Refractory Non-muscle Invasive Bladder Cancer Research Articles

Adverse effects and discontinuation of pembrolizumab in BCG refractory non-muscle invasive bladder cancer.

588 Background: Non-muscle invasive bladder cancer (NMIBC) is associated with high rates of recurrence and progression despite adequate intravesical treatment with Bacillus Calmette-Guerin (BCG). Pembrolizumab was found to be effective in treating BCG-refractory NMIBC in the KEYNOTE-057 trial with a 41% complete response after 3 months and minimal adverse effects. As a result it was approved by the FDA on January, 2020, for the treatment of high risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumors in patients ineligible for or unwilling to undergo cystectomy. This study reports a single institution’s experience using pembrolizumab in BCG refractory patients with high-risk NMIBC. Methods: Records of NMIBC patients who commenced treatment with pembrolizumab between January 2020 and January 2023 at a single institution were retrospectively reviewed. Demographic and clinicopathologic information was collected. Kaplan-Meier curves were generated to calculate progression-free survival (PFS), and treatment-specific survival (TSS). The combined positive score (CPS) of PD-L1 was assessed for each case treated by pembrolizumab. Results: Out of 250 patients with NMIBC who were screened for the study, 18 met the inclusion criteria. The median age was 74.1 years (IQR=67.8 – 81.4), male to female ratio of 3.5:1. The median follow-up time was 17.5 months (IQR= 8.1–22.5). A previous history of CIS was present in all patients as well as second-line chemotherapy for BCG refractory disease. At the start of pembrolizumab, stage distribution was as follows: 1 (5.6%) cTa, 6 (33.3%) had CIS, and 11 (61.1%) cT1. After an average of 8.9 cycles, 72.2% (13/18) stopped treatment. 27.8% (5/18) are still undergoing treatment, with an average of 12.6 cycles (SD=10.4). 1 out of the 13 patients who stopped treatment had a complete response. The remaining reasons for termination of treatment are Grade 2 or higher immune-related adverse events in 53.8% (7/13), progression in 30.8% (4/13), and recurrence in 7.7% (1/13). Four patients ultimately required radical cystectomy which revealed 1 pTa, 1 pTis, 1 pT1, and 1 pT4. Only 1 patient had CPS of PD-L1 > 10. Conclusions: There were higher rates of toxicity from pembrolizumab for the treatment of BCG-refractory NMIBC than expected. More research is needed to better define the patients who are likely to benefit from this treatment. Pembrolizumab for BCG refractory NMIBC can have high rates of Grade 2 or higher adverse events leading to early withdrawal from treatment. Early discussion about radical surgery remains an important part of the treatment guidelines for BCG refractory NMIBC.

Interview: Timothy Clinton

Interview: Timothy Clinton

Peripheral tuberculin purified protein derivative specific T cell immunoreactivity dynamics in non-muscle invasive bladder cancer patients receiving bacillus Calmette-Guerin instillation treatment.

Intravesical bacillus Calmette-Guerin (BCG) instillation is recommended as an adjuvant therapy for intermediate-risk and high-risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBt) with nearly 70% reoccurrence. In the present study, we investigated the dynamics of peripheral purified protein derivative (PPD)-specific immune responses along the treatment. Intravesical BCG instillation caused a significant increase in peripheral PPD-specific IFN-γ release of NMIBC patients, when compared to those receiving chemo-drug instillation. Through a follow-up study, we detected rapid increase in PPD-specific IFN-γ, IL-2, and IL-17A producing CD4+ and CD8+ T cells in the induction phase. Interestingly, the frequencies of PPD-specific IFN-γ and IL-2 producing CD4+ and CD8+ T cells decreased dramatically after induction treatment and were restored after BCG re-instillation, whereas IL-17A-producing T cells remained at the maintenance phase. However, we only observed that the percentages of peripheral CD8+ T cells were significantly higher in BCG responder patients than those in BCG refractory patients at the baseline with the potential of predicting the recurrence. A more dramatic increase in PPD-specific IFN-γ and IL-2 producing CD4+ and CD8+ T cells after one and two dose BCG instillations was observed in refractory NMIBC patients. Therefore, regional BCG instillation induced transient peripheral PPD-specific T cell responses, which could be restored through repetitive BCG instillation. Higher proportions of peripheral CD8+ T cells at baseline were associated with better responses to BCG instillation for the prevention of recurrence of bladder cancer.

Extraperitoneal cystectomy with ureterocutaneostomy derivation in fragile patients - should it be performed more often?

Radical cystectomy (RC) continues to be standard of care for muscle-invasive bladder cancer and recurrent or refractory nonmuscle invasive bladder cancer. Unfortunately, it has high rates of perioperative morbidity and mortality. One of the most important predictors of postoperative outcomes is frailty, while the majority of complications are diversion related. The aim of our study was to evaluate safety of extraperitoneal cystectomy with ureterocutaneostomy in patients considered as frail. We retrospectively collected data of frail patients who underwent extraperitoneal cystectomy with ureterocutaneostomy from October 2018 to August 2020 in a single center. We evaluated frailty by assessing patients' age, body mass index (BMI), nutritional status by Malnutrition Universal Screening Tool, overall health by RAI (Risk Analysis Index) and ASA (American Society of Anaesthesiologists) score, and laboratory analyses. We observed intraoperative outcomes and rates of perioperative (within 30 days) and early postoperative (within 90 days) complications (Clavien-Dindo classification). We defined extraperitoneal cystectomy with ureterocutaneostomy as safe if patients did not develop Clavien Dindo IIIb, or worse, complication. A total of 34 patients, 3 female and 31 male, were analyzed. The median age was 77, BMI 26, RAI 28, ASA 3 and the majority had preexisting renal insufficiency. Blood analyses revealed presence of severe preoperative hypoalbuminemia and anemia in half of our cohort. Intraoperative median blood loss was 250 cc, whilst operative time 245 min. During perioperative period 60% of our cohort developed Clavien Dindo II complication and during early postoperative period 32% of patients required readmission. One death occurred during early postoperative period (2.9%). After 12 months of follow-up, we observed stability of the renal function for most patients. We believe that extraperitoneal cystectomy with ureterocutaneostomy could be considered as a treatment option for elderly and/or frail patients.

Simultaneous laparoscopic nephroureterectomy and robot-assisted anterior pelvic exenteration with intracorporeal ileal conduit urinary diversion: step-by-step video-illustrated technique

ABSTRACTIntroduction:One of the most remarkable characteristics of urothelial carcinomas is multifocality. However, occurrence of synchronous bladder cancer and upper urinary tract urothelial cancer (UTUC) is exceptional. Minimally invasive approach for these synchronous tumors was just occasionally reported (1-4). The aim of this video article is to describe step-by-step the technique for simultaneous laparoscopic nephroureterectomy and robot-assisted anterior pelvic exenteration with intracorporeal ileal conduit urinary diversion (ICUD). Patients and methods: A 66-year-old female presented with synchronous BCG refractory non-muscle invasive bladder cancer and a right-side UTUC. She was a former smoker and had previously been submitted to multiple transurethral resections of bladder tumor, BCG and right distal ureterectomy with ureteral reimplant. We performed a simultaneous laparoscopic right nephroureterectomy and robot-assisted anterior pelvic exenteration with totally intracorporeal ICUD. Combination of robot-assisted and pure laparoscopic approaches was proposed focusing on optimization of total operative time (TOT).Results:Surgery was uneventful. TOT was of 330 minutes. Operative time for nephroureterectomy, anterior pelvic exenteration and ICUD were 48, 135, 87 minutes, respectively. Estimated blood loss was 150mL. Postoperative course was unremarkable and patient was discharged after 7 days.Histopathological evaluation showed a pT1 high grade urothelial carcinoma plus carcinoma in situ both in proximal right ureter and bladder, with negative margins. Twelve lymph nodes were excised, all of them negative.Conclusion:In our preliminary experience, totally minimally invasive simultaneous nephroureterectomy and cystectomy with intracorporeal ICUD is feasible. Pure laparoscopic approach to upper urinary tract may be a useful tactic to reduce total operative time.

Urothelial Carcinoma in The Era of Immune Checkpoint Inhibitors

Bladder cancer is the seventh most frequent cancer worldwide. The majority of patients present with nonmuscle invasive disease, while 20% of the patients are diagnosed with muscle-invasive bladder cancer. The treatment of nonmuscle invasive disease is endoscopic resection followed by intravesical adjuvant treatment for high risk patients. The standard treatment of localized muscle-invasive disease is neoadjuvant chemotherapy followed by radical cystectomy. Platinum-based chemotherapy is the first-line treatment in locally advanced or metastatic urothelial carcinoma. Immune checkpoint inhibitors have been approved for the treatment of metastatic urothelial carcinoma as second-line treatment or first-line in platinum-ineligible patients. Recently, pembrolizumab have been approved in bacillus Calmette-Guérin (BCG)-refractory nonmuscle invasive bladder cancer. This review summarizes the current evidence concerning immunotherapy in the treatment of urothelial carcinoma.

Peripheral Purified Protein Derivate Specific T Cell Immunoreactivity Dynamics in Non-Muscle Invasive Bladder Cancer Patients Receiving Bacillus Calmette-Guerin Instillation Treatment

Background : Intravesical Bacillus Calmette-Guerin (BCG) instillation is recommended as an adjuvant therapy for intermediate-risk and high-risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBt). The aim of this study was to investigate peripheral immune responses induced by intravesical BCG instillation and to figure out the putative indicators for predicting the recurrence of NMIBC. Methods: Thirty-six NMIBC patients receiving BCG instillation were recruited in the study among which 19 patients were followed up from the start of the instillation. Whole blood was collected before BCG instillation. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with purified protein derivate (PPD) in vitro. PPD-specific cellular responses were evaluated by an IFN-γ releasing assay. Cytokines-secreting CD4+ and CD8+ T cells were detected by flow cytometry. Findings: Intravesical BCG instillation evoked a dramatic increase in IFN-γ producing spot-forming units (SFUs) in PBMCs upon PPD stimulation when compared to those without BCG instillation, together with higher percentages of IFN-γ, IL-2 and IL-17A producing T cells in the periphery. In the follow-up study, IFN-γ producing SFUs elevated rapid after one instillation of BCG and maintained later. However, PPD-specific cytokine producing CCD4+ and CD8+ T cells reached the plateau after two times of BCG instillation. Interestingly, the frequencies of PPD-specific cytokine secreting CD4+ and CD8+ T cells decreased dramatically after induction treatment and restored after BCG re-instillation except IL-17A at the maintenance phase. Of note, more dramatic increase in PPD-specific IFN-γ and IL-2 releasing CCD4+ and CD8+ T cells after one and two BCG instillations was observed in refractory NMIBC patients. Interpretation: Regional BCG instillation can induce peripheral PPD-specific immune responses whereas attenuated after the termination of the instillation. The rapid and transient increase in peripheral PPD-specific Th1-type cytokine producing T cells, however, might be unfavorable indicators associated with the refractory of NMIBC. Funding Information: This work was supported by grants from Chinese National Mega Science and Technology Program on Infectious Diseases (2018ZX10731301-001-004, 2018ZX10302301-002-002 and 2013ZX10003007-003-003) and Shanghai Academic Research Leader Project (18XD1403300). Declaration of Interests: The authors report no conflict of interest. Ethics Approval Statement: All the patients have signed the informed consent forms. The study was approved by the Ethical Committee of Xinhua Hospital. The procedures performed in this study were in accordance with the 1964 Helsinki declaration.

A potential new therapeutic option for the treatment of nonmuscle invasive bladder cancer: Combination of intravesical oncotherad immunotherapy and platelet rich plasma (PRP).

461 Background: Effective intravesical therapies remain lacking for non-muscle invasive bladder cancer (NMIBC) when Bacillus Calmette-Guerin fails. OncoTherad is a nanostructured inorganic phosphate complex associated with glycosidic protein, developed by the University of Campinas/Brazil, which triggers immunomodulatory and antitumor activities. Previous studies have shown that Platelet Rich Plasma (PRP) acts on immune activation and exerts antitumor effects. This study characterized the effects of the OncoTherad associated with PRP in the treatment of NMIBC chemically induced in mice and the modulation promoted in the Toll-like receptors (TLRs) signaling pathway. Methods: Forty-two C57BL/6J mice were divided into groups: Control; Cancer (N-ethyl-N-nitrosourea carcinogen, 50 mg/ml); PRP (0.1 ml); OncoTherad (20 mg/ml); OncoTherad+PRP 10 mg/ml and OncoTherad+PRP 20 mg/ml. The intravesical doses (0.1 ml) were instilled once a week for 6 weeks after induction. Results: The NMIBC induction decreases (p<0.05) body weight, although after treatments the body weight was recovered similarly to the healthy mice. The treatments did not significantly alter the biochemical patterns of the urine and food and water consumption. There was no acute toxicity or kidney damage, and the presence of hydroureter was variable. The urinary bladders of mice treated with Oncotherad associated or not with PRP showed hyperemia associated with the inflammatory condition. The thickening of the urinary bladder wall in the Cancer group was more evident than in the treated groups, in which there were bladders without thickening or macroscopic lesions. Flat carcinoma in situ (pTis) was present in 100% of the mice in the Cancer group and the intensity of immunoreactivities for TLR2, IL-6, TLR4, and IRF-3 was significantly weaker in comparison with the Control, indicating suppression of the immune system in the tumor microenvironment. When treated intravesically with PRP only, mice showed 28.6% of tumor progression inhibition rate; with OncoTherad 85.7% and with OncoTherad+PRP 10 mg/ml or 20 mg/ml 71.4%. Intravesical treatments led to distinct activation of TLRs 2 and 4-mediated innate immune system in the interleukins (MyD88-dependent) and interferons (TRIF-dependent) signaling pathways. The combined treatment of OncoTherad+PRP increased (p<0.05) the percentage of positive TLR4 urothelial cells and the intensity of immunoreaction for TLR4 compared to the isolated treatments and the immunoreactivities of NF-kB, IL-6, TLR4, IRF-3, and IFN-γ in comparison to the Cancer. Conclusions: Intravesical treatment with OncoTherad plus PRP promoted significant inhibition of tumor progression, possibly due to immunomodulatory activity involving the TLR pathway. This association can constitute a therapeutic strategy for refractory NMIBC patients.

Impact of Perioperative Immunonutrition on Complications in Patients Undergoing Radical Cystectomy: A Retrospective Analysis.

Introduction:Radical cystectomy (RC) is the gold standard treatment for patients with muscle-invasive or refractory non-muscle invasive bladder cancer. It is estimated that approximately 64% and 13% of RC patients experience any complication and major complications, respectively. Specialized immunonutrition (SIM) aims to reduce the rates of complications after RC. We reported surgical complication rates in RC patients who received (SIM group) versus who did not receive (no-SIM group) perioperative SIM. Moreover, we investigated factors associated with complications after RC.Material and Methods:This is a retrospective cohort study of 52 patients who underwent RC between April 2016 and December 2017. Overall, 26 (50%) patients received perioperative SIM. We recorded age, gender, Charlson Comorbidity Index (CCI), body mass index (BMI), Malnutrition Universal Screening Tool (MUST) score, unintentional weight loss (UWL), SIM drinks consume, surgical approach, urinary diversion, neoadjuvant chemotherapy (NAC), use of total parenteral nutrition (TPN), final pathology, length of stay (LOS), and complications.Results:SIM was associated with higher rates of documented infections (P = .03). Conversely, post-operative ileus was associated with higher rates of overall infections (P = .03). Median LOS was comparable within the 2 groups. Overall, 4 (15.38%) versus 0 (0%) patients in SIM versus no-SIM group were readmitted to hospital (P = .03). Age, CCI, NAC, and TPN were not associated with complication rates.Conclusions:SIM is not associated with lower rates of post-operative complications in RC candidates. Moreover, higher rates of documented infections were observed in the SIM group. Patients with post-operative ileus experienced more infections. Age, CCI, NAC, and TPN were not predictive of complications.

Preclinical evaluation of a hypotonic docetaxel nanosuspension formulation for intravesical treatment of non-muscle-invasive bladder cancer.

Intravesical chemotherapy is a key approach for treating refractory non-muscle-invasive bladder cancer (NMIBC). However, the effectiveness of intravesical chemotherapy is limited by bladder tissue penetration and retention. Here, we describe the development of a docetaxel nanosuspension that, when paired with a low osmolality (hypotonic) vehicle, demonstrates increased uptake by the bladder urothelium with minimal systemic exposure. We compare the bladder residence time and efficacy in an immune-competent rat model of NMIBC to the clinical comparator, solubilized docetaxel (generic Taxotere) diluted for intravesical administration. We found that only the intravesical docetaxel nanosuspension significantly decreased cell proliferation compared to untreated tumor tissues. The results presented here suggest that the combination of nanoparticle-based chemotherapy and a hypotonic vehicle can provide more efficacious local drug delivery to bladder tissue for improved treatment of refractory NMIBC.

Current status and future directions of the use of novel immunotherapeutic agents in bladder cancer

To report the available information on the current status and future direction of the use of checkpoint inhibitors as novel immunotherapeutic agents in bladder cancer. In the past 3 years, five immunotherapies targeting programmed cell death 1 (Pembrolizumab and Durvalumab) or programmed cell death-ligand 1 (PD-L1) (Atezolizumab, nivolumab and Avelumab) pathways have been approved in second-line setting for patients who progressed during or after cisplatin-based chemotherapy. According to the most recent update, these patients should be PD-L1-positive to be eligible for immunotherapy. The use of novel checkpoint inhibitors was also very promising in other settings: Metastatic urothelial carcinoma without prior systemic treatment (IMvigor-130), as neoadjuvant treatment before radical cystectomy in patients with muscle invasive disease (PURE-01), and in Bacillus Calmette-Guérin (BCG) refractory nonmuscle invasive bladder cancer (KEYNOTE 057). Ongoing trials on the role of checkpoint inhibitors in bladder cancer may change our approach to different stages of bladder cancer. For metastatic urothelial carcinoma, the role of combined immune and chemotherapy may improve survival. For localized bladder cancer, immunotherapy as neoadjuvant therapy may be associated with less toxicity and better tolerability. Finally, in the setting of a BCG-refractory or BCG-naïve nonmuscle invasive disease checkpoint inhibitors may reduce/delay the risk of progression and subsequent cystectomy.

MP73-08 INTRAVESICAL GEMCITABINE AND DOCETAXOL IN HEAVILY PRE-TREATED PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC)

You have accessJournal of UrologyBladder Cancer: Non-invasive IV (MP73)1 Apr 2020MP73-08 INTRAVESICAL GEMCITABINE AND DOCETAXOL IN HEAVILY PRE-TREATED PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) Adele Caruso*, Roshan Ravishankar, Keith VanArsdalen, and Stanley Malkowicz Adele Caruso*Adele Caruso* More articles by this author , Roshan RavishankarRoshan Ravishankar More articles by this author , Keith VanArsdalenKeith VanArsdalen More articles by this author , and Stanley MalkowiczStanley Malkowicz More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000959.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Therapeutic options are limited for BCG resistant/ refractory NMIBC patients who are unfit or refuse radical cystectomy. Combination chemotherapy is not regularly used due to additive toxicity. The non-desiccant properties of Gemcitabine allow for combined therapy not previously employed. Docetaxol as a single agent demonstrates significant activity with acceptable toxicity. The objective of this study was to evaluate combination intravesical chemotherapy for its initial response and therapeutic durability in those patients heavily pre-treated with BCG. METHODS: Patients who had failed or were intolerant to BCG therapy were offered combination intravesical therapy per the following regimen 1000 mg of GEM in 100 cc’s of saline instilled for two hours followed by bladder emptying and reinstallation of 37.5 mg DOC in 50 mls saline. This was done weekly for 6 weeks. At twelve weeks patients underwent cystoscopy with full bladder mapping and cytology. Cystoscopy was performed every 3 months for one year and at 3 months or 6 months thereafter. Further biopsiy or resection was performed for positive cytology, distinct recurrent tumor or suspicious areas on cystoscopy. Failure was defined as positive cytology, tumor recurrence or distant failure. RESULTS: Between 12/2015 and 6/2019, thirty patients were recruited. 26 are eligible for evaluation and had a mean of 3.2 prior induction courses of intravesical therapy. There were 20 men and 6 women with a mean age of 77 (range 68-94). Twenty four of 26 patients demonstrated an initial negative evaluation. 16/26 patients recurred during this time period with a mean disease free interval of 12.45 months (range 3-34 months). Ten patients are NED for a mean of 9.6 months (range 3-15 months) 11 failures were local (2 muscle invasive progression), 4 cytology only, 1 pelvic lymph node progression. The regimen was well tolerated per patient complaints and AUA voiding scores. CONCLUSIONS: Sequential, combination Gemcitabine and Docetaxol intravesical chemotherapy is an active regimen in BCG pretreated patients who are unfit or unwilling to undergo cystectomy. A near universal initial response with a complete response maintained for over one year in responders suggests a role for maintenance therapy and supports continued study of this intravesical regimen. Source of Funding: NONE © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1124-e1124 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Adele Caruso* More articles by this author Roshan Ravishankar More articles by this author Keith VanArsdalen More articles by this author Stanley Malkowicz More articles by this author Expand All Advertisement PDF downloadLoading ...

461. The Testing Strategy to Determine the Pharmacological Activity of Gene Therapy Drug Product (rAd-IFN) to Treat Intravesical Non-Muscle Invasive Bladder Cancer

rAd-IFN is a recombinant adenoviral gene therapy vector encoding IFNα2b gene for the treatment of refractory non-muscle invasive bladder cancer. The vector transduces bladder wall cells where IFNα2b gene is expressed leading to death of cancer cells. The advanced testing strategy to determine the pharmacological activity of rAd-IFN drug product involves three key assays: 1. Infectious titer of the virus, quantitative assay 2. Expression of the transgene (IFNα2b), semiquantitative assay 3. Potency (IFNα2b mediated cell killing), quantitative assay The infectivity and transgene expression assays have been performed for batch release and stability monitoring of activity during Phase 2 and will remain unchanged in principle for Phase 3 and commercial use. In the infectivity assay the cells supporting adenovirus replication are infected with three concentrations of adenovirus and left to produce the virus for two days. The percentage of infected cells is then determined with a flow cytometer utilizing a fluorescently conjugated antibody against an adenoviral structural protein. Samples are analysed in parallel with a reference standard and infectivity is given as relative Infectious Units / ml. In expression assay, the IFNα expression capability of the virus preparation is determined by infecting IFN insensitive cells with the rAd-IFN virus and the concentration of produced IFNα is measured with a commercial IFNα ELISA (enzyme-linked immunosorbent assay) from cell culture supernatants For Phase 3 a new potency assay is developed and added to release and stability testing in order to provide evidence that batches of rAd-IFN are able to produce active IFNα2b which has a relevant pharmacological effect. In this assay cells are transduced using multiple dilutions of reference standard and test samples leading to expression of IFNα2b and subsequent cell death. Cell killing efficiency is determined using colorimetric method measuring dehydrogenase activity of the living cells. Relative potency of test sample is determined against reference standard response curve after testing parallelism by equivalence test. All activity assays will be fully validated according to ICH Q2 (R1) prior to release testing of Phase 3 clinical study material (Accuracy, Precision, Specificity, Linearity and Range, System Suitability and Robustness). The three validated assays will provide enhanced quantitative measure of biologic function of the rAd-IFN vector and thus demonstrate the quality and efficacy of drug product batches.

Valrubicin in refractory non-muscle invasive bladder cancer

The most effective intravesical regimen for the treatment of non-muscle invasive bladder cancer (NMIBC) refractory to Bacillus Calmette–Guérin (BCG) has still not been identified or optimized to minimize recurrence-free survival and prevent progression reliably and consistently. Valrubicin, however, is a cytotoxic chemotherapeutic agent that is used as an intravesical agent for BCG-refractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality. Here we analyze the literature regarding the treatment of non-muscle invasive urothelial malignancies with intravesical valrubicin for refractory bladder cancer, present our opinion on its current clinical impact and speculate on how its utilization will evolve in the near future.

Comparative study of sequential intravesical chemotherapy using gemcitabine and mitomycin C with mitomycin C alone for non-muscle invasive bladder carcinoma- a randomized trial

Meeting abstracts This study was conducted to investigate the ablative efficacy and safety of sequential intravesical gemcitabine and mitomycin C with mitomycin C alone in refractory non-muscle invasive bladder cancer (NMIBC). A total of 219 patients with refractory NMIBC were prospectively

A phase I/II multi-center study of intravesical nanoparticle albumin-bound rapamycin (ABI-009) in the treatment of BCG refractory non-muscle invasive bladder cancer.

TPS4576 Background: Inactivation of p53 and PTEN mutations promotes progression in bladder cancer via deregulation of the mammalian target of rapamycin signaling pathway (mTOR). mTOR expression inc...

The Role of Interferon in the Management of BCG Refractory Nonmuscle Invasive Bladder Cancer

Background. Thirty to forty percent of patients with high grade nonmuscle invasive bladder cancer (NMIBC) fail to respond to intravesical therapy with bacillus Calmette-Guerin (BCG). Interferon-α2B plus BCG has been shown to be effective in a subset of patients with NMIBC BCG refractory disease. Here we present a contemporary series on the effectiveness and safety of intravesical BCG plus interferon-α2B therapy in patients with BCG refractory NMIBC. Methods. From January of 2005 to April of 2014 we retrospectively found 44 patients who underwent induction with combination IFN/BCG for the management of BCG refractory NMIBC. A chart review was performed to assess initial pathological stage/grade, pathological stage/grade at the time of induction, time to IFN/BCG failure, pathological stage/grade at failure, postfailure therapy, and current disease state. Results. Of the 44 patients who met criteria for the analysis. High risk disease was found in 88.6% of patients at induction. The 12-month and 24-month recurrence-free survival were 38.6% and 18.2%, respectively. 25 (56.8%) ultimately had disease recurrence. Radical cystectomy was performed in 16 (36.4%) patients. Conclusion. Combination BCG plus interferon-α2B remains a reasonably safe alternative treatment for select patients with BCG refractory disease prior to proceeding to radical cystectomy.

Intravesical bacillus Calmette-Guérin Efficiently Reduces p70S6K1 but Not 4E-BP1 Phosphorylation in Nonmuscle Invasive Bladder Cancer

We characterized the functional consequences of intravesical bacillus Calmette-Guérin on the molecular mechanism of the AKT/mTOR signaling pathway in nonmuscle invasive bladder cancer. To our knowledge this has not been reported previously. At age 7 weeks female Fischer 344 rats received 1.5 mg/kg MNU intravesically every other week for 6 weeks. They were randomized at 10 per group to MNU (0.2 ml vehicle), bacillus Calmette-Guérin (10(6) cfu Connaught strain), rapamycin (15 μg/ml) and bacillus Calmette-Guérin plus simultaneous rapamycin, each intravesically for 6 weeks. At week 15 the bladders were collected for histopathology, immunohistochemistry and immunoblot to determine p-AKT, Rictor, Raptor, p-4E-BP1, p-p70S6K1, p-AMPK-α, p-mTOR and p-p53. Papillary carcinoma (pTa) and high grade intraepithelial neoplasia (pTis) predominated in the MNU group while normal urothelium, papillary and flat hyperplasia were more common in treated groups. Nonmuscle invasive bladder cancer treated with bacillus Calmette-Guérin showed suppression of p70S6K1 but not 4E-BP1 phosphorylation. This suggests that 4E-BP1 is regulated differently than p70S6K1, escaping the bacillus Calmette-Guérin action that occurs in a mTOR independent manner. The association of bacillus Calmette-Guérin with rapamycin but not rapamycin monotherapy affected p70S6K1 and 4E-BP1 phosphorylation with no features of in situ carcinoma (pTis). The activation status of p70S6K1 and 4E-BP1 might be used to stratify patients who could benefit from targeting such molecular elements with multitarget/multidrug intravesical therapy. In the future 4E-BP1 might be a worthwhile new target for bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer.

OP1-03 INTRAVESICAL BACILLUS CALMETTE-GUERIN (BCG) EFFICIENTLY TACKLES S6K1 BUT NOT 4E-BP1 PHOSPHORYLATION IN NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyOutstanding Posters: Research1 Apr 2014OP1-03 INTRAVESICAL BACILLUS CALMETTE-GUERIN (BCG) EFFICIENTLY TACKLES S6K1 BUT NOT 4E-BP1 PHOSPHORYLATION IN NON-MUSCLE INVASIVE BLADDER CANCER Karen Ferrari, Juliana A. de Camargo, Guilherme Z. Rocha, José B.C. Carvalheira, Athanase Billis, Mário J.A. Saad, and Leonardo O. Reis Karen FerrariKaren Ferrari More articles by this author , Juliana A. de CamargoJuliana A. de Camargo More articles by this author , Guilherme Z. RochaGuilherme Z. Rocha More articles by this author , José B.C. CarvalheiraJosé B.C. Carvalheira More articles by this author , Athanase BillisAthanase Billis More articles by this author , Mário J.A. SaadMário J.A. Saad More articles by this author , and Leonardo O. ReisLeonardo O. Reis More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.611AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Bacillus Calmette-Guérin (BCG) is the gold standard treatment of non-muscle invasive bladder cancer (NMIBC). We aimed to characterize the functional consequences of intravesical BCG on the molecular mechanism of the PI3K/AKT/mTOR signaling pathway in NMIBC, never reported to date. METHODS Female (Fischer 344) rats, 6 weeks old, received 1.5 mg/kg MNU (N-methyl-n-nitrosourea) intravesically every other week for 6 weeks and were randomly divided into 2 groups: - MNU tumor group (n=10) received 0.3 ml saline and - BCG treatment group (n=10) received 106 cfu of BCG intravesically for 6 weeks. At week 15 all bladders were collected for histopathology, immunohistochemistry, proliferation index (Ki-67), and immunoblotting (pAKT, pAMPK, pp53, pp70S6K, RICTOR, RAPTOR, mTOR, p4EBP1). Student’s t-test was used to compare groups. Two tailed p<0.05 was considered statistically significant. RESULTS Papillary carcinoma (pTa) and high-grade intraepithelial neoplasia (carcinoma in situ) predominated in the MNU group while normal urothelium, papillary and flat hyperplasia were more common in BCG treatment. NMIBC treated with BCG exhibited suppression of S6K1 (Figure 1 B) but not 4E-BP1 phosphorylation (Figure 1 A), suggesting that 4E-BP1 is regulated differently that S6K1, escaping the BCG action. The cellular proliferation index decreased in the BCG treatment compared to MNU (Figure 1 C). Table 1 shows the mammalian target of rapamycin pathway phosphorylation status of BCG treatment compared to MNU. CONCLUSIONS 4E-BP1 might be a worthwhile new target for BCG refractory NMIBC. In the future, activation status of S6K1 and 4E-BP1 might stratify patients that could benefit from targeting such molecular elements. This is the first study to explore the mammalian target of rapamycin pathway in the intravesical BCG treatment of NMIBC. Table 1. Mammalian target of rapamycin pathway phosphorylation status of BCG treatment compared to MNU Immunoblotting BCG/MNU (%) p values mTOR 66.84 0.5299 pAKT 56.74 0.3278 pAMPK 121.33 0.6399 pp53 73.40 0.5166 RICTOR 80.28 0.6448 RAPTOR 88.62 0.8867 p4EBP1 140.16 0.5069 pp70S6K 17.08 0.0034 © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e162-e163 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Karen Ferrari More articles by this author Juliana A. de Camargo More articles by this author Guilherme Z. Rocha More articles by this author José B.C. Carvalheira More articles by this author Athanase Billis More articles by this author Mário J.A. Saad More articles by this author Leonardo O. Reis More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

A pilot clinical trial of intravesical mitomycin-C and external deep pelvic hyperthermia for non-muscle-invasive bladder cancer

Purpose: This paper aims to evaluate the safety and heating efficiency of external deep pelvic hyperthermia combined with intravesical mitomycin C (MMC) as a novel therapy for non-muscle-invasive bladder cancer (NMIBC). Materials and methods: We enrolled subjects with bacillus Calmette-Guérin (BCG) refractory NMIBC to an early phase clinical trial of external deep pelvic hyperthermia (using a BSD-2000 device) combined with MMC. Bladders were heated to 42 °C for 1 h during intravesical MMC treatment. Treatments were given weekly for 6 weeks, then monthly for 4 months. Heating parameters, treatment toxicity, and clinical outcomes were systematically measured. Results: Fifteen patients were enrolled on the clinical trial. Median age was 66 years and 87% were male. Median European Organisation for Research and Treatment of Cancer (EORTC) recurrence and progression scores were 6 and 8, respectively. The full treatment course was attained in 73% of subjects. Effective bladder heating was possible in all but one patient who could not tolerate the supine position due to lung disease. Adverse events were all minor (grade 2 or less) and no systemic toxicity was observed. The most common adverse effects were Foley catheter pain (40%), abdominal discomfort (33%), chemical cystitis symptoms (27%), and abdominal skin swelling (27%). With a median follow-up of 3.18 years, 67% experienced another bladder cancer recurrence (none were muscle invasive) and 13% experienced an upper tract recurrence. Conclusions: External deep pelvic hyperthermia using the BSD-2000 device is a safe and reproducible method of heating the bladder in patients undergoing intravesical MMC. The efficacy of this treatment modality should be explored further in clinical trials.