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Purpose: Our primary aim was to compare changes in hematocrit in testosteronedeficient men treated with intranasal testosterone gel vs intramuscular testosterone cypionate. Materials and Methods: This 2-arm, open-label, randomized trial recruited men with testosterone deficiency at the University of Miami between August 2020 and October 2022. Men with 2 total testosterone levels <350 ng/dL and hypogonadal symptoms, aged 18-75 years were randomly assigned to receive either intranasal testosterone gel 11 mg 3 times daily or intramuscular testosterone cypionate 200 mg every 2 weeks. The primary outcome was change in hematocrit after 4 months of treatment. Secondary outcomes were changes in serum testosterone, estradiol, prostate-specific antigen, 17-hydroxyprogesterone, and the 6-itemInternational Index of Erectile Function. Results: Of the 81 men randomized, 54 completed treatment (intranasal n[23; intramuscular n[31). The mean age was 47.5 vs 49.5 years, with mean baseline testosterone of 244.6 vs 240.7 ng/dL and mean hematocrit of 44.4% vs 42.7% in intranasal vs intramuscular groups, respectively. Men who received intramuscular injections had a significant increase after 4 months of treatment in mean hematocrit from 42.7% to 46.6% (P < .0001), but there was no significant change in men who received intranasal gel (P [.233). Men in both groups experienced significantly increased serum testosterone levels throughout the study period, though a larger increasewas seen inmen treated with intramuscular injections (mean change 511 vs 283, P [.025). Men who received injections also experienced an increase in estradiol (mean change 22.9, P < .001), decrease in 17-hydroxyprogesterone (mean change >39.8, P < .0001), and increase in the 6-item International Index of Erectile Function score (mean change 4.8, P [.015); men treated with intranasal gel experienced no such changes. Prostate-specific antigen levels were stable in both groups. Conclusions: Intranasal testosterone gel does not appear to significantly affect hematocrit levels. Men who wish to avoid polycythemia or changes in estradiol or 17-hydroxyprogesterone levels may benefit from short-acting testosterone therapy formulations such as intranasal gel. [ABSTRACT FROM AUTHOR]

Purpose: In this review, we address adherence rates in clinical settings, barriers to compliance with dosing schedules, and potential strategies to overcome challenges in maintaining high levels of adherence. Materials and Methods: Four studies reporting real-world adherence to prostate cancer medications, 52 studies describing barriers to adherence, and 16 studies on methods to minimize poor adherence were reviewed. Results: Mean nonadherence rates of 25% to 51% have been identified in prostate cancer patients prescribed oral therapies, with higher rates in older patients. An extensive review of prostate cancer patients receiving gonadotropin hormone-releasing hormone agonist injections found an overall nonadherence rate of over 27%. Patients may encounter barriers to complying with dosing instructions related to the medication (eg, complex dosing schedules, the total burden of medication management, fasting or dietary requirements, high medication costs, adverse effects, and drug-drug interactions). Barriers may also be related to patient-specific factors (eg, suboptimal education regarding the importance of adherence, physical limitations and cognitive decline associated with advancing age, living alone without a care partner, high symptom burden, needle phobia, and comorbid mental disorders). Interventions to improve dosing adherence may include automated reminders, treatment diaries, educational materials, and the involvement of patients, family members, care partners, and health care teams. Conclusions: Many oral anticancer medications improve survival in men with prostate cancer, and therefore it is vital to establish good adherence by understanding the pitfalls that patients may encounter. In situations where both oral and injectable drugs are interchangeable, injections of long-acting drugs lead to fewer opportunities for dosing nonadherence than oral therapies. In contrast, oral medicines do not require scheduling for injections and travel for injection appointments. Therefore, maximizing adherence to all treatment regimens will reduce the chance of efficacy failures and likely lead to improved clinical outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Intravesical bacillus Calmette-Guérin is the current first-line treatment for high-grade nonmuscle-invasive bladder cancer; however, a substantial proportion of patients are unresponsive to bacillus Calmette-Guérin treatment. While cystectomy is often recommended in bladder cancer following bacillus Calmette-Guérin failure, there are numerous established therapeutic agents and pre-commercialized trials describing treatments for nonmuscle-invasive bladder cancer following failed bacillus Calmette-Guérin treatment. Our objective in this systematic review is to characterize the efficacy of these therapeutic agents by reporting their corresponding complete response rates and toxicity profiles. Materials and Methods: We conducted a systematic review of all available clinical trials evaluating therapies to treat recurring nonmuscle-invasive bladder cancer after previous intravesical bacillus Calmette-Guérin. Bacillus Calmette-Guérin failure patients who had previously failed 1 or more courses of prior bacillus Calmette-Guérin therapy were included. Studies that were not in the English language, included muscle-invasive bladder cancer patient populations, or lacked a post-treatment evaluation of response were excluded. We used PubMed/Medline, the Cochrane Library, and Embase to search for relevant studies. No formal risk of bias assessment was conducted. Complete response rates for 3, 6, 12, and 24 months post-treatment evaluation, progression rates, cystectomy rates, and 12 complications are reported. Results: A total of 70 studies with 73 reports evaluating 27 treatment options were retained for final analysis. These treatments were reported in 5 categories including intravesical chemotherapy, combination therapy, hyperthermia paired with intravesical chemotherapy, immunotherapy, and novel agents, with published years ranging from 1998 to 2021. Single intravesical chemotherapy and the combination of multiple intravesical chemotherapy agents demonstrate varied complete response rates of 10%-83% at 12 months. Limited clinical data evaluating hyperthermia paired with chemotherapy demonstrate 12-month complete response rates of 50%-85%. Despite these reported response rates, progression rates ranged from 0%-18%. Moreover, immunotherapeutic agents demonstrate progression rates of 7% to 22% at a median of 12 months of followup. Novel agents displayed a wide range of complete response rates (6% to 91%) at 12 months based on the treatment used. Total grade 3 toxicity rates range from 0%-55% for intravesical chemotherapy and combination intravesical chemotherapy agents, 0%-15% for hyperthermia paired with chemotherapy agents, 12%-13% for immunotherapy agents, and 0%-17% for novel agents. Conclusions: Bladder-preserving treatments accomplish moderate success in nonmuscle-invasive bladder cancer following bacillus Calmette-Guérin failure. As the majority of available clinical trials are single-armed uncontrolled cohorts and contain a limited number of patients, strength and comparability of the data are limited. In general, intravesical chemotherapy and hyperthermia paired with mitomycin C demonstrate some of the highest complete response rates at 12 and 24 months. Similarly, among the pre-commercialized novel agents, N-803 and gene therapy display promising results and may serve as potential future treatment for nonmuscle-invasive bladder cancer following failed bacillus Calmette-Guérin treatment. In terms of toxicity/complication rates, both commercially available and unavailable treatments showcase low toxicity profiles for bladder cancer following bacillus Calmette-Guérin failure. The comprehensive analysis provided by this systematic review can serve as a reference for treatment decisions and clinical trial design in the bacillus Calmette-Guérin-unresponsive domain. [ABSTRACT FROM AUTHOR]

Purpose We systematically review the benefits and harms of intravesical therapies for nonmuscle invasive bladder cancer. Materials and Methods Systematic literature searches were performed of Ovid MEDLINE (January 1990 through February 2016), the Cochrane databases and reference lists. Randomized and quasi-randomized trials of intravesical bacillus Calmette-Guérin, mitomycin C, gemcitabine, thiotepa, valrubicin, doxorubicin, epirubicin and interferon vs transurethral bladder tumor resection alone, and head-to-head trials of intravesical therapies were selected. Data were pooled using a random effects model. Results Overall 39 trials evaluated adjuvant intravesical therapy vs transurethral bladder tumor resection alone. Bacillus Calmette-Guérin was associated with a decreased risk of bladder cancer recurrence (3 trials, RR 0.56, 95% CI 0.43–0.71) and progression (4 trials, RR 0.39, 95% CI 0.24–0.64) (strength of evidence low). Mitomycin C, doxorubicin, epirubicin and thiotepa were also associated with a decreased risk of recurrence, with no difference in risk of progression (strength of evidence low). There were 55 trials that compared one intravesical therapy agent against another. There were no differences between bacillus Calmette-Guérin vs mitomycin C in recurrence risk (RR 0.95, 95% CI 0.81–1.11), but bacillus Calmette-Guérin was associated with a decreased risk of recurrence in the subgroup of trials of maintenance regimens (RR 0.79, 95% CI 0.71–0.87, strength of evidence low). Bacillus Calmette-Guérin was associated with a lower recurrence risk vs doxorubicin, epirubicin, interferon alpha-2a, bacillus Calmette-Guérin plus interferon alpha-2b, and thiotepa (strength of evidence low to moderate). Bacillus Calmette-Guérin was associated with higher rates of local and systemic adverse events than other intravesical agents (strength of evidence low). Head-to-head trials showed no clear differences between standard and lower doses of bacillus Calmette-Guérin in recurrence, progression or mortality risk (strength of evidence low). Limited evidence suggested that bacillus Calmette-Guérin maintenance regimens are associated with reduced recurrence risk vs no further intravesical therapy in responders to induction therapy (strength of evidence low). Conclusions For nonmuscle invasive bladder cancer several intravesical therapies are associated with a decreased risk of recurrence vs transurethral bladder tumor resection alone. Bacillus Calmette-Guérin is the only agent associated with a decreased progression risk vs transurethral bladder tumor resection alone, but may be associated with a higher risk of adverse events than other intravesical therapies, indicating trade-offs between potential benefits and harms. [ABSTRACT FROM AUTHOR]

Purpose We determined the maximum tolerated dose, safety and effectiveness of intravesical instillation of mistletoe extract after transurethral resection of nonmuscle invasive bladder cancer. Materials and Methods In this single group dose escalation study patients with nonmuscle invasive bladder cancer were treated with weekly instillations of mistletoe extract for 6 weeks. Four weeks before instillation therapy all patients underwent transurethral resection of bladder tumors. During this procedure a marker tumor was left. At 12 weeks after the start of instillation therapy transurethral resection of the marker tumor or biopsy of the former marker tumor location was done so that patients were tumor free when entering followup until week 48. During the followup clinical assessment laboratory tests for safety and cystoscopy were done every 12 weeks. Results A total of 36 patients were treated with increasing doses of mistletoe extract. We found no dose limiting toxicity up to a dose of 675 mg of plant extract. Besides local reactions we saw hints that pyrexia may develop. All adverse events were well manageable. At 12 weeks a marker tumor remission rate of 55.6% (95% CI 38.1 to 72.1) was achieved. At 1 year a recurrence rate of 26.3% (95% CI 9.1 to 51.2) was observed. Conclusions In this study intravesical instillation of mistletoe extract as treatment in patients with nonmuscle invasive bladder cancer was shown to be safe and well tolerated. Promising data on efficacy were observed and will be further investigated in a phase III study. [ABSTRACT FROM AUTHOR]

Purpose Low, intermediate and high risk categories have been defined to help guide the treatment of patients with nonmuscle invasive bladder cancer (Ta, T1, CIS). However, while low and high risk disease has been well classified, the intermediate risk category has traditionally comprised a heterogeneous group that does not fit into either of these categories. As a result, many urologists remain uncertain about the categorization of patients as intermediate risk as well as the selection of the most appropriate therapeutic option for this patient population. We review the current literature and clinical practice guidelines on intermediate risk nonmuscle invasive bladder cancer and, based on our findings, provide urologists with a better understanding of this heterogeneous risk group as well as practical recommendations for the treatment of intermediate risk patients. Materials and Methods The IBCG analyzed published clinical trials, meta-analyses and current clinical practice guidelines on intermediate risk nonmuscle invasive bladder cancer available as of September 2013. The definitions of intermediate risk, patient outcomes and guideline recommendations were considered, as were the limitations of the available literature and additional parameters that may be useful in guiding treatment decisions in intermediate risk patients. Results Current definitions and management recommendations for intermediate risk nonmuscle invasive bladder cancer vary. The most simple and practical definition is that proposed by the IBCG and the AUA of multiple and/or recurrent low grade Ta tumors. The IBCG suggests that several factors should be considered in clinical decisions in intermediate risk disease, including number (greater than 1) and size (greater than 3 cm) of tumors, timing (recurrence within 1 year) and frequency (more than 1 per year) of recurrence, and previous treatment. In patients without these risk factors a single, immediate instillation of chemotherapy is advised. In those with 1 to 2 risk factors adjuvant intravesical therapy (intravesical chemotherapy or maintenance bacillus Calmette-Guérin) is recommended, and previous intravesical therapy should be considered when choosing between these adjuvant therapies. For those patients with 3 to 4 risk factors, maintenance bacillus Calmette-Guérin is recommended. It is also important that all intermediate risk patients are accurately risk stratified at initial diagnosis and during subsequent followup. This requires appropriate transurethral resection of the bladder tumor, vigilance to rule out carcinoma in situ or other potential high risk tumors, and review of histological material directly with the pathologist. Conclusions Intermediate risk disease is a heterogeneous category, and there is a paucity of independent studies comparing therapies and outcomes in subgroups of intermediate risk patients. The IBCG has proposed a management algorithm that considers tumor characteristics, timing and frequency of recurrence, and previous treatment. Subgroup analyses of intermediate risk subjects in pivotal EORTC trials and meta-analyses will be important to validate the proposed algorithm and support clear evidence-based recommendations for subgroups of intermediate risk patients. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the efficacy and safety of a once monthly oxybutynin vaginal ring in women with overactive bladder. Materials and Methods: This randomized, multicenter, double-blind, 12-week phase 2 study compared oxybutynin vaginal ring (4 or 6 mg daily) to a placebo vaginal ring in women with well-defined overactive bladder symptoms. The primary efficacy variable was the change from baseline to week 12 in the total weekly number of incontinence episodes (stress and urge). Safety was measured in terms of treatment emergent adverse events, laboratory, physical, gynecologic examinations, electrocardiogram and vital signs. Results: After a 3-week post-randomization placebo run-in phase (sample size 720) 445 women entered the treatment phase (safety population). Of these women 323 met all 3 overactive bladder specific baseline characteristics of 10 or more urinary urge incontinence episodes weekly, urinary frequency 8 or more voids per 24 hours and voided volume 3 L or less per 24 hours) (analysis population). Women treated with 4 and 6 mg daily oxybutynin vaginal ring had significantly fewer incontinence episodes weekly (p = 0.036 and p = 0.018, respectively), lower daily urinary frequency (p = 0.014, p = 0.002) and a higher proportion had no incontinence episodes at week 12 (p = 0.026, p = 0.027) compared with placebo. The change in severity of urgency and voided volume was similar for all groups (p >0.05). Except for a higher incidence of dry mouth and urinary tract infections that were not always culture confirmed, the oxybutynin vaginal ring was well tolerated and had a safety profile similar to that of the placebo vaginal ring. Conclusions: The oxybutynin vaginal ring appears to be an effective and safe once monthly treatment option for women with overactive bladder characterized primarily by urinary urge incontinence that merits further evaluation in a phase 3 study. [Copyright &y& Elsevier]

Purpose: c-MYC is a promising target for cancer therapy but its use is restricted by unwanted, devastating side effects. We explored whether intravesical instillation of the c-MYC inhibitor KSI-3716 could suppress tumor growth in murine orthotopic bladder xenografts. Materials and Methods: The small molecule KSI-3716, which blocks c-MYC/MAX binding to target gene promoters, was used as an intravesical chemotherapy agent. KSI-3716 action was assessed by electrophoretic mobility shift assay, chromatin immunoprecipitation, transcription reporter assay and quantitative reverse transcriptase-polymerase chain reaction. Inhibition of cell proliferation and its mechanism was monitored by cell cytotoxicity assay, EdU incorporation assay and flow cytometry. The in vivo efficacy of KSI-3716 was examined by noninvasive luminescence imaging and histological analysis after intravesical instillation of KSI-3716 in murine orthotopic bladder xenografts. Results: KSI-3716 blocked c-MYC/MAX from forming a complex with target gene promoters. c-MYC mediated transcriptional activity was inhibited by KSI-3716 at concentrations as low as 1 μM. The expression of c-MYC target genes, such as cyclin D2, CDK4 and hTERT, was markedly decreased. KSI-3716 exerted cytotoxic effects on bladder cancer cells by inducing cell cycle arrest and apoptosis. Intravesical instillation of KSI-3716 at a dose of 5 mg/kg significantly suppressed tumor growth with minimal systemic toxicity. Conclusions: The c-MYC inhibitor KSI-3716 could be developed as an effective intravesical chemotherapy agent for bladder cancer. [ABSTRACT FROM AUTHOR]

Purpose: Despite being one of the most important clinical outcomes in nonmuscle invasive bladder cancer, there is currently no standard definition of disease progression. Major clinical trials and meta-analyses have used varying definitions or have failed to define this end point altogether. A standard definition of nonmuscle invasive bladder cancer progression as determined by reproducible and reliable procedures is needed. We examine current definitions of nonmuscle invasive bladder cancer progression, and propose a new definition that will be more clinically useful in determining patient prognosis and comparing treatment options. Materials and Methods: The IBCG (International Bladder Cancer Group) analyzed published clinical trials and meta-analyses that examined nonmuscle invasive bladder cancer progression as of December 2012. The limitations of the definitions of progression used in these trials were considered, as were additional parameters associated with the advancement of nonmuscle invasive bladder cancer. Results: The most commonly used definition of nonmuscle invasive bladder cancer progression is an increase in stage from nonmuscle invasive to muscle invasive disease. Although this definition is clinically important, it fails to include other important parameters of advancing disease such as progression to lamina propria invasion and increase in grade. Conclusions: The IBCG proposes the definition of nonmuscle invasive bladder cancer progression as an increase in T stage from CIS or Ta to T1 (lamina propria invasion), development of T2 or greater or lymph node (N+) disease or distant metastasis (M1), or an increase in grade from low to high. Investigators should consider the use of this new definition to help standardize protocols and improve the reporting of progression. [ABSTRACT FROM AUTHOR]

Purpose: In this clinical trial we evaluated the efficacy, safety and tolerability of a novel pressure attenuation device for the reduction or elimination of female stress urinary incontinence using a prospective, randomized, single-blind, multicenter design. Materials and Methods: A total of 166 female patients with stress urinary incontinence were randomized 2:1 to treatment with an intravesical pressure attenuation device (112) or sham procedure (54). In the treatment arm the device was replaced every 90 days and in the sham arm device replacement was simulated every 90 days. The primary outcome measure was Stamey score improvement of 1 or more at 6 months. An additional outcome measure evaluated at 6 months was a composite score combining data from a provocative pad test and patient impression of symptom improvement. Results: In the treatment arm 40.9% of women achieved the primary end point, compared to only 22.4% in the sham arm (p = 0.046 in per protocol analysis). In an intent to treat analysis, 28.6% of women in the treatment arm reached the primary end point vs 22.2% of women in the sham arm (p = 0.455). 50.8% of women in the treatment arm reached the composite end point compared to 16.3% of women in the control arm (p <0.001, intent to treat analysis). Three-day voiding diaries revealed a mean reduction in total daily leakage events after 6 months from 4.4 per day to 2.5 per day (43.2%) in the treatment group vs 5.4 per day to 4.1 per day (24.1% reduction) in the control group (p <0.001). Conclusions: Minimally invasive treatment for female stress urinary incontinence with a first-generation intravesical pressure attenuation device was safe and effective when evaluated by a composite end point. For those patients that can tolerate the device, the concept of pressure attenuation as a therapy for stress urinary incontinence is valid and feasible. Further modifications are anticipated for this device potentially resulting in improved outcomes. [Copyright &y& Elsevier]

Purpose: Perioperative instillation of intravesical chemotherapy after bladder tumor resection is supported by level I evidence showing a 30% decrease in tumor recurrence. However, studies of administrative data sets show poor use in practice. Materials and Methods: We prospectively evaluated the use of perioperative intravesical chemotherapy in a multipractice quality improvement collaborative. Cases were categorized as ideal for intravesical chemotherapy (1 or 2 papillary tumors, cTa/cT1 and completely resected) and nonideal. The reasons for not administering intravesical chemotherapy in ideal cases were classified as appropriate or modifiable. Before and after comparative feedback and educational interventions we calculated judicious use of intravesical chemotherapy (nonuse in nonideal cases plus use in ideal cases plus appropriate nonuse in ideal cases) and quality improvement potential (use in nonideal cases plus nonuse in ideal cases attributable to modifiable factors). Results: We accrued a total of 2,794 cases at the 5 sites in 22 months. The rate of use in ideal cases was 38% before and 34.8% after intervention (p = 0.36), while use in nonideal cases decreased from 15% to 12% (p = 0.08). Overall, intravesical chemotherapy was used judiciously in 83.0% to 85.7% of cases, while the remaining 14.3% to 17.0% represented quality improvement potential. Conclusions: Judicious use of perioperative intravesical chemotherapy is relatively high in routine practice. Most instances of nonuse represent appropriate clinical judgment. Utilization did not change after quality improvement interventions, suggesting that there may a ceiling effect that makes it difficult to improve care that is high quality at baseline. Moreover, decreasing unnecessary use of an intervention may be easier than encouraging appropriate use of potentially toxic therapy. [ABSTRACT FROM AUTHOR]

Purpose: Phosphodiesterase type 5 inhibitors were recently introduced as a new treatment option for men with lower urinary tract symptoms. Safety and clinical effectiveness are well documented but the mode of action is still unclear. We determined and compared the expression of phosphodiesterase type 5 in the spinal cord of normal (sham operated) rats and rats with partial urethral obstruction induced bladder overactivity. We also assessed the urodynamic effects of intravenously and intrathecally administered sildenafil in the rats to determine whether phosphodiesterase type 5 inhibitors exert effects on the sacral spinal cord. Materials and Methods: A total of 65 male Sprague-Dawley® rats were used for molecular/morphological and functional experiments. Bladder overactivity was induced via surgical partial urethral obstruction in 39 of 65 rats. Spinal phosphodiesterase type 5 expression was assessed by histology and polymerase chain reaction. The effects of sildenafil administered intravenously or intrathecally were studied urodynamically. Results: Phosphodiesterase type 5 was expressed in various regions of the lumbosacral spinal cord, including the sacral regions of micturition control. Expression was similar in normal rats and rats with partial urethral obstruction/bladder overactivity. In normal rats intravenous and intrathecal sildenafil had no urodynamic effect. When administered intravenously and intrathecally to rats with partial urethral obstruction/bladder overactivity, sildenafil decreased micturition frequency and bladder pressure. Doses tested intrathecally had no effect when given intravenously. Conclusions: Phosphodiesterase type 5 is expressed in the rat spinal cord. Intravenous sildenafil may exert part of its urodynamic effect in rats with partial urethral obstruction/bladder overactivity via an effect on the sacral spinal cord. [ABSTRACT FROM AUTHOR]

Purpose: Prior phase II studies of intravesical gemcitabine have shown it to be active and well tolerated, but durable responses in patients with nonmuscle invasive bladder cancer who have experienced recurrence after bacillus Calmette-Guérin treatment are uncommon. We performed a multi-institutional phase II study within the SWOG (Southwest Oncology Group) cooperative group to evaluate the potential role of gemcitabine induction plus maintenance therapy in this setting. Materials and Methods: Eligible patients had recurrent nonmuscle invasive bladder cancer, stage Tis (carcinoma in situ), T1, Ta high grade or multifocal Ta low grade after at least 2 prior courses of bacillus Calmette-Guérin. Patients were treated with 2 gm gemcitabine in 100 cc normal saline intravesically weekly × 6 and then monthly to 12 months. Cystoscopy and cytology were performed every 3 months, with biopsy at 3 months and then as clinically indicated. Initial complete response was defined as negative cystoscopy, cytology and biopsy at 3 months. Results: A total of 58 patients were enrolled in the study and 47 were evaluable for response. Median patient age was 70 years (range 50 to 88). Of the evaluable patients 42 (89%) had high risk disease, including high grade Ta in 12 (26%), high grade T1 in 2 (4%) and carcinoma in situ in 28 (60%) with or without papillary lesions. At the initial 3-month evaluation 47% of patients were free of disease. At 1 year disease had not recurred in 28% of the 47 patients, all except 2 from the high risk group, and at 2 years disease had not recurred in 21%. Conclusions: Intravesical gemcitabine has activity in high risk nonmuscle invasive bladder cancer and offers an option for patients with recurrence after bacillus Calmette-Guérin who are not suitable for cystectomy. However, less than 30% of patients had a durable response at 12 months even with maintenance therapy. [ABSTRACT FROM AUTHOR]

Purpose: Imiquimod, a toll like receptor 7 (TLR-7) agonist, is effective as a topical treatment for skin malignancies. TMX-101 is a liquid formulation of imiquimod. In this study we establish a safety profile of TMX-101 in patients with nonmuscle invasive bladder cancer. Materials and Methods: We conducted a multicenter phase 1 dose escalation study in patients with nonmuscle invasive bladder cancer. Patients were included in 1 of 4 dose groups (0.05%, 0.1%, 0.2% or 0.4%) and treated with 6 weekly instillations of TMX-101, starting 2 weeks after transurethral resection of bladder tumor. Patients were evaluated weekly, and pharmacokinetic and pharmacodynamic parameters were measured. Results: A total of 16 patients were included in the study with 4 per dose group. Two patients dropped out after instillation 2 in dose groups 1 and 2. Overall, 88 instillations were administered without serious adverse events. There were 118 adverse events, of which 84 were related to the study drug. All adverse events were mild or moderate and number or severity was not correlated with dose group. Of the related adverse events 70% were confined to the genitourinary tract and resolved without intervention. There was a dose dependent systemic uptake with low plasma levels up to dose group 3 (0.2%, 100 mg). Maximum plasma concentration in dose group 4 (0.4%, 200 mg) was 71.7 ng/ml. This is below plasma concentrations of 123 and 128 ng/ml without significant side effects measured in healthy volunteers after subcutaneous (30 mg) or oral intake (100 mg) of imiquimod, respectively. Conclusions: Intravesical treatment with TMX-101 is safe. The side effects are common but mild and mostly limited to the genitourinary tract. There is a low systemic uptake. [ABSTRACT FROM AUTHOR]

Purpose: Docetaxel is a safe agent for intravesical therapy. Adding monthly maintenance treatments can extend response durability. We report our cumulative experience with intravesical docetaxel in a larger cohort with extended followup. Materials and Methods: A total of 54 patients received salvage intravesical docetaxel for bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer between 2003 and 2012, including 18 treated during the original phase I trial. All patients received 6 weekly instillations of intravesical docetaxel. After the phase I trial, those with a complete response to induction treatment were offered single dose monthly maintenance treatments for a total of up to 12 months of docetaxel therapy. Recurrence was defined as positive biopsy or urine cytology. Recurrence-free, disease specific and overall survival was determined by Kaplan-Meier analysis. Results: Median followup was 39.1 months. Of the 54 patients 32 (59%) had a complete initial response after induction therapy, including 18 who received additional monthly maintenance treatments. Median time to recurrence in initial responders treated with vs without docetaxel maintenance was 39.3 vs 19.0 months. One and 3-year recurrence-free survival rates for the entire cohort were 40% and 25%, respectively. Of the 54 patients 17 (24%) underwent radical cystectomy at a median of 24 months of followup. Five-year disease specific and overall survival rates were 85% and 71%, respectively. Conclusions: Intravesical docetaxel appears to be a promising agent with significant efficacy and durability for bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer. Adding maintenance treatments may increase the duration of recurrence-free survival. [ABSTRACT FROM AUTHOR]

Purpose: Despite its established efficacy in reducing recurrence rates for patients with urothelial carcinoma, immediate intravesical chemotherapy is reportedly used infrequently. Accordingly, the Urological Surgery Quality Collaborative implemented a project aimed at understanding and improving the use of immediate intravesical chemotherapy. Materials and Methods: Surgeons in 5 Urological Surgery Quality Collaborative practices prospectively collected clinical and baseline intravesical chemotherapy use data for patients undergoing bladder biopsy or transurethral bladder tumor resection from September 2010 through January 2012. In the second phase of data collection (June 2011 through January 2012) treating surgeons also documented reasons for not administering intravesical chemotherapy. We defined patients with 1 to 2 clinical stage Ta/T1, completely resected, papillary tumor(s) as ideal candidates for treatment with immediate intravesical chemotherapy. For ideal and nonideal patients we examined baseline use of intravesical chemotherapy across Urological Surgery Quality Collaborative practices as well as reasons for not administering therapy among ideal patients. Results: Among 1,931 patients 37.2% met criteria as ideal cases for intravesical chemotherapy administration. We observed significant variation in the use of intravesical chemotherapy across Urological Surgery Quality Collaborative practices for ideal (range 27% to 50%) and nonideal cases (9% to 24%) (p <0.001). Reasons for not treating ideal candidates included lack of confirmation of malignancy (4, 2.8%), uncertainty regarding the benefits of intravesical chemotherapy (28, 19.6%) and logistic factors such as the unavailability of medication (34, 23.8%). Conclusions: Use of immediate intravesical chemotherapy by Urological Surgery Quality Collaborative practices is higher than reported elsewhere but still varies widely, even among ideal candidates. Efforts to optimize use will be aided by disseminating evidence supporting indications and benefits of intravesical chemotherapy, and by addressing local logistic factors that limit access to this evidence-based therapy. [Copyright &y& Elsevier]

Purpose: A phase II study was performed to assess the efficacy and tolerability of intravesical oportuzumab monatox in patients with urothelial carcinoma in situ of the bladder. Bacillus Calmette-Guérin treatment had previously failed in all patients. Materials and Methods: A total of 46 patients received 1 induction cycle of 6 (cohort 1) or 12 (cohort 2) weekly intravesical oportuzumab monatox (VB4-845) instillations of 30 mg, followed by up to 3 maintenance cycles of 3 weekly administrations every 3 months. Results: A complete response to oportuzumab monatox was seen in 9 of 22 patients (41%) in cohort 1 and 9 of 23 (39%) in cohort 2 at the 3-month evaluation. A total of 20 patients (44%) achieved a complete response. Two other patients without carcinoma in situ who achieved a complete response were not included in the study due to the development of noninvasive papillary (Ta) disease. Median time to recurrence in patients who achieved a complete response was 274 and 408 days in cohorts 1 and 2, respectively. Overall 7 patients (16%) remained disease-free. Post-study assessment demonstrated that these patients were still disease-free at last followup (18 to 25 months). The most common adverse events were mild to moderate reversible bladder symptoms. Conclusions: Oportuzumab monatox was effective and well tolerated in patients with bacillus Calmette-Guérin refractory carcinoma in situ of the bladder. These results demonstrate the clinical benefit of oportuzumab monatox and support its continued development for the second line treatment of nonmuscle invasive bladder cancer. [ABSTRACT FROM AUTHOR]

Purpose: We studied the safety and efficacy of multiple adjuvant apaziquone instillations in patients with high risk nonmuscle invasive bladder cancer. Materials and Methods: Patients with high risk nonmuscle invasive urothelial carcinoma of the bladder underwent transurethral resection of all bladder tumor(s), and received 6 weekly adjuvant intravesical apaziquone instillations of 4 mg in 40 ml. Patients with carcinoma in situ received 3 further maintenance instillations at months 3, 6 and 12. Followup consisted of cystoscopy, urine cytology and observation of adverse events every 3 months for 18 months. Results: A total of 53 patients were enrolled in the study. Although all patients were high risk according to the definitions used when the study was initiated, according to most recent guideline criteria, 80% and 20% of these patients would now be considered intermediate and high risk for recurrence, and 50% and 44% would be considered intermediate and high risk for progression, respectively. Intent to treat analysis of 49 patients with papillary tumors showed recurrent tumors in 34.7% and 44.9% at 12 and 18 months, respectively. One patient had progression to T2 or greater urothelial carcinoma after 9 months. There were 4 patients with carcinoma in situ who had complete responses at 3 months but discontinued treatment due to cystitis, recurrent papillary disease, urinary incontinence and dysuria. Most other side effects were mild (grade 1 to 2). Conclusions: Adjuvant intravesical instillations of apaziquone are generally well tolerated. The recurrence rates of 34.7% after 12 months and 44.9% after 18 months in these patients can be considered encouraging, and warrant further study. [ABSTRACT FROM AUTHOR]

Purpose: Although the European Association of Urology, First International Consultation on Bladder Tumors, National Comprehensive Cancer Network and American Urological Association guidelines all provide an excellent evidence-based framework for the management of nonmuscle invasive bladder cancer, these guidelines vary with respect to important issues such as risk level definitions and management strategies for these risk categories. Therefore, we built on the existing framework provided by current guidelines, and provide consensus on the definitions of low, intermediate and high risk nonmuscle invasive bladder cancer, as well as practical recommendations for the treatment of patients in each of these risk categories. Materials and Methods: An international committee of experts on bladder cancer management identified and analyzed the European Association of Urology, First International Consultation on Bladder Tumors, National Comprehensive Cancer Network and American Urological Association guidelines as well as the published English language literature related to the treatment and management of nonmuscle invasive bladder cancer available as of April 2010. Results: Based on review of the current guidelines and literature, the International Bladder Cancer Group developed practical recommendations for the management of nonmuscle invasive bladder cancer. Conclusions: Complete transurethral bladder tumor resection is recommended for all patients with nonmuscle invasive bladder cancer. For low risk disease a single, immediate chemotherapeutic instillation after transurethral bladder tumor resection is recommended. For intermediate or high risk disease there is no significant benefit from an immediate, postoperative chemotherapeutic instillation. For intermediate risk disease intravesical bacillus Calmette-Guérin with maintenance or intravesical chemotherapy is recommended. For high risk disease bacillus Calmette-Guérin induction plus maintenance is recommended. The appropriate management of recurrence depends on the patient level of risk as well as previous treatment, while the management of treatment failure depends on the type of failure as well as the level of risk for recurrence and disease progression. [ABSTRACT FROM AUTHOR]

Purpose: Inadequate urothelial delivery of drugs is considered a primary cause of current shortcomings in adjuvant intravesical chemotherapy for bladder cancer. We report what is to our knowledge a novel biorecognitive approach to achieve more regionally selective targeting of malignant tissue and improve urothelial uptake based on specific interaction between lectins and bladder cell glycocalyces. Materials and Methods: We assessed the cytoadhesive and cytoinvasive potential of selected plant lectins in 3 human urothelial cell lines, corresponding to healthy tissue, and low and high grade carcinoma, respectively. Flow cytometry and fluorimetry were used to determine binding capacity and specificity in single cells and confluent monolayers. Monensin quenching experiments, microscopic analysis and enzyme treatment allowed further characterization of internalization, the uptake pathway and the potential cause of tumor selectivity. Results: Wheat germ agglutinin had the highest bioadhesive potential while peanut agglutinin was the most potent discriminator between healthy and cancerous tissue (p <0.01). In each case cell interaction was highly specific (greater than 80%) and proved decisive for efficient uptake. Within 60 minutes after exposure greater than 50% of membrane bound lectins were internalized in acidic compartments. Cancer associated aberrant glycosylation likely represents the determining cause of peanut agglutinin selectivity. Conclusions: Given careful choice of the targeting ligand, the development of carbohydrate based delivery strategies for bladder cancer therapy seems feasible. Lectin bioadhesion may not only mediate preferential accumulation in malignant tissue but also promote cellular internalization via increased recruitment of membrane bound material to physiological uptake routes. [ABSTRACT FROM AUTHOR]

Purpose: Up to 50% of patients treated with intravesical agents for high grade nonmuscle invasive bladder cancer will have disease recurrence. Response rates to current second line intravesical therapies are low and for these high risk patients novel agents are necessary. Our previously completed phase I trial showed docetaxel was a safe agent for intravesical use. Nanoparticle albumin-bound paclitaxel (Abraxane®, ABI-007) has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy. Thus, we assessed the dose limiting toxicity and maximum deliverable dose of intravesical nanoparticle albumin-bound paclitaxel. Materials and Methods: Inclusion criteria for this institutional review board approved phase I trial were recurrent high grade Ta, T1 and Tis transitional cell carcinoma of the bladder for which at least 1 prior standard intravesical regimen failed. Six weekly instillations of nanoparticle albumin-bound paclitaxel were administered with a modified Fibonacci dose escalation model used until the maximum deliverable dose was achieved. The primary end point was dose limiting toxicity and the secondary end point was response rate. Results: A total of 18 patients were enrolled in the study. One patient demonstrated measurable systemic absorption after 1 infusion. Grade 1 local toxicities were experienced by 10 (56%) patients with dysuria being the most common, and no grade 2, 3 or 4 drug related local toxicities were encountered. Of the 18 patients 5 (28%) had no evidence of disease at posttreatment evaluation. Conclusions: Intravesical nanoparticle albumin-bound paclitaxel exhibited minimal toxicity and systemic absorption in the first human intravesical phase I trial to our knowledge. A larger phase II study has begun to formally evaluate the activity of this regimen. [ABSTRACT FROM AUTHOR]

Purpose: Co-administration of the 5α-reductase inhibitor dutasteride increases the oral testosterone bioavailability in men with experimentally induced hypogonadism. We examined oral testosterone with and without dutasteride administration in hypogonadal men for 28 days. Materials and Methods: We randomly assigned 43 hypogonadal men to twice daily oral doses of 150, 250 or 400 mg testosterone with 0.25 mg dutasteride, 400 mg testosterone alone or 0.25 mg dutasteride alone for 28 days in a multicenter study. Subjects underwent pharmacokinetic profiling of serum hormones on days 1 and 28. A total of 32 men completed all study procedures. Results: Serum testosterone increased in all groups on testosterone compared with that in the dutasteride only group. At the 400 mg dose the combination of testosterone and dutasteride resulted in average testosterone concentrations that were 2.7 and 4.6 times higher than in the testosterone only group on days 1 and 28, respectively (p <0.01). On day 28 average testosterone was 20% to 30% lower in all groups on testosterone and dutasteride, and 50% lower in the testosterone only group compared with day 1. Serum dihydrotestosterone was suppressed in all groups on dutasteride and increased in the testosterone only group. Conclusions: Oral testosterone administration resulted in a therapeutic serum testosterone concentration in hypogonadal men. Dutasteride improved the oral bioavailability of testosterone while suppressing dihydrotestosterone. Compared with day 1, testosterone was decreased after 28 days of administration. Additional study is warranted of oral testosterone with dutasteride for testosterone deficiency. [ABSTRACT FROM AUTHOR]

Purpose: Carcinoma in situ represents high grade anaplasia of the bladder mucosa. Intravesical immunotherapy with bacillus Calmette-Guérin is the gold standard treatment for patients with carcinoma in situ. Patients with carcinoma in situ refractory to bacillus Calmette-Guérin are candidates for major surgery such as radical cystectomy. We identified the maximum tolerated dose and the recommended dose, and evaluated the safety profile of paclitaxel-hyaluronic acid bioconjugate given by intravesical instillation to patients with carcinoma in situ refractory to bacillus Calmette-Guérin. Materials and Methods: A total of 16 patients with carcinoma in situ refractory to bacillus Calmette-Guérin were enrolled in a phase I, open label, single institution study. A minimum of 3 eligible patients were included per dose level. Paclitaxel-hyaluronic acid solution (ONCOFID-P-B™) was administered for 6 consecutive weeks. The primary objective was to identify the maximum tolerated dose and the recommended dose. As secondary objectives the safety profile of ONCOFID-P-B, the pharmacokinetic profile after each instillation and the tumor response were also evaluated. Results: No dose limiting toxicity occurred at any drug level evaluated. The plasma levels of the study drug were always below the lower limit of quantification at all tested doses after each instillation. A total of 11 adverse events were reported by 7 patients and 9 (60%) showed complete treatment response. Conclusions: Intravesical instillation of ONCOFID-P-B for carcinoma in situ refractory to bacillus Calmette-Guérin showed minimal toxicity and no systemic absorption in the first human intravesical clinical trial to our knowledge. Finally, satisfactory response rates were observed. [ABSTRACT FROM AUTHOR]

Purpose: We previously identified vitamin B12 deficiency as a potential long-term consequence in pediatric patients with prior ileocystoplasty despite adequate preservation of terminal ileum. Vitamin B12 deficiency can result in hematological and neurological deficits, of which some are irreversible. Deficiency discovered after ileocystoplasty is purportedly due to B12 malabsorption since the principal absorption site is ileum. B12 deficiency due to malabsorption is typically treated with intramuscular injection to ensure adequate treatment. We determined whether oral vitamin B12 supplementation could increase serum vitamin B12 in patients with deficiency who underwent ileocystoplasty. Materials and Methods: During followup after ileocystoplasty we identified patients with low (200 pg/dl or less) or low normal (200 to 300 pg/dl) vitamin B12. Oral vitamin B12 was begun at 250 μg. Serum B12 was assessed at 1, 2 and 3-month intervals after beginning therapy. Results: A total of 128 patients with a mean followup of 83 months after ileocystoplasty had vitamin B12 levels available for review. Of these patients 36 (28%) had a level of 300 pg/dl or less with a level of 200 pg/dl or less in 16 (13%). After oral vitamin B12 treatment serum levels increased from a mean 235 to 506 pg/dl (114%) upon initial measurement (p <0.001). Subsequent measurements continued to increase from the first posttreatment level (p <0.05). No adverse effects were noted during a mean 4-month followup. Conclusions: To our knowledge this is the first study to show that oral vitamin B12 effectively increases serum levels in pediatric patients with prior ileocystoplasty. [ABSTRACT FROM AUTHOR]

Purpose: We assessed the efficacy of prophylactic intravesical chemotherapy for primary upper urinary tract urothelial cancer after nephroureterectomy during long-term followup. Materials and Methods: From January 1985 to June 2007, 196 patients with primary upper urinary tract urothelial cancer were included in this study. Patients were divided into group 1—31 who received intravesical epirubicin instillation, group 2—27 who received intravesical mitomycin C instillation and group 3—138 who did not receive prophylactic instillation after nephroureterectomy. We compared the bladder tumor recurrence rate, number of recurrence episodes, time to first bladder tumor recurrence, tumor type, percent of patients with cystectomy and percent who died of urothelial cancer, and the recurrence-free survival rate. Results: Of the 196 patients 73 had subsequent bladder recurrence at a mean followup of 55.6 months. There were no significant differences in recurrence type, mean number of bladder tumor recurrences, percent of patients with cystectomy and the cancer specific survival rate. The bladder recurrence rate was lower in group 1 and 2 than in group 3. Mean time to first bladder tumor recurrence was longer in groups 1 and 2. Kaplan-Meier curves of recurrence-free survival rates were significantly increased in groups 1 and 2. Conclusions: Intravesical instillation of epirubicin or mitomycin C appears to be well tolerated and effective for preventing bladder recurrence and prolonging time to first bladder recurrence. Patients should receive prophylactic intravesical chemotherapy after nephroureterectomy. [Copyright &y& Elsevier]

Purpose: We assessed the clinical efficacy and safety of mycobacterial cell wall-DNA complex after intravesical administration in patients with carcinoma in situ in whom prior therapy with bacillus Calmette-Guerin failed or in those who were treatment naïve. Materials and Methods: Patients received 6 weekly instillations of 4 or 8 mg mycobacterial cell wall-DNA complex (formulated as an emulsion) followed by 3 weekly instillations at weeks 12 and 24. Efficacy and safety were evaluated throughout the treatment phase and at months 12 and 18. Results: A total of 55 patients (mean age 74 years, 74.6% male) received 4 mg (25) or 8 mg (30) mycobacterial cell wall-DNA complex emulsion. All patients were previously treated with bacillus Calmette-Guerin except for 8 who were treatment naïve and 2 who received chemotherapy. In the intent to treat population the complete response rate was 27.3% at weeks 12 and 26 in the 4 mg group while 46.4% of patients receiving 8 mg had a complete response at both points. Mycobacterial cell wall-DNA complex was well tolerated by both dose groups. Overall 90% of all adverse events were mild to moderate in severity. Conclusions: Mycobacterial cell wall-DNA complex has shown antineoplastic activity in patients with bladder cancer with less toxicity than that associated with bacillus Calmette-Guerin administration. The tolerance and efficacy of mycobacterial cell wall-DNA complex might hold promise for the treatment of carcinoma in situ of the bladder. [Copyright &y& Elsevier]

Purpose: Children with neurogenic bladder and poor bladder compliance are usually treated with bladder catheterization and oral anticholinergic medication. They may become nonresponders to the drug or present with severe side effects. We evaluated the effectiveness and tolerability of intravesical oxybutynin in children with poorly compliant neurogenic bladder. Materials and Methods: We conducted a search of MEDLINE®, EMBASE®, CINAHL®, SciELO, dissertations/theses in ProQuest®, LILACS, the Cochrane Library, protocol registries and the gray literature. Two reviewers independently assessed study quality and extracted data. Results: Eight studies (2 prospective, 6 retrospective) assessed the effectiveness and side effects of intravesical oxybutynin in children with neurogenic bladder. A total of 297 children started treatment, of whom 22% (66 patients) discontinued therapy, with 9% (28) quitting due to systemic side effects. Mean change in bladder compliance (primary outcome) was reported in only 2 studies (+7.4 and +7.5 ml/cm H2O). The pooled mean change in pressure at maximum bladder capacity was −16.4 cm H2O (95% CI −22.8 to −10.0). Incontinence improved significantly in most studies, with “dry and improved” rates ranging from 61% to 83%. The funnel plot of pressure at maximum bladder capacity suggested no publication bias. Conclusions: Adjunctive intravesical oxybutynin therapy increased mean maximum bladder capacity and decreased bladder pressure in children with neurogenic bladder. However, identified studies offered a low level of evidence, with most being poorly reported retrospective case series with potential biases. Although the incidence of side effects was lower with the intravesical route, side effects are still possible and should be discussed with patients and families. The evidence available is insufficient to recommend this therapy. Research of more sound study design such as a randomized controlled trial should be conducted to assess the efficacy and side effects of intravesical oxybutynin in children. [Copyright &y& Elsevier]

Purpose: We reviewed our 4-year experience with percutaneous cryoablation and laparoscopy for treating small renal masses. Materials and Methods: After institutional review board approval we retrospectively analyzed renal cryoablation procedures performed between March 2003 and October 2007. An in-depth analysis was performed concerning demographics, hospital course and short-term outcome with respect to percutaneous vs laparoscopic cryoablation. Results: A total of 37 patients underwent treatment for 43 renal masses. Of the 37 patients 19 underwent laparoscopic cryoablation (24 tumors) and 18 underwent percutaneous cryoablation (19 tumors) using computerized tomography fluoroscopy. For percutaneous cryoablation a saline instillation was used in 58% of cases to move nonrenal vital structures away from the targeted renal mass. There were 5 cases of hemorrhage requiring transfusion, all of which were associated with the use of multiple cryoprobes. The transfusion rate in the percutaneous and laparoscopic cryoablation groups was 11.1% and 27.8%, respectively. Operative time was significantly longer in the laparoscopic cryoablation group compared to the percutaneous cryoablation group at 147 (range 89 to 209) vs 250.2 (range 151 to 360) minutes, respectively. The overall complication rate (including transfusion) was lower in the percutaneous cryoablation group compared to the laparoscopic cryoablation group (4 of 18 [22.2%] vs 8 of 20 [40%], respectively). Hospital stay was significantly shorter in the percutaneous vs laparoscopic cryoablation group at 1.3 vs 3.1 days, p <0.0001, respectively. Narcotic use in the percutaneous cryoablation group was more than half that used by the laparoscopic cryoablation group (5.1 vs 17.8 mg, p = 0.03, respectively). Among patients with biopsy proven renal cell carcinoma during a median followup of 11.4 and 13.4 months in the percutaneous and laparoscopic cryoablation groups, cancer specific survival was 100% and 100%, respectively, and the treatment failure rate was 5.3% and 4.2%, respectively. Conclusions: Percutaneous cryoablation is an efficient, minimally morbid method for the treatment of small renal masses and it appears to be superior to the laparoscopic approach. Short-term followup has shown no difference in tumor recurrence or need for re-treatment. Of note, hemorrhage was solely associated with the use of multiple probes. [Copyright &y& Elsevier]

Purpose: We evaluated the impact of epirubicin perioperative instillation in improving subsequent bacillus Calmette-Guerin instillation efficacy in high risk patients with nonmuscle invasive bladder cancer. Materials and Methods: Between January 2005 and June 2007, 161 patients affected by high risk nonmuscle invasive bladder cancer were enrolled in this prospective, randomized, controlled, double-blind study. A total of 80 patients were assigned to group A (perioperative epirubicin 80 mg/50 ml normal saline) plus delayed bacillus Calmette-Guerin instillations (5 × 108 colony-forming units in 50 ml saline) and 81 to group B (delayed bacillus Calmette-Guerin alone). The main outcome measures were time to first recurrence and recurrence rate. All data obtained from a median followup of 15.3 months in group A and 14.8 months in group B, were analyzed. Results: At the end of followup 46 of 80 patients in group A (57.5%) had no evidence of disease, just like 41 of 81 in group B (50.6%). No statistical difference was observed between the 2 groups in terms of recurrence rate (p = 0.82) or time to first recurrence (p = 0.095). Kaplan-Meier analysis of recurrence showed no significant differences between group A and group B (p = 0.0952). On multivariate analysis the early single dose instillation of epirubicin was not indicated as an independent prognostic factor (HR 0.50, 95% CI 0.32–1.18). Conclusions: The present study showed no statistically significant differences in terms of disease-free time and recurrence rate between high risk patients with nonmuscle invasive bladder cancer who had undergone perioperative epirubicin instillation plus delayed bacillus Calmette-Guerin and those who had undergone delayed bacillus Calmette-Guerin alone. [Copyright &y& Elsevier]

Purpose: We studied the safety, tolerability and pharmacokinetics of a single immediate post-transurethral resection intravesical instillation of apaziquone for patients with nonmuscle invasive bladder cancer. Materials and Methods: Patients with cTa-T1, G1-G2 urothelial cell carcinoma of the bladder underwent transurethral resection of bladder tumor(s) followed by a single intravesical instillation of apaziquone 4 mg/40 ml for 1 hour within 6 hours of transurethral bladder tumor resection. Adverse events and safety parameters were assessed on days 8 and 15 after transurethral bladder tumor resection. Blood samples were drawn before and during the instillation for pharmacokinetic analyses. The first 10 patients with pTa-T1, G1-G2 nonmuscle invasive bladder cancer were also evaluated by cystoscopy 3 months after treatment to determine mucosal healing. Results: Of 20 patients receiving apaziquone 13 (65%) reported 35 adverse events, mostly grade 1 to 2. Eight patients (40%) reported 13 adverse events related to treatment, in particular dysuria, hematuria, bladder spasm, abdominal pain, asthenia and postoperative urinary retention. Three grade 3 and 1 grade 4 event(s) occurred, but these were considered unrelated to treatment. No other significant clinical changes were observed. Apaziquone and the active metabolite EO5a were not detected with pharmacokinetic analyses at any point of time. After 3 months no evidence of impaired mucosal healing was observed. Conclusions: A single immediate post-transurethral bladder tumor resection instillation of apaziquone was well tolerated with an expected good safety profile. Apaziquone and its metabolite EO5a were not detected systemically with pharmacokinetic analyses. These results have lead to further study of a single immediate instillation of apaziquone. [Copyright &y& Elsevier]

Purpose: We determined technical feasibility, safety and short-term outcomes following percutaneous renal cryoablation. Materials and Methods: We performed a retrospective review of 115 renal tumors in 110 patients treated with percutaneous cryoablation. Specific attention was directed to tumor characteristics, hospital course, complications, technical success and treatment success based on followup imaging. Results: Mean tumor size was 3.3 cm (range 1.5 to 7.3), including 29 tumors 4.0 cm or larger and 21 tumors in the anterior kidney. Of 90 renal mass biopsies performed 52 (58%) showed renal cell carcinoma. All patients were admitted to the hospital following cryoablation and most (87%) were discharged home the next day (range 1 to 12 days). There were 7 major complications associated with the 113 cryoablation procedures (6%). Technical success was achieved in 112 of the 115 (97%) treated tumors and 3 residual tumors were seen on 3-month followup imaging. There has been no local progression in 80 tumors (100% treatment success) followed 3 months or longer (mean 13.3 months). Conclusions: Percutaneous renal cryoablation is technically feasible and relatively safe. With experience many anterior tumors and tumors larger than 4 cm can be successfully treated. Long-term followup remains necessary to prove treatment durability. [Copyright &y& Elsevier]

Purpose: To obtain unambiguous evidence for the putative role of E-cadherin in the selective accumulation of hypericin after intravesical instillation in humans we investigated the accumulation of hypericin in spheroids from 3 clones of the human bladder carcinoma cell line T-24 that express different levels of E-cadherin, as determined by immunohistochemistry and reverse transcriptase-polymerase chain reaction. Materials and Methods: Clones of T-24 cells transfected with the E-cadherin gene were analyzed for E-cadherin expression and 3 cell lines with different expression levels were selected. Spheroids of these cell lines were incubated with 10 μM hypericin in cell culture medium supplemented or not with fetal calf serum for 2 hours. After the incubation period centrally cut sections were examined by fluorescence microscopy. An imaging software system was used to measure average fluorescence in concentric layers from rim to center. Results: Data showed that in the presence of serum the accumulation of hypericin in spheroids was inversely associated with the level of E-cadherin expressed by the T-24 transfectants used, whereas in the absence of serum differential accumulation of the compound was completely abolished. Conclusions: Spheroids composed of cancer cell lines expressing variable levels of E-cadherin represent an excellent model in which to study the role of intercellular adhesion in bladder cancer. The outcome of this study strongly suggests that E-cadherin is the key mediator in the selective accumulation of hypericin in superficial bladder cancer after intravesical instillation in humans. [Copyright &y& Elsevier]

Purpose: We examined the safety and the efficacy of a combination of intravesical and oral pentosan polysulfate sodium in comparison to only oral pentosan polysulfate sodium in treating interstitial cystitis. Materials and Methods: A total of 41 females diagnosed with interstitial cystitis were randomized to receive a combination of intravesical pentosan polysulfate sodium plus oral pentosan polysulfate sodium (21 in treatment group) or intravesical placebo plus oral pentosan polysulfate sodium (20 in placebo group) for 6 weeks. All subjects continued to receive oral pentosan polysulfate sodium for another 12 weeks. The primary outcome was the change in the O’Leary-Sant Interstitial Cystitis Symptoms/Problem Index from baseline to week 6, 12, and 18. Other outcomes included: the changes in Pelvic Pain and Urgency Frequency questionnaire, Health Related Quality of Life index: SF-36, pain scale, urgency scale, voiding log, patient global assessment, and sexual function scales. Results: The change in the total score of O’Leary-Sant Interstitial Cystitis Symptoms/Problems Index from baseline to week 12 among the treatment group (median −12 or approximately a 46% reduction) was significantly greater compared to the placebo group (median −5.5 or approximately a 24% reduction, p = 0.04). At week 18 the treatment group showed statistically significant improvement in all Health Related Quality of Life domains compared to the baseline (p ≤0.01), while the placebo group showed significant improvement in only 3 Health Related Quality of Life domains, (p ≤0.05) compared to the baseline. There were no significant differences within major categories of adverse events between treated and placebo groups. Conclusions: The use of intravesical pentosan polysulfate sodium simultaneously with oral pentosan polysulfate sodium is a safe and effective therapeutic option. These findings will open a new option for patients with interstitial cystitis to reduce their severely devastating symptoms and to improve their quality of life and well-being. [Copyright &y& Elsevier]

Purpose: We studied whether a single instillation of epirubicin after transurethral bladder tumor resection would influence the interval to and size of the first recurrence. Materials and Methods: A total of 404 patients from 13 hospitals were randomized to 1 instillation of 50 mg epirubicin or placebo within 6 hours after transurethral resection of bladder tumors. Results: Of 155 evaluable patients in the epirubicin group 79 (51.0%) had recurrence compared to 95 of 152 (62.5%) in the placebo group (p = 0.04). Of the recurrences 63.3% were small (1 to 5 mm). Tumor size was unknown in 5 patients. Of 79 patients with recurrence in the epirubicin arm 33 (42.9%) vs 29 (31.5%) of 95 in the placebo arm had larger (more than 5 mm) first recurrences (p = 0.12). Approximately half of the patients with first recurrences were treated as outpatients and the other half spent a total of 145 days in the hospital with no difference between the groups. Conclusions: We confirmed the results of previous studies showing that 8.5 patients must be treated with a single instillation to prevent 1 recurrence. Furthermore, our data may indicate that only small recurrences are prevented, which could easily be fulgurated using local anesthesia at followup cystoscopy. The benefit of single instillations can be questioned if this finding is confirmed by others. [Copyright &y& Elsevier]

Purpose: The standard approach to treatment for patients with high risk Ta, Tis, or T1 bladder cancer that persists or recurs after bacillus Calmette-Guerin is radical cystectomy in medically fit patients. Maintenance bacillus Calmette-Guerin has been shown in both SWOG (Southwest Oncology Group) and EORTC (European Organization for Research and Treatment of Cancer) studies to reduce the probability of disease worsening events. As new drugs come on line and experience with maintenance and combination immunotherapy increases, there may be a tendency to delay definitive local therapy and thereby expose patients to a higher risk of progression to invasive and potentially metastatic disease. We explored a large prospective data set from the SWOG 8507 randomized trial of maintenance bacillus Calmette-Guerin to better understand this risk and specifically to assess the impact of timing of recurrence on survival. Materials and Methods: The database includes 501 evaluable patients who were treated with induction bacillus Calmette-Guerin and then were randomized to maintenance bacillus Calmette-Guerin or observation. Recurrence patterns were defined as early (less than 12 months following randomization) or late (12 or more months after randomization). Patients were identified who underwent cystectomy at any time after induction bacillus Calmette-Guerin. All patients were followed for life for determination of vital status. Outcome measure of overall survival was assessed using Kaplan-Meier analysis and adjustment for covariates was done with proportional hazards models. Survival was defined from date of randomization to death from any cause. Results: A total of 501 patients were randomized after induction bacillus Calmette-Guerin, of whom 251 had recurrence and 229 died. Of the patients who died 59% had recurrence following randomization. Early recurrence was not associated with a higher risk of death compared to late recurrence (p = 0.68). There was no evidence that bacillus Calmette-Guerin affected the relationship of timing of relapse and survival. There was no difference in progression to T2 or greater between early and late recurrence (38 of 117, 32% vs 34 of 134, 25%; p = 0.21). Cystectomy was performed infrequently as 56 of 251 patients who had recurrence underwent the operation. Patients who had early recurrence had a slightly higher cystectomy rate than those with late recurrence (32 of 117, 27% vs 24 of 134, 18%; p = 0.07). Among 394 patients with no evidence of disease at randomization those who underwent cystectomy for T2 or greater disease had a higher risk of death compared to patients who underwent cystectomy for Tis or T1 disease (HR 1.76; 95% CI 0.77, 4.00; p = 0.18). Conclusions: There was no association of the timing of recurrence after induction bacillus Calmette-Guerin on long-term survival probability. When patients had early recurrence there was a slightly higher probability of cystectomy but not progression to muscle invasive cancer. When cystectomy was performed the 5-year postoperative survival probability was lower than that reported in contemporary series. [Copyright &y& Elsevier]

Purpose: We studied the ablative activity of intravesical apaziquone (EOquin™) on a papillary marker tumor and determined the incidence of side effects. Materials and Methods: A total of 46 patients with multiple pTa or pT1 bladder tumors underwent visible lesion resection except for 1 marker tumor. Patients were then treated with 6 instillations of apaziquone at weekly intervals. The response was determined 2 to 4 weeks after the last instillation. Results: One patient withdrew informed consent and refused the last treatment due to side effects. A histologically proven complete response was seen in 30 patients. Progression to invasive stage was not observed. Local side effects in this study were comparable to those due to other chemotherapy instillations, such as mitomycin C and epirubicin, but less severe and less frequent compared to those of bacillus Calmette-Guerin instillations. Conclusions: The histological complete response rate after 6 consecutive instillations of apaziquone in patients with superficial bladder cancer was 67% (95% CI 51 to 80). Local side effects were comparable to side effects due to other chemotherapy instillations. [Copyright &y& Elsevier]

Purpose: We report the incidence of calcifications developing at the bladder neck/urethra in pediatric patients treated with glutaraldehyde cross-linked collagen for urinary incontinence. Materials and Methods: We reviewed charts of patients treated with glutaraldehyde cross-linked collagen injections for urinary incontinence between 1994 and 1999. Etiology of incontinence, pertinent medical history, operative details and postoperative imaging were examined. Results: Of 31 patients 4 (13%) had development of submucosal calcifications in the bladder neck/urethra. All 4 patients had received multiple injections of glutaraldehyde cross-linked collagen for incontinence secondary to neurogenic bladder. The calcifications were confirmed surgically. Pathology reports available for 2 of 4 patients showed chronic inflammation without dysplasia or malignant changes. Mean followup was significantly different between calcified and noncalcified cases (10.3 vs 7.2 years, p = 0.009), as was total volume of collagen injected (21 vs 12 cc, p = 0.012). Mean time to diagnosis of calcifications was 8.8 years (range 7 to 11) after first injection. A total of 24 patients without calcification underwent bladder imaging at a mean of 6.8 years (±2.2) after glutaraldehyde cross-linked collagen injection, which was not significantly different than the time to diagnosis (p = 0.089). The number of injections was not significantly different between the 2 groups (p = 0.426). Conclusions: Of our patients 13% had development of calcifications at the site of prior glutaraldehyde cross-linked collagen injections for incontinence. These calcifications were surrounded by chronic inflammation. Patients who have undergone glutaraldehyde cross-linked collagen injections may benefit from long-term followup with bladder imaging to detect and follow calcifications at prior injection sites. [Copyright &y& Elsevier]

Purpose: Previous study has shown that multiple intravesical instillations of resiniferatoxin (Sigma®) at 10 nM has therapeutic effects in patients with detrusor overactivity. To our knowledge the placebo effect of multiple instillations of low dose resiniferatoxin for neurogenic and nonneurogenic detrusor overactivity has not been investigated. In this randomized, double-blind, placebo controlled study we evaluated the therapeutic effects of this resiniferatoxin treatment. Materials and Methods: A total of 54 patients with detrusor overactivity refractory to anticholinergics were enrolled and randomly treated with 4 weekly intravesical instillations of 10 nM resiniferatoxin (26) or vehicle, consisting of 10% ethanol in normal saline, as the control group (28). The clinical effects of treatment on incontinence grade, incontinence episodes, general satisfaction, lower urinary tract symptoms and urodynamic parameters were assessed. Results: Three months after completing the 4 intravesical treatments the resiniferatoxin treatment group had a significantly higher percent of patients with excellent and improved results compared to the control group (19.2% vs 7.1% and 42.3% vs 14.2%, respectively, each p <0.001). Treatment remained effective at 6 months in 13 patients (50%) in the resiniferatoxin group but in only 3 (11%) in the control group (p <0.001). Bladder capacity was significantly increased and symptom scores significantly improved 3 months after treatment in the resiniferatoxin group but not in the control group. Conclusions: Multiple intravesical instillations of 10 nM resiniferatoxin were effective for improving the incontinence grade in 62% of patients at 3 months, of whom 50% maintained a therapeutic effect 6 months after treatment. The therapeutic effect of resiniferatoxin was significantly superior to that of placebo. [Copyright &y& Elsevier]

Purpose: Intravesical therapy is an integral part of treatment in patients with superficial urothelial carcinoma of the bladder. The American Urological Association and European Association of Urology guidelines on bladder cancer incorporate it for the treatment of superficial bladder cancer. Given the extensive use of intravesical immunotherapy and chemotherapy, it is essential for the practicing urologist to be aware of the local and systemic side effects of these therapies. Materials and Methods: We reviewed the literature on intravesical immunotherapy and chemotherapy with particular emphasis on side effects, complications and their management. A Medline search of the English language literature for the last 25 years was done on Entrez PubMed and all relevant articles were studied in full. All side effects and complications were studied and their management was reviewed. Results: Intravesical therapy for transitional cell carcinoma of the bladder is generally safe. There is a high incidence of local, usually self-limiting, relatively minor side effects and infrequent, potentially severe local and systemic side effects. Most side effects are avoidable. Conclusions: Although intravesical therapy is generally safe, local and systemic side effects occur and it is important to be aware of them. Identifying complications early, preventing them when possible and managing them efficiently are critical. Most complications are preventable. Knowing the risks and benefits of chemotherapeutic and immunotherapeutic agents may decrease the short-term and long-term toxicity of these agents. Adherence to guidelines may prevent inappropriate use, which can lead to unnecessary complications, resulting in bladder dysfunction and even cystectomy. [Copyright &y& Elsevier]

Purpose: Recurrent urinary tract infections are common in complex pediatric urological cases, particularly those requiring clean intermittent catheterization. At our institution gentamicin bladder irrigations have been used for antimicrobial prophylaxis and to treat symptomatic bacteriuria, particularly when the infection does not involve the upper urinary tract. The purpose of this study was to assess the safety of this therapy. Materials and Methods: A retrospective study was performed of all children treated with gentamicin bladder irrigations from 1999 to 2004. The dose was 14 mg gentamicin in 30 ml saline instilled via catheter once or twice daily. Serum creatinine and random gentamicin levels were obtained according to a protocol based on risk of gentamicin toxicity. Patient demographics, laboratory results and outcomes were abstracted from the medical records. Results: A total of 80 patients (38 males and 42 females) were identified. Median patient age was 10 years and median duration of treatment was 90 days. No patient had detectable serum gentamicin levels greater than 0.4 mg/dl. Small increases in serum creatinine were seen in 3 patients, all of whom had chronic renal insufficiency. A total of 21 patients (26%) had breakthrough UTIs, of which 5 (24%) were gentamicin resistant. No adverse events were documented. Conclusions: Gentamicin bladder irrigations are a helpful adjunct in the management of complex pediatric urological cases involving recurrent symptomatic bacteriuria. We no longer require intensive laboratory monitoring of low risk patients at our institution. [Copyright &y& Elsevier]

Purpose: Micropapillary bladder carcinoma is a rare variant of UC. Due to paucity of data regarding treatment outcomes, patients with nonmuscle invasive micropapillary UC often receive intravesical therapy in an attempt at bladder preservation. Materials and Methods: We reviewed the records of all patients evaluated at our institution who had micropapillary UC of the bladder. Of these, 44 had nonmuscle invasive disease at presentation and form the basis of this report. Results: Mean patient age was 64.3 years (range 45 to 81) with a male-to-female ratio of 13:1. Stage distribution at presentation was 5 Ta (11%), 4 CIS (9%) and 35 T1 (80%). Median CSS was 81 months. Kaplan-Meier estimates of 5 and 10-year CSS rates were 64% and 26%, respectively. Intravesical BCG therapy was attempted in 27 patients (61%). Of these 27 patients, 67% (18 of 27) had progression (cT2 or greater), including 22% in whom metastatic disease developed. Only 19% of patients (5 of 27, all T1) remain disease-free with an intact bladder at a median followup of 30 months. A total of 30 patients (68%) underwent cystectomy. Among patients who underwent cystectomy after progression (18), median CSS was 61.7 months with no patient surviving 10 years, whereas among those undergoing cystectomy as initial therapy (12), median survival was not reached and the 10-year CSS rate was 72%. Conclusions: Intravesical BCG therapy appears to be ineffective against micropapillary UC. Our results suggest that the optimal treatment strategy for nonmuscle invasive micropapillary UC is radical cystectomy performed before progression. [Copyright &y& Elsevier]

ABSTRACT: Purpose:: We compared the efficacy and side effects of intravesical instillations of bacillus Calmette-Guerin (BCG) and epirubicin in patients with carcinoma in situ (CIS) of the bladder. Materials and Methods:: Patients with primary, secondary or concurrent CIS of the bladder were randomized to 81 mg BCG-Connaught (6 weekly instillations) or 50 mg epirubicin (8 weekly instillations). When a complete response (CR), defined as no Ta/T1 or CIS on biopsy and negative cytology, was obtained, patients in the 2 groups received maintenance instillations at months 3, 6, 12, 18, 24, 30 and 36. When no complete response was observed, the original treatment was repeated, followed again by cystoscopy and biopsies plus cytology. Results:: A total of 168 patients were randomized between March 1993 and April 1999 to receive BCG (84) or epirubicin (84), while 4 on epirubicin and 3 on BCG were ineligible. The majority (52%) had concurrent CIS. Primary and secondary CIS was found in 23% and 24% of cases, respectively. The overall CR rate was 56% for epirubicin and 65% for BCG (p = 0.21, 90% CI 21.5 to −2.9). When tumor was found following 2 instillation courses, further treatment was left to the investigator (BCG in 29 cases and epirubicin in 37). Time to bladder tumor recurrence after CR was longer in patients treated with BCG vs epirubicin (median 5.1 vs 1.4 years). CIS recurrences were more frequently observed in complete responders to epirubicin (45% vs 16%). No differences in time to progression or duration of survival were observed. Side effects were more frequently seen in patients on BCG with 26 on BCG and 8 on epirubicin stopping treatment due to side effects. Conclusions:: No significant difference in CR rates could be demonstrated with intravesical instillations of epirubicin or BCG. Time to recurrence was significantly longer in patients treated with BCG after having achieved a CR. More CIS recurrences were found in patients treated with epirubicin. For time to progression and survival longer followup is warranted. Side effects were more frequent in patients on BCG. [Copyright &y& Elsevier]

Purpose: Intravesical oxybutynin is prescribed for patients who do not tolerate the side effects of oral intake. Standard oral tablets are broken up, dissolved and instilled. For convenience some families create a large volume of solutions to use for weeks. We investigated the stability of oxybutynin concentration in these solutions and the effect of varying solvents and solutes. Materials and Methods: Solutions of oxybutynin were created with a starting concentration of 125 μg/ml. We varied the method of pill preparation (crushed vs passive dissolution), type of solvent (tap water vs normal saline) and the presence of the commonly instilled antibiotic, gentamicin sulfate (0.48 mg/ml). Solutions were aged for 1 to 4 weeks. Concentrations of oxybutynin were measured by gas chromatography. Results: Tap water as a solvent had the greatest decrease in concentration, declining below 50% by week 2 and reaching 25% by week 4. The mean concentration of the other solutions decreased less, maintaining 80% of the starting concentration at week 4. The use of normal saline as a solvent and the addition of gentamicin sulfate helped slow the decrease. Crushing vs passive dissolution showed no effect. Conclusions: Homemade oxybutynin solutions degrade with time. Tap water solvent alone should be avoided. Solutions and additives that lower pH and are more acidic help oxybutynin solubility and stability. Storing oxybutynin solutions for later intravesical use appears feasible up to 4 weeks. The clinical effect of the 20% degradation remains to be demonstrated. [Copyright &y& Elsevier]

Purpose: For patients with bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer, multi-agent intravesical trials have been limited. In this study we investigate the safety of intravesical cabazitaxel, gemcitabine and cisplatin in the salvage setting., Materials and Methods: This was a dose escalation, drug escalation trial for patients with bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer who declined or were ineligible for radical cystectomy. All patients underwent a 6-week induction regimen of sequentially administered cabazitaxel, gemcitabine and cisplatin. Complete response was defined as no cancer on post-induction transurethral bladder tumor resection and negative urine cytology, while partial response allowed for positive cytology. Responders continued with maintenance cabazitaxel and gemcitabine monthly for the first year and bimonthly for the second year., Results: A total of 18 patients were enrolled. Mean age was 71 years, median followup was 27.8 months (range 16.3 to 46.9) and mean number of previous rounds of intravesical therapies before trial enrollment was 3.7. Nine patients (50%) had received intravesical chemotherapy after bacillus Calmette-Guérin and 7 (39%) were previously treated in a phase I clinical trial setting. At enrollment 6 (33%) subjects had T1 disease and 13 (72%) had carcinoma in situ. There were no dose limiting toxicities. Initial partial and complete response rates were 94% and 89%, respectively. At 1 year recurrence-free survival was 0.83 (range 0.57 to 0.94) and at 2 years estimated recurrence-free survival was 0.64 (0.32 to 0.84)., Conclusions: In this high risk and highly pretreated cohort of bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer cases combination intravesical cabazitaxel, gemcitabine and cisplatin was a well tolerated and potentially effective regimen.

Purpose: Rescue intravesical therapies for patients with bacillus Calmette-Guérin failure nonmuscle invasive bladder cancer remain a critical focus of ongoing research. Sequential intravesical gemcitabine and docetaxel therapy has shown safety and efficacy in 2 retrospective, single institution cohorts. This doublet has since been adopted as an intravesical salvage option at multiple institutions. We report the results of a multi-institutional evaluation of gemcitabine and docetaxel., Materials and Methods: Each institution retrospectively reviewed all records of patients treated with intravesical gemcitabine and docetaxel for nonmuscle invasive bladder cancer between June 2009 and May 2018. Only patients with recurrent nonmuscle invasive bladder cancer and a history of bacillus Calmette-Guérin treatment were included in the analysis. If patients were disease-free after induction, maintenance was instituted at the treating physician's discretion. Posttreatment surveillance followed American Urological Association guidelines. Survival analysis was performed using the Kaplan-Meier method and risk factors for treatment failure were assessed with Cox regression models., Results: Overall 276 patients (median age 73 years, median followup 22.9 months) received treatment. Nine patients were unable to tolerate a full induction course. One and 2-year recurrence-free survival rates were 60% and 46%, and high grade recurrence-free survival rates were 65% and 52%, respectively. Ten patients (3.6%) had disease progression on transurethral resection. Forty-three patients (15.6%) went on to cystectomy (median 11.3 months from induction), of whom 11 (4.0%) had progression to muscle invasion. Analysis identified no patient, disease or prior treatment related factors associated with gemcitabine and docetaxel failure., Conclusions: Intravesical gemcitabine and docetaxel therapy is well tolerated and effective, providing a durable response in patients with recurrent nonmuscle invasive bladder cancer after bacillus Calmette-Guérin therapy. Further prospective study is warranted.

Purpose: The BCAN (Bladder Cancer Advocacy Network) Patient Survey Network identified pain during intravesical procedures as a research priority for patients. Although intraurethral lidocaine is the standard of care in this setting, evidence of its use is equivocal. We systematically reviewed studies of interventions to reduce discomfort during cystoscopy and intravesical therapy of bladder cancer. We performed a meta-analysis of interventions using available randomized, controlled trials., Materials and Methods: Search terms derived from the key questions were incorporated into the literature search constructed by a research librarian and the English medical literature from 1990 to 2017 was accessed. The initial search yielded 626 potential studies and the final review incorporated 62. We combined 12 trials into a meta-analysis with a random effects model of the efficacy of intraurethral lidocaine vs plain lubricant to reduce pain during flexible cystoscopy as measured on a 10-point visual analogue scale., Results: Data from 12 randomized controlled trials in a total of 1,549 patients were included in the final intraurethral lidocaine meta-analysis. The standardized mean difference between visual analogue scale pain scores in patients who underwent flexible cystoscopy with intraurethral lidocaine and plain lubricant was -0.22 (95% CI -0.39--0.05). Evidence was insufficient to evaluate other interventions to mitigate the discomfort of invasive bladder procedures., Conclusions: Intraurethral lidocaine provides statistically significant pain reduction in men who undergo flexible cystoscopy, particularly with a longer dwell time. The evidence was insufficient for other tested interventions. A prospective study is needed to further clarify interventions to decrease patient discomfort during cystoscopy and other intravesical procedures in a diverse population.