Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial.

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Advancing Clinical Trial Design for Non-Muscle Invasive Bladder Cancer.

BACKGROUND: Despite recent drug development for non-muscle invasive bladder cancer (NMIBC), few therapies have been approved by the US Food and Drug Administration (FDA), and there remains an unmet clinical need. Bacillus Calmette-Guerin (BCG) supply issues underscore the importance of developing safe and effective drugs for NMIBC. OBJECTIVE: On November 18-19, 2021, the FDA held a public virtual workshop to discuss NMIBC research needs and potential trial designs for future development of effective therapies. METHODS: Representatives from various disciplines including urologists, oncologists, pathologists, statisticians, basic and translational scientists, and the patient advocacy community participated. The workshop format included invited lectures, panel discussions, and opportunity for audience discussion and comment. RESULTS: In a pre-workshop survey, 92% of urologists surveyed considered the development of alternatives to BCG as a high drug development priority for BCG-naïve high-risk patients. Key topics discussed included definitions of disease states; trial design for BCG-naïve NMIBC, BCG-unresponsive carcinoma in situ, and BCG-unresponsive papillary carcinoma; strengths and limitations of single-arm trial designs; assessing patient-reported outcomes; and considerations for assessing avoidance of cystectomy as an efficacy measure. CONCLUSIONS: The workshop discussed several important opportunities for trial design refinement in NMIBC. FDA encourages sponsors to meet with the appropriate review division to discuss trial design proposals for NMIBC early in drug development.

Antiadenovirus Antibodies Predict Response Durability to Nadofaragene Firadenovec Therapy in BCG-unresponsive Non-muscle-invasive Bladder Cancer: Secondary Analysis of a Phase 3 Clinical Trial.

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.

Beta-Adrenergic Antagonists and Cancer Specific Survival in Patients With Advanced Prostate Cancer: A Veterans Administration Cohort Study.

OBJECTIVE: To interrogate the National Veterans Health Administration (VA) database to determine if beta-blocker use at time of initiation of androgen therapy deprivation (ADT) would result in improved oncological outcomes in advanced prostate cancer (PCa). METHODS: All men diagnosed with high risk PCa (PSA >20) from 2000-2008 who were on ADT ≥ 6 months were identified. Patients receiving ADT concurrently with primary radiation therapy were excluded. Pharmacy data was interrogated for all beta-blockers, but then focused on the selective beta-1 blocker metoprolol. Cox proportional hazards ratios were calculated for overall survival (OS), PCa specific survival (CSS) and skeletal related events (SREs). RESULTS: In 39,198 patients with high risk PCa on ADT, use of any beta-blocker was not associated with improvement in OS, CSS, or SREs. Further analyses focusing on metoprolol found that 10,224 (31.9%) had used metoprolol while 21,834 had no beta-blocker use. Multivariable analysis with Inverse Propensity Score Weighting, adjusted for factors including PSA, Gleason score, and duration ADT, found that utilization of metoprolol was not associated with improvement in OS (hazard ratio [HR] 0.97, P = .19), CSS (HR 0.94, P = .23) or SREs (HR 0.98, P = .79). CONCLUSION: In this large cohort, metoprolol use in conjunction with ADT in high risk PCa was not associated with improvement in OS, CSS, or risk of SRE. In contrast to a recent smaller clinical study, our data strongly suggests no cancer specific benefit to beta-blocker use in advanced PCa.

Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.

BACKGROUND: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849. FINDINGS: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. INTERPRETATION: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. FUNDING: FKD Therapies Oy.

Microhematuria: AUA/SUFU Guideline.

PURPOSE: Patients presenting with microhematuria represent a heterogeneous population with a broad spectrum of risk for genitourinary malignancy. Recognizing that patient-specific characteristics modify the risk of underlying malignant etiologies, this guideline sought to provide a personalized diagnostic testing strategy. MATERIALS AND METHODS: The systematic review incorporated evidence published from January 2010 through February 2019, with an updated literature search to include studies published up to December 2019. Evidence-based statements were developed by the expert Panel, with statement type linked to evidence strength, level of certainty, and the Panel's judgment regarding the balance between benefits and risks/burdens. RESULTS: Microhematuria should be defined as ≥ 3 red blood cells per high power field on microscopic evaluation of a single specimen. In patients diagnosed with gynecologic or non-malignant genitourinary sources of microhematuria, clinicians should repeat urinalysis following resolution of the gynecologic or non-malignant genitourinary cause. The Panel created a risk classification system for patients with microhematuria, stratified as low-, intermediate-, or high-risk for genitourinary malignancy. Risk groups were based on factors including age, sex, smoking and other urothelial cancer risk factors, degree and persistence of microhematuria, as well as prior gross hematuria. Diagnostic evaluation with cystoscopy and upper tract imaging was recommended according to patient risk and involving shared decision-making. Statements also inform follow-up after a negative microhematuria evaluation. CONCLUSIONS: Patients with microhematuria should be classified based on their risk of genitourinary malignancy and evaluated with a risk-based strategy. Future high-quality studies are required to improve the care of these patients.

Development and evaluation of a bladder Cancer specific survivorship care plan by patients and clinical care providers: a multi-methods approach.

BACKGROUND, CONTEXT AND PURPOSE: 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: Study HUM00056082.

Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on the clinical presentation and workup of suspected bladder cancer, treatment of non-muscle-invasive urothelial bladder cancer, and treatment of metastatic urothelial bladder cancer because important updates have recently been made to these sections. Some important updates include recommendations for optimal treatment of non-muscle-invasive bladder cancer in the event of a bacillus Calmette-Guérin (BCG) shortage and details about biomarker testing for advanced or metastatic disease. The systemic therapy recommendations for second-line or subsequent therapies have also been revised. Treatment and management of muscle-invasive, nonmetastatic disease is covered in the complete version of the NCCN Guidelines for Bladder Cancer available at NCCN.org. Additional topics covered in the complete version include treatment of nonurothelial histologies and recommendations for nonbladder urinary tract cancers such as upper tract urothelial carcinoma, urothelial carcinoma of the prostate, and primary carcinoma of the urethra.

Comparing Outcomes for Patients with Clinical T1b Renal Cell Carcinoma Treated With Either Percutaneous Microwave Ablation or Surgery.

OBJECTIVE: To compare perioperative and oncologic outcomes for patients with clinical T1b renal cell carcinoma following treatment with microwave ablation (MW), partial nephrectomy (PN), or radical nephrectomy (RN). METHODS: Comprehensive clinical and pathologic data were collected for nonmetastatic renal cell carcinoma patients with cT1b tumors following MW, PN, or RN from 2000 to 2018. Local recurrence-free, metastasis-free, cancer-specific and overall survival were estimated using Kaplan-Meier method. Prognostic factors for complications and survival were determined using logistic regression and Cox hazard models, respectively. RESULTS: A total of 325 patients (40 MW, 74 PN, and 211 RN) were identified. Patients treated with MW were older with higher Charlson comorbidity indices compared to surgical patients. Median length of hospitalization was shorter for MW compared to surgical patients (1 day vs 4 days, P <.0001). Post-treatment estimated glomerular filtration rate decreased by median 4.5% for MW compared to 3.2% for PN (P = .58) and 29% for RN (P <.001). Median follow-up was 34, 35, and 49 months following MW, PN, and RN, respectively. Estimated 5-year local recurrence-free survival was 94.5% for MW vs 97.9% for PN (P = .34) and 99.2% for RN (P = .02). Two patients recurred after MW and underwent repeat ablation without subsequent recurrence. No difference in 5-year metastasis-free survival or cancer-specific survival was found among MW, PN, or RN. Four (10%) MW patients had high-grade complication. Only prior abdominal surgery predicted high-grade complication (OR 6.29, P = .017). CONCLUSION: Microwave ablation is a feasible alternative to surgery in select comorbid patients with clinical T1b renal cell carcinoma.

American Urological Association Nonmuscle Invasive Bladder Cancer Risk Model Validation-Should Patient Age be Added to the Risk Model?

PURPOSE: We evaluated the AUA (American Urological Association)/SUO (Society of Urologic Oncology) nonmuscle invasive bladder cancer risk model to predict nonmuscle invasive bladder cancer recurrence and progression prior to death. MATERIALS AND METHODS: We performed a retrospective analysis using electronic medical records and cancer registry data of patients with nonmuscle invasive bladder cancer in a multicenter United States patient population. We evaluated recurrence-free and progression-free survival according to the AUA/SUO nonmuscle invasive bladder cancer risk model. We then assessed discriminative performance with the c-index and compared the cumulative incidence of recurrence, progression and death across 4 age groups. RESULTS: We identified 1,297 patients with nonmuscle invasive bladder cancer. Median followup in the cohort was 3.2 years. The c-index of the AUA/SUO recurrence model was 0.62 and for progression it was higher at 0.77. Patients younger than 60 years had a 40% greater probability of recurrent nonmuscle invasive bladder cancer vs death while patients 84 years old or older had a 12% greater probability of death prior to recurrence at 5 years. This study was limited by its retrospective design. CONCLUSIONS: The AUA/SUO nonmuscle invasive bladder cancer risk model provides predictive performance of recurrence and progression similar to that of previous similar risk models, such as the models of the European Organization for Research and Treatment of Cancer, the Club Urológico Español de Tratamiento Oncológico and the National Comprehensive Cancer Network®. This work illustrates the need to consider age in predictive tools for clinicians who treat patients with nonmuscle invasive bladder cancer.

Impact of bilateral biopsy-detected prostate cancer on an active surveillance population.

BACKGROUND: To assess factors that can predict active surveillance (AS) failure on serial transrectal ultrasound guided biopsies in patients with low-risk prostate cancer. METHODS: We evaluated the records of 144 consecutive patients enrolled in AS between 2007 and 2014 at a single academic institution. Low risk inclusion criteria included PSA < 10 ng/ml, cT1c or cT2a, Grade Group (GG) 1, < 3 positive cores, and < 50% tumor in a single core with the majority having a PSA density of < 0.15. AS reclassification was defined as progression to GG ≥2, 3 or more cores, or core tumor volume ≥ 50%. Univariate and multivariate Cox proportional hazards regression analysis was used to determine predictors of reclassification and a match-pair analysis performed on a control group of patients choosing surgery. RESULTS: Inclusion criteria were met by 130 men with a median follow-up of 52 months. The reclassification or AS failure rate was 38.5%, with the majority 41/50 (82%) finding GG ≥ 2 cancer. Most patients had unilateral disease on diagnostic biopsy (94.6%), but 40.7% had bilateral cancer detected during follow-up. Men with bilateral detected tumor were more likely to ultimately fail AS than patients with unilateral tumors (HR 4.089; P < 0.0001) and failed earlier with a reclassification-free survival of 32 vs 119 months respectively. In a matched-pair analysis using a population of 211 concurrent patients that chose radical prostatectomy rather than AS, 76% of patients with unilateral cancer on biopsy had bilateral cancer on final pathology. CONCLUSIONS: The finding of bilateral prostate cancer on biopsy is associated with earlier AS reclassification. Finding bilateral disease may not represent disease progression, but rather enhanced detection of more extensive disease highlighting the importance of confirmatory biopsy.

The Impact of Agent Orange Exposure on Prostate Cancer Outcomes.

PURPOSE: In this study we explored the effect of Agent Orange exposure on prostate cancer survival in VA (Veterans Affairs) patients receiving androgen deprivation therapy for advanced prostate cancer. MATERIALS AND METHODS: We retrospectively examined the association between Agent Orange exposure in men with prostate cancer in national VA databases who were being treated with androgen deprivation therapy. Patients were diagnosed with prostate cancer from 2000 to 2008 with followup through May 2016. Clinical, pathological and demographic variables were compared by Agent Orange exposure. Associations of Agent Orange with overall survival, skeletal related events and cancer specific survival were performed using adjusted Cox proportional hazard models after IPSW (inverse propensity score weighted) adjustment. RESULTS: Overall 87,344 patients were identified. The 3,475 Agent Orange exposed patients were younger (p <0.001), had lower prostate specific antigen (p = 0.002) and were more likely to receive local therapy and chemotherapy (p <0.001) than the 83,869 nonexposed patients. The Charlson comorbidity index was similar in the groups (p = 0.40). After IPSW adjustment Agent Orange exposure was associated with improved overall survival (HR 0.84, 95% CI 0.73-0.97, p = 0.02). However, no difference was observed in the risk of skeletal related events (HR 1.04, 95% CI 0.80-1.35, p = 0.77) or cancer specific survival (HR 0.79, 95% CI 0.60-1.03, p = 0.08). CONCLUSIONS: Agent Orange exposure was associated with a decreased risk of death in men receiving androgen deprivation therapy for advanced prostate cancer. It does not appear to be associated with worse oncologic outcomes.

The impact of statins in combination with androgen deprivation therapyin patients with advanced prostate cancer: A large observational study.

BACKGROUND: Statins are thought to possess antineoplastic properties related to their effect on cell proliferation and steroidogenesis. Progression to castrate resistant prostate cancer (CaP) includes de-regulation of androgen synthesis suggesting a role for statins in this setting. Our goal was to assess the role of statin use on oncologic outcomes in patients with advanced CaP being treated with androgen deprivation therapy (ADT). METHODS: The national VA database was used to identify all men diagnosed with CaP who were treated with ADT for at least 6 months between 2000 and 2008 with follow-up through May 2016. Our cohort was stratified based on statin use of at least 6 months duration during the same time. Multivariable Cox proportional hazards analyses with inverse propensity score weighted (IPSW) adjustment were calculated to assess for primary outcomes of CaP-specific survival (CSS), overall survival (OS) and skeletal related events (SREs). RESULTS: A total of 87,346 patients on ADT were included in the study cohort, 53,360 patients used statins and 33,986 did not. Statin users were younger in age (median 73 vs. 76, P < 0.001), more likely to have a higher Charlson comorbidity index (CCI) >3 (3.1% vs. 2.5%, P < 0.001) and more likely to have a high grade (Gleason score 8-10) cancer (12.3% vs. 10.9%, P < 0.001). Statin users had longer OS (median 6.5 vs. 4.0 years P < 0.001) and decreased death from CaP (5-year CSS 94.0% vs. 87.3%, P < 0.001). Statin use was also associated with longer time to a SRE (median 5.9 vs. 3.7 years, P < 0.001). On multivariable Cox proportional hazards analysis with inverse propensity score weighted, statin use was an independent predictor of improved OS (hazard ratio [HR] 0.66, confidence interval [CI] 0.63-0.68; P < 0.001), CSS (HR 0.56, 95% CI 0.53-0.60; P < 0.001), and SREs (HR 0.64, 95%CI 0.59-0.71; P < 0.001) when controlling for age, race, Charlson comorbidity index, prostate-specific antigen, and Gleason score. CONCLUSION: The use of statins in men on ADT for CaP is associated with improved CSS and OS. Statins are inexpensive, well-tolerated medications that offer a promising adjunct to ADT, but require further prospective studies.

NCCN Guidelines Insights: Bladder Cancer, Version 5.2018.

The NCCN Clinical Practice Guidelines in Oncology for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer. These NCCN Guidelines Insights discuss important updates to the 2018 version of the guidelines, including implications of the 8th edition of the AJCC Cancer Staging Manual on treatment of muscle-invasive bladder cancer and incorporating newly approved immune checkpoint inhibitor therapies into treatment options for patients with locally advanced or metastatic disease.

The impact of celecoxib on outcomes in advanced prostate cancer patients undergoing androgen deprivation therapy.

Recent work suggests the selective Cox-2 inhibitor celecoxib delays progression to androgen independence in hormone sensitive prostate cancer (HSPC) through inhibition of the androgen receptor (AR) and ErbB signaling. However, human studies examining its effect on delaying disease progression while on hormone therapy are limited. This study explores the effect of celecoxib use on PC survival in VA patients undergoing androgen deprivation therapy (ADT) for advanced PC. We retrospectively examined the association between celecoxib use (defined as duration of medication use ≥180 days) in men with PC being treated with ADT in national VA databases. Patients were diagnosed with PC from 2000-2008 and had follow-up through May 2016. Clinical, pathologic and demographic variables were compared by celecoxib use, using Mann-Whitney U test and Chi-squared tests. Associations between celecoxib use and overall survival (OS), skeletal related events (SRE), and cancer specific survival (CSS) were performed using adjusted Cox proportional hazard models. Overall, 87,344 patients with PC on ADT were identified. Patients on celecoxib (n=1,581) had lower PSA levels at both diagnosis (7.0 versus 8.7 ng/mL, P<0.001) and initiation of ADT (6.2 versus 7.3 ng/mL, P=0.002) compared to patients not taking celecoxib (n=85,763). Gleason score (P=0.14), death from PC (P=0.07), and number of SREs (P=0.18) were similar between groups. In the Cox multivariable analysis, celecoxib use was not associated with improved OS (hazard ratio, HR, 1.06, 95% confidence interval, CI, 0.93-1.21, P=0.38), risk of SRE (HR 0.95, 95% CI 0.62-1.44, P=0.80), or improved CSS (HR 1.00, 95% CI 0.78-1.28, P=0.98). Despite an association with lower PSA levels, celecoxib use in PC patients on ADT was not associated with improved cancer outcomes.

Metformin Use is Associated with Improved Survival for Patients with Advanced Prostate Cancer on Androgen Deprivation Therapy.

PURPOSE: Metformin is commonly prescribed for patients with type 2 diabetes mellitus. We hypothesized that metformin plus androgen deprivation therapy may be beneficial in combination. Our objective was to assess this combination in a retrospective cohort of patients with advanced prostate cancer. MATERIALS AND METHODS: Using national Veterans Affairs databases we identified all men diagnosed with prostate cancer between 2000 and 2008 who were treated with androgen deprivation therapy with followup through May 2016. Study exclusions included treatment with androgen deprivation therapy for 6 months or longer, or receipt of androgen deprivation therapy concurrently with localized radiation. Three patient cohorts were developed, including no diabetes mellitus, diabetes mellitus with no metformin and diabetes mellitus with metformin. Cox proportional HRs were calculated for overall survival, skeletal related events and cancer specific survival. RESULTS: After exclusions the cohort consisted of 87,344 patients, including 61% with no diabetes mellitus, 22% with diabetes mellitus and no metformin, and 17% with diabetes mellitus on metformin. Cox proportional hazard analysis of overall survival showed improved survival in men with diabetes mellitus on metformin (HR 0.82, 95% CI 0.78-0.86) compared to those with diabetes mellitus who were not on metformin (HR 1.03, 95% CI 0.99-1.08). The reference group was men with no diabetes mellitus. Cox proportional hazard analysis of predictors of skeletal related events revealed a HR of 0.82 (95% CI 0.72-0.93) in men with diabetes mellitus on metformin. Cox proportional hazard analysis of cancer specific survival showed improved survival in men with diabetes mellitus on metformin (HR 0.70, 95% CI 0.64-0.77) vs those with diabetes mellitus without metformin (HR 0.93, 95% CI 0.85- 1.00). The reference group was men with no diabetes mellitus. CONCLUSIONS: Metformin use in veterans with prostate cancer who receive androgen deprivation therapy is associated with improved oncologic outcomes. This association should be evaluated in a prospective clinical trial.

Effectiveness of a transrectal prostate needle biopsy protocol with risk-tailored antimicrobials in a veterans cohort.

PURPOSE: To prospectively implement a prostate biopsy protocol to identify high-risk patients for bleeding or infectious complications and use risk-tailored antimicrobials, patient education, and postbiopsy monitoring with the objective of reducing complications. MATERIALS AND METHODS: Overall, 637 consecutive patients from June 2014 to August 2016 underwent prostate biopsy at our Veterans Affairs hospital. In the protocol cohort, patients were screened before biopsy and prophylaxis was tailored (high risk = ceftriaxone; low risk = ciprofloxacin). Patients were also provided additional education about bleeding and monitored for up to 1-hour. We defined complications as any deviation from normal postbiopsy activities. Comparisons were made between preprotocol/postprotocol cohorts. Logistic regression was used to identify risk factors for admissions or complications. RESULTS: Median age was 67 years (IQR: 64-69, P = 0.29) in both groups (pre n = 334, post n = 303). Preprotocol, 99% patients received ciprofloxacin; postprotocol, 86% received ciprofloxacin and 14% received ceftriaxone (P<0.001). There were no deaths in either group. There were decreased 30-day complication and hospitalization rates in the postprotocol group (pre 15% vs. post 8.9%, P = 0.025; 3.3% vs. 1.0%, P = 0.048). Sepsis occurred in 2 patients preprotocol and no patients postprotocol. Postprotocol group was associated with decreased 30-day complications on multivariable logistic regression (OR = 0.58, 95% CI: 0.35-0.95, P = 0.031). CONCLUSIONS: A screening protocol before prostate biopsy is a targeted approach for selecting prophylactic antimicrobials and closer monitoring postbiopsy for bleeding. Our results suggest that the protocol has a favorable effect on complication and hospitalization rates.

Diagnostic evaluation of patients presenting with hematuria: An electronic health record-based study.

BACKGROUND: To gain new insights into the origin and prevention of diagnostic delays in the evaluation of hematuria in an electronic health record (EHR)-based integrated care setting. METHODS: We performed a retrospective review of 298 consecutive patients with new-onset hematuria at a Veterans Affairs facility from January 1, 2011 to December 31, 2013 excluding those where diagnostic evaluation was unnecessary (i.e., cystoscopy within 3 years prior). We collected data on presentation, such as red flags of painless gross hematuria (PGH) or asymptomatic microhematuria (AMH) and subsequent evaluation (imaging, urologic referral, and cystoscopy). Delay was defined when evaluation was not completed within 60 days. Logistic regression was performed to identify predictors of delay. RESULTS: Of 201 patients, 149 had delays. PGH was present in 99 patients. These patients had a higher rate of urology referral within 1 year than patients with AMH (86.7% vs. 64.7%; P<0.01) and were more likely to undergo cystoscopy (75.8% vs. 52%; P<0.01). Delays occurred in 67% of PGH patients vs. 81% of AMH patients (OR 0.46; P = 0.02), and roughly a third were related to scheduling/coordination, patient-related issues, or delay in primary care referral. Bladder neoplasms were detected in 18% of patients with PGH and 2% of those with AMH. CONCLUSION: Delays in evaluation for hematuria occur commonly, regardless of strength of the red-flag. Many delays were preventable and could be targeted with interventions including EHR-based tracking systems or reformed scheduling practices.

Bladder Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on systemic therapy for muscle-invasive urothelial bladder cancer, as substantial revisions were made in the 2017 updates, such as new recommendations for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. The complete version of the NCCN Guidelines for Bladder Cancer addresses additional aspects of the management of bladder cancer, including non-muscle-invasive urothelial bladder cancer and nonurothelial histologies, as well as staging, evaluation, and follow-up.