Treatment Of Non-muscle Invasive Bladder Cancer Research Articles

Immunotherapy in Bacillus Calmette-Guerin (BCG) unresponsive nonmuscle invasive bladder cancer.

A number of promising therapies for Bacillus Calmette-Guerin (BCG) unresponsive nonmuscle invasive bladder cancer (NMIBC) are in the pipeline. In this review, we discuss the history of immunotherapy for the treatment of NMIBC and future developments, focusing on novel intravesical treatments. The term BCG unresponsive NMIBC encompasses patients with both BCG refractory and BCG relapsing disease. This definition was adopted to standardize inclusion criteria for patients enrolling in clinical trials in this setting. A host of intravesical immuno-oncologic therapies that include gene therapies, oncolytic viruses, cell surface molecule delivered immunotoxins, and cytokine driven agonism of cellular immunity, are in various phases of the drug development pipeline. In addition, pembrolizumab, an immune-checkpoint inhibitor, has recently been approved as a treatment option for BCG unresponsive NMIBC. Patients with BCG unresponsive disease face many difficulties. Although radical cystectomy is the most effective treatment option for these patients, it is associated with significant morbidity, difficult recovery challenges, and refusal by many patients. Cancer immunotherapies may provide bladder sparing options for some patients who develop BCG unresponsive disease.

Synthesis, Characterization, and Biological Activity of Anthraquinone-Substituted Imidazolium Salts for the Treatment of Bladder Cancer

BACKGROUND: Bladder cancer is one of the most common types of cancer diagnosed each year, and more than half of patients have non-muscle invasive bladder cancer (NMIBC). The standard of care for patients with high-grade NMIBC is Bacillus Calmette-Guerin (BCG). Unfortunately, multiple BCG shortages have limited access to this treatment. Available alternatives using intravesical administration of chemotherapy have some efficacy, but lack prospective validation and long-term outcomes. Development of novel intravesical therapies may provide more active alternatives to BCG for patients with high-grade NMIBC. OBJECTIVE: To develop an optimal imidazolium salt for the intravesical treatment of NMIBC and determine preliminary in vitro activity of anthraquinone-substituted imidazolium salts. METHODS: The development of the anthraquinone-substituted imidazolium salts was undertaken in an attempt to increase the potency of this class of compounds by incorporating the quinone functional group observed in the chemotherapeutics doxorubicin, valrubicin, and mitomycin. All compounds were characterized by 1H and 13C NMR spectroscopy and infrared spectroscopy. Furthermore, these imidazolium salts were tested for in vitro cytotoxicity by the Developmental Therapeutics Program (DTP) on the NCI-60 human tumor cell line screening. Additional in vitro testing was performed against diverse bladder cancer cell lines (RT112, TCCSUP, J82, and UMUC13) using CellTiter-Glo® assays and colony-forming assays. RESULTS: The NCI-60 cell line screening indicated that compound 7 had the highest activity and was concluded to be the optimal compound for further study. Using CellTiter-Glo® assays on bladder cancer cell lines, 50% growth inhibitory concentration (IC50) values were determined to range from 32–50μM after an exposure of 1 h, for compound 7. Further evaluation of the compound by colony-forming assays showed the complete inhibition of growth at 10 days post a 100μM dose of compound 7 for 1 h. CONCLUSIONS: The most active lipophilic anthraquinone imidazolium salt, compound 7, could be a viable treatment for non-muscle invasive bladder cancer as it exhibits a cell-killing effect at a 1 h time period and completely inhibits cancer regrowth in colony-forming assays.

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.

Immunotherapy in non-muscle-invasive bladder cancer: current status and future directions.

Patients harboring high-grade non-muscle-invasive bladder cancer (NMIBC) experience high rates of both recurrence and progression. Currently, few treatment options besides cystectomy exist for this at-risk population, especially those with BCG-unresponsive disease. The purpose of this review is to present the current status and describe future directions of immunotherapy in NMIBC. The PubMed and Google Scholar databases were searched for articles pertaining to immunotherapy in NMIBC. Relevant planned and ongoing clinical trials were identified using www.ClinicalTrials.gov . Published randomized control trials, reviews, other retrospective and prospective studies deemed relevant were used in this review paper. Novel immunotherapies used in the treatment of high-grade NMIBC and BCG-unresponsive disease allow patients more options and have the potential to reduce the need for radical cystectomy. Currently, several options target the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis as this mechanism of immunotherapy has been shown to be effective in several cancers, including bladder, melanoma, and lung cancers. In addition, other immunotherapy options for the treatment of NMIBC include viral gene therapies, interleukin-15 superagonists, small molecule inhibitors of indoleamine (2,3)-dioxygenase 1, and vaccines. The current landscape of immunotherapy in bladder cancer is rapidly evolving, with much literature pertaining to muscle-invasive and metastatic disease. However, the implementation of these treatment options in high-grade NMIBC may allow patients to avoid life-altering surgery. Reliable biomarkers for response are needed to further select patients who may benefit from such therapies.

Role of immunotherapy in Bacillus Calmette-Guérin unresponsive: non-muscle invasive bladder cancer.

Bacillus Calmette-Guérin (BCG) is recommended as the first-line treatment option for intermediate to high risk non-muscle invasive bladder cancer (NMIBC) by current clinical guidelines. However, despite the intravesical instillation of BCG, a significant proportion of patients with intermediate to high risk NMIBC develop intravesical recurrence. Moreover, the treatment of BCG-unresponsive NMIBC is currently challenging. There are no reliable treatment options for these patients with BCG-unresponsive NMIBC except radical cystectomy, which reported to show acceptable oncological outcomes. In this regards, reliable and safe non-invasive or less-invasive treatment options with acceptable oncological outcomes are awaited for the treatment of BCG-unresponsive NMIBC. The treatment of advanced or metastatic urothelial carcinoma has greatly advanced following the recent introduction of immunotherapeutic agents. These advancements have triggered an increasing interest in the use of immunotherapeutic agents for NMIBC, and especially for BCG-unresponsive NMIBC. The current review article aims to introduce and discuss the cutting-edge knowledge on the role of immunotherapy in BCG-unresponsive NMIBC and the currently available therapeutic strategies for its treatment. In addition, this article also summarizes the ongoing studies in this field.

A Systematic Review and Meta- Analysis of Green-Light Laser Vaporization for Superficial Bladder.

The related research of green-light laser vaporization in the treatment of non-muscle invasive bladder cancer (NMIBC) is limited. This study focused on analyzing the effectiveness and safety of it from the perspective of an extensive literature review. A comprehensive search of CNKI, WanFang, VIP, PubMed, Embase, and CENTRAL databases for photoselective vaporization of bladder tumor and transurethral resection of bladder tumor treatment of non-muscle invasive bladder cancer (NMIBC). The search included studies from January 1996 to December 2019. Two reviewers independently screened literature, extracted data, assessed the risk of bias of included studies. RevMan 5.3 software was used for Meta-analysis. A total of 18 RCTs involving 1648 patients met the predefined criteria. Meta-analysis data demonstrated that the PVBT group exhibited a significant advantage over the TURBT group in intraoperative obturator nerve reflex (RR = 0.09, 95% CI [0.04, 0.18], P< 0.001)and bladder perforation (RR = 0.14, 95% CI [0.07, 0.28], P< 0.001) and postoperative 1-year recurrence (RR = 0.52, 95% CI [0.40, 0.67], P< 0.001). The PVBT procedure has advantages over TURBT in the amount of surgical bleeding (MD = -17.27, 95% CI [-24.73, -9.81], P< 0.001) and the length of hospital stay (MD = -2.80, 95% CI [-3.82, -1.87], P< 0.001), bladder irrigation time (MD = -0.95, 95% CI [-1.49, -0.42], P< 0.001), and catheter indwelling time (MD = -2.60, 95% CI [-3.30, -1.90], P< 0.001). There was no difference between the two types of surgery in the incidence of postoperative urethral stricture (RR = 0.53, 95% CI [0.15, 1.83], P = 0.32) and the length of surgery (MD = -2.46, 95% CI [-5.37, 0.46], P = 0.10). Our systematic review and meta-analysis suggests that PVBT is better than TURBT as an alternative treatment for patients with NMIBC in safe aspect. However, whether it is equally effective in terms of oncological control remains to be elucidated, and additional high quality RCTs are needed to confirm our findings.

Patient-reported outcomes in non-muscle invasive bladder cancer: a mixed-methods systematic review.

Non-muscle invasive bladder cancer (NMIBC) is a chronic condition requiring repeated treatment and endoscopic examinations that can occur life-long. In this context, patient-reported outcomes (PROs) are important considerations to patients and managing clinicians. We undertook a systematic review to synthesise PRO results relevant to NMIBC treatment to explore trajectories overtime and differences between treatment options. We searched databases AMED, MEDLINE, EMbase, PsycINFO, Web of Knowledge and Scopus (inception to 5th December 2019), reference lists and contactedkey authors to identify studies that reported PROs after NMIBC treatment. Two reviewers independently applied inclusion and quality criteria and extracted findings. Results for PROs were synthesised for treatment groups across three time periods: acute/during induction therapy; during maintenance therapy; and long-term follow-up (> 1year). Of 3193 papers screened, 29 were eligible. These provided evidence about induction treatment effects, but few reported maintenance or long-term evidence, and evidence about differences between NMIBC treatment options was lacking. A range of symptoms (pain in bladder area, urinary frequency and urgency, pain or burning during urination) were commonly experienced during and soon after treatment for NMIBC. Less common symptoms included fatigue, disrupted sleep and gastrointestinal problems. Treatments for NMIBC can cause symptoms and functional impairment during the acute treatment phase and reduce quality of life. Clinicians should be aware of these impairments to prepare patients for short-term sequelae and enable those with treatment options to exercise preferences in choosing among them. However, gaps in current evidence limit our understanding of PRO trajectories from diagnosis through to long-term survivorship and treatment effects.

Monopolar versus bipolar transurethral resection of bladder tumors: An updated systematic review and meta-analysis of existing studies.

Background:To compare the efficacy and safety of bipolar and monopolar transurethral resection of bladder tumors (TURBT) in non-muscle invasive bladder cancer (NMIBC) treatment.Methods:This protocol established in this study has been reported following the preferred reporting items for systematic review and meta-analysis protocols. Web of Science, PubMed, EMBASE, and the Cochrane Library were searched for all randomized controlled trials comparing bipolar TURBT and monopolar TURBT in NMIBC treatment until 31st of June 2020. We will use a combination of Medical Subject Heading and free-text terms with various synonyms to search based on the eligibility criteria. Two investigators independently reviewed the included studies and extracted relevant data. The odds ratio and 95% confidence intervals of were used as effect estimate. I-square (I2) test, substantial heterogeneity, sensitivity analysis, and publication bias assessment will be performed accordingly. Stata 15.0 and Review Manger 5.3 are used for meta-analysis and systematic review.Results:The results will be published in a peer-reviewed journal.Conclusion:The results of this review will be widely disseminated through peer-reviewed publications and conference presentations. This evidence may also provide helpful evidence of the efficacy and safety of bipolar and monopolar transurethral resection of TURBT in NMIBC treatment.PROSPERO registration number:CRD42020151997

Contemporary Treatment Patterns for Non-muscle-invasive Bladder Cancer: Has the Use of Radical Cystectomy Changed in the BCG Shortage Era?

To examine recent treatment trends for non-muscle-invasive bladder cancer (NMIBC), and specifically, to assess whether there was a change in use radical cystectomy (RC) between 2008 and 2015 using data from the Surveillance, Epidemiology, and End Results database. We identified patients presenting with high-grade T1 (T1HG) NMIBC at diagnosis during the study period. Treatment was dichotomized into "RC" and "local treatment" (which included transurethral resection and intravesical therapies). We then employed multivariable logistic regression models to assess the odds of undergoing RC across the study period. Additionally we examined the rates of RC for T1HG NMIBC during the period of BCG-shortage, defined as 2012-2015. We identified 21,817 individuals diagnosed with T1HG bladder cancer during the study period. The majority of patients underwent local treatment (94.5%). During the shortage period, the rate of RC for T1HG NMIBC was significantly lower compared to the preshortage era (5.1% vs 5.9%, P=.007). Across the study period, the utilization of RC for T1HG NMIBC decreased significantly (odds ratio 0.99 per quarter, 95% confidence interval 0.98-0.99, P=.017). In our cohort of patients diagnosed with T1HG bladder cancer, we found a significant decrease in the use of radical cystectomy across the study period. Contrary to the hypothesis of increasing rates of RC in the face of BCG shortage, the rate of RC was significantly higher in the pre-shortage era. Further examination of NMIBC treatment patterns will be necessary to assess the impact of BCG availability on therapeutic pathways and oncologic outcomes in patients with high-grade NMIBC.

Effects of P-MAPA as Immunomodulator on Markers for Energy Metabolism in Bladder Cancer

Introduction This study characterized and compared cellular energetic metabolism features in the treatment of chemically induced non-muscle invasive bladder cancer (NMIBC) in Fischer 344 rats that were submitted to intravesical immunotherapies with P-MAPA (Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride) and Bacillus Calmette-Guérin (BCG). Methods Rat urinary bladder samples from Control, NMIBC (Cancer), NMIBC+BCG and NMIBC+P-MAPA groups were submitted to histopathological and western blotting analyses for the following proteins: GLUT 1, PFK, GAPDH, HADHSC, β-F1-ATPase, AMPK and mTOR. Results P-MAPA Intravesical treatment was effective in tumor regression and histologic recovery of the urinary bladder in the NMIBC. There was a significant increase in protein levels of GLUT 1, mTOR, GAPDH and HADHSC in the NMIBC+P-MAPA group. It was observed an increase in protein levels of PFK and β-F1-ATPase and a significant reduction in protein levels of AMPk in the NMIBC group. Conclusions Our results showed that immunotherapy with P-MAPA may be an alternative in the treatment of NMIBC, especially in cases where BCG therapy failure, as evidenced by the effect of P-MAPA on tumor regression.

Hybrid graphene oxide as carrier of doxorubicin: cytotoxicity and preliminary in vivo assays against bladder cancer

Two types of graphene oxide (GO) hybrids were synthesised for the administration of doxorubicin (DOX, named GO-CO-DOX) and interfering RNA - siRNA (named GO-PEG-PEI/siRNA). These nanomaterials were used for intervention on vascular endothelial growth factor (VEGF) that represents an important strategy to block the formation of new vessels to inhibit cancer progression. For the delivery of DOX, it was incorporated into GO, while for the delivery of siRNA, GO was covalently bonded with the cationic polyethyleneimine (PEI) and then complexed with siRNA. The nanostructures were characterised by attenuated total reflection ATR-FTIR, zeta potential, x-ray photoelectron spectroscopy (XPS), x-ray diffraction (XRD), and transmission electron microscopy (TEM). The cytotoxicity studies with GO-PEG-PEI and GO-PEG-PEI/siRNA systems showed that both formulations have IC50 values of around 100 μg ml−1. The systems were administered in vivo to investigate their antitumor effects against non-muscle-invasive bladder cancer (NMIBC) and showed to be promising for the treatment of NMIBC.

Pembrolizumab (pembro) for the treatment of patients with Bacillus Calmette-Guérin (BCG) unresponsive, high-risk (HR) non–muscle-invasive bladder cancer (NMIBC): Over two years follow-up of KEYNOTE-057.

5041 Background: Pembro was recently approved for the treatment of HR NMIBC based on results from the phase 2 KEYNOTE-057 (NCT02625961) study. Herein we present safety, efficacy, and posttreatment outcomes with &gt; 2 y follow-up from KEYNOTE-057 cohort A. Methods: Patients with histologically confirmed HR BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors who received adequate BCG therapy and were ineligible for or opted out of radical cystectomy (RC) received pembro 200 mg Q3W for up to 2 y or until disease recurrence, progression, or unacceptable toxicity. The primary end point was complete response rate (CRR). Key secondary end points were duration of response (DOR) and safety. Results: Overall, 102 patients were initially enrolled, and 96 were included in the efficacy analysis. Median time from enrollment to data cut off was 28.4 months (range, 18.2-40.5). CRR was 40.6% (95% CI, 30.7-51.1), and median DOR was 16.2 months (range, 0+ to 30.4+). Among 39 patients with CR, 18 (46.2%) had a DOR ≥12 months. No patient’s disease progressed to muscle-invasive or metastatic bladder cancer while on study treatment. Median PFS and OS were not reached. At 12 months, PFS was 82.7% and OS was 97.9%. A total of 36 patients (37.5%) underwent RC after discontinuation from study treatment, which included 9 of 22 patients (40.9%) who had recurrence after initial CR and 27 of 57 (47.4%) nonresponders. Of the 36 who underwent RC, 33 (91.6%) had no pathological upstaging to MIBC and 3 (8.3%) had at least pT2 disease at time of RC. For subsequent treatments other than RC, 27 of 96 (28.1%) patients received additional intravesical therapy (eg, BCG, gemcitabine, or mitomycin), 21 of 96 (21.9%) underwent local procedures (eg, TURBT), and 3 of 96 (3.1%) received systemic therapy (eg, pembro). In 102 patients treated with pembro, treatment-related AEs (TRAEs) occurred in 67 (65.7%) patients; most frequently reported TRAEs were fatigue, pruritus, and diarrhea (10.8% each). Grade 3/4 TRAEs occurred in 13 patients (12.7%), and 21 patients (20.6%) experienced immune-mediated AEs. There were no grade 5 TRAEs. Conclusions: After &gt; 2 y of follow-up, durable and clinically meaningful activity of pembro was observed in patients who had HR BCG-unresponsive CIS with or without papillary tumors and who were ineligible for or opted out of RC. Pembro did not seem to limit the opportunity for subsequent therapies, including RC. The safety profile was consistent with what is reported in the literature. Clinical trial information: NCT02625961 .

The role of device-assisted therapies in the management of non-muscle invasive bladder cancer: A systematic review

Despite optimal treatment, patients affected by non-muscle invasive bladder cancer (NMIBC) suffer from high risk of recurrence and progression. Intravescical device assisted therapies such as radiofrequency induced thermochemotherapeutic effect (RITE) and electromotive drug administration (EMDA) have shown promising effect in enhancing the effect of intravescical chemotherapies. The aim of the study was to assess clinical outcomes of these two devices in non-muscle invasive bladder cancer. A systematic literature review was performed in December 2019 using the Medline, Embase, and Web of Science databases. Only articles published in the last 10 years were considered (2009-2019). The articles were selected using the following keywords association: "bladder cancer" AND "EMDA' AND "synergo" AND "hyperchemotherapy" AND "electromotive drug administration", AND "radiofrequency induced thermochemotherapeutic" AND "RITE". We found 16 studies published in the last ten years regarding the efficacy of RITE (12 studies) and EMDA (4 studies) in the treatment of NMIBC. Both RITE and EMDA showed promising results in the treatment of intermediate and high risk NMIBC as well as in patients affected by recurrent BCa after BCG failure. In high-risk BCG naïve NMIBC patients treated with EMDA recurrence and progression rates were 68% and 95%, respectively. Considering RITE, recurrence and progression range rates were 43%-88% and 62%-97%, respectively. Discordance results were reported regarding its effect on patients with carcinoma in situ. However, only few studies could be compared since differences exist regarding inclusion criteria with high patients' heterogeneity. Considering recurrence after BCG, recurrence and progression range rates were 29%-29.2% and 62%-83% for RITE and 25% and 75% for EMDA, respectively. Delivery of intravescical hyperthermia seems to enhance the normal effect of intravescical chemotherapy instillation. Although prospective trials supported its effect on both BCG naïve and BCG failure patients, data are urgently required to validate these findings and to understand its effect on patients with carcinoma in situ. 3.

PD12-08 DEVELOPMENT OF A PATIENT-REPORTED SYMPTOM INDEX FOR USE WITH NON-MUSCLE INVASIVE BLADDER CANCER PATIENTS USING MIXED METHODS

INTRODUCTION AND OBJECTIVE: Non-muscle invasive bladder cancer (NMIBC), a chronic condition, requires treatment and lifelong monitoring with regular endoscopic examinations. In this clinical context, symptom burden and quality of life are important patient reported outcomes (PROs) for consideration when making decisions about treatment. Current PRO measures inadequately assess NMIBC-specific symptoms and side effects of contemporary treatments. This study aimed to develop a patient-reported NMIBC Symptom Index (NMIBC-SI) acceptable to patients and clinicians and fit-for-purpose as a clinical trial endpoint. METHODS: We conducted a systematic review and interviewed 26 patients and 20 clinicians to develop a conceptual framework of PROs important to NMIBC. The 125 issues in the conceptual framework were phrased as questions and pre-tested in 12 cognitive interviews to develop a draft 104-item NMIBC-SI understood by and relevant to NMIBC patients. In Field Test 1 (FT1), we administered the draft NMIBC-SI to patients on active treatment from nine Australian sites. Items with low prevalence, conceptual similarity or high correlations (≥0.50) were flagged for exclusion. Nine Urologists agreed the final NMIBC-SI items. In Field Test 2 (FT2), patients from 16 sites across four countries completed the final version NMIBC-SI. This prospective longitudinal study evaluates the validity and reliability of the NMIBC-SI, assessing key PROs across treatments, disease trajectory, and risk categories. RESULTS: Planned accrual for FT1, n=220, was reached (178 male, mean age 69) representing Low 27.7%; Intermediate 13.2%; High 50.9% risk categories. 80% patients did not experience 21 items, 7 items were highly correlated, and 4 excluded as >50% of urologists rated them as not related to NMIBC treatment (e.g. coughing). The final 56-item NMIBC-SI used in FT2 included a 23-item symptom burden scale, 2 treatment specific modules, and 3 function scales. FT2 began July 2018. As of 30 Oct 2019, 168 patients have completed the NMIBC-SI before treatment (n=143), 1 week post-surgery (n=106), at end of induction therapy (n=72), and 1 year follow-up (n=10), across high (29%), intermediate (3%), and low (68%) risk categories. CONCLUSIONS: The NMIBC-SI allows comprehensive assessment of patients’ symptom burden and functioning impairment. The validated NMIBC-SI will be suitable to use in clinical trials of NMIBC treatments. In clinical practice, it will allow assessment of the impact of treatments for NMIBC on patients and allow greater patient involvement in the decision-making process. Source of Funding: Cancer Australia & Cancer Council NSW [PdCCRS Grant #1103036]

Modifying the Non-muscle Invasive Bladder Cancer Immune Microenvironment for Optimal Therapeutic Response.

It is now well-recognized that the tumor microenvironment (TME) is not only a key regulator of cancer progression but also plays a crucial role in cancer treatment responses. Recently, several high-profile publications have demonstrated the importance of particular immune parameters and cell types that dictate responsiveness to immunotherapies. With this increased understanding of TME-mediated therapy, approaches that increase therapeutic efficacy by remodeling the TME are actively being pursued. A classic example of this, in practice by urologists for over 40 years, is the manipulation of the bladder microenvironment for the treatment of non-muscle invasive bladder cancer (NMIBC) by instillation of intravesical bacillus Calmette-Guerin (BCG). The success of BCG treatment is thought to be due to its ability to induce a massive influx of Th1-polarized inflammatory cells, production of Th1 inflammatory cytokines and the generation of tumor-targeted Th1-mediated cytotoxic responses. Whilst BCG immunotherapy is currently the best treatment for NMIBC, ~30% of patients show no response to this treatment. Here we present a review highlighting a variety of promising alternative immunotherapies being developed that remodel the bladder tumor microenvironment. These include (1) the use of oncolytic viruses which selectively replicate within cancer cells whilst also modifying the immunological components of the TME, (2) manipulation of the bladder microbiome to augment the response to BCG or other immunotherapies (3) utilizing Toll-like Receptor agonists as anti-tumor agents due to their potent stimulation of innate and adaptive immunity and (4) the growing recognition that immunotherapeutic strategies that will have the largest impact on patients may require multiple therapeutic approaches combined together. The accumulating knowledge on TME remodeling holds promise for providing an alternative therapy for patients with BCG-unresponsive NMIBC.

Reasons for intravesical instillation postponement during adjuvant treatment of non-muscle-invasive bladder cancer: A prospective study

Intravesical instillations for adjuvant treatment of non-muscle-invasive bladder cancer (NMIBC) may be postponed of necessity. However, the frequency and reasons for postponement are unclear. We carried out a prospective, epidemiological study in an Urology department of the Île-de-France, between August 2016 and March 2017, to determine the frequency and reasons for postponement of intravesical instillations during adjuvant treatment of NMIBC. One-hundred consecutive patients treated by intravesical instillations of mitomycin C (MMC) or Bacillus Calmette-Guérin (BCG) were included. At each session and in case of instillation postponement, the medical team completed a specially designed questionnaire. A total of 541 instillations were performed in the 100 patients. Twenty-four instillations (4.4%) were postponed in 19 patients. The major cause of postponement was an untreated positive urine analysis and culture (UAC) in 13/24 (54%) cases. The causes of cancellation did not differ significantly between MMC and BCG. The most frequently cancelled instillations were the first in the therapeutic protocol in 26% of cases. The number of instillations preceding those cancelled did not differ significantly between MMC and BCG (2.1±2.0 instillations for MMC vs. 1.5±1.6 for BCG; P=0.64). There was a low rate of postponed instillations (4.4%). The main reasons, namely an untreated UAC and a positive dipstick test, based on the jurisprudence, are not included in the latest CC-AFU guidelines. 3.

BCG-Unresponsive Bladder Cancer: New Frontiers in the Treatment Landscape

This Ferring-organised Meet-The-Expert symposium at the European Society of Medical Oncology (ESMO) 2019 meeting aimed to discuss new treatment modalities in the management of high-risk, non-muscle invasive bladder cancer (NMIBC). The chairperson Prof Palou commenced the session by discussing the need for newer interventions to address the failure of bacillus Calmette–Guérin (BCG), the first-line treatment against NMIBC, in a substantial proportion of patients. Prof Palou emphasised the need to clearly define refractory disease to optimise second-line treatments, before introducing immune checkpoint inhibitors as a promising class of drug for the treatment of BCG-unresponsive NMIBC. Prof Shariat discussed a case study to define key clinical timepoints for evaluating therapeutic outcomes of BCG treatment. He further outlined factors to be considered before deciding on radical cystectomy in BCG-unresponsive NMIBC. Prof Babjuk listed some of the landmark trials conducted recently to investigate chemotherapeutic agents such as mitomycin C (MMC) and docetaxel in BCG-unresponsive patients before highlighting the role of advanced drug delivery technologies such as electromotive drug administration (EMDA), hyperthermic intravesical chemotherapy, and radiofrequency-induced thermo-chemotherapy effect (RITE) in improving the effectiveness of these agents. Prof Powles shared data from some of the trials investigating immune checkpoint inhibitors such as PURE-01, ABACUS, KEYNOTE, to underscore the importance of biomarkers in selecting appropriate treatment strategies for NMIBC.

Update on the guideline of guidelines: non-muscle-invasive bladder cancer.

Non-muscle-invasive bladder cancer (NMIBC) is the most common form of bladder cancer, with frequent recurrences and risk of progression. Risk-stratified treatment and surveillance protocols are often used to guide management. In 2017, BJUI reviewed guidelines on NMIBC from four major organizations: the American Urological Association/Society of Urological Oncology, the European Association of Urology, the National Comprehensive Cancer Network, and the National Institute for Health and Care Excellence. The present update will review major changes in the guidelines and broadly summarize new recommendations for treatment of NMIBC in an era of bacillus Calmette-Guérin shortage and immense novel therapy development.

OncoTherad: A New Nanobiological Response Modifier, its Toxicological and Anticancer Activities

This study reports the effects of a promising therapeutic option for non-muscle invasive bladder cancer (NMIBC) based on OncoTherad intravesical immunotherapy in an appropriated animal model. OncoTherad is a nanostructured inorganic phosphate complex associated to glycosidic protein, which exhibits immunomodulatory and antitumor properties. Biochemical parameters in rats, mice and rabbits treated intravesically with OncoTherad at doses of 20-100 mg/kg, did not differed statistically from their respective controls, exhibiting no systemic toxic effects. All the target organs did not present inflammation and histopathological changes. NMIBC was induced by treating female Fischer 344 rats with N-methyl-N-nitrosourea (MNU). Bacillus Calmette-Guérin (BCG) were used as positive control in the animal models. The results demonstrated that animals treated with OncoTherad distinctly showed a significant histopathological recovery from the cancer state of animals (80%) when compared to BCG treatment. In addition, BCG and OncoTherad intravesical immunotherapies were able to restore TLR2 levels. However, OncoTherad increased of TLR4 levels when compared to BCG. Thus, the activation of TLR4 by Oncotherad was efficient in reducing urothelial neoplastic progression. All data are indicative that of OncoTherad is a feasible candidate for the NMIBC treatment.

Intravesical Treatment with Electro-Mediated Administration of Mytomicin C as Prophylaxis for Intermediate and High-Risk Nonmuscle-Invasive Bladder Cancer: A Retrospective Multicenter Study

Background: Topical therapy of nonmuscle-invasive bladder cancer (NMIBC) is based on immunotherapy with Bacillus Calmette-Guerin and chemotherapy administered by passive instillation, but an active drug administration achieves a better concentration of the drugs in the bladder. Aim: This study aimed to investigate the effectiveness of electromotive drug administration (EMDA) of mitomycin C (EMDA/MMC) in intermediate- and high-risk NMIBC patients 6 months after the end of induction treatment. Materials and Methods: Sixty-five patients diagnosed with histologically confirmed NMIBC, with a complete transurethral resection of all visible tumors underwent EMDA/MMC. Primary endpoint was the proportion of responders at 3 or 6 months. Results: Data on follow-up were available for 62 subjects at 3 months and 45 at 6 months. EMDA was effective in intermediate- and high-risk patients: because of the small number of cases no conclusions can be drawn on the efficacy in the low-risk group. No difference in the response to treatment between intermediate- (83.3%) and high-risk (84%) patients could be seen. Conclusions: EMDA/MMC is a useful technique for an effective and safe treatment of primary and recurrent NMIBC, and a valuable therapeutic option in intermediate- and high-risk NMIBC patients.