Non-muscle Invasive Bladder Cancer Patients Research Articles

PCR235 Drivers of Treatment Preferences in High-Risk Non-Muscle Invasive Bladder Cancer (HR-NMIBC) Patients: Qualitative Interviews to Inform a Patient-Preference Study

PCR235 Drivers of Treatment Preferences in High-Risk Non-Muscle Invasive Bladder Cancer (HR-NMIBC) Patients: Qualitative Interviews to Inform a Patient-Preference Study

The bladder microbiota is not significantly altered by intravesical BCG therapy

IntroductionBladder microbiota dysbiosis has been associated with several urological disorders. However, dysbiosis markers in bladder cancer have not been identified and little is known about the effect of Bacillus Calmette-Guérin (BCG) intravesical therapy on the bladder microbiota. In this study, we compared the bladder microbiota of patients with non-muscle-invasive bladder cancer (NMIBC) undergoing BCG therapy to nononcological controls. We also longitudinally analyzed the impact of BCG therapy on the bladder microbiota of NMIBC patients and addressed whether bladder microbiota is associated with BCG efficacy. MethodsWe collected catheterized urine samples from males with intermediate/high-risk NMIBC (cancer group, n = 32) or benign prostatic hyperplasia (control group, n = 41). The cancer group also provided urine samples during and after BCG induction. We used 16S rRNA gene sequencing to characterize the bladder microbiota. Bladder microbiota parameters, such as diversity and taxonomic composition, were compared between groups and associated with clinicopathological data and BCG efficacy. ResultsWe observed no significant differences between the bladder microbiota of NMIBC patients and controls. BCG intravesical instillations did not significantly alter the bladder microbiota of NMIBC patients, and BCG was rarely detected in the bladder during and after BCG therapy. Microbiota diversity and overall composition before BCG induction did not influence disease persistence at 3 months. However, higher abundance of Lactobacillus, Streptococcus, and Cutibacterium in the pre-BCG bladder microbiota was associated with BCG effectiveness. ConclusionWe were unable to identify markers of bladder microbiota dysbiosis among male NMIBC patients. Moreover, we demonstrated for the first time using longitudinally collected samples that BCG cannot persist in the bladder microbiota nor significantly alter its diversity and composition. The associations found between bladder microbes and BCG efficacy highlight the potential of microbial-based therapeutic and risk-stratification strategies in the intermediate/high-risk NMIBC setting.

Pilot study on quantifying the epithelial/mesenchymal hybrid state in the non-muscle invasive and muscle invasive bladder tumors: A promising marker of diagnosis and prognosis

BackgroundManifestation of epithelial-to-mesenchymal transition (EMT) program in tumor cells is associated with the occurrence of multiple intermediate phenotypic states namely epithelial (E), mesenchymal (M) and hybrid E/M across the epithelial-mesenchymal spectrum and these states exhibit different invasive properties. Understanding the cellular and molecular mechanisms defining the E/M hybrid state of the cells during bladder tumor development may significantly aid in the identification of novel diagnostic and prognostic markers. Materials and methodsThe present study is taken up to identify hybrid E/M score based on the immunohistochemical localization and surface expressions of epithelial proteins [E-cadherin and Beta-catenin] and mesenchymal marker proteins [N-cadherin and Vimentin] on formalin fixed paraffin embedded tumor sections of the prospective series of 99 non-muscle invasive bladder cancer (NMIBC) and 87 muscle invasive bladder cancer (MIBC) patients. E/M score was then statistically examined with patients’ demographics to assess its potential in the diagnosis and prognosis of UCB patients. ResultsAmong the E (E-cadherinhigh, β-cateninhigh), hybrid E/M (E-cadherinlow, β-cateninlow, N- cadherinhigh and Vimentinhigh) and M (N-cadherinhigh and Vimentinhigh) phenotypes, E/M phenotype was observed to be more prevalent in MIBC compared to E phenotype in NMIBC subtype. The current study reports the statistical association of tumor stage and tumor grade with the hybrid E/M state of urothelial tumor cells across both the subtypes. Hybrid E/M phenotype in MIBC patients was significantly shown to lower the overall survival time period compared to NMIBC patients. This supports the contribution of hybrid E/M state of tumor cells to the.aggressiveness of the disease. ConclusionsCharacterizing the hybrid E/M state instead of all or none phenotype becomes an imperative to understand the dynamics of EMT and MET in the tumor pathophysiology of NMIBC and MIBC subtypes, and could contribute to better patient stratification and therapeutic strategies.

The relationship between BCG immunotherapy and oxidative stress parameters in patients with nonmuscle invasive bladder cancer

IntroductionEnvironmental chemicals have been associated with the regulation of oxidative stress markers, which have the potential for the development of bladder cancer. However, limited studies on the function of oxidative stress parameters and nonmuscle invasive bladder cancer (NMIBC) in therapy response are available. Here we studied the oxidative stress parameters in response to BCG immunotherapy in NMIBC patients. Material and MethodsA total of 120 patients with NMIBC and treatment with BCG were enrolled and categorized into 2 groups on BCG response, 50 patients were BCG-responsive (BCG-R) and 70 were BCG-nonresponsive (BCG-N). BCG-R have no evidence of tumor recurrence or advancement after 1 year of BCG immunotherapy, but BCG-N has a recurrence of tumor after 3 to 6 months cycles of BCG instillation, as determined by cystoscopy. In all groups, we measured the levels of oxidative stress markers- malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and catalase (CAT). ResultsThe levels of oxidative stress markers viz. MDA, NO, and SOD in the BCG-N group were significantly higher (P < 0.001) than in the BCG-R group. Furthermore, the data demonstrated a significant correlation between oxidative stress marker and NMIBC T1 high grade and tumor size >2.5 cm. However, no statistically significant difference was found between studied groups with CAT. ConclusionThe findings suggest that the carcinogenesis of NMIBC is associated with oxidative damage of biomolecules and indicates the involvement of oxidative stress markers in the development and recurrence of NMIBC.; Therefore, it is critical to ensure the management for T1 high grade and tumor size of >2.5 cm for antioxidant protection.

Diet, Physical Activity, and Smoking in Patients Living with Non-Muscle Invasive Bladder Cancer

Background Modifiable lifestyle factors have been implicated in bladder cancer outcomes. Further study is warranted to inform future strategies in patients with non-muscle invasive bladder cancer (NMIBC). Objective We aim to describe modifiable behaviors (smoking, diet, and physical activity) in a cohort of patients with NMIBC. Methods We conducted an observational cross-sectional study in patients undergoing surveillance for NMIBC. A comprehensive survey comprised of validated measures of physical activity, diet, and mutagen consumption was administered. We assessed a “healthy lifestyle score” consisting of body mass index (BMI) &lt;25, smoking status, and physical activity (aerobic exercise minutes). We examined differences in lifestyle factors by stage, grade, recurrence, BMI, age, gender, and education level. Results In a cohort of 113 NMIBC patients, median age was 67 years (IQR: 59, 73) and median time since initial diagnosis was 26 months (IQR: 9, 42). Low levels of healthy habits are common among patients with NMIBC. Those with a BMI of ≥25 has greater red and processed meat intake, higher mutagen intake, and lower physical activity. Older patients reported more supplement use and lower physical activity. Low education level was associated with a less healthy lifestyle (higher processed meat consumption, higher Meiqx mutagen consumption, and lower physical activity). Conclusions In patients undergoing surveillance for NMIBC, 25% had all three components reflecting a healthy lifestyle. Older age, lower education, and higher body mass index were associated with fewer healthy habits. Education on healthy lifestyle changes should be a key component in NMIBC survivorship care.

P245 - Uromonitor-V2®: Clinical Validation and Performance Assessment of a Urinary Biomarker for Recurrence in Non-Muscle Invasive Bladder Cancer Patients

P245 - Uromonitor-V2®: Clinical Validation and Performance Assessment of a Urinary Biomarker for Recurrence in Non-Muscle Invasive Bladder Cancer Patients

The optimal intravesical maintenance chemotherapy scheme for the intermediate-risk group non-muscle-invasive bladder cancer

ObjectiveAlthough the current European Association of Urology(EAU) guideline recommends that patients with intermediate-risk non-muscle-invasive bladder cancer (NMIBC) should accept intravesical chemotherapy or Calmette-Guerin (BCG) for no more than one year after transurethral resection of bladder tumor(TURBT), there is no consensus on the optimal duration of chemotherapy. Hence, we explored the optimal duration of maintenance intravesical chemotherapy in patients with intermediate-risk NMIBC.Subjects and MethodsThis was a real-world single-center retrospective cohort study. In total 158 patients with pathologically confirmed intermediate-risk NMIBC were included, who were divided into 4 subgroups based on the number of instillations given. We used Cox regression analysis and survival analysis chart to explore the 3-yr recurrence outcomes of tumor.The optimal duration was determined by receive operating characteristic curve (ROC).ResultsThe median follow-up was 5.2 years. Compared with instillation for 1–2 months, the Hazard Ratios(HR) values of instillation for less than 1 month, maintenance instillation for 3–6 months and > 6 months were 3.57、1.57 and 0.22(95% CI 1.27–12.41;0.26–9.28;0.07–0.80, P = 0.03;0.62;0.02, respectively). We found a significant improvement in 3-yr relapse-free survival in intermediate-risk NMIBC patients who maintained intravesical instillation chemotherapy for longer than 6 months, and the best benefit was achieved with 10.5 months of maintenance chemotherapy by ROC.ConclusionsIn our scheme, the optimal duration of intravesical instillation with pirrubicin is 10.5 months. This new understanding provides valuable experience for the precise medical treatment model of intermediate-risk NMIBC.

Bacillus Calmette-Guerin (BCG) therapy is safe and effective in non-muscle invasive bladder cancer (NMIBC) patients with immunomodulating conditions

IntroductionBacillus Calmette-Guerin (BCG) is the most effective therapy available to treat high-risk nonmuscle invasive bladder cancer (NMIBC) patients. However, for patients with immunomodulating conditions BCG is a relative contraindication due to efficacy and safety concerns. To our knowledge, no population-level study evaluating the efficacy and safety profile of BCG for immunomodulated patients exists. MethodsNMIBC patients aged 66 years or older were identified in the Surveillance, Epidemiology, and End Results (SEER) – Medicare database from 1975–2013. All patients completed adequate BCG (at least 5 plus 2 treatments completed within 12 months of diagnosis). Two groups were defined: an immunomodulated population identified by immunomodulating conditions such as solid-organ transplantation, HIV, and autoimmune conditions, and an immunocompetent group. The primary endpoint was 5-year progression-free survival defined as progression to systemic chemotherapy, checkpoint inhibitors, radical or partial cystectomy, metastasis, or cancer-specific death. A safety analysis was performed as a secondary outcome. ResultsIn a total of 4,277 patients with NMIBC who completed adequate BCG, 606 (14.2%) were immunomodulated. The immunomodulated group was older at diagnosis (P < 0.001), more likely to be female (P < 0.001), more likely to live in a metropolitan area (P < 0.001), and had higher Charlson comorbidity scores (P < 0.001). There were no differences in progression to chemotherapy (P = 0.17), checkpoint inhibitors (P > 0.99), radical cystectomy (P = 0.40), partial cystectomy (P = 0.93), metastasis (P = 0.19), cancer-specific death (P = 0.18) or 5-year total bladder cancer progression (P = 0.30) between the groups. For the safety analysis, rates of disseminated BCG were similar between immunomodulated and immunocompetent patients (0.7% vs. <1.8%, P = 0.51). On multivariable analysis 5-year total bladder cancer progression (HR 1.07 [CI 0.88–1.30]) was similar between the groups. ConclusionRates of bladder cancer progression and disseminated BCG complications 5-years after BCG therapy were similar regardless of immunomodulation status. These findings suggest that BCG intravesical therapy can be offered to immunomodulated patients with high-risk NMIBC although theoretical infectious complication risks remain.

A HER2-targeted Antibody-Drug Conjugate, RC48-ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder Cancer.

More than half of non-muscle-invasive bladder cancer (NMIBC) patients eventually relapse even if treated with surgery and BCG without optional bladder-preserving therapy. This study aims to investigate the antitumor activity and safety of a HER2-targeted antibody-drug conjugate, RC48-ADC, intravesical instillation for NMIBC treatment. In this preclinical study, itis revealed that human epidermal growth factor receptor 2 (HER2) expression scores of 1+, 2+, and 3+ are recorded for 16.7%, 56.2%, and 14.6% of NMIBC cases. The antitumor effect of RC48-ADC is positively correlated with HER2 expression in bladder cancer (BCa) cell lines and organoid models. Furthermore, RC48-ADC is revealed to exert its antitumor effect by inducing G2/M arrest and caspase-dependent apoptosis. In an orthotopic BCa model, tumor growth is significantly inhibited by intravesical instillation of RC48-ADC versus disitamab, monomethyl auristatin E, epirubicin, or phosphate-buffered saline control. The potential toxicity of intravesical RC48-ADC is also assessed by dose escalation in normal nude mice and revealed that administration of RC48-ADC by intravesical instillation is safe within the range of effective therapeutic doses. Taken together, RC48-ADC demonstrates promising antitumor effects and safety with intravesical administration in multiple preclinical models. These findings provide a rational for clinical trials of intravesical RC48-ADC in NMIBC patients.

A Territory-wide Study Investigating the Dose and Efficacy of Different Bacillus Calmette-Guérin Strains in Patients with Intermediate- and High-risk Non–muscle-invasive Bladder Cancer

BackgroundCurrent European Association of Urology (EAU) guidelines support adjuvant intravesical Bacillus Calmette-Guérin (BCG) treatment after Transurethral Resection of Bladder Tumor (TURB) for intermediate- or high-risk Non–Muscle-Invasive Bladder Cancer (NMIBC) patients, aiming to reduce the risk of tumor recurrence. The quality of data, however, does not allow definitive conclusions on whether different strains and dosages of BCG have different efficacies on long-term survival outcomes. ObjectiveTo evaluate the long-term survival outcomes of different strains and dosages of BCG in patients with NMIBC. Design, setting, and participantsAll NMIBC patients treated with intravesical BCG therapy from 2001 to 2020 were identified using a territory-wide database in Hong Kong. InterventionBCG strains and dosages (Connaught strain 81 mg, Connaught strain 27 mg, Tokyo strain 80 mg, and Danish strain 30 mg) were retrieved from medical records. Outcome measurements and statistical analysisOverall Survival (OS), Cancer-Specific Survival (CSS), Recurrence-Free Survival (RFS), and Progression-Free Survival (PFS) were analyzed using the Kaplan-Meier method. A multivariable Cox regression analysis was used to adjust potential confounding factors, and to estimate Hazard Ratio (HR) and 95% confidence interval (CI) of different BCG strains. A further subgroup analysis on adequate versus inadequate BCG treatment was performed. Results and limitationsA total of 2602 NMIBC patients treated with intravesical BCG were identified. Among them, 1291 (49.6%) received Connaught strain 81 mg, 199 (7.6%) received Connaught strain 27 mg, 1014 (39.0%) received Tokyo strain, and 98 (3.8%) received Danish strain. The median follow-up was 11.0 years. No statistically significant differences in OS, CSS, RFS, and PFS were detected among the different groups. At the multivariable analysis, the Connaught strain 27 mg group was inferior to the Connaught strain 81 mg group in terms of OS (HR: 1.26, 95% CI: 1.05–1.51), CSS (HR: 1.69, 95% CI: 1.08–2.66), and PFS (HR: 1.86, 95% CI: 1.20–2.88). Adequate BCG treatment was associated with improved OS (HR: 0.82, 95% CI: 0.73–0.92), CSS (HR: 0.64, 95% CI: 0.47–0.86), RFS (HR: 0.80, 95% CI: 0.70–0.92), and PFS (HR: 0.52, 95% CI: 0.39–0.68). Among patients treated with adequate BCG, at the multivariable analysis the Connaught strain 27 mg group showed worse results than the Connaught strain 81 mg group in terms of CSS (HR: 1.93, 95% CI: 1.07–3.51). Compared with the Connaught strain 81 mg group, both Tokyo and Danish strains had similar survival outcomes in the whole cohort and the adequate BCG treatment subgroup. ConclusionsOur findings suggest that adequate BCG remains the most important factor in optimizing survival outcomes in patients with intermediate- and high-risk NMIBC. No significant differences in survival outcomes were observed between full-dose Connaught, Tokyo, and Danish strains. Reduced-dose Connaught strain was associated with the worst survival outcomes. Patient summaryWe evaluated the efficacy of different strains and dosages of bacillus Calmette-Guérin (BCG) in patients with intermediate- or high-risk non–muscle-invasive bladder cancer in the past two decades in Hong Kong. We conclude no significant differences in long-term survival outcomes in terms of full-dose Connaught, Tokyo, and Danish strains, while reduced-dose Connaught strain was inferior to the full-dose group. Adequate BCG treatment benefits long-term survival.

Risk stratification and management of non-muscle-invasive bladder cancer: A physician survey in six Asia-Pacific territories.

Multiple clinical practice guidelines, conflicting evidence, and physician perceptions result in variations in risk stratification among patients with non-muscle-invasive bladder cancer (NMIBC). This study aims to describe the extent of this variation and its impact on management approaches in the Asia-Pacific region. We conducted a cross-sectional survey involving 32 urologists and seven medical oncologists with ≥8 years of experience managing early-stage bladder cancer patients across Australia, Hong Kong, Japan, South Korea, Singapore, and Taiwan. The physicians completed an anonymous questionnaire that assessed their risk stratification and respective management approaches, based on 19 NMIBC characteristics. For each NMIBC characteristic, they were required to select one risk group, and their most preferred management approach. Our results demonstrated a higher consensus on risk classification versus management approaches. More than 50% of the respondents agreed on the risk classification of all NMIBC characteristics, but 42% or fewer chose the same treatment option as their preferred choice for all but two characteristics-existence of variant histology (55%) and persistent high-grade T1 disease on repeat resection (52%). Across territories, there was the greatest variation in preferred treatment options (i.e., no treatment, intravesical chemotherapy, or Bacillus Calmette-Guérin [BCG] treatment) for intermediate-risk patients and the highest consensus on the treatment of very high-risk patients, namely radical cystectomy. Our study revealed considerable variation in risk stratification and management of NMIBC in the region. It is critical to develop practical algorithms to facilitate the recognition of NMIBC and standardize the treatment of NMIBC patients.

Controversies in terminology associated with management of BCG-unresponsive NMIBC in Asia-Pacific.

Examine the understanding of terminologies and management patterns of bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle invasive bladder cancer (NMIBC) in six territories in Asia-Pacific. This study involved two phases: (1) a survey with 32 urologists and 7 medical oncologists (MOs) and (2) a factorial experiment and in-depth interviews with 23 urologists and 2 MOs. All clinicians had ≥8 years' experience managing NMIBC patients in Australia, Hong Kong, Japan, South Korea, Singapore, and Taiwan. Data from Phase 1 were summarized using descriptive statistics; content and thematic analyses applied in Phase 2. In phase 1, 35% of clinicians defined BCG-unresponsive as BCG-refractory, -relapse and -resistant, 6% defined it as BCG-refractory and -relapse; 22% classified BCG-failure as BCG-refractory, -relapse, -resistant, and when muscle-invasive bladder cancer is detected. If eligible and willing, 50% (interquartile range [IQR], 50%-80%) of BCG-unresponsive patients would undergo radical cystectomy (RC), and 50% (IQR 20%-50%) of RC-eligible patients would receive bladder-sparing treatment or surveillance. In phase 2, we found that 32%, 88%, and 48% of clinicians, respectively, used "BCG-unresponsive," "BCG-refractory," and "BCG-relapse" in clinical practice but with no consistent interpretation of the terms. Compared with EAU definitions, 8%-60% of clinicians appropriately classified 9 tumor types that are persistent or recurrent after adequate BCG. Fifty percent of clinicians mentioned a lack of bladder-preserving treatment that outperforms RC in quality of life as a reason to retreat BCG-unresponsive patients with BCG. Our study revealed varied understanding and application of BCG-unresponsive terminologies in practice. There is a need for a uniform and simple definition of BCG-unresponsive disease in Asia-Pacific.

Single-Dose Post-Office Fulguration Mitomycin C Instillation Appears to Improve Recurrence-Free Survival in Patients With Low-Grade Noninvasive Bladder Cancer.

Perioperative instillation of mitomycin-C (MMC) has shown effectiveness in reducing the recurrence of low-grade non-muscle invasive bladder cancer (NMIBC). Data is lacking about the impact of single-dose MMC following office fulguration of low-grade urothelial carcinoma. We compared the outcomes of small-volume low-grade recurrent NMIBC in patients treated with office-fulguration - with and without an immediate single-dose instillation of MMC. A retrospective analysis of medical records of patients with recurrent small-volume (≤1 cm) low-grade papillary urothelial cancer who underwent fulguration in a single institution between January 2017 and April 2021 either with or without instillation of post-fulguration MMC (40mg/50 mL). The primary outcome was recurrence-free survival (RFS). Of 108 patients (27% women) who underwent fulguration, 41% received intravesical MMC. The treatment and control groups had similar sex ratio, mean age, mass size, tumor multifocality and or tumor grade. Median RFS was 20 months (95% CI 4-36) in the MMC group and 9 months (95% CI 5-13) in the control group (P=.038). Multivariate Cox regression analysis showed that MMC instillation was associated with longer RFS (OR=0.552, 95% CI 0.320-0.955, P=.034) and multifocality was associated with shorter RFS (OR=1.866, 1.078-3.229, P=.026). A higher rate of grade 1-2 adverse events was observed in the MMC group (18.2%) vs. the control (6.8%, P=.048). No complications grade 3 or higher were observed. A single dose of MMC instilled after office fulguration is associated with longer RFS compared to patients who did not receive MMC after the procedure, with no associated high-grade complications.

Quality of Life in Patients with High-grade Non-muscle-invasive Bladder Cancer Undergoing Standard Versus Reduced Frequency of Bacillus Calmette-Guérin Instillations: The EAU-RF NIMBUS Trial.

Adverse events induced by intravesical bacillus Calmette-Guérin (BCG) to treat high-grade non-muscle-invasive bladder cancer (NMIBC) often lead to treatment discontinuation. The EAU-RF NIMBUS trial found a reduced number of standard-dose BCG instillations to be inferior with the standard regimen. Nonetheless, it remains important to evaluate whether patients in the reduced BCG treatment arm had better quality of life (QoL) due to a possible reduction in toxicity or burden. To evaluate whether patients in the EAU-RF NIMBUS trial experienced better QoL after a reduced BCG instillation frequency. A total of 359 patients from 51 European sites were randomized to one of two treatment arms between December 2013 and July 2019. The standard frequency arm (n=182) was 6 weeks of BCG induction followed by 3 weeks of maintenance at months 3, 6, and 12. The reduced frequency arm (n=177) was BCG induction at weeks 1, 2, and 6, followed by maintenance instillations at weeks 1 and 3 of months 3, 6, and 12. Analyses were performed using an intention-to-treat analysis and a per-protocol analysis. QoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 version 3.0 (QLQ-C30 v.03) prior to the first and last instillations of each BCG cycle. Group differences were determined using linear regression corrected for QoL at baseline. Differences in QoL over time were tested for significance using a linear mixed model. Side effects were recorded by the treating physician using a standardized form. Chi-square tests were used to compare the side-effect frequency between the arms. There were no significant differences in the means of each QoL scale between the two arms. There were also no significant changes over time in all QoL domains for both arms. However, differences in the incidence of general malaise at T1 (before the last induction instillation), frequency, urgency, and dysuria at T7 (before the last maintenance instillation) were detected in favor of the reduced frequency arm. Reducing the BCG instillation frequency does not improve the QoL in NMIBC patients despite lower storage symptoms. In this study, we evaluated whether a reduction in the number of received bacillus Calmette-Guérin instillations led to better quality of life in patients with high-grade non-muscle-invasive bladder cancer. We found no difference in the quality of life between the standard and the reduced bacillus Calmette-Guérin instillation frequency. We conclude that reducing the number of instillations does not lead to better quality of life in patients with high-grade non-muscle-invasive bladder cancer.

Adjuvant Hyperthermic Intravesical Chemotherapy in Intermediate- and High-Risk Non-muscle Invasive Bladder Cancer.

Non-muscle invasive bladder cancer (NMIBC) is a frequently diagnosed neoplasm, which is typically managed with transurethral resection of bladder tumor (TURBT) eventually followed by intravesical therapies. Bacillus Calmette-Guérin (BCG) is used as first-line adjuvant treatment in high- (HR) and intermediate-risk (IR) NMIBC, although, in the latter, mitomycin C (MMC) may also be used. Multiple limitations to the use of BCG encouraged the search for therapeutic alternatives. In this context, hyperthermic intravesical chemotherapy with MMC (HIVEC-MMC) emerged as a promising therapy in the adjuvant setting for NMIBC. The aim of our study was to evaluate the tolerability, compliance, and survival outcomes of HIVEC-MMC in patients with IR- and HR-NMIBC. This was a single-center retrospective analysis of IR- and HR- NMIBC patients who received HIVEC-MMC after TURBT between August 2018 and August 2022. Levels of risk stratification were defined using the European Association of Urology (EAU) criteria. The protocol consisted of four weekly HIVEC-MMC instillations (induction) followed by six monthly instillations (maintenance). The primary outcomes were to evaluate the tolerability and compliance with the HIVEC-MMC protocol and secondary outcomes were disease-free survival (DFS) and overall survival (OS). For the purpose of statistical analysis, methods of descriptive statistics, survival analysis (Kaplan-Meier estimation), and multivariate analysis (Cox regression, and binary logistic regression) were used. Fifty-seven patients were enrolled with a median age of 67.9 (34.4-83.5) years old. In this cohort, 40 patients (70.2%) had primary tumors. At the time of referral for HIVEC-MMC, the majority of the patients had IR-NMIBC (n= 33, 57.9%). A total of 41 patients (71.9%)completed the HIVEC-MMC protocol. Disease recurrence and adverse events (AEs) were the most common reasons to stop the protocol. After a median follow-up of 31 months (95% CI, 5.0-54.0), 32 patients (61.4%) were disease-free, 22 (38.6%) experienced recurrent disease and six patients (10.5%) died, although only one death was directly attributable to bladder cancer. The median DFS was 42 months (95% CI, 28.0-56.0). Completion of the HIVEC-MMC maintenance phase protocol stood as a predictive factor for DFS (44 months, 95% CI 29.1-58.9 vs. 14 months, 95% CI 0.0-29.6, p < 0.001; HR 4.48, 95% CI 1.65-12.15). The median OS was not reached; the 24- and 48-monthOS were 92.6% and 82.7%, respectively. EAU risk group, ECOG-PS, and completion of HIVEC protocol were found to be significant predictive factors of OS but lost their significance on multivariate analysis. However, if we exclude those who experienced recurrence during the maintenance phase protocol, treatment completion had a significant positive impact on OS (HR: 42.8, 95% CI 1.75-1045.072, p= 0.021). Our study suggests that HIVEC is a secure and well-tolerated treatment with promising efficacy data, making this therapeutic approach a feasible option in IR- and HR-NMIBC patients, mainly in those who cannot tolerate or have contraindications to BCG therapy, but also as an alternative during BCG shortages.

A urinary assay for mutation and methylation biomarkers in the diagnosis and recurrence prediction of non-muscle invasive bladder cancer patients

BackgroundCurrently, the clinical strategy for diagnosis of non-muscle invasive bladder cancer (NMIBC) such as cystoscopy and cytology are invasive and/or with limited accuracy. OncoUrine, a urinary assay for mutation and methylation biomarkers, have showed a high accuracy in the detection of upper tract urinary carcinoma (UTUC) patients with hematuria. The aim of this study is to evaluate the performance of OncoUrine in diagnosis of NMIBC patients.MethodsIn this multicenter prospective study, a total of 203 patients were enrolled, including 60 patients present with hematuria and 143 NMIBC patients under recurrence surveillance. Urine samples were collected before cystoscopy to undergo OncoUrine test. OncoUrine performance was calculated compared to clinical standard methods in hematuria cohort and recurrence surveillance cohort, respectively. Furthermore, NMIBC patients were followed up with a median time of 20.5 months (range 0.03 to 24.03 months) to assess the predictive value of OncoUrine during recurrence monitoring.ResultsFor bladder cancer diagnosis, OncoUrine tested 47 samples and achieved a sensitivity/specificity/positive predictive value (PPV)/negative predictive value (NPV) of 80% (95% CI 44.2–96.5)/91.9% (95% CI 77.0–97.9)/72.7% (95% CI 39.3–92.7)/94.4% (95% CI 80.0–99.0) (kappa value 69.4%, 95% CI 44.4–94.3), indicating 72.3% of unnecessary cystoscopy. For recurrence diagnosis, OncoUrine tested 93 samples, and the sensitivity/specificity/PPV/NPV was 100% (95% CI 59.8–100.0)/68.2% (95% CI 57.1–77.7)/22.9% (95% CI 11.0–40.6)/100% (95% CI 92.3–100.0) (kappa value 27.0%, 95% CI 11.1–42.8), indicating 62.4% of spared cystoscopy. What is more, OncoUrine correctly predicted 80% (20/25) of final recurrence with 12/25 (48%) patients who were OncoUrine positive, but cystoscopy negative was followed with recurrence during follow-up. The test result of OncoUrine was also found significantly correlated with recurrence free survival (RFS) of NMIBC patients (median 34.4-month vs unreached; HR 6.0, 95% CI 2.7–13.5, P < 0.0001).ConclusionsOncoUrine showed potential value to reduce the frequency of unnecessary cystoscopy and the healthcare cost of bladder cancer patients. Patients with positive test results represented a population who were at high risk of recurrence and thus should be subject to frequent surveillance to ensure timely detection of any potential recurrence. This study has been registered in ClinicalTrials.gov with the number NCT04994197 posted on August 2021.

Analysis of Risk Factors for Recurrence after Transurethral Resection of Bladder Tumor in Patients with Non-Muscle Invasive Bladder Cancer: 2-Year Follow-Up Outcomes.

The aim was to investigate the risk factors for recurrence after transurethral resection of bladder tumor (TURBT) in patients with non-muscle invasive bladder cancer (NMIBC) and to provide a basis for clinical prevention of recurrence of NMIBC. From January 2012 to December 2020, 592 patients with NMIBC who underwent TURBT attending the Second Affiliated Hospital of Xi'an Jiaotong University were retrospectively included in this study. Patients were divided into relapse and relapse-free groups according to whether relapse occurred within 2 years. Ultimately, 72 patients were included in the relapse group and 350 patients were included in the relapse-free group. Observation indicators included age, sex, smoking, underlying disease (hypertension, diabetes, coronary heart disease), two or more lesions, tumor size, hematuria, pathology grading (low, medium, high), staging (Ta, T1), muscular invasion in initial pathology, tumor base (sessile, pedunculated), use of intravesical drug (pirarubicin, bacillus Calmette-Guerin [BCG], mitomycin, hydroxycamptothecin, gemcitabine). In this study, the 2-year recurrence rate of NMIBC patients after TURBT was 17.06%. There were significant differences in comparison of pirarubicin, BCG, and mitomycin treatment between the two groups (p &lt; 0.05). To avoid missing risk factors for recurrence, factors with p &lt; 0.1 were analyzed. The results of univariate logistic regression analysis showed that NMIBC patients with BCG treatment (OR = 5.088, 95% CI = 1.444-17.73, p = 0.012), high pathology grading (OR = 0.415, 95% CI = 0.197-0.880, p = 0.023), T1 stage (OR = 2.097, 95% CI = 0.996-4.618, p = 0.059), mitomycin treatment (OR = 5.029, 95% CI = 1.149-21.77, p = 0.031), and pirarubicin treatment (OR = 1.794, 95% CI = 1.079-3.030, p = 0.024) had significantly higher risk of recurrence within 2 years after TURBT. The results of multivariate logistic regression analysis showed that NMIBC patients with high pathology grading (OR = 0.4030, 95% CI = 0.1702-0.8426, p = 0.0241), pirarubicin treatment (OR = 1.961, 95% CI = 1.159-3.348, p = 0.0125), and BCG treatment (OR = 6.201, 95% CI = 1.275-29.73, p = 0.0190) had significantly higher risk of recurrence within 2 years after TURBT. Our study highlights the importance of postoperative surveillance and individualized treatment for patients with NMIBC. Our findings show that high pathology grading, pirarubicin treatment, and BCG treatment are independent risk factors for recurrence after TURBT in patients with NMIBC. However, caution is warranted when interpreting our findings due to the small sample size and the need for further research to confirm the negative impact of mitomycin and BCG on recurrence rates.

Effect of neoadjuvant chemotherapy on survival in patients with T1 high-grade non-muscle-invasive bladder cancer who underwent radical cystectomy.

Patients with non-muscle-invasive bladder cancer (NMIBC) who are at high and very high risk of disease progression are recommended for radical cystectomy (RC). However, the impact of neoadjuvant chemotherapy (NAC) on survival outcomes in NMIBC patients undergoing RC remains unclear. Patients diagnosed with T1 high-grade NMIBC who underwent RC were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) was assessed using the Kaplan-Meier technique, and multivariable Cox regression analysis was conducted to determine the independent factors of OS. A total of 1268 T1 high-grade NMIBC patients who underwent RC between 2004 and 2015 were included in the study. NAC was administered to 76 (6.0%) patients. At a median follow-up of 75 months, there was no significant difference in the OS between the NAC and non-NAC groups (HR = 0.89, 95% CI 0.61-1.30, P = .539). However, in the multivariate Cox regression model, NAC demonstrated a more pronounced improvement in OS approaching statistical significance (HR = 0.7, 95% CI 0.47-1.05, P = .088). Subgroup analysis revealed a survival benefit of NAC in patients with lymph node metastasis. In summary, the results of this study suggest that NAC has the potential to confer a survival advantage in patients diagnosed with T1 high-grade NMIBC who undergo RC, but additional studies are needed. Nonetheless, the survival benefits of NAC in patients with lymph node involvement are apparent.

Effects of intravenous chemotherapy after TURBT for high-risk nonmuscle invasive bladder cancer: results of a retrospective study.

This study compared the efficacy and safety of intravenous chemotherapy combined with intravesical chemotherapy versus intravesical chemotherapy alone for high-risk nonmuscle invasive bladder cancer (HRNMIBC) patients after transurethral resection of the bladder tumor (TURBT) surgery. A retrospective analysis was performed on 349 HRNMIBC cases admitted to TangDu hospital between January 2014 and June 2019. After TURBT, 262 patients received intravesical chemotherapy alone, whereas 87 patients underwent intravesical chemotherapy in combination with intravenous chemotherapy. The recurrence rate and progression rate were assessed by Chi-square test, the prognostic factors for tumor recurrence were predicted by univariable and multivariable Cox hazards analyses, recurrence-free survival (RFS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. In this study, the recurrence rate was 24.7% (19/77) in the intravenous chemotherapy combined group and 41.6% (102/245) in the intravesical chemotherapy group, while the progression rate was 6.5% (5/77) and 14.3% (35/245) in the two groups respectively. The two groups differed significantly in recurrence rate (p = 0.007) while the progression rate did not show a significant difference (p = 0.071). Multivariable analyses revealed that additional intravenous chemotherapy treatment was an independent prognostic factor for tumor recurrence in the cohort (hazard ratio [HR], 0.495, 95% confidence interval [CI], 0.275-0.892, p = 0.019). Kaplan-Meier curves showed significant differences in RFS and PFS between the two groups, with a log-rank P value of p < 0.005 and p = 0.045, respectively. Grade 3/4 toxicity was reported in 2 of 77 patients in the intravenous chemotherapy combined group, including nausea/vomiting 1.3% (1/77) and hypoleukemia 1.3% (1/77). Intravenous chemotherapy of gemcitabine and cisplatin combined with intravesical chemotherapy after TURBT can effectively reduce the postoperative recurrence rate, most toxicities were minor and reversible, and it may be considered as a new choice for HRNMIBC patients.

International Bladder Cancer Group Intermediate-risk Non-muscle Invasive Bladder Cancer (IBCG IR-NMIBC) Scoring System Predicts Outcomes of Patients on Active Surveillance.

To determine if the International Bladder Cancer Group (IBCG) intermediate risk (IR)-NMIBC scoring system can predict the requirement of delayed transurethral resection of bladder tumor (TURBT) in low grade (LG) non-muscle invasive bladder cancer (NMIBC) managed by active surveillance (AS). A prospective study of recurrent LG Ta/T1 NMIBC patients managed with AS with the following characteristics were used: LG papillary NMIBC, ≤5 apparent LG NMIBC, tumor diameter ≤1 cm, absence of gross hematuria and negative urinary cytology. Subsequent TURBT was offered to patients who no longer met the inclusion criteria or patient choice. The ability of the IBCG IR-NMIBC scoring system to predict receipt of subsequent TURBT was determined. Multivariable Cox proportional-hazards analysis was used to determine factors associated with subsequent TURBT. A total of 163 patients with LG Ta/T1 NMIBC were included for analysis. After a median follow-up of 33 months (21-46), TURBT was performed on 109 patients. At landmark timepoint of 24 months, patients with 0 RF factors were over two-fold more likely to continue AS compared to patients with ≥3 RF (59% versus 24%). Multivariable Cox regression suggest that the IBCG IR-NMIBC scoring system was associated with subsequent TURBT (1-2 RF [HR: 1.66, 95% CI: 0.96-2.90, P = .072], ≥3 RF [HR: 3.21, 95% CI: 1.70-6.09, P < .001]) after adjusting for age, T-stage and sex. The IBCG IR-NMIBC scoring system can predict the risk of a subsequent TURBT in patients with LG NMIBC on AS.