Safety and efficacy of intravesical chemotherapy and hyperthermia in the bladder: results of a porcine study.

BACKGROUND: Hyperthermia (heating to 43 °C) activates the innate immune system and improves bladder cancer chemosensitivity. OBJECTIVE: To evaluate the tissue penetration and safety of convective hyperthermia combined with intravesical mitomycin C (MMC) pharmacokinetics in live porcine bladder models using the Combat bladder recirculation system (BRS). METHODS: Forty 60 kg-female swine were anesthetized and catheterized with a 3-way, 16 F catheter. The Combat device was used to heat the bladders to a target temperature of 43 °C with recirculating intravesical MMC at doses of 40, 80, and 120 mg. Dwell-heat time varied from 30-180 min. Rapid necropsy with immediate flash freezing of tissues, blood and urine occurred. MMC concentrations were measured by liquid chromatography tandem-mass spectrometry. RESULTS: The Combat BRS system was able to achieve target range temperature (42-44 °C) in 12 mins, and this temperature was maintained as long as the device was running. Two factors increased tissue penetration of MMC in the bladder: drug concentration, and the presence of heat. In the hyperthermia arm, MMC penetration saturated at 80 mg, suggesting that with heating, drug absorption may saturate and not require higher doses to achieve the maximal biological effect. Convective hyperthermia did not increase the MMC concentration in the liver, heart, kidney, spleen, lung, and lymph node tissue even at the 120 mg dose. CONCLUSIONS: Convective bladder hyperthermia using the Combat BRS device is safe and the temperature can be maintained at 43 °C. Hyperthermia therapy may increase MMC penetration into the bladder wall but does not result in an increase of MMC levels in other organs.

Bone scan positivity in non-metastatic, castrate-resistant prostate cancer: external validation study.

INTRODUCTION: Tables predicting the probability of a positive bone scan in men with non-metastatic, castrate-resistant prostate cancer have recently been reported. We performed an external validation study of these bone scan positivity tables. MATERIALS AND METHODS: We performed a retrospective cohort study of patients seen at a tertiary care medical center (1996-2012) to select patients with non-metastatic, castrate-resistant prostate cancer. Abstracted data included demographic, anthropometric, and disease-specific data such as patient race, BMI, PSA kinetics, and primary treatment. Primary outcome was metastasis on bone scan. Multivariable logistic regression was performed using generalized estimating equations to adjust for repeated measures. Risk table performance was assessed using ROC curves. RESULTS: We identified 6.509 patients with prostate cancer who had received hormonal therapy with a post-hormonal therapy PSA ≥2ng/mL, 363 of whom had non-metastatic, castrate-resistant prostate cancer. Of these, 187 patients (356 bone scans) had calculable PSA kinetics and ≥1 bone scan. Median follow-up after castrate-resistant prostate cancer diagnosis was 32 months (IQR: 19-48). There were 227 (64%) negative and 129 (36%) positive bone scans. On multivariable analysis, higher PSA at castrate-resistant prostate cancer (4.67 vs. 4.4ng/mL, OR=0.57, P=0.02), shorter time from castrate-resistant prostate cancer to scan (7.9 vs. 14.6 months, OR=0.97, P=0.006) and higher PSA at scan (OR=2.91, P<0.0001) were significantly predictive of bone scan positivity. The AUC of the previously published risk tables for predicting scan positivity was 0.72. CONCLUSION: Previously published risk tables predicted bone scan positivity in men with non-metastatic, castrate-resistant prostate cancer with reasonable accuracy.

Anticipatory Positive Urine Tests for Bladder Cancer.

PURPOSE: The aim of this study was to establish the criteria defining an anticipatory positive test for bladder cancer. METHODS: We reviewed all patients at our institution who underwent urine cytology or UroVysion fluorescence in situ hybridization (FISH) and cystoscopy from 2003 to 2012. Test performance and cancer anticipation was assessed using generalized linear mixed models, mixed-effects proportional hazards models, and cumulative incidence curves using tests performed within 30 days of each other as well as within a lag time of 1 year. RESULTS: Overall, 6729 urine tests (4729 cytology and 2040 UroVysion FISH) were paired with gold-standard cystoscopies. Sensitivity and specificity were 63 and 41% for cytology, and 37 and 84% for UroVysion FISH, respectively. A 1-year lag time allowed for cancer anticipation and neither test improved. Among patients with positive cytology and initially negative cystoscopy, the hazard ratio of developing a bladder tumor at 1 year was 1.83; 76% of these patients developed a tumor within 1 year. Similarly, among patients with a positive FISH and initially negative cystoscopy, the hazard ratio of developing a bladder tumor at 1 year was 1.56; 40% of these patients developed a tumor within 1 year. CONCLUSIONS: Urine-based tests for bladder cancer are frequently falsely positive. With further follow-up time, some of these false positive tests are vindicated as true (anticipatory) positive tests, although many will remain false positives. We developed statistical criteria to determine if a test anticipates future cancers or not.

Over half of contemporary clinical Gleason 8 on prostate biopsy are downgraded at radical prostatectomy.

INTRODUCTION: Contemporary clinical guidelines utilize the highest Gleason sum (HGS) in any one core on prostate biopsy to determine prostate cancer treatment. Here, we present a large discrepancy between prostate cancer risk stratified as high risk on biopsy and their pathology after radical prostatectomy. MATERIALS AND METHODS: We retrospectively reviewed 1424 men who underwent either open or robotic-assisted prostatectomy between 2004 and 2015. We analyzed 148 men who were diagnosed with HGS 8 on prostate biopsy. Biopsy and prostatectomy pathology were compared in aggregate and over 1 year time intervals. Chi-squared test, Fisher's exact test, Student's t-test, and Wilcoxon Rank-Sum test were used for statistical analysis. RESULTS: A total of 61.5% (91/148) of clinical HGS 8 diagnoses were downgraded on prostatectomy, with 58.8% (87/148) downgraded to Gleason 7 (Gleason 4 + 3 n = 59; Gleason 3 + 4 n = 28). Factors associated with downgrading include lower prostate-specific antigen (PSA) at biopsy (median 6.8 ng/mL versus 9.1 ng/mL, p < 0.001), number of Gleason 8 biopsy cores (median 1 versus 2, p < 0.02), presence of Gleason pattern 3 on biopsy cores (67.9% versus 44.8%, p < 0.03), pT2 staging (72.4% versus 55.1%, p < 0.04), positive margins (53.9% versus 69.1%, p < 0.04), extracapsular extension (53.4% versus 74.1%, p < 0.02), and smaller percent tumor (median 10% versus 15%, p < 0.004). CONCLUSION: The large percentage of pathology downgrading of biopsy-diagnosed HGS 8 suggests suboptimal risk-stratification that may lead to suboptimal treatment strategies and much patient distress. Our study adds great urgency to the efforts refining prostate cancer clinical assessment.

A systematic review of regional hyperthermia therapy in bladder cancer.

CONTEXT: Bladder cancer therapy remains suboptimal as morbidity and mortality remain high amongst those with non-muscle-invasive and muscle-invasive disease. Regional hyperthermia therapy (RHT) is a promising adjunctive therapy being tested in multiple clinical contexts. OBJECTIVE: The aim of this study was to systematically review the literature on the efficacy and toxicity of RHT. EVIDENCE ACQUISITION: This systematic review was registered with the PROSPERO database (Registration number: CRD42015025780) and was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. We queried PubMed, EMBASE, and Cochrane libraries. Two reviewers reviewed abstracts independently and a third reviewer arbitrated disagreements. The last search was performed on 28 August 2015. A descriptive analysis was performed and quality assessment was conducted using the Newcastle-Ottawa Quality Assessment Scale for observational studies, and the Cochrane Risk of Bias Assessment Tool for trials. EVIDENCE SYNTHESIS: We identified 859 publications in the initial search, of which 24 met inclusion criteria for full-text review. Of these, we were able to obtain data on the outcomes of interest for 15 publications. CONCLUSIONS: The review underscores the limited nature of the evidence; definitive conclusions are elusive. However, the promising results of RHT in the setting of intravesical chemotherapy, chemotherapy and radiotherapy show a trend towards legitimate efficacy.

The diagnostic accuracy of urine-based tests for bladder cancer varies greatly by patient.

BACKGROUND: Spectrum effects refer to the phenomenon that test performance varies across subgroups of a population. When spectrum effects occur during diagnostic testing for cancer, difficult patient misdiagnoses can occur. Our objective was to evaluate the effect of test indication, age, gender, race, and smoking status on the performance characteristics of two commonly used diagnostic tests for bladder cancer, urine cytology and fluorescence in situ hybridization (FISH). METHODS: We assessed all subjects who underwent cystoscopy, cytology, and FISH at our institution from 2003 to 2012. The standard diagnostic test performance metrics were calculated using marginal models to account for clustered/repeated measures within subjects. We calculated test performance for the overall cohort by test indication as well as by key patient variables: age, gender, race, and smoking status. RESULTS: A total of 4023 cystoscopy-cytology pairs and 1696 FISH-cystoscopy pairs were included in the analysis. In both FISH and cytology, increasing age, male gender, and history of smoking were associated with increased sensitivity and decreased specificity. FISH performance was most impacted by age, with an increase in sensitivity from 17 % at age 40 to 49 % at age 80. The same was true of cytology, with an increase in sensitivity from 50 % at age 40 to 67 % at age 80. Sensitivity of FISH was higher for a previous diagnosis of bladder cancer (46 %) than for hematuria (26 %). Test indication had no impact on the performance of cytology and race had no significant impact on the performance of either test. CONCLUSIONS: The diagnostic performance of urine cytology and FISH vary significantly according to the patient demographic in which they were tested. Hence, the reporting of spectrum effects in diagnostic tests should become part of standard practice. Patient-related factors must contextualize the clinicians' interpretation of test results and their decision-making.

Heated Intravesical Chemotherapy: Biology and Clinical Utility.

Non-muscle-invasive bladder cancer can be a challenging disease to manage. In recent years, hyperthermia therapy in conjunction with intravesical therapy has been gaining traction as a treatment option for bladder cancer, especially if Bacillus Calmette-Guerin might not be available. Trials of intravesical chemotherapy with heat are few and there has been considerable heterogeneity between studies. However, multiple new trials have accrued and high-quality data are forthcoming. In this review, we discuss the role of combined intravesical hyperthermia and chemotherapy as a novel approach for the treatment of bladder cancer.

Dietary patterns and health-related quality of life in bladder cancer survivors.

PURPOSE: A nutritious diet has been associated with better health-related quality of life (HRQOL) in a variety of cancer survivors. However, little is known about dietary habits and its association with HRQOL in bladder cancer survivors. The objective of this cross-sectional study is to describe dietary intake patterns and its relationship to HRQOL in a large cohort of bladder cancer survivors. METHODS: Bladder cancer survivors within our institutional database were mailed surveys to assess dietary intake patterns utilizing the Diet History Questionnaire II and assessing HRQOL utilizing the Functional Assessment of Cancer Therapy-Bladder Cancer. Diet quality was assessed via Healthy Eating Index 2010 scores based on subjects' Diet History Questionnaire II results. Univariate and multivariate analyses of HRQOL based on diet quality were used to evaluate whether diet quality was associated with HRQOL. RESULTS: Four hundred and fifty-nine patients (48%) returned questionnaires. Mean age was 74 years, 81% were male and 28% underwent radical cystectomy. Diet quality and quantity in our cohort was similar to the general older U.S. population and did not differ significantly between those managed conservatively or long-term following cystectomy. Our cohort had low intake of whole grains and fat-soluble vitamins, particularly vitamin D. Diet quality was significantly associated with HRQOL in the univariate analysis but lost statistical significance in our multivariate analysis. Elixhauser Comorbidity Index was significantly associated with HRQOL in the multivariate analysis. CONCLUSIONS: This study demonstrates a similar diet quality of bladder cancer survivors to the older general U.S. population that, on average, "needs improvement." Dietary intake is particularly lacking in whole grain and vitamin D intake. Future studies are warranted to determine the impact on long-term outcome, but bladder cancer survivors should be counseled on the importance and benefits of adherence to dietary guidelines, including its potential contribution toward better HRQOL.

Atezolizumab: A PD-L1-Blocking Antibody for Bladder Cancer.

Atezolizumab (Tecentriq, MPDL3280A; Genentech/Roche) is an FcγR binding-deficient, fully humanized IgG1 mAb designed to interfere with the binding of PD-L1 ligand to its two receptors, PD-1 and B7.1. By blocking the PD-L1/PD-1 immune checkpoint, atezolizumab reduces immunosuppressive signals found within the tumor microenvironment and, consequently, increases T-cell-mediated immunity against the tumor. Atezolizumab has been FDA approved as second-line therapy for advanced bladder cancer. This accelerated approval was based on phase II trial data in patients with metastatic bladder cancer that showed unexpected and durable tumor responses. In subjects whose tumors progressed on first-line platinum-based chemotherapy, the objective response rate was 15%, the complete response rate was 5%, and 1-year overall survival was 36%. In subjects that were chemotherapy naïve and cisplatin ineligible, the objective response rate was 24%, the complete response rate was 7%, and 1-year overall survival was 57%. Better responses were associated with higher PD-L1 expression on the tumor-infiltrating leukocytes. These data suggest that patients with advanced bladder cancer treated with atezolizumab have significantly better response rates and survival than historical controls treated with other second-line regimens. The toxicity profile of atezolizumab is also favorable. Trials are currently assessing whether atezolizumab is effective in earlier bladder cancer stages and in the first-line metastatic setting. Clin Cancer Res; 23(8); 1886-90. ©2016 AACR.

Physical activity patterns and associations with health-related quality of life in bladder cancer survivors.

INTRODUCTION: Physical activity has been shown to significantly improve health-related quality of life (HRQOL) and survivorship in a variety of patients with cancer . However, little is known about the physical activity patterns of bladder cancer survivors and how these are related to HRQOL in the United States. Our objective was to describe self-reported physical activity patterns and HRQOL and examine the association between these measures in a large cohort of bladder cancer survivors. MATERIAL AND METHODS: In this cross-sectional study, long-term bladder cancer survivors identified through an institutional database were mailed a survey that included the Functional Assessment of Cancer Therapy Bladder Cancer (FACT-BL) and the International Physical Activity Questionnaire (IPAQ). Associations between HRQOL, as assessed by the FACT-BL, and physical activity, as assessed by the IPAQ, were examined by stratified analyses of HRQOL by different levels of physical activity, proportional odds ordinal logistic regression models, and local polynomial regression models. RESULTS: A total of 472 subjects (49% response rate) completed the survey. The mean age was 74 years; 81% were male and 87% were white. The median total weekly physical activity was 2,794 MET-min. Subjects reporting "high" physical activity had a median FACT-BL score of 129 compared with 119 among those reporting "low" physical activity, a statistically and clinically significant difference. Similarly, subjects reporting "high" physical activity had a 2.2-fold increased odds of reporting higher global HRQOL compared with subjects reporting "low" physical activity. CONCLUSIONS: This large cohort of bladder cancer survivors reported high levels of physical activity. Physical activity was positively associated with HRQOL. Further studies investigating the causal relationship between physical activity and HRQOL in the posttreatment setting in bladder cancer survivors are warranted.

Urinary NID2 and TWIST1 methylation to augment conventional urine cytology for the detection of bladder cancer.

BACKGROUND: Abnormal methylation of urinary TWIST1 and NID2 conferred high sensitivity and specificity for the detection of urothelial carcinoma. OBJECTIVE: We examine the performance of the urine-based TWIST1/NID2 methylation assay with the addition of urine cytology for the detection of urothelial carcinoma. MATERIALS AND METHODS: A prospective multi-institutional study was conducted to assess the performance of a methylation assay for patients with hematuria or under surveillance for non-muscle invasive bladder cancer (NMIBC). All patients underwent cystoscopy, a methylation assay, and cytology. Receiver operator characteristic (ROC) curves were constructed for cytology alone, the methylation assay alone, and a combined model. Areas under the curve (AUC) were compared using likelihood ratio tests. RESULTS: A total of 172 patients were enrolled (37% for hematuria and 63% NMIBC). The AUC for cytology alone with equivocal cytologies positive was 0.704, and improved to 0.773 with the addition of the DNA methylation assay (p < 0.001). When the equivocal cytologies were considered negative, the AUC improved from 0.558 to 0.697 with the addition of the DNA methylation assay (p = 0.003). CONCLUSIONS: Addition of a TWIST1/NID2-based DNA methylation assay adds diagnostic value to urine cytology and the model is sensitive to the classification of equivocal cytology.

Lifestyle factors and health-related quality of life in bladder cancer survivors: a systematic review.

PURPOSE: Diet, physical activity, and smoking cessation are modifiable lifestyle factors that have been shown to improve health-related quality of life (HRQOL) in many cancer survivors. Our objective was to systematically review the literature on the associations between lifestyle factors, namely diet, physical activity, smoking status, and HRQOL in bladder cancer survivors. METHODS: We queried PubMed, EMBASE, and Cochrane libraries. Two reviewers reviewed abstracts independently, and a third reviewer arbitrated disagreements. A descriptive analysis was performed. Quality assessment was conducted using the Newcastle-Ottawa Quality Assessment Scale for observational studies and the Cochrane Risk of Bias Tool for clinical trials. RESULTS: We identified 1167 publications in the initial search, of which 9 met inclusion criteria for full-text review. We were able to obtain data on the outcomes of interest for 5 publications. A total of 1288 patients who underwent treatment for bladder cancer were included. Three studies were observational by design and two were randomized controlled trials. Physical activity was addressed by 4 studies, smoking status by 2 studies, and diet by 1 study. CONCLUSIONS: The review highlights the limited evidence around lifestyle factors and quality of life in bladder cancer survivors. There is some evidence for a positive association between HRQOL and physical activity, but insufficient evidence upon which to draw conclusions about the effects of consuming fruits and vegetables or non-smoking. IMPLICATIONS FOR CANCER SURVIVORS: There is limited evidence to support a positive association between health-related quality of life and physical activity, but insufficient evidence upon which to base any conclusions about consumption of fruits and vegetables or smoking cessation in bladder cancer survivors.

High rates of venous thromboembolic events in patients undergoing systemic therapy for urothelial carcinoma: A systematic review and meta-analysis.

BACKGROUND: Patients undergoing systemic therapy for urothelial carcinoma (UC) are at increased risk for venous thromboembolic (VTE) events. The objective of the current study was to determine the rate of VTE events in patients undergoing systemic therapy for UC and assess factors affecting this rate. METHODS: This study was registered with the PROSPERO database (CRD42015025774). We searched Pubmed, MEDLINE, EMBASE, The Cochrane Library, CINAHL, and Web of Science libraries through August 2014. As per PRISMA guidelines, 2 reviewers independently reviewed titles and abstracts. Disagreements were arbitrated by a third reviewer. After full text review, data were abstracted and pooled using a random effects model. Authors were contacted for clarification of data. To determine VTE risk factors, subgroup analyses and meta-regression were conducted. RESULTS: We identified 3,635 publications in the initial search, of which 410 met inclusion criteria for full text review. Of these, we were able to obtain data on the outcome of interest for 62 publications. A total of 5,082 patients, of which 77% were male, underwent systemic therapy for UC, with 373 VTE events. The proportion of patients who had had prior surgery, chemotherapy, or radiation was 55%, 25%, and 9%, respectively. Fixed effects and random effects models were used to estimate the VTE rate, yielding event rates of 6.7% and 5.4%, respectively. CONCLUSIONS: VTE occurs frequently in patients undergoing systemic therapy for UC. The VTE rate was affected by the country of origin, history of radiation, as well as by the systemic treatment class. The study was limited by the incomplete reporting of all variables of interest.

Bone scan positivity in non-metastatic, castrate-resistant prostate cancer: external validation study

ABSTRACT Introduction: Tables predicting the probability of a positive bone scan in men with non-metastatic, castrate-resistant prostate cancer have recently been reported. We performed an external validation study of these bone scan positivity tables. Materials and Methods: We performed a retrospective cohort study of patients seen at a tertiary care medical center (1996-2012) to select patients with non-metastatic, castrate-resistant prostate cancer. Abstracted data included demographic, anthropometric, and disease-specific data such as patient race, BMI, PSA kinetics, and primary treatment. Primary outcome was metastasis on bone scan. Multivariable logistic regression was performed using generalized estimating equations to adjust for repeated measures. Risk table performance was assessed using ROC curves. Results: We identified 6.509 patients with prostate cancer who had received hormonal therapy with a post-hormonal therapy PSA ≥2ng/mL, 363 of whom had non-metastatic, castrate-resistant prostate cancer. Of these, 187 patients (356 bone scans) had calculable PSA kinetics and ≥1 bone scan. Median follow-up after castrate-resistant prostate cancer diagnosis was 32 months (IQR: 19-48). There were 227 (64%) negative and 129 (36%) positive bone scans. On multivariable analysis, higher PSA at castrate-resistant prostate cancer (4.67 vs. 4.4ng/mL, OR=0.57, P=0.02), shorter time from castrate-resistant prostate cancer to scan (7.9 vs. 14.6 months, OR=0.97, P=0.006) and higher PSA at scan (OR=2.91, P <0.0001) were significantly predictive of bone scan positivity. The AUC of the previously published risk tables for predicting scan positivity was 0.72. Conclusion: Previously published risk tables predicted bone scan positivity in men with non-metastatic, castrate-resistant prostate cancer with reasonable accuracy.