Faculty Bibliography

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.

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.

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.

INTRODUCTION:Urethral squamous cell cancer is a rare disease with limited clinical recommendations regarding management of the inguinal lymph nodes. Despite the similarities to penile cancer in terms of squamous cell carcinoma (SCC) histology and lymphatic drainage, there is not enough evidence to recommend for or against a prophylactic inguinal lymph node dissection (ILND) in patients with clinically negative groins and a primary tumor stage of T1b or higher. The objective of the study was to identify the rate of prophylactic inguinal lymph node dissection, node positive rate, and overall survival in patients with clinical T1 to T4 stage. The patients were separated into clinical N stage and the rates of node positivity were compared. We hypothesize that the node positivity rate would be similar to that observed in penile cancer of similar clinical T and N stage and provide evidence for prophylactic inguinal lymph node dissection in urethral squamous cancer. We also sought to determine the value of ILND in clinically node positive (cN+) and clinically node negative (cN-) patients. METHODS:The National Cancer Database was queried for all cases of primary urethral cancer in men from 2004 to 2014. Patients with other cancer diagnoses, metastasis, nonsquamous histology, female patients, and patients with a history of radiation therapy were excluded. Male patients with urethral squamous cell cancer of the anterior urethra with T1 or higher T stage were included in this study. All-cause mortality was compared using multivariable Cox regression controlling for covariates. RESULTS:The study included 725 men with urethral SCC with T1 or higher clinical T stage. The median age was 63 years (33-83 interquartile range). Of the 725 men, 536 men did not receive an ILND and 189 (26%) underwent ILND. Patients who received LND had significantly higher clinical T and clinical N stage. There was no difference in age, sex, or histology between those with ILND versus no ILND. In patients with T1 to T4 and clinical N0, the ILND rate was 21.8% (89/396). The lymph node positive rate in patients with N0 and T1 to T4 primary tumor was 9%. In patients with clinically node positive disease (N1/N2), the overall ILND rate was 76%. The lymph node positive rate for patients with clinical nodal disease was 84%. On multivariable analysis cox regression, lymph node positivity was associated with worse overall survival when controlling for T stage, clinical N stage, and age (HR 1.56, 95% 1.3-1.9, P = 0.000). On multivariable analysis after controlling for T stage, sex, and age, having an ILND was associated with improved OS in patients with clinical N1 or N2 disease (HR 0.46, 95% 0.28-0.78 P = 0.002). CONCLUSION:The node positivity rate in patients with T1 to T4 and N0 is 9%, much lower than reported in penile cancer with a high-risk primary tumor but clinically negative groins. This argues against routine prophylactic inguinal ILND in patients with urethral SCC who are clinically N0, perhaps suggesting different biological behavior of urethral SCC compared to penile SCC. Performing a lymph node dissection in patients with clinically N1 or N2 disease is associated with improved OS.

OBJECTIVES:CG0070 is a replication-competent oncolytic adenovirus that targets bladder tumor cells through their defective retinoblastoma pathway. Prior reports of intravesical CG0070 have shown promising activity in patients with high-grade non-muscle invasive bladder cancer (NMIBC) who previously did not respond to bacillus Calmette-Guérin (BCG). However, limited accrual has hindered analysis of efficacy, particularly for pathologic subsets. We evaluated interim results of a phase II trial for intravesical CG0070 in patients with BCG-unresponsive NMIBC who refused cystectomy. PATIENTS AND METHODS:At interim analysis (April 2017), 45 patients with residual high-grade Ta, T1, or carcinoma-in-situ (CIS) ± Ta/T1 had evaluable 6-month follow-up in this phase II single-arm multicenter trial (NCT02365818). All patients received at least 2 prior courses of intravesical therapy for CIS, with at least 1 being a course of BCG. Patients had either failed BCG induction therapy within 6 months or had been successfully treated with BCG with subsequent recurrence. Complete response (CR) at 6 months was defined as absence of disease on cytology, cystoscopy, and random biopsies. RESULTS:Of 45 patients, there were 24 pure CIS, 8 CIS + Ta, 4 CIS + T1, 6 Ta, 3 T1. Overall 6-month CR (95% CI) was 47% (32%-62%). Considering 6-month CR for pathologic subsets, pure CIS was 58% (37%-78%), CIS ± Ta/T1 50% (33%-67%), and pure Ta/T1 33% (8%-70%). At 6 months, the single patient that progressed to muscle-invasive disease had Ta and T1 tumors at baseline. No patients with pure T1 had 6-month CR. Treatment-related adverse events (AEs) at 6 months were most commonly urinary bladder spasms (36%), hematuria (28%), dysuria (25%), and urgency (22%). Immunologic treatment-related AEs included flu-like symptoms (12%) and fatigue (6%). Grade III treatment-related AEs included dysuria (3%) and hypotension (1.5%). There were no Grade IV/V treatment-related AEs. CONCLUSIONS:This phase II study demonstrates that intravesical CG0070 yielded an overall 47% CR rate at 6 months for all patients and 50% for patients with CIS, with an acceptable level of toxicity for patients with high-risk BCG-unresponsive NMIBC. There is a particularly strong response and limited progression in patients with pure CIS.

PURPOSE:To evaluate the accuracy of the American College of Surgeons National Surgical Quality Improvement Programs (ACS-NSQIP) surgical risk calculator in patients undergoing radical cystectomy (RC) with urinary diversion. MATERIALS AND METHODS:Preoperative characteristics of patients who underwent RC with ileal conduit or orthotropic neobladder (ONB) between 2007 and 2016 were entered into the proprietary online ACS-NSQIP calculator to generate 30-day predicted risk profiles. Predicted and observed outcomes were compared by measuring Brier score (BS) and area under the receiver operating characteristic curve (AUC). RESULTS:Of 954 patients undergoing RC, 609 (64%) received ileal conduit and 345 (36%) received ONB. The calculator underestimated most risks by 10%-81%. The BSs exceeded the acceptable threshold of 0.01 and AUC were less than 0.8 for all outcomes in the overall cohort. The mean (standard deviation) predicted vs. observed length of stay was 9 (1.5) vs. 10.6 (7.4) days (Pearson's r = 0.09). Among patients who received ONB, adequate BS (<0.01) was observed for pneumonia, cardiac complications, and death. The receiver operating characteristic curve analysis revealed moderate accuracy of calculator for cardiac complications (AUC = 0.69) and discharge to rehab center (AUC = 0.75) among patients who underwent RC with ONB. CONCLUSIONS:The universal ACS-NSQIP calculator poorly predicts most postoperative complications among patients undergoing RC with urinary diversion. A procedure-specific risk calculator is required to better counsel patients in the preoperative setting and generate realistic quality measures.

Radical cystectomy (RC) with urinary diversion is associated with significant morbidity, much of which arises from the interposition of bowel segments in the urinary system. A tissue-engineered alternative for urinary diversion could dramatically reduce the perioperative and long-term morbidity associated with RC. Attempts at developing a tissue-engineered incontinent urinary conduit (TEUC) have involved mechanical scaffolds and promoting tissue growth within them. Despite some preclinical success, significant obstacles remain before a TEUC is ready for clinical use. A further understanding of tissue and materials engineering may help overcome these obstacles or help to develop a new approach to tissue engineering entirely.

Purpose/UNASSIGNED:Our prospective, randomized clinical study aims to evaluate the utility of intraoperative transesophageal echocardiography (TEE) in patients undergoing radical cystectomy. Materials and Methods/UNASSIGNED:percentile), or numbers and percentages. Characteristics were compared between groups using independent sample t-tests, Wilcoxon-Mann-Whitney tests or Chi-square tests, as appropriate. All tests were two-sided and P < 0.05 was considered to indicate statistical significance. Results/UNASSIGNED:Both groups had similar preoperative demographic characteristics. There was a significant difference between central line insertion with all insertions in the control group (15%, 6 vs. 0%, 0; P < 0.003). Of all the perioperative complications, 80% occurred in the control group versus 20% in the TEE group, with 21% of controls experiencing a cardiac or pulmonary complication compared to 5% in the TEE group (8 vs. 2, P < 0.04). The control group patients were more likely to have adverse cardiac complications than the TEE group (15%, 6 vs. 3%, 1; P < 0.040). Postoperative cardiac arrhythmia was observed only in the control group (13%, 5 vs. 0%, 0; P <.007). Prolonged intubation was only observed in the control group (10%, 4 vs. 0%, 0; P < 0.017). Conclusion/UNASSIGNED:TEE can be a useful monitoring tool in patients undergoing radical cystectomy, limiting the use of central line insertion and potentially translating into earlier extubation and decreased postoperative cardiac morbidities.

Context/UNASSIGNED:Radical cystectomy continues to be associated with a significant risk of morbidity and all-cause mortality (ACM). Practice pattern data demonstrating underuse of surgery for patients with muscle-invasive and high-risk non-muscle invasive bladder cancer (BC) have been linked to the advanced age and higher comorbidity status of such patients, which suggests that rates of ACM as well as cancer-specific mortality should be incorporated into patient counseling and guideline recommendations. Objective/UNASSIGNED:To review the literature on risk assessment tools for preoperative comorbidity in BC that may aid in treatment decision-making. Evidence acquisition/UNASSIGNED:A systematic search was conducted using Ovid and Medline according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to identify studies between 1970 and 2017 reporting on comorbidity risk assessment (CRA) tools for BC. Prospective and retrospective studies were included. Evidence synthesis/UNASSIGNED:There are no published randomized control trials comparing CRA tools for BC. Patients undergoing radical cystectomy with combined high-risk comorbidity and performance scores may face up to a sevenfold greater risk of other-cause mortality compared to those with low scores. The Charlson Comorbidity Index is one of the most widely studied indices for 90-d perioperative mortality and overall and cancer-specific survival, with an area under the receiver operating characteristic curve of up to 0.810. Prospective studies of CRA tools for BC have consistently shown that patients with higher comorbidity have worse outcomes. While not specific for BC, comorbidity indices provide useful assessment of competing risks. Competing-risks assessment tools are lacking, with limited studies assessing the impact of these tools on treatment decision-making by patients and providers. We provide the impetus for incorporation of comorbidity risks into practice guidelines when discussing treatment options with patients. Conclusions/UNASSIGNED:CRA tools should be incorporated into preoperative treatment counseling and the assessment of postoperative outcomes. While retrospective evidence supports the use of CRA tools for BC, further comparative studies evaluating the effectiveness of these tools and identifying the patients most likely to benefit from a treatment according to competing-risks assessment are needed. Patient summary/UNASSIGNED:In this review we explored the clinical evidence for comorbidity risk assessment tools in bladder cancer. We found evidence to support incorporation of comorbidity risks into practice guidelines when discussing treatment options with patients.