue to be associated with significant peri-operative complication rates. Nevertheless, SRP may benefit carefully selected patients through durable oncologic control.

BACKGROUND:Bladder cancer is commonly diagnosed in patients ineligible for radical cystectomy or chemoradiotherapy (chemo-RT) with cisplatin or fluorouracil with mitomycin. We assessed tolerability, efficacy, and toxicity of hypofractionated radiotherapy with capecitabine in this challenging population. PATIENTS AND METHODS/METHODS:per day 2 times a day) and radiation (median, 55 Gy in 2.2 Gy per fraction). Patients underwent surveillance cystoscopy and imaging, and were evaluated for toxicity, freedom from local failure and freedom from distant metastasis, progression-free survival, and overall survival. RESULTS:Eleven patients (median age, 80 years) with localized disease (n = 7), locally advanced disease (n = 3), or local-only recurrence after cystectomy (n = 1) were treated. Four patients (35%) had an Eastern Cooperative Oncology Group performance status of 2; median Charlson comorbidity index was 5. There was 1 acute grade 3 genitourinary event (9%), 6 acute grade 3 hematologic events (55%) of lymphopenia, and no acute grade 4 or higher events or hospitalizations. Ten patients (91%) completed radiotherapy, while 4 patients (36%) temporarily discontinued capecitabine. The complete response rate in the bladder was 64%. Two patients (18%) experienced late grade 1/2 genitourinary toxicities, and 1 (9%) experienced a transient late grade 4 genitourinary toxicity. With a median follow-up of 16.6 months, overall survival, progression-free survival, freedom from local failure, and freedom from distant metastasis at 1 year were 82%, 55%, 100%, and 55%, respectively, and at 2 years were 61%, 41%, 80%, and 55%, respectively. CONCLUSION/CONCLUSIONS:Hypofractionated chemo-RT was well tolerated and was associated with a high rate of local control in this comorbid population, thus providing a treatment option for select bladder cancer patients.

PURPOSE:To determine the association of micropapillary urothelial carcinoma (MUC) variant histology with bladder cancer outcomes after radical cystectomy. MATERIALS AND METHODS:Information on MUC patients treated with radical cystectomy was obtained from five academic centers. Data on 1,497 patients were assembled in a relational database. Tumor histology was categorized as urothelial carcinoma without any histological variants (UC; n = 1,346) or MUC (n = 151). Univariable and multivariable models were used to analyze associations with recurrence-free (RFS) and overall (OS) survival. RESULTS:Median follow-up was 10.0 and 7.8 years for the UC and MUC groups, respectively. No significant differences were noted between UC and MUC groups with regard to age, gender, clinical disease stage, and administration of neoadjuvant and adjuvant chemotherapy (all, P ≥ 0.10). When compared with UC, presence of MUC was associated with higher pathologic stage (organ-confined, 60% vs. 27%; extravesical, 18% vs. 23%; node-positive, 22% vs. 50%; P < 0.01) and lymphovascular invasion (29% vs. 58%; P < 0.01) at cystectomy. In comparison with UC, MUC patients had poorer 5-year RFS (70% vs. 44%; P < 0.01) and OS (61% vs. 38%; P < 0.01). However, on multivariable analysis, tumor histology was not independently associated with the risks of recurrence (P = 0.27) or mortality (P = 0.12). CONCLUSIONS:This multi-institutional analysis demonstrated that the presence of MUC was associated with locally advanced disease at radical cystectomy. However, clinical outcomes were comparable to those with pure UC after controlling for standard clinicopathologic predictors.