Intravesical sequential gemcitabine and docetaxel versus bacillus calmette-guerin (BCG) plus interferon in patients with recurrent non-muscle invasive bladder cancer following a single induction course of BCG.

INTRODUCTION: Repeat BCG induction remains an option for select non-muscle invasive bladder cancer (NMIBC) patients who fail initial therapy. Alternative salvage intravesical regimens such as Gemcitabine and Docetaxel (Gem/Doce) have been investigated. We aimed to compare the efficacy BCG plus interferon a-2b (BCG/IFN) and Gem/Doce in patients with recurrent NMIBC after a single prior BCG course. METHODS: The National Phase II BCG/IFN trial database and multi-institutional Gem/Doce database were queried for patients with recurrent NMIBC after one prior BCG induction course, excluding those with BCG unresponsive disease. Stabilized inverse probability treatment weighted survival curves were estimated using the Kaplan-Meier method and compared. Propensity scores were derived from a logistic regression model. The primary outcome was recurrence free survival (RFS); secondary outcomes were high-grade (HG) RFS and risk factors for treatment failure. RESULTS: We identified 197 BCG/IFN and 93 Gem/Doce patients who met study criteria. Patients receiving Gem/Doce were older and more likely to have HG disease, CIS, and persistent disease following induction BCG (all P < 0.01). After propensity score-based weighting, the adjusted 1- and 2-year RFS was 61% and 53% after BCG/IFN versus 68% and 46% after Gem/Doce (P = 0.95). Adjusted 1- and 2-year HG-RFS was 60% and 51% after BCG/IFN versus 63% and 42% after Gem/Doce (P = 0.68). Multivariable Cox regression revealed that Gem/Doce treatment was not associated with an increased risk of failure (HR = 0.97, P = 0.89) as compared to BCG/IFN. CONCLUSION: Patients with recurrent NMIBC after a single induction BCG failure and not deemed BCG unresponsive had similar oncologic outcomes with Gem/Doce and BCG/IFN in a post-hoc analysis. Additional prospective studies are needed.

Comparison of Major Complications at 30 and 90 Days Following Radical Cystectomy.

OBJECTIVES: To better understand the time-course in which major complications occur after radical cystectomy and to describe associations with complications at 30 and 90 days. METHODS: A database of radical cystectomy cases was queried for preoperative, perioperative, and postoperative data. Follow-up extended to 90 days postsurgery and included major complications (Clavien III-V). Early (30-day) and late (90-day) complication rates were compared via McNemar's test, and patient characteristics were compared across complication time groups by one-way ANOVA or Fisher's exact tests. Multinomial logistic regression was used to explore associations between patient characteristics and complication timing. RESULTS: Of 969 patients undergoing radical cystectomy, 210/969 (21.7%) experienced a complication within 90 days. The rate of major complication significantly differed at 30 and 90 days (14.4% [conflict of interest (CI): 12.4%-16.9%] vs 21.7% [CI: 19.2%-24.4%] respectively, P ≤.0001). Chronic obstructive pulmonary disease (COPD) (P = .03), Charlson Comorbidity Index (P = .02), and Indiana pouch diversion (P = .002) were significant predictors of early complication. Diabetes was the strongest predictor for late complication (OR: 2.42; P = 0.01). Diabetes was also a significant predictor for late genitourinary complications (OR 3.39; P = .01), and smoking history was a significant predictor for late infectious complications (OR 3.61; P = .01). CONCLUSION: We identified a significant number of complications occurring after 30 days postcystectomy, including the majority of deaths and genitourinary complications. These findings suggest that assessment of complications exclusively at 30 days would fail to capture a large proportion of major complications and deaths. Understanding the time-course of complications postcystectomy will serve to better inform design of future outcome studies.

Uretero-Enteric Anastomotic Stricture Following Radical Cystectomy: A Comparison of Open, Robotic Extracorporeal, and Robotic Intracorporeal Approaches.

OBJECTIVES: To compare the incidence of benign uretero-enteric anastomotic strictures between open cystectomy, robotic cystectomy with extracorporeal urinary diversion, and robotic cystectomy with intracorporeal urinary diversion. The effect of surgeon learning curve on stricture incidence following intracorporeal diversion was investigated as a secondary outcome. PATIENTS AND METHODS: Patients who underwent radical cystectomy at an academic hospital between 2011 and 2018 were retrospectively reviewed. The primary outcome, incidence of anastomotic stricture over time, was assessed by a multivariable Cox proportional hazards regression. A Cox regression model adjusting for sequential case number in a surgeon's experience was used to assess intracorporeal learning curve. RESULTS: Nine hundred sixty-eight patients were included: 279 open, 382 robotic extracorporeal, and 307 robotic intracorporeal. Benign stricture incidence was 11.3% overall: 26 (9.3%) after open, 43 (11.3%) after robotic extracorporeal, and 40 (13.0%) after robotic intracorporeal. An intracorporeal approach was associated with anastomotic stricture on multivariable analysis (HR 1.66; P = .05). After 75 intracorporeal cases, stricture incidence declined from 17.5% to 4.9%. Higher sequential case volume was independently associated with reduced stricture incidence (Hazard Ratio per 10 cases: 0.90; P = .02). CONCLUSION: An intracorporeal approach to urinary reconstruction following robotic radical cystectomy was associated with an increased risk of benign uretero-enteric anastomotic stricture. In surgeons' early experience with intracorporeal diversion the difference in stricture incidence was more pronounced compared to alternative approaches; however, increased intracorporeal case volume was associated with a decline in stricture incidence leading to a modest difference between the 3 surgical approaches overall.

Obesity induces limited changes to systemic and local immune profiles in treatment-naive human clear cell renal cell carcinoma.

Understanding the effects of obesity on the immune profile of renal cell carcinoma (RCC) patients is critical, given the rising use of immunotherapies to treat advanced disease and recent reports of differential cancer immunotherapy outcomes with obesity. Here, we evaluated multiple immune parameters at the genetic, soluble protein, and cellular levels in peripheral blood and renal tumors from treatment-naive clear cell RCC (ccRCC) subjects (n = 69), to better understand the effects of host obesity (Body Mass Index "BMI" ≥ 30 kg/m2) in the absence of immunotherapy. Tumor-free donors (n = 38) with or without obesity were used as controls. In our ccRCC cohort, increasing BMI was associated with decreased percentages of circulating activated PD-1+CD8+ T cells, CD14+CD16neg classical monocytes, and Foxp3+ regulatory T cells (Tregs). Only CD14+CD16neg classical monocytes and Tregs were reduced when obesity was examined as a categorical variable. Obesity did not alter the percentages of circulating IFNγ+ CD8 T cells or IFNγ+, IL-4+, or IL-17A+ CD4 T cells in ccRCC subjects. Of 38 plasma proteins analyzed, six (CCL3, IL-1ß, IL-1RA, IL-10, IL-17, and TNFα) were upregulated specifically in ccRCC subjects with obesity versus tumor-free controls with obesity. IGFBP-1 was uniquely decreased in ccRCC subjects with obesity versus non-obese ccRCC subjects. Immunogenetic profiling of ccRCC tumors revealed that 93% of examined genes were equivalently expressed and no changes in cell type scores were found in stage-matched tumors from obesity category II/III versus normal weight (BMI ≥ 35 kg/m2 versus 18.5-24.9 kg/m2, respectively) subjects. Intratumoral PLGF and VEGF-A proteins were elevated in ccRCC subjects with obesity. Thus, in ccRCC patients with localized disease, obesity is not associated with widespread detrimental alterations in systemic or intratumoral immune profiles. The effects of combined obesity and immunotherapy administration on immune parameters remains to be determined.

Neurogenic bladder monitoring using the cystomanometer and cystoelastometer.

INTRODUCTION: Patients with neurogenic bladder (NGB) require periodic urodynamics (UDS) to evaluate bladder function, which in turn helps guide management. At times, bladder decompensation or hydronephrosis may develop in patients between urodynamic testing intervals. Increased surveillance has improved outcomes in other chronic conditions (e.g., diabetes). Two novel devices, the cystomanometer (CM) and cystoelastometer (CEM), have been developed at the authors' institution to allow for home bladder pressure monitoring. The handheld CM can be attached to the end of any catheter and records the opening bladder pressure along with a time stamp. In addition, the CEM actively evacuates urine via a pump and records the urine volume evacuated. For safety, the pump slows and stops as it detects increasing resistance. Data are stored and transmitted wirelessly from both devices to a smartphone. A novel phone application stores, displays, and transmits data to a secure hospital server. OBJECTIVE: This aim of this study was to validate the function of the CM and CEM and their accuracy relative to UDS. STUDY DESIGN: Institutional review board approval was obtained. All patients with NGB managed with intermittent catheterization undergoing routine UDS were eligible for study inclusion. At the completion of UDS, the instillation port of the 6-French dual-lumen UDS catheter was connected to the CM or CEM. Bladder parameters were simultaneously recorded using the device and UDS during bladder emptying. Correlative statistics were calculated. RESULTS: A total of 36 patients (30 children/6 adults; age range from 1.2 to 38 years [median: 7.5 years]) underwent CM testing. Strong pressure correlation with UDS was identified (R2 = 0.89). A total of 42 patients (30 children/12 adults; age range of 2.9-85.2 years [median: 12.2 years]) underwent CEM testing. Again, strong pressure correlation was found (R2 = 0.77). Cystoelastometer volume measurements were highly correlated with measured volumes (Fig. 4, R2 = 0.98). DISCUSSION: Both the CM and CEM functioned well and transmitted the data wirelessly to a smartphone. The data from these devices were strongly correlated with simultaneous data from the UDS. A limitation is that these devices were used by healthcare providers, and therefore, use by patients or their parents/caregivers at home has not been demonstrated. CONCLUSION: The CM and CEM devices provide accurate bladder pressure and volume measurements. The potential for improved patient monitoring and care is promising. Reliability testing and the effects of such monitoring on patient outcomes remain to be determined.

Large Single Institution Comparison of Perioperative Outcomes and Complications of Open Radical Cystectomy, Intracorporeal Robot-Assisted Radical Cystectomy and Robotic Extracorporeal Approach.

PURPOSE: Bladder cancer management options include open radical cystectomy and robot-assisted radical cystectomy with intracorporeal or extracorporeal urinary diversion. The existing literature shows no difference in the major complication rate between open radical cystectomy and extracorporeal urinary diversion. However, the emerging popularity of intracorporeal urinary diversion has exposed the need to compare a completely intracorporeal method to alternative approaches. To our knowledge the robotic intracorporeal advantage regarding major complications has not yet been established in an evaluation of all 3 modalities. We compared outcomes and complications of open, intracorporeal and extracorporeal cystectomy techniques at a high volume institution. MATERIALS AND METHODS: We queried a prospectively maintained database for patients who underwent radical cystectomy from 2011 to 2018 for an oncologic indication. Perioperative and pathological outcomes, and 30 and 90-day major complications were assessed. Statistical analyses were done using the Pearson chi-square, Kruskal-Wallis and Kaplan-Meier tests, and multivariable regression. RESULTS: A total of 948 patients met the study criteria, including 272, 301 and 375 treated with open radical cystectomy, intracorporeal urinary diversion and extracorporeal urinary diversion, respectively. Median followup was 26 months. Intracorporeal urinary diversion cases had lower estimated blood loss (p <0.001), shorter hospitalization (p <0.001) and a lower ileus rate (p=0.023) than extracorporeal urinary diversion and open radical cystectomy cases. Importantly, intracorporeal urinary diversion was associated with lower 30 and 90-day major complication rates vs extracorporeal urinary diversion and open radical cystectomy (90-day Clavien-Dindo III-V 16.9% vs 24.8% and 26.1%, respectively, p=0.015). There was no significant difference in the readmission rate according to the surgical approach. Multivariable predictors of increased 90-day major complications were patient age, the Charlson Comorbidity Index and operative time. On multivariable analysis intracorporeal urinary diversion was associated with reduced 90-day major complications (OR 0.58, p=0.037). CONCLUSIONS: In a 3-way comparison intracorporeal urinary diversion demonstrated a lower major complication rate and perioperative benefits compared to extracorporeal urinary diversion and open radical cystectomy.

Diagnostic Accuracy of Prostate Biopsy for Detecting Cribriform Gleason Pattern 4 Carcinoma and Intraductal Carcinoma in Paired Radical Prostatectomy Specimens: Implications for Active Surveillance.

PURPOSE: Prostatic adenocarcinoma with cribriform morphology and/or intraductal carcinoma has higher recurrence and mortality rates after radiation and surgery. While the prognostic impact of these features is well studied, concordance with cribriform morphology and/or intraductal carcinoma on biopsy and prostatectomy has only recently gained attention. Our primary objective was to evaluate the diagnostic performance of biopsy to detect cribriform morphology and/or intraductal carcinoma in paired biopsy and prostatectomy specimens in a large contemporary cohort. MATERIALS AND METHODS: Patients who underwent prostate biopsy or had biopsies reviewed prior to prostatectomy at a tertiary hospital between November 2017 and November 2018 were included in study. Sensitivity and specificity were calculated to assess concordance with cribriform morphology and/or intraductal carcinoma on biopsy and prostatectomy. The association of biopsy diagnosed with cribriform morphology and/or intraductal carcinoma with adverse pathology was assessed by multivariable regression. RESULTS: Of the 455 men who underwent prostatectomy 216 (47.5%) had biopsy identified with cribriform morphology and/or intraductal carcinoma. For cribriform morphology and/or intraductal carcinoma the sensitivity and specificity of biopsy was 56.5% and 87.2%, respectively. In men eligible for active surveillance sensitivity was 34.1% and specificity was 88.1%. Magnetic resonance imaging targeted biopsies did not improve sensitivity (53.5%). Cribriform morphology and/or intraductal carcinoma identified on prostatectomy correlated with adverse pathological findings. However, compared to cribriform morphology and/or intraductal carcinoma negative biopsies, biopsies identified with cribriform morphology and/or intraductal carcinoma were not independently associated with adverse pathology. This was likely due to biopsy low sensitivity. CONCLUSIONS: In this cohort biopsy was not sensitive for detecting cribriform morphology and/or intraductal carcinoma and this was not improved by magnetic resonance imaging fusion. However, specificity was high, suggesting that when present on biopsy, cribriform morphology and/or intraductal carcinoma may be considered in treatment planning algorithms.

Multi-Institution Evaluation of Sequential Gemcitabine and Docetaxel as Rescue Therapy for Nonmuscle Invasive Bladder Cancer.

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.

The Role of Imaging in the Diagnosis, Staging, Response to Treatment, and Surveillance of Patients with Germ Cell Tumors of the Testis.

Germ cell tumors (GCTs) of the testis are cured with the successful integration of surgery, chemotherapy, and/or radiation therapy in most cases. The favorable results are a consequence of improved risk stratification, risk-adapted chemotherapy, reduced morbidity of treatment, and appropriate integration of multimodal therapy. The success of these approaches depends on accurate staging with imaging studies of the testis, retroperitoneum, and thorax. This article reviews the indications for imaging and performance characteristics of modalities in the diagnosis, staging, surveillance, and follow-up of patients with GCTs. We also highlight the current guideline recommendations for imaging in treatment of patients with GCTs.

Combination Intravesical Chemotherapy for Non-muscle-invasive Bladder Cancer.

Bacillus Calmette-Guérin (BCG) replaced early intravesical chemotherapeutic agents as the standard of care for non-muscle-invasive bladder cancer (NMIBC) with its US Food and Drug Administration approval in 1990. Multiple studies have proven the superiority of BCG to surgery alone, and to older single-agent intravesical chemotherapy regimens. However, new multiagent intravesical chemotherapy regimens have been developed and tested in recent years. Such regimens offer the possibility of better efficacy and/or tolerability compared to BCG. However, high-quality data comparing such regimens to BCG remain scant. We briefly review the literature regarding combination intravesical chemotherapy for NMIBC.

Quadruple immunotherapy of Bacillus Calmette-Guérin, interferon, interleukin-2, and granulocyte-macrophage colony-stimulating factor as salvage therapy for non-muscle-invasive bladder cancer.

BACKGROUND: Bacillus Calmette-Guérin (BCG) is the most effective initial intravesical therapy for high-grade non-muscle invasive bladder cancer, but many patients still fail. Combination intravesical BCG and interferon (IFN) will salvage some patients but results remain suboptimal. OBJECTIVE: We hypothesized that further immunostimulation with intravesical interleukin-2 and subcutaneous granulocyte-macrophage colony-stimulating factor may improve response to intravesical BCG and IFN in patient with prior BCG failure(s). METHODS: A retrospective review was performed. Patients received 6 treatments of quadruple immunotherapy (intravesical solution with one-third dose BCG, 50 million units IFN, and 22 million units interleukin-2, along with a 250-mcg subcutaneous sargramostim injection). Surveillance began 4 to 6 weeks after treatment completion. Patients received maintenance if recurrence-free. Success was defined as no recurrence (bladder or extravesical) and bladder preservation. Analysis was performed by Kaplan-Meier method (P<0.05). RESULTS: Fifty-two patients received treatment with a median recurrence follow-up of 16.3 months and overall follow-up of 41.8 months. All patients had at least 1 prior BCG failure and 13% had 2 or more prior failures. Only 3 patients (6%) were unable to tolerate full induction. Treatment success was 55% at 1 year, and 53% at 2 years. Thirteen patients (25%) underwent cystectomy at a median time of 17.3 months with disease progression to T2 in 1 patient and T3 in 2 patients. No patients had positive surgical margins or positive lymph nodes. CONCLUSIONS: In patients with non-muscle-invasive bladder cancer with prior BCG failure, quadruple immunotherapy demonstrated good treatment success in some patients and warrants further evaluation.

Obesity as defined by waist circumference but not body mass index is associated with higher renal mass complexity.

OBJECTIVES: Obesity, typically defined as a body mass index (BMI)≥30kg/m2, is an established risk factor for renal cell carcinoma (RCC) but is paradoxically linked to less advanced disease at diagnosis and improved outcomes. However, BMI has inherent flaws, and alternate obesity-defining metrics that emphasize abdominal fat are available. We investigated 3 obesity-defining metrics, to better examine the associations of abdominal fat vs. generalized obesity with renal tumor stage, grade, or R.E.N.A.L. nephrometry score. METHODS AND MATERIALS: In a prospective cohort of 99 subjects with renal masses undergoing resection and no evidence of metastatic disease, obesity was assessed using 3 metrics: body mass index (BMI), radiographic waist circumference (WC), and retrorenal fat (RRF) pad distance. R.E.N.A.L. nephrometry scores were calculated based on preoperative CT or MRI. Univariate and multivariate analyses were performed to identify associations between obesity metrics and nephrometry score, tumor grade, and tumor stage. RESULTS: In the 99 subjects, surgery was partial nephrectomy in 51 and radical nephrectomy in 48. Pathology showed benign masses in 11 and RCC in 88 (of which 20 had stage T3 disease). WC was positively correlated with nephrometry score, even after controlling for age, sex, race, and diabetes status (P = 0.02), whereas BMI and RRF were not (P = 0.13, and P = 0.57, respectively). WC in stage T2/T3 subjects was higher than in subjects with benign masses (P = 0.03). In contrast, subjects with Fuhrman grade 1 and 2 tumors had higher BMI (P<0.01) and WC (P = 0.04) than subjects with grade 3 and 4 tumors. CONCLUSIONS: Our data suggest that obesity measured by WC, but not BMI or RRF, is associated with increased renal mass complexity. Tumor Fuhrman grade exhibited a different trend, with both high WC and BMI associated with lower-grade tumors. Our findings indicate that WC and BMI are not interchangeable obesity metrics. Further evaluation of RCC-specific outcomes using WC vs. BMI is warranted to better understand the complex relationship between general vs. abdominal obesity and RCC characteristics.

Bacillus Calmette-Guerin strain may not effect recurrence-free survival when used intravesically with interferon-alpha2b for non-muscle-invasive bladder cancer.

OBJECTIVES: Adjuvant intravesical Bacillus Calmette-Guerin (BCG) remains the standard-of-care for high-grade non-muscle-invasive bladder cancer (NMIBC). Conflicting reports exist regarding disparate outcomes among BCG strains. We sought to determine whether a difference in recurrence-free survival (RFS) existed between TICE BCG and Connaught BCG strains used with interferon (IFN) for the treatment of NMBIC. MATERIALS AND METHODS: A post hoc analysis of the phase 2 BCG/IFN study, conducted from May 1999 to February 2001. A total of 901 patients had sufficient records for analysis. Enrollment criteria were liberal and included primary and recurrent NMIBC, patients with and without carcinoma in situ, and patients with prior BCG failure. At the beginning, 3 to 8 weeks after transurethral resection or biopsy, patients received induction with 6 weekly intravesical treatments of BCG (TICE or Connaught) with 50 million units of IFN. Surveillance for recurrence began 4 to 6 weeks after induction and quarterly thereafter for 2 years. If no recurrence was identified, patients received maintenance therapy. Separate models were created for BCG naïve and failure patients. Multivariable analysis was performed using Cox proportional hazards regression. RESULTS: Overall, 609 patients received TICE BCG and 292 received Connaught BCG with similar baseline characteristics. BCG strain was not associated with worse RFS in both the multivariable BCG naïve model (P = 0.28) and BCG failure model (P = 0.53). Duration of disease, tumor focality, tumor size, and BCG failure interval (in the BCG failure model) were associated with worse RFS. CONCLUSION: No significant difference in RFS was observed among patients treated with TICE BCG or Connaught BCG in combination with IFN.

Bacillus Calmette-Guérin (BCG) Treatment Failures with Non-Muscle Invasive Bladder Cancer: A Data-Driven Definition for BCG Unresponsive Disease.

Objective: To create the first data-driven definition for those unlikely to benefit from further BCG treatment. Materials and Methods: The database created for the Phase 2 BCG-Interferon-α 2B (IFN) study was queried and BCG failure patients were identified (n = 334). Full study protocols have previously been published. Separate models were constructed for analysis of patients with any CIS (pure or concomitant) and pure papillary disease. Variables considered included age, gender, stage, grade, tumor size and focality (for papillary only), number of prior BCG courses, and prior BCG failure interval. Results: Patients with recurrent CIS within 6 months of their most recent prior BCG course (HR 2.56, p <  0.01) and ≥2 prior BCG failures (HR 1.54, p <  0.01) responded worst to repeat intravesical therapy. Those with CIS recurrence at 6-12 months did not differ from those recurring within 6 months (HR = 0.88, p = 0.71). Patients with recurrent papillary disease within 6 months (HR 1.82, p = 0.02), ≥2 BCG failures (HR 1.54, p = 0.03), and multifocal disease (HR 2.05, p <  0.01) responded worst to therapy. Patients with T1 disease remained disease free in 38% of cases (24-51% 95% CI) at 2 years with low rates of progression. Conclusions: Patients who fail two courses of BCG with either persistent or recurrent multifocal papillary disease within 6 months or CIS within 12 months of their prior BCG should be considered BCG unresponsive. Recurrent T1 disease respond reasonably well to another course with low progression rates but further investigation is warranted.

Experience with Sequential Intravesical Gemcitabine and Docetaxel as Salvage Therapy for Non-Muscle Invasive Bladder Cancer.

Patients with high-grade muscle invasive bladder cancer (NMIBC) receive intravesical therapy with bacillus Calmette-Guérin (BCG) as the well-established standard-of-care. However, even with prompt induction of intravesical therapy, approximately 40 % of patients will recur within 2 years. For patients who fail BCG, options include radical cystectomy, repeat BCG therapy, or alternative intravesical salvage therapy. In this review, we will discuss the most recent published evidence on salvage intravesical therapy with an emphasis on a more in-depth report of our therapeutic strategy with sequential gemcitabine and docetaxel intravesical therapy for this treatment-refractory population. In addition, we will provide practical advice on our approach to this challenging patient population including the use of operative staging to aid early identification of treatment failures.

Intravesical and alternative bladder-preservation therapies in the management of non-muscle-invasive bladder cancer unresponsive to bacillus Calmette-Guérin.

Intravesical Bacillus Calmette-Guérin (BCG) remains the standard of care in the treatment of bladder carcinoma in situ and as adjuvant therapy after thorough transurethral resection of high-grade non-muscle-invasive bladder cancer. Despite BCG therapy, in up to 40% of patients it would recur and 60% to 70% of those would fail repeat BCG induction be deemed BCG unresponsive. For such patients, cystectomy remains the preferred treatment option per the American Urological Association and European Association of Urology, though some patients would be medically unfit or refuse radical surgery. Further intravesical therapy for bladder-preservation therapies may preserve quality of life in these patients and in some cases can be curative. There are numerous non-BCG intravesical salvage options available, including immunotherapy, single-agent chemotherapy, combination chemotherapy, and device-assisted chemotherapy. In addition, investigation of radiation-based treatment and other novel therapies including checkpoint inhibitors (programmed death-1/programmed death ligand-1), are currently underway. In this review, we examine the current status of alternatives to BCG in salvage therapy for bladder preservation.

Bacillus Calmette-Guérin (BCG) Treatment Failures in Non-Muscle Invasive Bladder Cancer: What Truly Constitutes Unresponsive Disease.

Bacillus Calmette-Guérin (BCG) remains the most effective intravesical therapy for non-muscle invasive bladder cancer but will fail in up to 40% of patients. The ability to identify patients who are least likely to respond to further BCG therapy allows urologists to pursue secondary treatments more likely to convey a recurrence or survival benefit to the patient. We examined the literature to determine what constitutes BCG unresponsive disease. After review, we believe that BCG unresponsive disease should be defined as (1) patients with recurrent high grade T1 disease within 6 months of their primary tumor after at least one course of BCG or patients who have failed at least 2 courses of BCG with either (2) persistent or recurrent pure papillary (Ta) disease within 6 months or (3) persistent or recurrent carcinoma in situ (CIS) within 12 months.

Sequential Intravesical Gemcitabine and Docetaxel for the Salvage Treatment of Non-Muscle Invasive Bladder Cancer.

BACKGROUND: Bacillus Calmette-Guerin (BCG) is the most effective intravesical therapy for non-muscle invasive bladder cancer (NMIBC), but patients can fail or supply shortages can develop. For BCG failures, radical cystectomy is recommended. However, in patients who desire bladder preservation or are poor surgical candidates, alternative salvage intravesical therapies should be explored. OBJECTIVE: To determine whether dual sequential intravesical gemcitabine and docetaxel is effective in treating NMIBC. METHODS: We evaluated our initial experience with 45 patients treated with intravesical gemcitabine and docetaxel between June 2009 and May 2014. Patients were treated with 6 weekly instillations of gemcitabine (1 gram of gemcitabine in 50 ml of sterile water) followed immediately by docetaxel (37.5 mg of docetaxel in 50 mL of saline). Treatment success was defined as no bladder cancer recurrence and no cystectomy. Intention-to-treat analysis was performed using the Kaplan Meier method. RESULTS: Forty-five patients received treatment with a median overall follow-up of 15 months. Median follow up for treatment success was 6 months in all patients and 13 months for responders. Five patients were unable to tolerate a full induction course. Treatment success was 66% at first surveillance, 54% at 1 year, and 34% at 2 years after initiating induction. Ten patients received cystectomy (median of 5.6 months from starting induction) with no positive margins or lymph nodes on final pathology. CONCLUSIONS: Sequential dual intravesical gemcitabine and docetaxel can salvage some patients in a challenging NMIBC cohort.