Bladder Cancer Journal Vol. 4 Issue 4

Urinary Biomarkers in the Evaluation of Primary Hematuria: A Systematic Review and Meta-Analysis

Introduction: Urinary biomarkers are entering the clinical landscape as a non-invasive method to evaluate patients for bladder cancer, however it is currently predominantly used in the surveillance setting. The use of biomarkers in the setting of primary hematuria is not widespread despite initial promising results. This study comprehensively reviews the literature on the diagnostic performance of FDA-approved biomarkers in the evaluation of primary hematuria. Methods: According to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement, MEDLINE, EMBASE, ScienceDirect, Cochrane Libraries, HTA database, Google Scholar and Web of Science were searched up to June 2017 for studies assessing the diagnostic accuracy of FDA-approved urinary biomarkers amongst patients presenting with primary hematuria. The quality of included studies was assessed using the QUADAS-2 tool. Results: Fourteen studies met the pre-specified eligibility criteria and were included for analysis. The biomarkers assessed in these studies were AssureMDx, Bladder tumor antigen, CxBladder, NMP22, UroVysion and uCyt+. Across these four biomarkers, the sensitivity ranged from 0.67 to 0.95, and specificity from 0.68 to 0.93, respectively. There was significant heterogeneity between the included studies. Limited head-to-head comparison with urine cytology demonstrated that in general, the biomarkers have superior sensitivity but inferior specificity. Overall, the quality of evidence was graded as moderate primarily because of inadequate blinding. Conclusion: The current diagnostic performance of biomarkers are inadequate to replace cystoscopy in the primary hematuria setting. However, AssureMDx in particular may have a role as a triage test for cystoscopy but further prospective data is required to validate these findings. Given the current evidence, the use of these markers as an adjunct to cystoscopy for the evaluation of hematuria should be considered investigational.

Intravesical Radiofrequency-Induced Chemohyperthermia for Carcinomain Situ of the Urinary Bladder: A Retrospective Multicentre Study

Objective: To examine the effect of intravesical radiofrequency-induced chemohyperthermia (RF-CHT) in carcinoma in-situ (CIS) patients overall and split according to previously received therapy. Methods: CIS patients that underwent an induction and maintenance phase of≥6 RF-CHT instillations, and had either pathology or cystoscopy plus cytology available at 6 months of follow-up were retrospectively included. Complete response (CR), recurrences, cystectomy-free rate, overall survival (OS), and adverse events were evaluated. Analysis was performed for overall, bacillus Calmette-Guérin (BCG)-unresponsive, other BCG-treated, and treatment naïve patients. Results: Patients (n  = 150) had a mean of 17.5, 9.2, or 0 previous BCG instillations in the BCG-unresponsive (n  = 50), other BCG-treated (n  = 46, missing n  = 4), and treatment naïve groups (n  = 47, missing n  = 3), respectively. After 6 months, a CR of 46.0%, 71.7%, and 83.0% was found (p  < 0.001). Subsequent 2-year recurrence rates were 17.4%, 27.3%, and 12.8%, respectively. The overall cystectomy-free rate and OS at mean follow-up (35.8 months) were 78.5% and 78.0%, respectively. These were 71.4% vs. 84.1% vs. 86.7% (cystectomy-free rate, p  = 0.006) and 76.0% vs. 69.6% vs. 87.2% (OS, p  = 0.06) for BCG-unresponsive vs. other BCG-treated vs. treatment naïve patients. Progression to muscle-invasive disease was seen in 13.3% of patients. Patients stopped induction or maintenance RF-CHT instillations due to adverse events in respectively 13.4% and 17.8%. Conclusions: Intravesical RF-CHT showed good results in both treatment naïve and BCG-treated CIS patients, avoiding the need for cystectomy in 78.5% of cases for at least 3 years with a modest risk of progression. Thus, RF-CHT proves an alternative to cystectomy in selected high-risk patients. 

Early Complications and Mortality following Radical Cystectomy: Associations with Malnutrition and Obesity

Background: There are conflicting data regarding the impact of obesity on postoperative outcomes following radical cystectomy (RC) and how obesity and malnutrition interact in patients undergoing RC. Objective: To evaluate associations of body mass index (BMI), significant preoperative weight loss, and hypoalbuminemia with 30-day complications and mortality after RC. Methods: Review of the American College of Surgeons National Surgical Quality Improvement Program database identified 2,055 patients who underwent RC (2006-12). Univariate and multivariable logistic regression models were developed to assess associations between hypoalbuminemia (<3.5 g/dL), >10% preoperative weight loss, obesity as characterized by BMI (class I: 30–34.9, II: 35–39.9, III: ≥40 kg/m2 ), and 30-day complications and mortality. Results: The median BMI of the study cohort was 27.82 kg/m2 with 22.4% classified as having class I, 7.5% class II, and 4.2% class III obesity, respectively. Hypoalbuminemia and >10% weight loss were present in 16.7% and 3.5%, respectively. Among obese patients, 13.4% had hypoalbuminemia. On multivariable analysis, class I (OR 1.43, p = 0.01), class II (OR 1.92, p < 0.001), and class III (OR 2.32, p < 0.001) obesity and hypoalbuminemia (OR 1.47, p = 0.02) were independently associated with 30-day complications, and class III obesity (OR 2.96, p = 0.02) and hypoalbuminemia (OR 2.33, p = 0.03) were independently associated with 30-day mortality. Conclusion: Increasing class of obesity and hypoalbuminemia were independently associated with increased complications following RC. Hypoalbuminemia and class III obesity were associated with early mortality. This study highlights the fact that malnutrition may coexist in obese patients and underscores the need to identify patients with malnutrition who may be candidates for preoperative nutritional optimization.

Evaluation of Intraoperative Versus Postoperative Adjuvant Mitomycin C with Nephroureterectomy for Urothelial Carcinoma of the Upper Urinary Tract

Background: Results of randomized trials support a single dose of intravesical chemotherapy following radical nephroureterectomy (RNU) for urothelial carcinoma. Objective: To evaluate the impact of the timing of intravesical mitomycin C (MMC) administration on the rate of bladder tumor recurrence (BTR) following RNU. Methods: We performed a retrospective review of patients who underwent RNU for upper tract urothelial carcinoma (UTUC) and received intravesical MMC between 2008 and 2016. Patients were categorized into two separate groups based on the timing of MMC administration: patients who received MMC intraoperatively (IO) and patients who received MMC on post-operative day 1 or later (PO). Our primary endpoint was BTR rate within the first year after surgery. Results: Fifty-one patients met our inclusion criteria: (IO: n = 30; PO: n = 21). There were no statistically significant differences in baseline characteristics of age, gender, race, surgical approach, tumor grade, tumor stage, surgical margins, nodal status, concomitant CIS, or history of bladder cancer. The median length of follow-up for each group was 22 months for IO and 12 months for PO (P = 0.10). The estimated probability of 1-year BTR rates for the IO and PO groups were 16% and 33%, respectively (p = 0.09). Cox analysis noted that the IO patients had a significantly lower rate of BTR in the first year postoperatively (HR = 0.113, 95% CI = 0.28–0.63, p = 0.01). Conclusions: The use of intraoperative MMC at the time of RNU was associated with a decrease in the risk of 1-year recurrence within the bladder. 

Hyperthermic Intravesical Chemotherapy for BCG Unresponsive Non-Muscle Invasive Bladder Cancer Patients

Background: Adjuvant intravesical instillations with bacillus Calmette-Guérin (BCG) is the recommended treatment option for patients with intermediate-and high-risk non-muscle invasive bladder cancer (NMIBC). Despite adequate BCG treatment, a large proportion of patients experience a recurrence. Although radical cystectomy is the gold standard for BCG unresponsive NMIBC, some patients are unfit or unwilling to consider this option. Objective: To assess the effectiveness of Hyperthermic IntraVEsical Chemotherapy (HIVEC® ) in BCG unresponsive NMIBC patients. Methods: A post-hoc analysis was conducted of prospectively included intermediate-and high-risk NMIBC patients who were planned to receive HIVEC® treatment between October 2014 and November 2017. For the present analysis, only patients who met the BCG unresponsive definition were included. Patients were followed by cystoscopy and cytology every 3 months and a CT-urography scan yearly. The primary outcome was the disease-free survival (DFS). The Common Terminology Criteria for Adverse Events (CTCAE) was used to assess side-effects. Results: The study population consisted of 55 BCG unresponsive NMIBC patients of whom 52 underwent≥5 HIVEC® treatments. The median age and follow-up were 73 years and 14.0 months (IQR 7.6 – 24.6). The median DFS was 17.7 months (SE 6.72) and progression occurred in four patients. The 1-year cumulative incidence rate of disease recurrence/progression was 53%. Two patients experienced severe side-effects (CTCAE≥3). Conclusions: HIVEC® seems a valid treatment option for BCG unresponsive NMIBC patients. We report a median DFS of 17.7 months (SE 6.72), potentially avoiding or postponing the need for radical surgery in a proportion of these patients.

Increased Surgical Complications in Smokers Undergoing Radical Cystectomy

Background: Not only is smoking a risk factor for the development of bladder cancer, it has also been implicated in increasing surgical morbidity and mortality. In general, the demographic and clinical characteristics of smokers are different to non-smokers which can bias the results of the impact of smoking. Objective: To evaluate the impact of smoking on radical cystectomy outcomes. Methods: Radical cystectomy cases were identified in the National Surgical Quality Improvement Program database from 2007–2015. Smokers were matched with non-smokers using propensity scores in a 1:1 ratio. Multivariate logistic regression was performed to evaluate the overall incidence of Clavien III-V complications. Secondary analysis was performed for the incidence of each complication recorded in NSQIP. Results: A total of 850 smokers undergoing radical cystectomy were matched to 850 non-smokers. The matching process improved the balance of covariates between smokers and non-smokers. The overall incidence of Clavien III-V complications was higher in smokers (13.1% vs 7.4%, p  < 0.001). This corresponded to an adjusted odds ratio of 1.9 [95% CI 1.4–2.6, p  = 0.028]. Other comorbid conditions worsened post-operative complications amongst smokers. When evaluating each complication recorded in the database, smokers had a higher incidence of wound dehiscence, pneumonia and myocardial infarction. Conclusion: Current smokers have a greater risk of morbidity following radical cystectomy. This should be considered when evaluating safety of surgery and patients should be counseled accordingly. Furthermore, even a short period of pre-operative smoking cessation can improve surgical outcomes.

Changes in Lean Muscle Mass Associated with Neoadjuvant Platinum-Based Chemotherapy in Patients with Muscle Invasive Bladder Cancer

Background: Baseline sarcopenia or severe lean muscle deficiency is independently associated with increased mortality after cystectomy for muscle-invasive urothelial carcinoma of the bladder (MIUC). The impact of chemotherapy on muscle mass in MIUC patients remains undefined Objectives: To describe preoperative changes in body composition in MIUC patients receiving platinum-based neoadjuvant chemotherapy (NC). Methods: Patients with cT2-4 N0-1 M0 UC of the bladder who received NC were identified. Lumbar skeletal muscle index (SMI, cm2 /m2 ), visceral adipose index (VAI, cm2 /m2 ), and the subcutaneous and intramuscular adipose index (SAI, cm2 /m2 )were calculated using validated methodology (cross sectional area of skeletal muscle/height2 at L3) from measurement of soft tissue areas on pre- (pre-NC) and post-NC (post-NC) computed tomography. Patients were classified as sarcopenic according to consensus definitions: Male: SMI <55 cm2 /m2 , Female: SMI <38.5 cm2 /m2 . Pre-NC and post-NC median body mass index (BMI kg/m2 ), SMI, and adipose indices were compared. Results: The study cohort consisted of 26 patients, with a median age 70 years, including 7 females (27%). Chemotherapy regimens included dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (31%), gemcitabine/cisplatin (62%) and gemcitabine/carboplatin (3.8%) with a median of 3.5 (range 2–6) cycles. Median pre- and post-NC BMI were 27.1 kg/m2 and 27.2 kg/m2 (p  = 0.36). Median pre- and post-NC SMI were 49.1 cm2 /m2 and 44.5 (p  < 0.001) respectively. Median percent change in SMI was –6.4% (range –30% to 10%). Pre-NC, 18 (69%) patients were sarcopenic vs. 21 (81%, p  = 0.002) post-NC. Median time between initiation of chemotherapy and cystectomy was 110 days. Conclusions: We observed a significant decrease in lean muscle mass among MIUC patients treated with platinum-based NC prior to cystectomy, with an associated increase in the prevalence of sarcopenia. Patients undergoing NC may benefit from pre-habilitative interventions to mitigate lean muscle loss prior to cystectomy.

Venous Thromboembolism and Peri-Operative Chemotherapy for Muscle-Invasive Bladder Cancer: A Population-based Study

Background: Chemotherapy and major pelvic surgery are established risk factors for venous thromboembolism (VTE). We evaluate the incidence rate, timing, and factors associated with VTE in patients with bladder cancer who underwent radical cystectomy and peri-operative chemotherapy in routine clinical practice. Methods: Electronic records of treatment were linked to the population-based Ontario Cancer Registry to identify all patients who underwent cystectomy for bladder cancer in Ontario 1994–2013. VTE events within 6 months of before or after cystectomy were identified using diagnostic codes recorded on hospital admissions and emergency department visits. Multivariable logistic regression was used to analyze factors associated with VTE prior to surgery, within 90-days of cystectomy, and 120-days after the start of adjuvant chemotherapy. Results: 4205 patients had cystectomy and 26% (1084/4205) received peri-operative chemotherapy. The overall incidence rate of VTE within 6 months of cystectomy was 9% (363/4205). VTE rate was highest among those patients treated with neoadjuvant chemotherapy (NACT) compared to patients treated with no chemotherapy or only adjuvant chemotherapy (ACT) (12% vs 8% vs 9%, p  = 0.002). Among all VTE events, 10%, 28%, and 61% occurred before, during, and after hospitalization for cystectomy. Pre-operative VTE rate was highest among cases treated with NACT (4%) compared to patients with no chemotherapy (<1%) or ACT (<1%) (p  < 0.001). VTE within 90 days of surgery was associated with greater length of hospital admission (p  < 0.001) across all treatment groups. Conclusions: A substantial proportion of patients treated with peri-operative chemotherapy will develop VTE. The majority of these occur after discharge from hospital following cystectomy. Extended thromboprophylaxis treatment in high-risk patients including those who receive peri-operative chemotherapy should be considered.

Immunology, Immunotherapy, and Translating Basic Science into the Clinic for Bladder Cancer

The Fourth Annual Albert Institute Bladder Cancer Care and Research Symposium was held from September 14th–16th in Houston, Texas. The symposium covered a range of topics relevant to bladder cancer, including basic science aspects of immunology and immunotherapy that inform clinical management; intravesical therapy for non-muscle invasive disease; understanding the nuances of carcinoma in situ ; and optimizing patient care and outcomes following therapy. The moving landscape of bladder cancer from an industry perspective was also discussed. In the following sections we discuss intrinsic and extrinsic factors, including the immune microenvironment and sex bias, in the context of bladder cancer; how these influence tumor development, progression, and treatment strategies; and how the interpretation of immune features in relation to molecular subtypes informs both treatment decisions and response. We conclude with a summary of key points that will need to be addressed to ensure best use of new knowledge in this area for improved clinical management of patients with bladder cancer. 

Challenging Cases in Urothelial Cancer

This is a healthy appearing 77 year old man with bladder cancer. He presented in April 2016 with an episode of gross hematuria. He lives in Central America and was seen by a urologist there. His past medical history is uneventful. He has adult onset type 2 diabetes and takes metformin. He was never a cigarette smoker. The only surgery he had was a right inguinal hernia repair. He is not overweight.

Perioperative Blood Transfusions and Bladder Cancer Outcomes

There are many reasons to restrict administration of allogeneic perioperative blood transfusions (PBTs) including avoiding transfusion reactions, transmission of infections, sensitization against future transfusions and organ transplantations, and of course, “waste” of a precious and scarce resource. However, the one that concerns bladder cancer surgeons the most is having worse oncologic outcomes, particularly reducing cause specific (CSS) and overall survival (OS) for patients undergoing radical cystectomy. The most compelling articles which point to this possibility are two structured reviews [1, 2] which show marginal improvements in OS and CSS and reduction in all-cause mortality (ACM) in patients who have not received a PBT. However, neither review has had the opportunity to analyze patient specific data and very few of the individual studies comprising the reviews actually show a benefit on their own. Moreover, the two structured reviews share 6 studies. The biggest concern with this type of analysis is that they only included retrospective studies with many uncontrolled variables, including different thresholds for administering transfusions, and of course, complicating factors such as prior surgery and or radiation therapy, which lengthen cases and increase the likelihood of administering PBTs. While demographics and stage of disease were often controlled for in the studies, other factors including tumor size, patient frailty, and specific comorbidities were not. Each of these greatly impacts surgeons’ and anesthesiologists’ decisions to administer blood.

Clinical Trials Corner

A Phase I/II Study of IMMU-132 (hRS7-SN38 Antibody Drug Conjugate) in Patients With Epithelial Cancers

Patients with advanced epithelial cancers, including metastatic urothelial cancer (mUC), have a poor prognosis and this phase I/II trial looks at the safety and efficacy of a novel antibody-drug conjugate, IMMU-132 (hRS7-SN38), also known as Sacituzumab Govitecan. The antibody, hRS7, is a humanized anti-Trop-2 monoclonal antibody attached to SN38 which is the active metabolite of irinotecan (CPT-11). The drug targets Trop-2 which is overexpressed in aggressive epithelial cancers including up to 83% of urothelial tumors and the conjugate binds to Trop-2 and delivers the active metabolite of a topoisomerase I inhibitor.